total synthesis of taxol. 1. retrosynthesis - researchgate

624 J. Am. Chem. SOC. 1995,117, 624-633

Total Synthesis of Taxol. 1. Retrosynthesis, Degradation, and Reconstitution

K. C. Nicolaou,* P. G. Nantermet, H. Ueno, R. K. Guy, E. A. Couladouros, and E. J. Sorensen

Contribution from the Department of Chemistry, The Scripps Research Institute, 10666 North Torrey Pines Road, La Jolla, Califomia 92037, and Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093

Received July 7, 1994@

Abstract: A successful strategy for the enantioselective synthesis of the natural stereoisomer of Taxol (1) has been developed. This strategy utilized the convergent assembly of Taxol's central eight-membered B ring from preformed synthons for rings A (10) and C (9) followed by late introduction of the D ring and side chain. Degradative studies conf i ied the viability of certain crucial manipulations including oxidation of the C13 position (35 - 3) and regioselective introduction of the C I-hydroxyl, CZbenzoyloxy moiety (29 - 31). Additionally, a convenient method for the large-scale production of 29, a derivative useful for C2 analog production, was developed.

Introduction

Taxol (Figure 1, 1),lq2 a diterpene produced by several plants of the genus was isolated from the cytotoxic methanolic extract of the bark of T. brevifolia." Taxol interacts with microtubules, important cellular structural proteins,5 in a manner that catalyzes their formation from tubulin and stabilizes the resulting structures.6 In cells this phenomenon leads to an altered morphology with the microtubules forming stable bundles and the cell being unable to assemble a normal mitotic spindle.' Cells treated with Taxol normally arrest at the transition between interphase and mitosis and die. The elucida- tion of this unique mechanism of action during the late 1970s and early 1980s sped Taxol's development as an anticancer drug. Since that time, Taxol has revealed unusual efficacy as a clinical agent,* experiencing rapid development for the treatment of b r e a ~ t , ~ ovarian,'O skin," lung,12 and head and neck13 cancers.

0

1: Taxol

2: 10-deacetylbaccatin 111

Figure 1. Structure of Taxol (1) and 10-deacetylbaccatin III (2). * Address correspondence to this author at The Scripps Research Institute

@ Abstract published in Advance ACS Abstracts, December 15, 1994. or the University of California.

(l)Nicola~u, K. C.; Dai, W.-M.; Guy, R. K. Angew. Chem., In?. Ed.

(21 Kingston. D. G. I. Fortschr. Chem. Ora. Narurst. 1993, 61, 1. Engl. 1994, 33, 15.

(3) ApGndino, G. Fitoterapia 1993, 54, Sippl . NI, 5 . (4) Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggen, P.; McPhail, A.

T. J. Am. Chem. SOC. 1971, 93, 2325. (5) (a) Mandelkow, E.; Mundelkow, E.-M. Curr. Opin. Struct. Biol. 1994,

4, 171. (b) Avila, J. Life Sci. 1991, 50, 327. (6) Manfredi, J. J.; Horwitz, S. B. Pharmacal. Ther. 1984,25,83. Schiff,

P. B.; Fant, J.; Horwitz, S. B. NarUre 1979, 277, 665. (7) Schiff, P. B.; Horwitz, S. B. Proc. Natl. Acad. Sci. USA. 1980, 77,

1561. (8) Lavelle, F. Curr. Opin. Invest. Drugs 1993, 2, 627. Rowinsky, E.

K.; Onetto, N.; Canetta, R. M.; Arbuck, S. G. Semin. Oncol. 1992, 19, 646.

(9) Holmes, F. A,; Waters, R. J.; Theriault, R. I.; Forman, A. D.; Newton, L. K.; Raber, M. N.; Buzdar, A. U.; Frye, D. K.; Hortobagyi, G. N. J. Natl. Cancer Inst. U S A . 1991, 83, 1797.

(10) McGuire, W. P.; Rowinsky, E. K.; Rosenshein, N. B.; Grumbine, F. C.; Ettinger, D. S.; Armstrong, D. K.; Donehower, R. C. Ann. Intern. Med. 1989, 111, 273. Einzig, A. I.; Wiemik, P. H.; Sasloff, J.; Garl, S.; Runowicz, C.; O'Hanlan, K. A.; Goldberg, G. Proc. Am. Assoc. Cancer Res. 1990, 31, 187 (Abstract 1114). Pazdur, R.; Ho, D. H.; Lassere, Y.; Bready, B.; Kvakoff, I. H.; Raber, M. N. Proc. Am. SOC. Clin. Oncol. 1992, 11, 1 1 1 (Abstract 265). Caldas, C.; McGuire, W. P., III. Semin. Oncol. 1993, 20 (4 Suppl. 3), 50.

(1 1) Einzig, A. I.; Hochster, H.; Wiemik, P. H.; Trump, D. L.; Dutcher, J. P.; Garowski, E.; Sasloff, J.; Smith. T. J. Invest. New Drum 1991.9.59. Legha, S. S.; Ring, S.; Papadopoulos, N.; Raber, M. N.{Benjamin, R. Cancer 1990, 65, 2478.

0002-7863/95/15 17-0624$09.00/0

In 1993, Taxol was approved by the FDA for use in the U.S. for treatment of breast and ovarian cancers.

Taxol's development as a therapeutic agent precipitated a fundamental problem with its production: the original source of its isolation, T. brevifolia, was a slowly growing and rare tree whose content of Taxol could not possibly meet the demand.14 The public's perception of the ecological disaster involved in harvesting these trees from the last remaining old growth forests of the Pacific Northwest caused an ongoing debate about the ethics of producing Tax01.l~ A wide range of research was carried out to solve this problem, including plantation farming, cellular culture, semisynthesis, and total synthesis. l4 A semisynthetic process utilizing 10-deacetylbaccatin 111 (2, Figure l), derived from the common T. baccata shrub, as the starting material has, at least temporarily, resolved this dilemma.14 Over the past two decades some 30 synthetic

(12) Chang, A.; Kim, K.; Glick, J.; Anderson, T.; Karp, D.; Johnson, D. J. Natl. Cancer Inst. USA. 1993, 85, 388. Murphey, W. K.; Winn, R. J.; Fossella, F. V.; Shin, D. M.; Hynes, H. E.; Gross, H. M.; Davila, E.; Leimert, J. T.; Dhinga, H. M.; Raber, M. N.; Krakoff, I. H.; Hong, W. K. Proc. Am. SOC. Clin. Oncol. 1993,85, 384. Ettinger, D. S. Semin. Oncol. 1993,ZO (4 Suppl. 3), 46.

(13) Forastiere, A. A. Semin. Oncol. 1993, 20 (4 Suppl. 3), 56. (14) Borman, S. Chem. Eng. News 1991, Sept 2, 11. (15)Hartzell, H. The Yew Tree, A Thousand Whispers; Hulogosi:

Eugene, OR, 1991.

0 1995 American Chemical Society

Total Synthesis of Taxol. 1

groups, attracted by the molecule's challenging architecture and importance in medicine, undertook the task of the total synthesis of Taxo1.l~~ Herein and in the following articles16-18 we report the total synthesis of Taxol (l).l9

Retrosynthetic Analysis and Strategy

The retrosynthetic analysis and final synthetic strategy discussed below emerged after considering several options and examining information gathered during preliminary studies in this program. Aspects of alternative plans originally considered will be discussed in the context of the overall story as revealed in this and the following papers in this series.

In considering a strategy for the total synthesis of Taxol (l), we set the following postulate as a condition: the route should be short and flexible to allow for the eventuality of producing the natural product and a variety of its analogs in a practical way and to deliver the target molecule in its enantiomerically pure and correct form. To best fulfill this criteria, a convergent sequence was chosen in which rings A and C were to be constructed separately and then brought together to form the 8-membered ring B. Examples already in the literature and knowledge derived from our own experience led us to conclude that we could leave for the final stages the attachment of the side chain,20,21 the oxygenation of the C13 position,22 and the formation of the oxetane ring.23-25

Scheme 1 shows the retrosynthetic analysis of Taxol (1) on which the synthetic strategy was based. Thus, appropriate protection, removal of the side chain, and deoxygenation transforms at C13 led, retrosynthetically, to the baccatin derivative 3. Functional group manipulation at C1 and C2 led to the 5-membered ring derivative 4 which was envisioned as a precursor to the 1-hydroxy-2-benzoate system of Taxol. Retrosynthetic disassembly of the oxetane ring in 4 and introduction of a double bond in ring C allowed the generation of intermediate 5 as a possible precursor. The carbocyclic ABC taxoid core 5 was then retrosynthetically broken by standard functional group manipulations and disconnection of the C9- C10 bond leading to dialdehyde 6. The latter was considered

(16) Nicolaou, K. C.; Liu, J.-J.; Yang, Z.; Ueno, H.; Sorensen, E. J.; Claiborne, C. F.; Guy, R. K.; Hwang, C.-K.; Nakada, M.; Nantermet, P. G. J. Am. Chem. SOC. 1995, 1 17, 634.

(17) Nicolaou, K. C.; Yang, Z.; Liu, J.-J.; Nantermet, P. G.; Claiborne, C. F.; Renaud, J.; Guy, R. K.; Shibayama, K. J . Am. Chem. SOC. 1995, I 1 7, xxx.

(18) Nicolaou, K. C.; Ueno, H.; Liu, J.-J.; Nantermet, P. G.; Yang, Z.; Renaud, J.; Paulvannan, K.; Chadha, R. J . Am. Chem. SOC. 1995,117, xxx.

(19) Nicolaou, K. C.; Yang, Z.; Liu, J.-J.; Ueno, H.; Nantermet, P. G.; Guy, R. K.; Claiborne, C. F.; Renaud, J.; Couladouros, E. A.; Paulvannan, K.; Sorensen, E. J. Nature 1994, 367, 630. Holton, R. A.; Somoza, C.; Kim, H.-B.; Liang, F. F.; Biediger, R. J.; Boatman, P. D.; Shindo, M.; Smith, C. C.; Kim, S.; Nadizadeh, H.; Suzuki, Y.; Tao, C.; Vu, P.; Tang, S.; Zhang, P.; Murthi, K. K.; Gentile, L. N.; Liu, J. H. J.Am. Chem. SOC. 1994, 116, 1597. Holton, R. A.; Kim, H. B.; Somoza, C.; Liang, F.; Biediger, R. J.; Boatman, P. D.; Shindo, M.; Smith, C. C.; Kim, S.; Nadizadeh, H.; Suzuki, Y.; Tao, C.; Vu, P.; Tang, S.; Zhang, P.; Murthi, K. K.; Gentile, L. N.; Liu, J. H. J . Am. Chem. SOC. 1994, 116, 1599.

(20) Holton, R. A. Workshop on Taxol and Taxus, 1991. Holton, R. A. Eur. Pat. Appl. EP400,971 1990; Chem. Abstr. 1990, 114, 16456817.

(21) Ojima, I.; Habus, I.; Zhao, M.; Georg, G. I.; Jayasinghe, L. R. J . Org. Chem. 1991, 56, 1681. Ojima, I.; Habus, I.; Zhao, M.; Zucco, M.; Park, Y. H.; Sun, C. M.; Brigaud, T. Tetrahedron 1992,48, 6985. Ojima, I.; Sun, C. M.; Zucco, M.; Park, Y. M.; Duclos, 0.; Kuduk, S. Tetrahedron Lett. 1993, 34, 4149.

(22) Ulman Page, P. C.; McCarthy, T. J. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Ley, S. V., FRS, Eds.; Pergamon Press: New York, 1991; Vol. 7, p 99.

(23) Ettouati, L.; Ahond, A.; Poupat, C.; Potier, P. Tetrahedron 1991, 47, 9823.

(24) Magee, T. V.; Bornmann, W. G.; Isaccs, R. C. A.; Danishefsky, S . J. J . Org. Chem. 1992, 57, 3274.

(25) Nicolaou, K. C.; Liu, J.-J.; Hwang, C.-K.; Dai, W.-M.; Guy, R. K. J . Chem. SOC., Chem. Commun. 1992, 1118.

J. Am. Chem. SOC., Vol. 117, No. 2, 1995 625

Scheme 1. Retrosynthetic Analysis of Taxol (1)"

0

i)H

X

i

6

\

0 R3

i NNHS0,Ar

10 a +OAC 11 + =? CN 12

3

i

'0 R3

7

3 HO OH

13 14

a Bz = COPh; R, R1, Rz, RJ, %, Rs = protecting groups.

as a good candidate to afford, in the synthetic direction, compound 5 via a McMurry pinacol coupling.26 Continuing with the simplification of structure, intermediate 6 was traced back to diol 7 and then to allylic alcohol 8 as potential progenitors. Finally, disconnection of 8 via a Shapiro2' transform led to hydrazone 10 representing ring A and aldehyde

(26) McMurry, J. E. Chem. Rev. 1989,89, 1513. McMurry, J. E. Acc. Chem. Res. 1983, 16, 405. Lenoir, D. Synthesis 1989, 883.

626 J. Am. Chem. SOC., Vol. 117, No. 2, 1995

Scheme 2. Preparation of 7-TES-baccatin III (17)a 0

Nicolaou et al.

Scheme 3. Benzylation of the C7 Position and Oxetane Ring Opening"

1 : taxol IS: baccatin 111

Ib I

1 6 : R = H d L 17:R=Ac

2: 10-deacetyl baccatin Ill

Reagents and conditions: (a) excess n-B@B&, CHzClz, 25 "C, 7 h, then AcOH, 77%; (b) 30 equiv of EtsSiCl, pyridine, 25 "C, 24 h, 85%; (c) 20 equiv of Et3SiC1, pyridine, 25 "C, 17 h, 91%; (d) 5 equiv of AcCl, pyridine, 0 "C, 48 h, 82%. TES = SiEt3, Bz = COPh.

9 representing ring C. The cyclohexene derivatives 10 and 9 were then disassembled by Diels- Alder transforms to afford olefins 11-14 as potential starting materials.

The synthetic strategy derived from the analysis discussed above included a number of sensitive and rather daring steps in its final stages. In order to explore these final steps and establish their viability, we embarked, in parallel with the forward execution of the scheme, on degradation studies starting with Taxol (1) and 10-deacetylbaccatin 111 (2).** Included amongst our goals in this program were the following: deoxygenation of the C13 position and exploration of its allylic oxidation, establishment of a suitable cyclic protecting group for the C1 and C2 hydroxyl groups and its regioselective conversion to the requisite C1 hydroxy, C2 benzoate functionality, and cleavage of the C9-C10 bond in order to obtain intermediates suitable for exploring the McMurry pinacol coupling as a means to construct the 8-membered ring of Taxol.

Preparation of 7-TES-baccatin I11

Since 7-benzyl and 7-triethylsilyl (TES) baccatin 111 were projected as advanced intermediates in our synthesis, one of our early objectives was to prepare these compounds from the naturally occumng Taxol (1) and 10-deacetylbaccatin III (2). While the former natural product is found in the bark of the Pacific Yew tree (T. Brevifolia) in rather limited amounts, the latter compound is readily available from the needles of the European Yew tree (T. baccata). Scheme 2 summarizes the chemistry that led to the preparation of 17 from 1 and 2. Thus removal of the side chain from Taxol (1) via reduction of the C13 ester linkage proceeded according to Kingston's method ( ~ - B U ~ N B H ~ ) * ~ to afford baccatin I11 (15) in 77% yield. Our synthetic strategy was best served by a 7-benzyl derivative and we, therefore, first considered the preparation of such an intermediate. Basic conditions were, however, unacceptable because of the well-documented epimerization at C7 via a retroaldoValdo1 s e q u e n ~ e . ~ ~ ~ ~ ~ ~ ~ Acidic conditions (benzyl trichlo-

(27) Chamberlin, A. R.; Bloom, S. H. Org. React. 1990, 39, 1. (28) Nicolaou, K. C.; Nantermet, P. G.; Ueno, H.; Guy, R. K. J. Chem.

(29) Magri, N. F.; Kingston, D. G. I.; Jitrangsri, C.; Piccariello, T. J .

(30) Kingston, D. G. I. P h a m c o l . Ther. 1991, 52, 1.

SOC., Chem. Commun. 1994, 295.

Org. Chem. 1986, 51, 3239.

15: baccatin 111

I H+

1 q ! H - A0

1s

OBn

20

OBn

H 21

Reagents and conditions: (a) 20 equiv of benzyl tsichloroacetimi- date, 1.0 equiv of triflic acid, CHzC12.25 "C, 40 h, 50%. Bz = COPh, Bn = CHZPh.

roacetimidateitriflic acid),32 also proved too destructive: giving opening of the oxetane ring30 and leading to compound 18 (Scheme 3) as a major product (C7 stereochemistry not defined, acid-catalyzed epimerization at this position has also been r e p ~ r t e d ) . ~ ~ This compound was presumably formed via intermediates 19-21 as shown in Scheme 3 by a mechanism similar to that proposed by Kingston in his oxetane opening reaction induced by Meerwein's reagent.31

Failing to introduce a benzyl group at the C7 hydroxyl, we then turned to a silyl group. In agreement with Greene,34 we observed that a tert-butyldimethylsilyl (TBS) group could not be efficiently introduced. Installation of a triethylsilyl (TES) group at C7, however, was smoothly accomplished with TESCl in pyridine34 (85% yield) to afford 7-TES-baccatin IIX (17). The same compound was obtained from 10-deacetylbaccatin I11 (2) following Greene' s procedure34 involving selective silylation at the C7 hydroxyl group followed by acetylation of the C10 hydroxyl group. The latter step (AcCl, pyridine, 0 "C) proved rather capricious on a larger scale, presumably due to the oxetane opening and ring A skeletal rearrangements-although the byproducts were not isolated.31~33~35-37 As we will see later in this discussion, however, a more reliable method for this transformation was discovered and utilized.

Formation of the 1,2-Carbonate Ring and Reconversion to the 1-Hydroxy, 2-Benzoate System

With 7-TES-baccatin III (17) in hand, we then turned our attention to the hydrolysis of the C2-benzoate and the C10- acetate in order to gain access to further degradation products (Scheme 4). Early trials using hydrolysis, methanolysis, or

(31) Samaranayake, G.; Magri, N. F.; Jitrangsri, C.; Kingston, D. G. I. J. Org. Chem. 1991, 56, 5114.

(32) Iversen, T.; Bundle, K. R.; J . Chem. Soc., Chem. Commun. 1981, 1240. White, J . D.; Reddy, G. N.; Spessard, G. 0. J. Am. Chem. SOC. 1988, 110, 1624. Widmer, U. Synthesis 1987, 568.

(33) Wahl, A.; GuBritte-Voegelein, F.; GuBnard, D.; Le Goff, M.-T.; Potier, P. Tetrahedron 1992, 48, 6965.

(34) Denis, J. N.; Greene, A. E.; Gutnard, D.; Gutritte-Voegelein, F.; Mangatal, L.; Potier, P. J . Am. Chem. SOC. 1988, 110, 5917.

(35) Appendino, G.; Ozen, H. C.; Gariboldi, P.; Torregiani, E.; Gabetta, B.; Nizzola, R.; Bombardelli, E. J. Chem. SOC. Perkin Trans. 11993, 1563.

(36) Kingston, D. G. I.; Samaranayake, G.; Ivey, C. A. J. Nat. Prod. 1990,53, 1.

(37) Gutritte-Voegelein, F.; Gutnard, D.; Potier, P. J . Nar. Prod. 1987, 50, 9.

Total Synthesis of Taxol. I

Scheme 4. Early Attempts at C2 and C10 Hydrolysis"


17: 7-TES baccatin 111 22

Scheme 5. Preparation of Carbonate 30 from 7-TES-baccatin III (17) and Its Transformation to Enone 25"

a - 17: 7-TES baccatin Ill

23 24

Reagents and conditions: (a) excess LiAlK, THF, -78 "C or -30 "C, 1-5 h; (b) excess K2CO3, MeOH, H20, 0 OC or 25 OC, 1-5 h. TES = SEt3, BZ = COPh.

metal hydride reductions gave poor yields of tetrol 22, in agreement with previous observation^.^^^^^^^^ The principal byproducts seemed to result from deacetylation at C4 and various intramolecular reactions such as the opening of the oxetane ring by the newly liberated C2 hydroxyl group to form compound 23 (Scheme 4). The intramolecular engagement of the C4 acetate and C13 hydroxyl in a hydrogen-bonding arrangement (structure 24, Scheme 4) is presumably responsible for the ease of deacetylation of the C4 oxygen. Similar structures have previously been invoked to explain deacetylation of C4 in analogous s i t ~ a t i o n s . ~ , ~ ~ , ~ ~ It was, therefore, decided to remove any possible interference from the C13 hydroxyl group by either oxidizing it to the enone or removing it altogether. Such manipulations would also further our exploration of degradative and synthetic chemistry.

Oxidation of C l p was projected not only as a means to remove the troublesome hydroxyl group but also as a way to change the conformation of the molecule to the extent that might affect the rate of hydrolysis of the C4 acetate and prevent attack of the C2 alkoxide on the oxetane ring. This 0pera t ion~9~~ (17 -+ 25, Scheme 5) was smoothly carried out in 98% yield using Ley's TPAPNMO system.42 As hoped, enone 25 was readily hydrolyzed in basic conditions (K2CO3, MeOH, HzO, 0 "C) to provide triol 26 in 91% yield. Contrary to the previously accepted order of ester reactivity in taxoids (C9, C10 > C2),2 it was observed that, if so desired, the C10-acetate of compound 26 could be partially retained, as it reacts more slowly than the C2-benzoate under the above conditions.

Initial attempts to introduce a ben~ylidene,"~ a potential precursor to the C1-hydroxy, C2-benzoate system,44 or an a ~ e t o n i d e ~ ~ protecting group at the Cl-C2 site met with failure,

(38) Klein, L. L. Tetrahedron Lett. 1993, 34, 2047. (39) Chen, S.-H.; Wei, J.-M.; Farina, V. Tetrahedron Len. 1993,34, 3205.

(40)Harrison, J. W.; Scrowsten, R. M.; Lythgoe, B. J . Chem. Soc. C

(41) Senilh, V.; Gutritte, F.; GuCnard, D.; Colin, M.; Potier, P. C. R.

(42) Griffith, W. P.; Ley, S. V. Aldrichimica Acta 1990, 23, 13. (43) Albert, R.; Dax, K.; Pleschko, R.; Stutz, K. Carbohydr. Res. 1985,

137, 282. Yamanoi, T.; Akiyama, E.; Inazu, T. Chem. Lett. 1989, 335. Crimmins, M. T.; Hollis, W. G., Jr.; Lever, G. J. Tetrahedron Lett. 1987, 28, 3647.

(44) Binkley, R. W.; Goewey, G. S.; Johnston, J. C. J . Org. Chem. 1984, 49, 992.

(45) Evans, M. E.; Parrish, F. W.; Long, L., Jr. Carbohydr. Res. 1967, 3, 453. Lipshutz, B. H.; Barton, J. C. J . Org. Chem. 1988, 53, 4495.

1966, 1932.

Acad. Sei. Pans 1984, 299, 1039.

25

lb

2 9 : R = H 30 : R = AC

28

9

31 25

a Reagents and conditions: (a) 1.5 equiv of 4-methylmorpholine N-oxide (NMO), 0.05 equiv of tetrapropylammonium permthenate (TPAP), CH3CN, 25 "C, 1.5 h, 98%; (b) excess KzC03, MeOH, HzO, 0 "C, 4 h, 91%; (c) 0.05 equiv of camphorsulfonic acid (CSA), 1.0 equiv of benzaldehyde dimethyl acetal or excess 2,2-dimethoxypropane, CHzC12, 25 "C, 20 h; (d) 10 equiv of phosgene, pyridine, 0 "C, 0.5 h, 85% or 6 equiv of carbonyldiimidazole, THF, 40 "C, 0.5 h, then 1 N aqueous HC1, THF, 25 "C, 15 min, 93%; (e) 4.5 equiv of AczO, 9 equiv of 4-(dimethylamino)pyridine (DMAP), CHzClZ, 25 "C, 0.5 h, 95%; (f) 10 equiv of PhLi, THF, -78 "C, 0.5 h, 85%; (g) 10 equiv of AczO, 5 equiv of DMAP, CH&, 25 "C, 2.5 h, 95%; (h) 5 equiv of PhLi, THF, -78 "C, 15 min, 70% plus 10% of 31. TES = SiEt3, Bz = COPh.

as the C2-hydroxyl group opened the oxetane ring under the acidic conditions used. In both instances the resulting product was the tetrahydrofuran derivative 28 (Scheme 5).33.38,46 At- tention then focused on constructing a carbonate ring at the C1- C2 site, an operation that required basic rather than acidic conditions. Despite the scarcity of reports of nucleophilic additions to carbonates to form we entertained the possibility of converting such functionality directly to the desired 1,2-hydroxybenzoate of Taxol(1) in the synthetic direction, by addition of nucleophilic phenyl species (Scheme 5 ) . Even though the regiospecificity of such an opening was questionable,

(46) Farina, V.; Huang, S . Tetrahedron Lett. 1992, 33, 3979. (47) Satyanarayana, G.; Sivaram, S . Synth. Commun. 1990, 20, 3273. (48) Wender, P. A.; Kogen, H.; Lee, H. Y.; Munger, J. D.; Wilhelm, R.

S.; Williams, P. D. J . Am. Chem. Soc. 1989, Ill, 8957.

628 J. Am. Chem. SOC., Vol. 117, No. 2, 1995 Nicolaou et al.

we expected the distinctly different steric environment of the two positions to favor the less crowded C2 regioisomer. Treatment of triol 26 with phosgene in pyridine provided the desired carbonate 29 in 85% yield.49 It was later discovered that the carbonate 29 could be obtained in 93% yield by using carb~nyldiimidazole~~ and 4-(dimethy1amino)pyridine (DMAP) in THF followed by acidic hydrolysis of the imidazole carbamate at C10.

With a practical preparation of carbonate 29 secured, we then proceeded to investigate the anhydrous nucleophilic opening of the carbonate ring with organometallic species-a rather daring proposition considering the presence of four additional carbonyl groups within the molecule. To our pleasant surprise, exposure of 29 to excess phenyllithium in THF at -78 "C for 0.5 h resulted in the regioselective formation of the CZbenzoate 31 in 85% yield. This product was readily acetylated (95% yield) at the C10 hydroxyl position to afford compound 25. The carbonate ring opening was also performed on the C10-acetate derivative 30, resulting in the formation of a mixture of 25 (70%) and the corresponding 10-deacetyl derivative 31 (10%). Acety- lation of the crude reaction mixture under standard conditions followed by chromatographic purification afforded 25 in 80% overall yield from 30. The resistance of the other carbonyl moieties in these substrates to phenyllithium attack is, presumably, due to their steric shielding by the surrounding groups. In addition to providing a clear path for some of the final steps in the projected synthesis of Taxol (l), this chemistry was exploited to deliver a variety of C2 analogs of the natural p r o d u ~ t . ~ ~ , ~ ~

Attempts To Cleave the C9-C10 Bond of the Taxol Skeleton. Preparation of Enone 26

With the Cl-C2 diol system protected and the C9-C10 site free as a hydroxy ketone, as in compound 29 (Scheme 6), we attempted the cleavage of the C9-C10 bond under a variety of oxidative conditions. Unfortunately, however, none of these methods (including Pb(OAc)4, Na104,53 and Baeyer-Villiger/ hydr~ lys i s~~) led to the expected aldehyde 32 (Scheme 6) or any other cleavage product. Steric crowding is presumably again responsible for this inertness. This phenomenon also manifested itself in the reluctance of 7-TES-10-deacetylbaccatin III (16) to enter in any cleavage process to afford 33 (Scheme 6) under similar conditions. In the reaction of 16 with Pb(OAc)4, it was surprising to observe a 20% yield of the C13- oxidized product, namely enone 31 (Scheme 6), in addition to recovered starting material (60%). This selective oxidation (16 - 31) could be carried out more efficiently with TPAP-NM@* in methylene chloride (96% yield). Subsequent hydrolysis (K2- C03, MeOH, HzO, 0 "C) of the C2-benzoate from 31 provided triol 26 in 93% yield. This sequence allows the conversion of naturally occurring 10-deacetylbaccatin III (2) to compound 26 in three steps and in 81% overall yield, avoiding the problematic acetylation at C10.

(49) Haworth, W. N.; Porter, C. R. J . Chem. Soc. 1930, 151. (50) Kutney, J. P.; Ratcliffe, A. H. Synth. Commun. 1975, 5, 47. (51) Nicolaou, K. C.; Couladouros, E. A.; Nantermet, P. G.; Renaud, J.;

Guy, R. K.; Wrasidlo, Angew. Chem., Int. Ed. Engl. 1994, 33, 1581. (52) Nicolaou, K. C.; Renaud, J.; Nantermet, P. G.; Guy, R. K.;

Couladouros, E. A.; Wrasidlo, W. Submitted. (53) Shing, T. K. M. In Comprehensive Organic Synthesis; Trost, B.

M., Fleming, I., Ley, S. V., FRS, Eds.; Pergamon Press: New York, 1991; Vol. 7, p 708. Crimmins, M. T.; Jung, D. K.; Gray, J. L. J . Am. Chem. Soc. 1993, 115, 3146.

(54) Krow, G. R. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Ley, S. V., FRS, Eds.; Pergamon Press: New York, 1991; Vol. 7, p 671. Ogata, Y.; Sawaki, Y.; Shiroyama, M. J. Org. Chem. 1977, 42, 4061.

Scheme 6. Selective Oxidation of the C13 Hydroxyl Group and Preparation of Enone 26"

0 29 32: R = H. Me

0

1s 33

I C

31 2s "Reagents and conditions: (a) 15 equiv of Pb(OAc)4, MeOH,

benzene, 0 - 50 OC; or excess of NaI04, MeOH, H20, 25 'C; or 2 equiv of HzOz, 8 equiv of NaOH, MeOH, HzO, 0 "C, 1.25 h; (b) 15 equiv of Pb(OAc)d, MeOH, benzene, 50 "C, 24 h; (c) 1.0 equiv of 4-methylmorpholine N-oxide (NMO), 0.05 equiv of tetrapropylammonium permthenate (TPAP), CHzClz, 25 "C, 2 h, 96%; (d) 10 equiv of KzCO3, MeOH, H20,O OC, 2.5 h, 93% based on 81% conversion. TES = SiEt3, BZ = COPh.

C13 Deoxygenation, Reoxygenation, and Side-Chain Attachment

In order to delve further into our planned synthetic strategy, we focused our efforts on the deoxygenation of the C13 position and on its subsequent reoxygenation. The fust objective proved rather problematic as initial attempts of Wolf-Kishner reduc- tionJ5 of enone 25 (Scheme 5) and thioacetal formation/ reduction56 of the same compound failed. A Barton deoxygen- ation5' was then considered. Although a C13 xanthate could not be produced, strenuous conditions (excess (thiocarbony1)- diimidazole and DMAP, 75 "C, 18 h) allowed the conversion of 7-TES-baccatin 111 (17) to thiocarbamate 34 (Scheme 7) in 86% yield. Treatment of 34 with excess n-Bu3SnH in toluene at 85 "C in the presence of a catalytic amount of AIBN provided the desired C13 deoxy derivative 35 in 59% yield, together with its A12J3 regioisomer 36 (17% yield). Increasing the concentration of n-Bu3SnH in an attempt to trap the initially formed C13 radical before it rearranges to its C11 isomer, responsible for the formation of the byproduct 36, did not change the ratio of the two products.

The desired oxidation of the C13 allylic position22 to a carbonyl function was demonstrated on intermediate 35 by

(55) Todd. Org. React. 1962, 12, 356. (56) Van Tamelen. Org. React. 1948,4, 378. Dailey, 0. D., Jr. J. Org.

Chem. 1987,52, 1984. Corey, E. J.; Shimoji. Tetrahedron Lett. 1983, 24, 169.

(57) Barton, D. H. R.; McCombie, S. W. J . Chem. SOC., Perkin Trans. 11975, 1574. Barton, D. H. R.; Dorchak, J.; Jaszberenyi Tetrahedron 1992, 48, 7435. Hartwig Tetrahedron 1983, 39, 2609.


Scheme 7. C13 Deoxygenation and Oxygenation"


Scheme 8. Taxol's Side-Chain Attachment"

17 7-TES baccatin 111

36

34

Ib

35

IC

0

37

35 25

Reagents and conditions: (a) 20 equiv of (thiocarbonyl)diimidazole, 30 equiv of 4-(dimethylamino)pyridine (DMAP), THF, 75 "C, sealed tube, 18 h, 86%; (b) 10 equiv of n-BusSnH, 0.1 equiv of azobis(isobu- tyronitile) (AIBN), toluene, 85 "C, 2 h, 59% of 35 plus 17% of 36; (c) 20 equiv of KzC03, MeOH, THF, H20,O "C, 6 h, then -20 "C, 10 h, 94% based on 62% conversion; (d) 10 equiv of phosgene, pyridine, 25 "C, 15 min, 86%; (e) m-pyridine, THF, 25 "C, 2 h, 88%; (f) 50 equiv of Et3SiC1, pyridine, 25 "C, 24 h, 85%; (g) 5 equiv of PhLi, THF, -78 OC, 15 min, 80%; (h) 30 equiv of pyridinium chlorochromate (PCC), 30 equiv of NaOAc, Celite, benzene reflux, 1 h, 75%. TES = SiEt3, Bz = COPh.

exposure to pyridinium chlorochromate (PCC)58 in the presence of NaOAc and Celite in refluxing benzene to afford, in 75% yield, enone 25 (Scheme 7).

The C13 deoxy intermediate 35 was converted to the corresponding diol 37 (Scheme 7) via selective benzoate hydrolysis (K2CO3, MeOH, H20, THF, 0 "C, 94% yield based on 62% conversion). The carbonate ring was installed at the Cl-C2 positions of the latter compound by the phosgene- pyridine method,49 furnishing intermediate 38 in 86% yield. Desilylation of the C7 hydroxyl group by exposure to H F ~ y r i d i n e ~ ~ led to 39, in 88% yield, a compound that was projected as an advanced intermediate in our synthetic scheme.

Using the key intermediate 39 (Scheme 7), obtained from 10-deacetylbaccatin III(2) as described above, a sequence was

(58) Parish, E. J. ; Wei, T. Y. Synrh. Commun. 1987.17, 1227. Rathore, R.; Saxena, N.; Chadrasekaran Synfh. Commun. 1986, 16, 1493.

(59) Nicolaou, K. C.; Webber, S. E. Synthesis 1986, 453.

40: R = TES 41:R=EE

0

42: R = TES 43: R = EE

0 t

1 : Taxd

Reagents and conditions: (a) excess NaBK, MeOH, 25 OC, 3 h, 94% based on 88% conversion; (b) for 42, 3 equiv of NaN- (SiMe3)2, 3.5 equiv of B-lactam 40, THF, 0 "C, 0.5 h, 86% based on 89% conversion; for 43, 2.5 equiv of NaN(SiMe&, 1.2 equiv of B-lactam 41, THF, 0 "C, 20 min, 80% based on 54% conversion; (c) for 42, HF-pyridine, THF, 25 "C, 1.25 h, 80%; for 43, EtOH, 0.5% aqueous HC1, 0 "C, 72 h, 80%. TES = SiEt3, Bz = COPh, EE = ethoxyethyl.

established toward Taxol (1) as follows: (a) silylation with TESCl under standard condition^^^,^ to afford 38 (85% yield); (b) carbonate ring opening with phenyllithium, as described above, to convert 38 to 35 (80% yield, Scheme 7); (c) allylic oxidation (75%); (d) stereoselective reduction of the enone carbonyl of 25 with N a B b according to Potier's m e t h ~ d ~ ~ v ~ l to provide 7-TES-baccatin 111 (17, Scheme 8) in 94% yield, based on 88% conversion; and finally (e) attachment of the side chain onto 17 using the Ojima-Holton p-lactam method20q21 (Scheme 8). To the latter end, both optically active p-lactams 40 and 41 were prepared according to Ojima's procedure and coupled to 17 using NaN(SiMe3)z to provide the 2',7-diprotected Taxol derivatives 42 and 43, respectively. Deprotection of 42 with H F ~ y r i d i n e ~ ~ in THF furnished Taxol (1) in 80% yield, whereas exposure of 43 to dilute HCl in EtOH61 led to the same target (1) in a similar fashion (80%).

Conclusion

The chemistry described in this article shed light on the chemical properties of Taxol (1) and its derivatives and opened

(60) Hart, T. W.; Metcalfe, D. A.; Scheinmann, F. J. Chem. SOC., Chem. Commun. 1979, 156. Roush, W. R.; Russo-Rodrigez, S. J. Org. Chem. 1987, 52, 598.

(61) Ogilvie, K. K.; Thompson, E. A.; Quiliam, M. A,; Westmore, J. B. Tetrahedron Left. 1974, 2865.


access to a number of valuable taxoid intermediates. Specifi- cally, it allowed the definition of a series of key intermediates and of a track along which our total synthesis was to follow (39 - 38 - 35 - 25 - 17 - 1). Furthermore, the easy access to the 5-membered ring carbonate intermediate 29 developed in this program was crucial to providing a practical entry into a plethora of C2 analogs of Taxol (1) via nucleophilic opening of the carbonate ring with a variety of reagents. The following papers in this series describe the total synthesid6-18 of Taxol (1) and a variety of its a n a l ~ g s . ~ l * ~ ~

Experimental Section General Techniques. All reactions were canied out under an argon

atmosphere with dry, freshly distilled solvents under anhydrous conditions, unless otherwise noted. Tetrahydrofuran (THF) and ethyl ether (EtZO) were distilled from sodium-benzophenone, and methylene chloride (CHzClz), benzene (PhH), and toluene from calcium hydride. Yields refer to chromatographically and spectroscopically ('H NMR) homogeneous materials, unless otherwise stated. All solutions used in workup procedures are saturated unless otherwise noted. All reagents were purchased at highest commercial quality and used without further purification unless otherwise stated. All reactions were monitored by thin-layer chromatography canied

out on 0.25 mm E. Merck silica gel plates (6OF-254) using W light as visualizing agent and 7% ethanolic phosphomolybdic acid or p-anisaldehyde solution and heat as developing agents. E. Merck silica gel (60, particle size 0.040-0.063 mm) was used for flash column chromatography.62 Preparative thin-layer chromatography (F'TLC) separations were carried out on 0.25 or 0.50 mm E. Merck silica gel plates (6OF-254). NMR spectra were recorded on Brucker AMX-500 or AM-300

instruments and calibrated using residual undeuterated solvent as an intemal reference. The following abbreviations were used to explain the multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; band, several overlapping signals; b, broad. The carbon numbering of Taxol (1) was used to assign protons. IR spectra were recorded on a Perkin-Elmer 1600 series FT-IR spectrometer. Optical rotations were recorded on a Perkin-Elmer 241 polarimeter. High-resolution mass spectra (HRMS) were recorded on a VG ZAB-ZSE mass spectrometer under fast atom bombardment (FAB) conditions. Melting points (mp) are uncorrected, recorded on a Thomas Hoover capillary melting point apparatus.

Experimental techniques and data for compounds 15, 16, 18, and 28 may be found in the supplementary material.

7-TES-baccatin III (17). A. Silylation of 15 to 17. To a solution of baccatin III (15,165 mg, 0.28 "01) in pyridine (14 mL) was added chlorotriethylsilane (1.42 mL, 8.45 m o l ) dropwise. The solution was stirred at 25 "C for 24 h. After dilution with Et20 (100 mL), the solution was washed with aqueous CuSO4 (3 x 20 mL) and brine (20 mL). The organic extract was dried (MgSOd), concentrated, and purified by flash chromatography (silica, 35 - 50% EtOAc in petroleum ether) to give 17 (168 mg, 85%) as a white solid.

B. Acetylation of 16 to 17. To a solution of 7-TES-10-deacetylbaccatin ID (16, 0.21 g, 0.318 m o l ) in pyridine (8 mL) at 0 "C was added acetyl chloride (0.1 13 mL, 1.59 "01) dropwise. The solution was stirred at 0 "C for 48 h. After dilution with Et20 (20 mL), the reaction was quenched with aqueous NaHCO3 (10 mL). The organic layer was separated, washed with aqueous CuSO4 (2 x 10 mL) and brine (5 mL), dried (MgSOd), concentrated, and purified by flash chromatography (silica, 25 - 50% EtOAc in petroleum ether) to give 7-TES-baccatin LII (17, 183 mg, 82%) as a white solid.

C. Reduction of Enone 25 to 17. A solution of enone 25 (10 mg, 0.014 mmol) in MeOH (2 mL) was treated with an excess of N a B a for 3 h at 25 "C. The reaction was quenched with aqueous NH&l(l mL), and the resulting mixture was stirred at 25 "C for 15 min. After dilution with water (5 mL), the reaction mixture was extracted with CHzClz (3 x 10 mL). The combined organic layer was dried (Naz- sod), concentrated, and purified by flash chromatography (silica, 25 - 50% EtOAc in petroleum ether) to give starting enone 25 (1.2 mg,

(62) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.

12%) and 7-TES-baccatin IJJ (17, 8.3 mg, 94% based on 88% conversion) as a white powder: Rj = 0.43 (silica, 50% EtOAc in hexanes); [aIZZ~ -49 (c 0.4, MeOH); IR (thin film) vm 3518, 2914, 1723, 1448, 1237 cm-'; 'H NMR (500 MHz, CDCl3) 6 8.08 (d, J = 7.5 Hz, 2 H, Bz), 7.58 (t, J = 7.4 Hz, 1 H, Bz), 7.46 (t, J = 7.4 Hz,

J = 9.5 Hz, 1 H, 5-H), 4.82 (m, 1 H, 13-H), 4.47 (dd, J = 10.5, 6.8 2 H, Bz), 6.44 (s, 1 H, 10-H), 5.61 (d, J = 7.0 Hz, 1 H, 2-H), 4.94 (d,

Hz,lH,7-H),4.28(AofAB,d,J=8.3H~,lH,20-H),4.12(Bof AB, d, J = 8.3 Hz, 1 H, 20-H), 3.86 (d, J = 7.0 Hz, 1 H, 3-H), 2.51 (m, 1 H, 6-H), 2.27 (s, 3 H, OAc), 2.25 (m, 1 H, 14-H), 2.17 (s, 3 H, OAc), 2.16 (s, 3 H, 18-CH3), 2.05 (m, 1 H, 14-H), 1.85 (m, 1 H, 6-H),

0.90 (t, J = 8.0 Hz, 9 H, Si(CHzCH3)3). 0.62-0.50 (band, 6 H, Si(CH2-

143.9, 133.6, 132.6, 130.1, 129.4, 128.6, 84.2, 80.8, 78.7, 76.5, 75.8, 74.7, 72.3, 67.9, 58.6, 47.2, 42.7, 38.2, 37.2, 26.8, 22.7, 21.0, 20.1, 15.0, 9.9, 6.7, 5.2; FAB HRMS (NBNCsI) d e 833.2339, M + Csf calcd for C37HszOllSi 833.2333.

Enone 25. A. Oxidation of Alcohol 17 to 25. To a solution of 7-TES-baccatin III (17,30 mg, 0.043 "01) and 4-methylmorpholine N-oxide (NMO, 7.5 mg, 0.064 "01) in acetonitrile (5 mL) was added 4-A molecular sieves (20 mg), and the suspension was stirred at 25 "C for 5 min. A catalytic amount of tetrapropylammonium permthenate (TPAP) was added, and the reaction mixture was stirred at 25 "C for 1.5 h. The reaction mixture was concentrated, suspended in CHzClz (20 mL), and filtered through silica gel. Elution with CHzClz (20 mL) and 50% EtOAc in hexanes (20 mL), followed by concentration, gave enone 25 (29 mg, 98%) as a white solid.

B. Conversion of Carbonate 30 to 25. A solution of carbonate 30 (17.6 mg, 0.028 "01) in THF (2 mL) at -78 "C was treated with PhLi (0.070 mL, 2 M in cyclohexane, 0.14 "01) and stirred at -78 "C for 15 min. The reaction was quenched with aqueous NH&l (1 mL), and the resulting mixture was allowed to warm to 25 "C. After dilution with Et20 (10 mL), the organic layer was separated, dried (MgSOd), and concentrated to give hydroxy benzoate 25 containing ca. 10% of the 10-deacetylated compound ('H NMR). The crude mixture was dissolved in CHzClz (1.5 mL), treated with 4-(dimethy- 1amino)pyridine (DMAP, 61.0 mg, 0.50 mmol) and acetic anhydride (0.024 mL, 0.25 mmol), and stirred at 25 "C for 1 h. The reaction mixture was diluted with Et20 (10 mL), washed with 10% aqueous HCl (5 mL), 10% aqueous NaOH (5 mL), and brine (5 mL), dried (MgS04), concentrated, and purified by flash chromatography (silica, 25 - 50% EtOAc in petroleum ether) to give hydroxy benzoate 25 (15.9 mg, 80%) as a white solid.

C. Acetylation of Alcohol 31 to 25. To a solution of alcohol 31 (650 mg, 0.989 mmol) in CH2C12 (50 mL) were added 4-(dimethylamino)pyridine (DMAP, 600 mg, 4.9 "01) and acetic anhydride (0.9 mL, 9.89 "01). The solution was stirred at 25 "C for 2.5 h, the reaction was quenched with aqueous NaHC03 (10 mL), and the resulting mixture was diluted with Et20 (100 mL), washed with 10% aqueous HCl (50 mL), 10% aqueous NaOH (50 mL), and brine (30 mL), dried (MgSOd), concentrated, and purified by flash chromatography (silica, 35% EtOAc in petroleum ether) to give acetate 25 (657 mg, 95%) as a white solid.

D. Allylic Oxidation of 35 to 25. A solution of 35 (1.3 mg, 0.0019 "01) in benzene (0.5 mL) was treated with anhydrous NaOAc (4.7 mg, 0.057 mmol), anhydrous Celite (12.0 mg), and pyridinium chlorochromate (12.0 mg, 0.056 m o l ) and stirred at reflux for 1 h. The reaction mixture was filtered through silica gel, eluted with Et20 (20 mL), concentrated, and purified by preparative TLC (silica, 30% Et20 in benzene) to give enone 25 (1.0 mg, 75%) as a film: Rj = 0.5 (silica, 50% EtOAc in hexanes); [aIz2~ - 19.8 (c 0.85, CHC13); IR (thin film) vmax 3499, 2956, 1758, 1732, 1673, 1657, 1604 cm-'; 'H

1.55 (s, 3 H, Ig-CHs), 1.17 (s, 3 H, 16-CH3), 1.02 (s, 3 H, 17-CH3),

CH3)3); I3C NMR (125 MHz, CDCl3) 6 202.2, 171.0, 169.4, 167.1,

N M R ( ~ ~ ~ M H Z , C D C I ~ ) ~ ~ . O ~ ( ~ , J = ~ . ~ H ~ , ~ H , B Z ) , ~ . ~ ~ ( ~ , J = 7.5 Hz, 1 H, Bz), 7.47 (t, J = 7.8 Hz, 2 H, Bz), 6.57 (s, 1 H, 10-H), 5.67 (d, J = 6.7 Hz, 1 H, 2-H), 4.90 (d, J = 8.4 Hz, 1 H, 5-H), 4.46 (dd, J = 10.4, 6.8 Hz, 1 H, 7-H), 4.31 (A of AB, d, J = 8.5 Hz, 1 H, 20-H), 4.09 (B of AB, d, J = 8.5 Hz, 1 H, 20-H), 3.89 (d, J = 6.7 Hz, 1 H, 3-H), 2.92 (A' Of A'B', d, J = 19.9 Hz, 1 H, 14-H), 2.63 (B' of A'B', d, J = 19.9 Hz, 1 H, 14-H), 2.50 (m, 1 H, 6-H), 2.21 (s, 3 H, OAc), 2.17 (s, 3 H, OAc), 2.16 (s, 3 H, 18-CH3), 1.82 (m, 1 H, 6-H), 1.65 (s, 3 H, 19-CH3), 1.25 (s, 3 H, 16-CH3), 1.17 (s, 3 H, 17-CH3),


0.90 (t, J = 7.9 Hz, 9 H, Si(CHzCH3)3), 0.65-0.45 (band, 6 H, Si(CH2-

166.8, 153.0, 140.2, 133.9, 130.0, 128.8, 128.7, 83.9, 80.5,78.4, 76.1, 76.0, 72.8, 72.2, 59.4, 46.2, 43.4, 42.4, 37.1, 33.0, 21.7, 21.0, 18.2, 13.5, 9.5, 6.7, 5.1; FAB HRMS (NBA) m/e 699.3220, M + Hf calcd for C37H50011Si 699.3201.

Diol 26. A. Hydrolysis of 25 to 26. To a solution of enone 25 (124 mg, 0.034 mmol) in MeOH (29 mL) at 0 "C was added an aqueous solution of KzC03 (291 mg in 7.3 mL HzO). The solution was stirred at 0 "C for 4 h. The reaction was quenched with aqueous NH&1(30 mL), and the resulting mixture was extracted with CHC13 (2 x 50 mL). The organic layer was dried (MgSOd), concentrated, and purified by flash chromatography (silica, 25 - 50% EtOAc in petroleum ether) to give triol 26 (96 mg, 91%) containing a small amount of the 10-acetylated product ('H NMR).

B. Hydrolysis of 31 to 26. To a solution of enone 31 (1.44 g, 2.19 mmol) in MeOH (300 mL) at 0 "C was slowly added an aqueous solution of KzC03 (3.0 g in 32 mL of HzO). The solution was stirred at 0 "C for 2.5 h. The reaction was quenched with aqueous NH&l (150 mL), and the resulting mixture was extracted with CHzClz (2 x 200 mL). The organic layer was dried (NazSOd), concentrated, and purified by flash chromatography (silica, 35 - 50% EtOAc in petroleum ether) to give enone 31 (270 mg, 19%) and triol 26 (912 mg, 93% based on 81% conversion): Rj = 0.24 (silica, 50% EtOAc in hexanes); [a]*% +38 (c 0.15, CHC13); IR (thin film) vmax 3414, 2957, 2881, 1727, 1664, 1370 cm-'; IH NMR (500 MHz, CDC13) 6 5.23 (d,

CH3)3); 13C NMR (125 MHz, CDC13) 6 200.2, 198.3, 170.1, 168.9,

J = 9.5 Hz, 1 H, 10-H), 4.89 (d, J = 9.5 Hz, 1 H, 5-H), 4.63 (A of AB, d, J = 9.5 Hz, 1 H, 20-H), 4.56 (B of AB, d, J = 9.5 Hz, 1 H, 20-H), 4.32 (dd, J = 11.0, 7.0 Hz, 1 H, 7-H), 4.28 (d, J = 2.5 Hz, 1 H, 10-OH), 3.89 (dd, J = 6.5, 4.0 Hz, 1 H, 2-H), 3.57 (d, J = 6.5 Hz, 1 H, 3-H), 2.78 (A' of A'B', d, J = 19.5 Hz, 1 H, 14-H), 2.58 (d, 4.0 Hz, 1 H, 2-OH), 2.52 (B' of A'B', d, J = 19.5 Hz, 1 H, 14-H), 2.46 (m. 1 H, 6-H), 2.03 (s, 3 H, OAc), 1.88 (m, 1 H, 6-H), 1.68 (s, 3 H,

Hz, 9 H, Si(CHzCH&), 0.60-0.40 (band, 6 H, Si(CHzCH&); 13C NMR (125 MHz, CDC13) 6 208.9, 198.5, 170.1, 156.7, 138.8, 83.8, 81.2, 77.6, 75.7, 72.8, 72.5, 58.8, 45.8, 43.1, 42.8, 37.3, 32.7, 21.6, 17.5, 13.6, 9.7, 6.7, 5.1; FAB HRMS (NBA/NaI) m/e 575.2648, M + Na+ calcd for CzgH4409Si 575.2652.

Carbonate 29. Method A. To a solution of diol 26 (96.0 mg, 0.187 mmol) in pyridine (10 mL) at 0 "C was added phosgene (0.97 mL of a 1.93 M solution in toluene, 1.87 mmol). The solution was stirred at 0 "C for 0.5 h and poured onto ice (10 mL). After dilution with Et20 (25 mL), the organic layer was separated, washed with aqueous CuSO4 (2 x 15 mL) and aqueous NaHC03 (20 mL), dried (MgS04), and concentrated to give carbonate 29 (86 mg, 85%) as an amorphous solid.

Method B. A solution of diol 26 (60.0 mg, 0.109 mmol) in THF (2 mL) was treated with carbonyldiimidazole ( 1 10.0 mg, 0.678 m o l ) and stirred at 40 "C for 0.5 h. The reaction mixture was concentrated and redissolved in THF (5 mL). TLC analysis confmed total consumption of starting material. Then 1 N aqueous HCl(5 mL) was added, and the resulting solution was allowed to stir for 15 min at 25 OC. Et20 (25 mL) was added, and the organic layer was separated, washed with aqueous NaHCO3 (10 mL) and brine (10 mL), dried (MgS04), and concentrated to give carbonate 29 (58 mg, 93%) as a white foam: Rf = 0.50 (silica, 35% EtOAc in hexanes); [alZZ~ +48 (c 0.5, CHCh); IR (thin film) vmax 3438, 2957, 2882, 1820, 1731, 1685, 1370, 1236 cm-'; 'H NMR (500 MHz, CDC13) 6 5.27 (d, J = 2.5 Hz,

18-CH3), 1.21 ( s , 3 H, 16-CH3), 1.04 ( s , 3 H, I"-CHs), 0.90 (t, J = 8.0

1 H, 10-H), 4.89 (d, J = 9.0 Hz, 1 H, 5-H), 4.60 (A of AB, d, J = 9.0 Hz, 1 H, 20-H), 4.45 (B of AB, d, J = 9.0 Hz, 1 H, 20-H), 4.43 (d, J = 6.0 Hz, 1 H, 2-H), 4.33 (dd, J = 10.0, 7.5 Hz, 1 H, 7-H), 4.28 (d, J = 2.5 Hz, 1 H, lO-OH), 3.54 (d, J = 6.0 Hz, 1 H, 3-H), 2.88 (A' of AB', d, J = 20.0 Hz, 1 H, 14-H), 2.75 (B' of A'B', d, J = 20.0 Hz, 1 H, 14-H), 2.50 (m, 1 H, 6-H), 2.08 (s, 3 H, OAc), 2.06 (s, 3 H, 18- CH,), 1.88 (m, 1 H, 6-H), 1.77 (s, 3 H, 19-C&), 1.31 (s, 3 H, 16- CH3), 1.15 (s, 3 H, 17-CH3), 0.88 (t. J = 8.5 Hz, 9 H, Si(CHzCH&), 0.55-0.45 (band, 6 H, Si(CHzCH&); 13C NMR (125 MHz, CDC13) 6 208.4, 195.5, 170.5, 154.0, 152.0, 141.2, 88.4, 83.9, 79.8, 79.0, 76.7, 75.7, 71.9, 60.3, 43.0,41.6, 39.8, 37.7, 31.6, 21.5, 17.8, 14.4,9.7, 6.6, 5.0; FAB HRMS (NBA) m/e 579.2652, M + H+ calcd for CZ~&ZO~O- Si 579.2626.

J. Am. Chem. Soc., Vol. 117, No. 2, 1995 631

Acetate 30. To a solution of carbonate 29 (86.0 mg, 0.159 mmol) in CHzClz (2 mL) were added 4-(dimethy1amino)pyridine (DMAP, 177.0 mg, 1.45 mmol) and acetic anhydride (0.069 mL, 0.723 mmol). The solution was stirred at 25 "C for 0.5 h, diluted with Et20 (100 mL), washed with 10% aqueous HCl(5 mL), 10% aqueous NaOH (5 mL) and brine (5 mL), dried (MgSOd), concentrated, and purified by flash chromatography (silica, 10 - 50% EtOAc in petroleum ether) to give carbonate 30 (94 mg, 95%) as an amorphous solid Rj = 0.50 (silica, 35% EtOAc in hexanes); [alZz~ +14 (c 0.5, CHC13); IR (thin film) vmax 2926, 1823, 1754, 1731, 1689 cm-'; 'H NMR (500 MHz, CDCl3) 6 6.52 (s, 1 H, IO-H), 4.89 (d, J = 9.0 Hz, 1 H, 5-H), 4.60 (A of AB, d, J = 9.0 Hz, 1 H, 20-H), 4.48 (d, J = 5.5 Hz, 1 H, 2-H), 4.45 (B of AB, d, J = 9.0 Hz, 1 H, 20-H), 4.42 (dd, J = 9.5, 7.0 Hz, 1 H, 7-H), 3.49 (d, J = 5.5 Hz, 1 H, 3-H), 2.90 (A' of AB', d, J = 20.0 Hz, 1 H, 14-H), 2.78 (B' of A'B', d, J = 20.0 Hz, 1 H, 14-H), 2.55 (m, 1

CH3), 1.87 (m, 1 H, 6-H), 1.71 (s, 3 H, 19-CH3), 1.28 (s, 3 H, 16- CH3), 1.26 (s, 3 H, 17-CH3), 0.89 (t, J = 8.0 Hz, 9 H, Si(CHzCH&), 0.60-0.50 (band, 6 H, Si(CHzCH3)3); 13C NMR (125 MHz, CDCl,) 6 200.2, 195.7, 170.5, 168.7, 152.0, 150.4, 142.5, 88.2, 83.9, 79.8, 79.2, 76.6, 75.7, 71.5, 61.0, 43.1, 39.8, 37.7, 31.6, 21.5, 20.7, 18.4, 14.4, 9.7, 6.7, 5.1; FAB HRMS (NBA) m/e 621.2745, M + Hf calcd for C~lH44011Si 621.273 1.

Enone 31. A. Oxidation of 16 to 31. To a solution of 7-TES- deacetylbaccatin 111 (16, 1.5 g, 2.28 mmol) and 4-methylmorpholine N-oxide (NMO, 240 mg, 2.05 mmol) in CHzClz (5 mL) was added 4-A molecular sieves (200 mg), and the suspension was stirred at 25 "C for 10 min. A catalytic amount of tetrapropylammonium permthenate (TPAP, 40 mg, 0.11 mmol) was added by portions, and the reaction mixture was stirred at 25 "C for 0.5 h. Small amounts of 4-methylmorpholine N-oxide and TPAP were added altematively at 0.5 h intervals until the starting material was consumed to the extent of ca. 95% by TLC. The reaction mixture was filtered through silica gel, eluted with CHzClz (100 mL), and concentrated to give enone 31 (1.44 g, 96%) as a white solid.

B. Conversion of Carbonate 29 to 31. A solution of carbonate 29 (1.5 mg, 0.0026 mmol) in THF (0.3 mL) at -78 "C was treated with PhLi (0.013 mL, 0.026 mmol) and stirred at -78 "C for 0.5 h. The reaction was quenched with aqueous W C l (10 mL). After dilution with Et20 (20 mL), the organic layer was separated, washed with brine (10 mL), dried (NazSOd), and purified by flash chromatography (silica, 25 - 35% EtOAc in petroleum ether) to give hydroxy benzoate 31 (1.4 mg, 85%) as a film: Rf = 0.5 (silica, 50% EtOAc in hexanes); [a]*'D +11 (c 0.56, CHC13); IR (thin film) vm 3446, 2957, 2882, 1726, 1672, 1456, 1367, 1243, 1106 cm-'; IH NMR (500 MHz, CDC13) 6 8.05 (dd, J = 8.0, 1.0 Hz, 2 H, Bz), 7.61 (t, J = 7.5 Hz, 1 H, Bz), 7.45 (t, J = 7.5 Hz, 2 H, Bz), 5.63 (d, J = 7.5 Hz, 1 H, 2-H), 5.30 (d, J = 2.0 Hz, 1 H, 10-H), 4.90 (d, J = 8.0 Hz, 1 H, 5-H), 4.36 (dd, J = 10.5, 7.0 Hz, 1 H, 7-H), 4.31 (A of AB, d, J = 8.5 Hz, 1 H, 20-H), 4.30 (d, J = 2.0 Hz, 1 H, 10-OH), 4.11 (B of AB, d, J = 8.5 Hz, 1 H, 20-H), 3.93 (d, J = 7.5 Hz, 1 H, 3-H), 2.92 (A' of A'B', d, J = 19.5 Hz, 1 H, 14-H), 2.62 (B'of A'B', d, J = 19.5 Hz, 1 H, 14-H),

H, 6-H), 2.19 (s, 3 H, OAC), 2.16 (s, 3 H, OAC), 2.07 ( s , 3 H, 18-

2.46 (m, 1 H, 6-H), 2.17 (s, 3 H, OAc), 2.08 (s, 3 H, 18-CH3), 1.87 (m, 1 H, 6-H), 1.77 (s, 1 H, 1-OH), 1.70 (s, 3 H, 19-CH3), 1.21 (s, 3

Si(CHzCH3)3), 0.60-0.42 (band, 6 H, Si(CHzCH3)3); 13C NMR (125 MHz, CDC13) 6 208.2, 198.1, 170.2, 166.8, 156.6, 139.1, 134.0, 130.0, 128.8, 128.8, 84.0, 80.4, 78.5, 76.2, 75.7, 72.9, 72.8, 58.8, 45.9, 43.4, 42.5, 37.2, 33.0, 21.7, 17.5, 13.6, 9.6, 6.7, 5.1; FAB HRMS (NBA/ NaI) d e 657.3070, M + Na+ calcd for C35&g010Si 657.3095.

Thiocarbamate 34. A solution of 7-TES-baccatin I11 (17, 48 mg, 0.069 mmol) in THF (1 mL) was treated with 4-(dimethylamino)- pyridine (DMAP, 251 mg, 2.05 mmol) and (thiocarbony1)diimidazole (244 mg, 1.37 mmol) and stirred at 75 "C in a sealed flask for 18 h. The reaction mixture was diluted with EtOAc (15 mL), washed with 10% aqueous HC1 (5 mL) and aqueous NaHC03 (10 mL), dried (MgS04), concentrated, and purified by flash chromatography (silica, 20 - 50% EtOAc in petroleum ether) to give thiocarbamate 34 (48 ing, 86%) as a white solid Rf = 0.27 (silica, 25% EtOAc in benzene);

1388, 1284, 1238, 1104 cm-'; 'H NMR (500 MHz, CDC13) 6 8.50 (s, 1 H, imid.), 8.01 (d, J = 7.5 Hz, 2 H, Bz), 7.79 (s, 1 H, imid.), 7.56

H, 16-CH3), 1.14 ( s , 3 H, 17-CH3), 0.90 (t, J = 8.0 Hz, 9 H,

-59 (C 0.17, CHCls); IR (thin film) v,, 3478,2954,1726, 1465,


1237 cm-I; 'H NMR (500 MHz, CDC13) 6 6.38 (s, 1 H, 10-H), 4.95 (dd, J = 9.5, 1.5 Hz, 1 H, 5-H), 4.64 (A of AB, d, J = 9.0 Hz, 1 H, 20-H), 4.55 (B of AB, d, J = 9.0 Hz, 1 H, 20-H), 4.40 (dd, J = 10.5, 7.0 Hz, 1 H, 7-H), 3.83 (dd, J = 6.5, 4.5 Hz, 1 H, 2-H), 3.38 (d, J = 6.5 Hz, 1 H, 3-H), 2.69-2.58 (band, 1 H, 13-H), 2.54 (d, 4.5 Hz, 1 H, 2-OH), 2.51 (m, 1 H, 6-H), 2.16 (s, 3 H, OAc), 2.14 (s, 3 H, OAc),

2 H, 14-CH2), 1.78 (m, 1 H, 6-H), 1.62 (s, 3 H, 19-C&), 1.07 (s, 3 H, 16-CH3), 1.05 (s, 3 H, 17-C&), 0.88 (t, J = 7.5 Hz, 9 H, Si(CHzCH&), 0.61-0.48 (band, 6 H, Si(CH2CHs)s); FAB HRMS (NBA/NaI) m/e 603.2970, M -t Naf calcd for C3&809Si 603.2965.

Carbonate 38. A. Conversion of Diol 37 to Carbonate 38. To a solution of diol 37 (16 mg, 0.028 "01) in pyridine (2 mL) at 25 "C was added phosgene (0.143 mL of a 1.93 M solution in toluene, 0.28 m o l ) . The solution was stirred at 25 "C for 15 min. After dilution with Et20 (20 mL), the organic layer was separated, washed with aqueous CuSO4 (3 x 10 mL) and aqueous NaHC03 (10 mL), dried (MgSOd), concentrated, and purified by flash chromatography (silica, 10 - 35% EtOAc in petroleum ether) to give carbonate 38 (14.4 mg, 86%) as a white foam.

B. Silylation of 39 to 38. A solution of alcohol 39 (1.0 mg, 0.002 m o l ) in pyridine (0.5 mL) was treated with chlorotriethylsilane (TESCl, 0.017 mL, 0.1 m o l ) and stirred at 25 "C for 24 h. After dilution with Et20 (10 mL), the organic layer was separated, washed with aqueous CuSO4 (3 x 5 mL), dried (MgSOd), concentrated, and purified by flash chromatography (silica, 10 - 35% EtOAc in petroleum ether) to give carbonate 38 (1.0 mg, 85%) as a colorless film: Rf= 0.82 (silica, 50% EtOAc in hexanes); [ a ] " ~ -49.4 (c 0.93, CHCb); IR (thin film) v, 2924, 1814, 1728,1461, 1372,1238 cm-I;

2.13-2.01 (band, 1 H, 13-H), 2.01 (s, 3 H, 18-CH3), 1.92-1.83 (band,

'H NMR (500 MHz, cDc13) 6 6.40 (s, 1 H, 10-H), 4.95 (d, J = 9.0 Hz, 1 H, 5-H), 4.60 (A of AB, d, J = 9.0 Hz, 1 H, 20-H), 4.47 (B of AB, d, J = 9.0 Hz, 1 H, 20-H), 4.43 (dd, J = 10.0,7.5 Hz, 1 H, 7-H), 4.39 (d, J = 5.5 Hz, 1 H, 2-H), 3.36 (d, J = 5.5 Hz, 1 H, 3-H), 2.71 (m, 1 H, 13-H), 2.56 (m, 1 H, 13-H), 2.17 (s, 3 H, OAc), 2.15 (s, 3 H, OAc), 2.12 (m. 1 H), 2.07 (s, 3 H, 18-CH3), 1.97 (m, 1 H), 1.88 (m, 2 H), 1.78 (s, 3 ,H, 19-CH3), 1.23 (s, 3 H, 16-CH3), 1.17 (s, 3 H, 17- CH,), 0.88 (t, J = 7.5 Hz, 9 H, Si(CH2CH3)3), 0.60-0.50 (band, 6 H, Si(CHzCH&); 13C NMR (125 MHz, CDC13) 6 202.6, 170.3, 169.2, 153.1, 144.0, 130.7, 92.8, 84.0, 80.3, 80.0,76.4,76.1,60.3,43.5, 38.0, 29.7,29.4,25.5,23.1,21.9,21.1,19.1,9.8,6.7,5.2;FABHRMS(NBN CsI) d e 739.1929, M + Cs+ calcd for C31&010Si 739.1915.

Alcohol 39. A solution of silyl ether 38 (3.0 mg, 0.0049 "01) in THF (1.5 mL) was treated with HF-pyridine (0.5 mL) and stirred for 2 h at 25 "C. The reaction mixture was diluted with EtOAc (10 mL), and the reaction was quenched with aqueous NaHC03 (10 mL). The organic layer was separated, washed with 10% aqueous NaOH (10 mL) and brine (10 mL), dried (MgSOd), and purified by preparative TLC (silica, 30% EtOAc in petroleum ether) to give alcohol 39 (2.1 mg, 88%) as a colorless film: Rf = 0.22 (silica, 50% EtOAc in petroleum ether); [a12% -23 (c 1.0, CHC13); IR (thin film) vmax 2923,2854, 1809, 1723, 1460, 1374, 1238, 1018 cm-'; 'H NMR (500 MHz, CDC13) 6 6.25 (s, 1 H, 10-H), 4.94 (d, J = 8.0 Hz, 1 H, 5-H), 4.56 (A of AB, d, J = 9.0 Hz, 1 H, 20-H), 4.41 (B of AB, dd, J = 9.0, 0.5 Hz, 1 H, 20-H), 4.38 (m, 1 H, 7-H), 4.31 (d, J = 5.5 Hz, 1 H, 2-H), 3.33 (d, J = 5.5 Hz, 1 H, 3-H), 2.73 (m, 1 H, 13-H), 2.57 (m, 1 H, 6-H), 2.28 (d, J 4.0 Hz, 1 H, OH), 2.15 (s, 3 H, OAc), 2.13 (s, 3 H, OAc), 2.12- 2.02 (band, 2 H, 14-CH2), 1.94 (d, J = 1.0 Hz, 3 H, 18-CH3), 1.95- 1.80 (band, 2 H, 13-H and 6-H), 1.65 (s, 3 H, 19-CH3), 1.18 (s, 3 H, 16-CH3), 1.08 (s, 3 H, 17-CH3); 13C NMR (125 MHz, CDCl3) 6 204.3, 170.9, 170.2, 153.0, 146.4,92.8,84.2, 80.4,76.7,75.9,71.5,60.3,43.0, 36.4, 31.0, 29.7, 29.6, 25.5, 23.2, 21.9, 21.6, 20.9, 19.0, 9.2.

2',7-diTES-Taxol (42). To a solution of 7-TES-baccatin III (17, 20.0 mg, 0.0285 "01) and B-lactam 40 (38 mg, 0.0998 mmol) in THF (1.5 mL) at 0 "C was added NaN(SiMe& (0.086 mL of a 1.0 M solution in THF, 0.086 "01) dropwise. The reaction mixture was stirred at 0 "C for 0.5 h, and the reaction was quenched with aqueous m C 1 (2 mL). After dilution with Et20 (15 mL), the organic layer was separated, washed with brine (5 mL), dried (MgSOd), concentrated, and purified by flash chromatography (silica, 10 - 50% EtOAc in petroleum ether) to give starting material 17 (2.2 mg, 11%) and 2',7- diTES-Taxol(42) (23.7 mg, 86% based on 89% conversion) as a white solid: Rf = 0.59 (silica, 50% EtOAc in hexanes); [a]22D -48 (c 0.4,

(t, J = 7.5 Hz, 1 H, Bz), 7.42 (t. J = 7.5 Hz, 2 H, Bz), 7.10 (s, 1 H, imid.), 6.53 (t, J = 9.0 Hz, 1 H, 13-H), 6.46 (s, 1 H, 10-H), 5.66 (d, J = 7.0 Hz, 1 H, 2-H), 4.89 (d, J = 8.5 Hz, 1 H, 5-H), 4.46 (dd, J = 10.5, 7.0 Hz, 1 H, 7-H), 4.25 (A of AB, d, J = 8.5 Hz, 1 H, 20-H), 4.13 (B of AB, d, J = 8.5 Hz, 1 H, 20-H), 3.85 (d, J = 7.0 Hz, 1 H, 3-H), 2.72 (dd, J = 15.0, 9.0 Hz, 1 H, 14-H), 2.53 (m, 1 H, 6-H), 2.21 (s, 3 H, OAc), 2.17 (s, 3 H, OAc), 2.12 (dd, J = 15.0, 7.5 Hz, 1 H, 14-H), 1.91 (s, 3 H, 18-CH3), 1.88 (m, 1 H, 6-H), 1.65 (s, 3 H, 19-

Hz, 9 H, Si(CHzCH3)3), 0.62-0.51 (band, 6 H, Si(CHzCH,)3); 13C NMR

134.8, 133.8, 131.3, 130.0, 128.9, 128.6, 118.3, 84.1, 81.3, 80.1, 78.9, 76.6, 75.0, 74.3, 72.5, 58.9, 46.8, 43.3, 37.4, 35.0, 29.7, 26.9, 21.9, 20.9, 20.3, 15.4, 9.9, 6.7, 5.2; FAB HRMS (NBA/NaI) d e 833.3110, M + Naf calcd for C41H5401lN~SSi 833.3115.

Benzoate 35. A. Deoxygenation of 34 to 35. To a solution of thiocarbamate 34 (960 mg, 1.18 mmol) in degased toluene (250 mL) stirred at 85 "C were added tributyltin hydride (3.2 mL, 11.8 "01) and azobis(isobutyronitri1e) (AIBN, 16.4 mg in 1 mL of toluene, 0.1 mmol). The reaction mixture was stirred at 85 "C for 2 h, concentrated, and purified by flash chromatography (silica, 15 - 25% EtOAc in petroleum ether) to give a mixture of alcohol 35 and isomer 36 (620 mg, 76%) as one single fraction containing 77% of 35 (59% yield) and 23% of 36 (17% yield). Analytical samples of both isomers were obtained by preparative TLC (silica, 30% EtOAc in benzene).

Isomer 35: Rf = 0.47 (silica, 25% EtOAc in benzene); [alZz~ -50.6 (c 0.5, CHC13); IR (thin film) vmax 3517,2922, 1728, 1456, 1371, 1242, 1109 cm-'; 'H NMR (500 MHz, CDC13) 6 8.06 (d, J = 8.0 Hz, 2 H, Bz), 7.58 (t, J = 7.5 Hz, 1 H, Bz), 7.45 (t, J = 7.5 Hz, 2 H, Bz), 6.45

CH3), 1.25 (s, 3 H, 16-CH3), 1.17 (s, 3 H, 17-CH3), 0.91 (t, J = 8.0

(125 MHz, CDCl3) 6 201.5, 183.5, 170.0, 169.3, 166.9, 138.7, 137.7,

(s, 1 H, 10-H), 5.59 (d, J = 7.0 Hz, 1 H, 2-H), 4.95 (d, J = 9.0 Hz, 1 H, 5-H), 4.45 (dd, J = 10.5, 7.0 Hz, 1 H, 7-H), 4.30 (A of AB, d, J = 8.5 Hz, 1 H, 20-H), 4.14 (B of AB, d, J = 8.5 Hz, 1 H, 20-H), 3.75 (d,

(s, 3 H, OAC), 2.30-2.17 (band, 2 H, 6-CH2), 2.16 (s, 3 H, OAc), 2.07 (s, 3 H, 18-CH3), 1.93-1.81 (band, 2 H, 14-CH2), 1.64 (s, 3 H, 19- CH3). 1.18 (s, 3 H, 16-CH3), 1.04 (s, 3 H, 17-C&), 0.89 (t, J = 8.0

(125 MHz, CDCl3) 6 202.5, 169.8, 169.5, 167.0, 141.6, 133.6, 132.3,

J = 7.0 Hz, 1 H, 3-H), 2.65 (m, 1 H, 13-H), 2.53 (m, 1 H, 13-H), 2.30

Hz, 9 H, Si(CHtCH&), 0.65-0.49 (band, 6 H, Si(CHzCH3)3); 13C NMR

130.0, 129.3, 128.6, 84.0, 81.4, 80.6, 76.5,75.9,73.8,72.4,58.8,46.8, 42.2, 37.4, 30.0, 26.7, 25.2, 22.1, 21.1, 20.5, 19.0, 9.6, 6.7, 5.3; FAB HRMS (NBNCsI) m/e 817.2380, M + Csf calcd for C37H52010Si 817.2384.

Isomer 36: Ry = 0.48 (silica, 25% EtOAc in benzene); 'H NMR (500 MHz, CDC13) 6 8.04 (d, J = 7.0 Hz, 2 H, Bz), 7.58 (t, J = 7.5 Hz, 1 H, Bz), 7.47 (t, J = 7.5 Hz, 2 H, Bz), 5.96 (s, 1 H, 10-H), 5.48 (dd, J = 5.0, 1.5 Hz, 1 H, 2-H), 5.45 (m, 1 H, 13-H), 4.98 (dd, J = 8.3, 1.9Hz, lH ,5 -H) ,4 .39 (AofAB,d ,J=8 .5Hz , 1H,20-H),4.35 (dd, J = 10.4, 6.5 Hz, 1 H, 7-H), 4.25 (B of AB, d, J = 8.5 Hz, 1 H, 20-H), 4.00 (d, J = 5.0 Hz, 1 H, 3-H), 2.72 (m, 1 H, 14-H), 2.48 (m,

2 H, 6-H and 14-H), 1.89 (s, 3 H, 18-CH3), 1.60 (s, 3 H, 19-C&), 1.23 (s, 3 H, 16-CH3), 1.07 (s, 3 H, 17-C&), 0.88 (t, J = 8.0 Hz, 9 H, Si(CH2CH3)3), 0.65-0.49 (band, 6 H, Si(CH&H&).

B. Conversion of Carbonate 38 to 35. A solution of carbonate 38 (1 mg, 0.0016 "01) in THF (1 mL) at -78 "C was treated with PhLi (0.016 mL, 2 M in cyclohexane, 0.008 mmol) and stirred at -78 "C for 15 min. The reaction was quenched with aqueous W C l (2 mL). After dilution with Et20 (10 mL), the organic layer was separated, dried (MgSOd), concentrated, and purified by preparative TLC (silica, 25% Et20 in benzene) to give benzoate 35 (0.9 mg, 80%) as a colorless film.

Diol 37. To a mixture of benzoates 35 and 36 (71.8 mg, 0.105 mmol, ca. 77:23) in MeOH (13.5 mL) and THF (3.6 mL) at 0 "C was added an aqueous solution of KzCO3 (270 mg in 3.5 mL of H20). The solution was stirred at 0 "C for 6 h and at -20 OC for 10 h. The reaction was quenched with aqueous W C l ( 2 0 mL), and the resulting mixture was extracted with CHC13 (2 x 100 mL). The organic layer was dried (MgSOd), concentrated, and purified by flash chromatography (silica, 20 - 40% EtOAc in petroleum ether) to give the benzoate mixture 35/36 (27 mg, 38%) and diol 37 (27 mg, 94% based on 62% conversion): Rf= 0.18 (silica, 50% EtOAc in hexanes); -43.6 (c 0.28, CHCl3); IR (thin film) vmiu 3479, 2923, 1721, 1461, 1372,

1 H, 6-H), 2.29 (s, 3 H, OAC), 2.16 (s, 3 H, OAC), 2.05-1.93 (band,

Total Synthesis of Taxol. I

CHCl3); IR (thin film) Y,, 3440, 2958, 1719, 1664 cm-'; 'H NMR (500 MHz, CDC13) 6 8.11 (d, J = 7.0 Hz, 2 H, Bz), 7.72 (d, J = 7.5 Hz, 2 H, Bz), 7.60-7.25 (band, 11 H, Ar), 7.11 (d, J = 9.0 Hz, 1 H, NH), 6.43 (s, 1 H, 10-H), 6.22 (b t, J = 8.5 Hz, 1 H, 13-H), 5.69 (m, 2 H, 3'-H and 2-H), 4.93 (b d, J = 8.0 Hz, 1 H, 5-H), 4.69 (d, J = 2.0 H~,lH,2'-H),4.45(dd,J=11.0,7.0H~,lH,7-H),4.30(AofAB, d, J 8.5 Hz, 1 H, 20-H), 4.19 (B of AB, d, J = 8.5 Hz, 1 H, 20-H), 3.82 (d, J = 7.0 Hz, 1 H, 3-H), 2.53 ( s , 3 H, OAC), 2.38 (dd, J = 9.5, 15.0 Hz, 1 H, 14-H), 2.18 (s, 3 H, OAC), 2.12 (dd, J = 15.0, 8.0 Hz,

19-CH3), 1.20 (s, 3 H, 16-CH3), 1.16 (s, 3 H, 17-CH3), 0.89 (t, J = 8.0 1 H, 14-H), 2.00 (s, 3 H, 18-CH3). 1.89 (m, 2 H, 6-CHz), 1.68 (s, 3 H,

Hz, 9 H, Si(CHzCH&), 0.80 (t, J = 8.0 Hz, 9 H, Si(CHzCH&), 0.62- 0.51 (band, 6 H, Si(CHzCH3)3), 0.51-0.35 (band, 6 H, Si(CHzCH&); '3CNMR(125MH~,CDcb)6201.7, 170.1, 169.3, 167.2, 167.0, 140.1, 138.3, 134.2, 133.7, 133.6, 131.8, 130.2, 130.1, 129.2, 128.7, 128.3, 127.9, 127.0, 126.4, 84.2, 81.2, 78.7,76.6, 75.0,74.9, 74.8,72.2, 71.5, 58.4, 55.7, 46.6, 43.3, 37.2, 35.5, 26.5, 23.1, 21.5, 20.9, 14.1, 10.1, 6.7, 6.5, 5.3, 4.3; FAB HRMS (NBA/CsI) mle 1214.4089, M + Cs+ calcd for C59H79014NSi~ 1214.4093.

Taxol (1). A solution of silyl ether 42 (22 mg, 0.020 m o l ) in THF (1 mL) was treated with HFTyridine (0.2 mL) and stirred for 1.25 h at 25 "C. The reaction mixture was diluted with Et20 (15 mL), and the reaction was quenched with aqueous NaHCO3 (5 mL). The organic layer was separated, washed with aqueous CuS04 (2 x 5 mL) and brine (5 mL), dried (Na~S04), and purified by flash chromatography (silica, 50 - 75% EtOAc in petroleum ether) to give Taxol (1, 13.9 mg, 80%) as a white solid Rf= 0.125 (silica, 50% EtOAc in hexanes);

-49 (c 0.45, MeOH); IR (thin film) vmax 3432,2937,1720, 1652, 1520, 1241 cm-I; 'H NMR (500 MHz, CDC13) 6 8.13 (dd, J = 8.5, 1 .2Hz ,2H,Bz) ,7 .74 (dd ,J=8 .2 , 1 .2Hz,2H,Bz) ,7 .62,(t ,J=7.5 Hz, 1 H, Bz), 7.52-7.32 (band, 7 H, Ar), 7.02 (d, J = 9.0 Hz, 1 H, NH), 6.27 (s, 1 H, 10-H), 6.23 (b t, J = 9.0 Hz, 1 H, 13-H), 5.79 (dd, J = 9.0, 2.5 Hz, 1 H, 3'-H), 5.67 (d, J = 7.0 Hz, 1 H, 2-H), 4.95 (b d, J = 8.0 Hz, 1 H, 5-H), 4.79 (dd, J = 2.5, 5.5 Hz, 1 H, 2'-H), 4.40 (m,


lH,7-H),4.31(AOfAB,d,J=8.5H~,lH,20-H),4.19(BofAB, d, J = 8.5 Hz, 1 H, 20-H), 3.79 (d, J = 7.0 Hz, 1 H, 3-H), 3.61 (d, J = 5.5 Hz, 1 H, 2'-OH), 2.55 (m, 1 H, 6-H), 2.49 (d, J = 4.0 Hz, 1 H,

H, OAc), 1.88 (m, 1 H, 6-H), 1.82 (s, 1 H, 1-OH), 1.79 (s, 3 H, 18- 7-OH), 2.39 (s, 3 H, OAC), 2.40-2.25 (band, 2 H, 14-CHz), 2.24 ( s , 3

CH3), 1.69 (S, 3 H, 19-CH3), 1.24 (s, 3 H, 16-CH3), 1.14 ( s , 3 H, 17- CH3); I3C NMR (125 MHz, CDC13) 6 203.6, 172.7, 171.3, 170.4, 167.0, 167.0, 142.0, 137.9, 133.7, 133.6, 133.1, 132.0, 130.2, 129.1, 129.0, 128.7, 128.7, 128.4, 127.1, 127.0, 84.4, 81.1, 79.0, 76.5, 75.5, 74.9, 73.2, 72.3, 72.2, 58.6, 55.0, 45.6, 43.1, 35.6, 35.6, 26.8, 22.6, 21.8, 20.9, 14.9, 9.5; FAB HFWS (NBA) mle 854.3360, M + H+ calcd for C47H51014N 854.3388.

Acknowledgment. We thank Dr. E. Bombardelli for a generous gift of 10-deacetylbaccatin III and Drs. Dee H. Huang and Gary Siuzdak for NMR and mass spectroscopic assistance, respectively. This work was financially supported by NIH, The Scripps Research Institute, fellowships from Mitsubishi Kasei Corporation (H.U.), Rh8ne-Poulenc Rorer (P.G.N.), The Office of Naval Research (R.K.G.), The Agricultural University of Athens (E.A.C.), R.W. Johnson-ACS Division of Organic Chemistry (E.J.S.), and grants from Merck Sharp & Dohme, Pfizer, Inc., Schering Plough and the ALSAM Foundation.

Supplementary Material Available: Experiment techniques and data for compounds 15, 16, 18, and 28 (3 pages). This material is contained in many libraries on microfiche, immediately follows this article in the microfilm version of the journal, and can be ordered from the ACS: See any current masthead page for ordering information.

JA9421922

634 J. Am. Chem. SOC. 1995,117, 634-644

Total Synthesis of Taxol. 2. Construction of A and C Ring Intermediates and Initial Attempts To Construct the ABC Ring System

K. C. Nicolaou,* J.-J. Liu, Z. Yang, H. Ueno, E. J. Sorensen, C. F. Claiborne, R. K. Guy, C.-K. Hwang, M. Nakada, and P. G. Nantermet

Contribution from the Department of Chemistry, The Scripps Research Institute, 10666 North Torrey Pines Road, La Jolla, California 92037, and Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093

Received July 7, 1994@

Abstract: A method for the formation of Taxol's ABC ring system has been developed. General methods for the synthesis of versatile synthons for Taxol's A ring (8) and C ring (55) are presented. A model study using a simplified C ring synthon (17) conf i ied the viability of the sequential Shapiro-McMurry strategy for formation of Taxol's B ring. Careful exploration of the chemistry of various A-B ring conjugates allowed the development of a successful method for formation of the B ring in a more functionalized system.

Introduction

The preceding paper' established a convergent strategy toward Taxol(1, Figure 1) and described a number of chemical studies that provided direction toward the appropriate intermediates and final path. In this article we describe the construction of rings A and C and discuss the refinements to these methods that were necessary to arrive at the key building blocks that were utilized in the synthesis.

Construction of Ring A

In keeping with the themes of convergency and of using the Diels-Alder reaction as a means to construct both rings A and C of Taxol (l), we embarked on the synthesis of intermediates 9 and 10 as summarized in Scheme 1. The possibility of steric hindrance ovemding the well-known electronic induction of regiocontrol in the Diels- Alder reaction2 warranted concem initially. This worry proved unfounded, however, as the readily prepared diene S3s4 and 1-chloroacrylonitrile (6) provided, through a Diels-Alder reaction that proceeded smoothly at 130 "C in a sealed tube, an 80% yield of desired product 7 as a single regioisomer, whose structure was conf i ied by both spectroscopic and X-ray crystallographic analyses. Application of the protocol of Shine$s6 (KOH, 'BuOH, 70 "C) freed the latent carbonyl group at C1 with concomitant acetate removal to give hydroxy ketone 8 (90%, based on 70% conversion). Reprotection of the primary hydroxyl group of 8 as either a

* Address correspondence to this author at the Scripps Research Institute

@Abstract published in Advance ACS Abstracts, December 15, 1994. (1) Nicolaou, K. C.; Nantennet, P. G.; Ueno, H.; Guy, R. K.; Coula-

douros, E. A,; Sorensen, E. J. J . Am. Chem. SOC. 1995, 117, 624. (2) Carruthers, W. Cycloaddition Reactions in Organic Synthesis in

Tetrahedron Organic Chemistry Series; Baldwin, J. E., FRS, Magnus, P. D., FRS, Eds.; Pergamon Press: New York 1990; Vol. 8, p 1.

(3) Kazi, M. A.; Khan, I. H.; Khan, M. H. J. Chem. SOC. 1964, 1511. (4) Alkonyi, I.; Szabo, D. Chem. Ber. 1967, 2773. (5) Shiner, C. S.; Fisher, A. M.; Yacobi, F. Tetrahedron Lett. 1983.24,

5687. (6)See also: Madge, N. C.; Holmes, A. B. J. Chem. SOC., Chem.

Commun. 1980, 956. Evans, D. A.; Scott, W. L.; Truesdale, L. K. Tetrahedron Len. 1972, 121. Monti, S. A.; Chen, S. C.; Yang, Y. L.; Yuan, S. S.; Bourgeois, 0. P. J. Org. Chem. 1978, 43, 4062.

or the University of California.

1:Taxol

Figure 1. Structure and numbering of Taxol (1).

Scheme 1. Construction of Ring A Key Intermediates 8-1W OR COzEt -

2

10 \ r O R

3

Ac

9: R = TBS e 10: R = MEM

7

Reagents and conditions: (a) 1.2 equiv of MeMgBr, EtzO, 0 - 25 "C, 8 h, then 0.2 equiv of p-TsOH, benzene, 65 "C, 3 h, 70%; (b) 2.2 equiv of i-BuzAIH, CHzClz, -78 - 25 "C, 12 h, 92%; (c) 1.1 equiv of AczO, 1.2 equiv of Et,N, 0.2 equiv of 4-(dimethy1amino)pyridine (DMAP), CHZC12, 0 - 25 "C, 1 h, 96%; (d) 1.0 equiv of 5, 1.5 equiv of 6, 130 "C, 72 h, 80%; (e) 6.0 equiv of KOH, t-BuOH, 70 "C, 4 h, 90% based on 70% conversion; (f) for 9, 1.1 equiv of TBSCl, 1.2 equiv of imidazole, CHZC12, 25 "C, 2 h, 85%; for 10, 1.2 equiv of MEMCl, 1.3 equiv of i-PrzNEt, CHzClz, 25 "C, 3 h, 95%. TBS = Si-t-BuMez, MEM = (methoxyethoxy)methyl.

tert-butyldimethylsily18 or (methoxyethoxy)methy17 ether afforded compounds 9 (85% yield) and 10 (95% yield), respectively.

(7) Jacobson, R. M.; Clader, J. W. Synth. Commun. 1979, 9, 57. (8) Corey, E. J.; Venkateswarlu, A. J . Am. Chem. SOC. 1972, 94, 6190.

0002-7863/95/1517-0634$09.00/0 0 1995 American Chemical Society


Scheme 2. Chemistry of A Ring Ketones 8-10 and Construction of Hydrazones 15 and 16"


of a hydrazone, a precursor to vinyllithium species, was then attempted. To our surprise and delight, hydrazones 15 and 16 were both easily prepared from the corresponding ketones 9 and 10 via addition of (triisopropylsulfonyl)hydrazine.ll As will be discussed below, these hydrazones served admirably in Shapiro c o ~ p l i n g s ' ~ J ~ with appropriately functionalized ring C partners.

a 11

\\

10

0 \

12

0 Tf

4 KEM

\ SnMe,

14 13

v NNHS0,Ar

9: R = TBS 10: R = MEM

15: R = TBS 18: R = MEM

Reagents and conditions: (a) 1.1 equiv of KH, 1.05 equiv of PhCHZBr, THF, 0 - 25 "C, 1.5 h, 37%; (b) 1.1 equiv of LiN-i-Pr2, DME, -78 "C, 2 h, then 1.07 equiv of N-phenyltrifluoromethanesulfonimide, DME, -78 - 0 "C, 4 h, 80%; (c) 0.90 equiv of MesSnSnMes, 6.35 equiv of LiCl, 0.02 equiv of (PhsP)Pd, THF, 60 "C, 18 h, 90%; (d) 1.0 equiv of PhCOCl, 0.05 equiv of PhCHzPd(Cl)(PhsP)z, HMPA, 65 "C, 18 h, 65%; (e) for 15, 1.0 equiv of (2,4,6-t1iisopropylbenzenesulfonyl)hydrazine, THF, 25 "C, 24 h, 88%; for 16, 1 .O equiv of (2,4,6-t1iisopropylbenzenesulfonyl)hydrazine, MeOH 25 "C, 4 h, 85%. Ar = 2,4,6-triisopropylbenzene, TBS = Si-t- BuMe2, MEM = (methoxyethoxy)methyl, HMPA = hexamethylphosphoramide.

Early attempts to engage ketones 9 or 10 in coupling with nucleophiles revealed their reluctance to enter in such reactions, probably due to both steric hindrance and ease of enolization. The reaction of 8 with benzyl bromide under basic conditions evidenced the latter by giving rise to dibenzyl derivative 11 (37%, Scheme 2), rather than the expected benzyl ether.

Having failed to induce the ring A derivatives 8-10 to undergo nucleophilic additions at their carbonyl site, it was then decided to umpolung the system, that is to convert it into a nucleophilic species. Early attempts utilized the vinyltin derivative 13 (Scheme 2), prepared from ketone 10 via triflate U9 as summarized in Scheme 2, as a vinyllithium precursor or a nucleophillic partner in a Stille couplinglo reaction. However, neither reaction proved fruitful with a functionalized ring C partner, even though a Stille coupling of 13 with benzoyl chloride did afford enone 14 (65% yield, Scheme 2). With some reluctance due to the expected steric hindrance, the formation

(9) McMurry, J. E.; Scott, W. I. Tetrahedron Len. 1983,24,979. Wulff, W. D.; Peterson, G. A.; Bauta, W. E.; Chan, K.-S.; Faron, K. L.; Gilbertson, S. R.; Kaesler, R. W.; Yang, D. C.; Murray, C. K. J . Org. Chem. 1986,51, 277.

(10) (a) Milstein, D.; Stille, J. K. J . Am. Chem. SOC. 1978, 3636. (b) Milstein, D.; Stille, J. K. J . Org. Chem. 1979, 44, 1613. (c) For a review, see: Stille, J. K. Angew. Chem., Znt. Ed. Engl. 1986, 25, 508.

A Feasibility Study for the Shapiro-McMurry Strategy

With a suitable ring A vinyllithium precursor in hand, we were now ready to test the feasibility for the proposed Shapiro- McMurry strategy toward the taxoid skeleton. To this end the model aldehyde 21,14 representing Taxol's ring C, was prepared from diester 1715 via the sequence summarized in Scheme 3 . Then, reaction of hydrazone 16 with 2.1 equiv of n-BuLi in THF at -78 "C followed by warming to 0 "C and addition of aldehyde 21 furnished a mixture of diastereomeric C2 alcohols (ca. 2:l) in 83% total yield. The major diastereoisomer, isolated chromatographically, was proven to be of the desired stereochemistry, as indicated in stmcture 22, by X-ray crystallographic analysis on a subsequent intermediate (vide infra). Vanadium- catalyzed epoxidation of allylic alcohol 22 according to the Sharpless procedure16 proceeded regio- and stereoselectively to afford epoxide 23 in 91% yield. Regioselective opening of this epoxide using lithium aluminum hydride" in Et20 at 0-25 "C provided diol 24 in 96% yield. Following our tactical intention to preorganize the substrate prior to McMurry reactions,I8 we engaged the vicinal 1,Zdiol system in 24 as the acetonide 25.19 Sequential removal of the primary alcohols' protecting groups and oxidationz0 with TPAP-NMO furnished dialdehyde 30 in 50% overall yield from 25 (Scheme 4). An X-ray crystallographic analysis of compound 30 confirmed its structure and those of its precursors (see ORTEP drawing, Figure 2).

Having secured dialdehyde 30 we were within sight of a tricyclic taxoid skeleton provided the pending McMurry coupling'* would be successful. Mindful of Kende's precedentz1 which resulted in the formation of an olefin at the C9-C10 site instead of the C9-C10 diol system that we desired, we proceeded cautiously and systematically to develop proper conditions for this ring closure. After considerable experimentation it was found that exposure of dialdehyde 30 to Ti(0) generated from Tic13 and Zn-Cu couple in DME at 50 "C under high-dilution conditions gave the desired diol 31 in 40% yield

(11) Cusack, N. J.; Reese, C. B.; Risius, A. C.; Roozpeikar, B. Tetrahedron 1976, 32, 2157.

(12)Shapiro, R. H. Org. React. 1976, 23, 405. Chamberlin, A. R.; Bloom, S. H. Org. React. 1990, 39, 1-83. Martin, S . F.; Daniel, D.; Cherney, R. J.; Liras, S. J . Org. Chem. 1992, 57, 2523.

(13) This strategy was later used by others to accomplish similar couplings: Di Grandi, M. J.; Jung, D. K.; Krol, W. J.; Danishefsky, S . J. J . Org. Chem. 1993, 58,4989. Masters, J. J.; Jung, D. K.; Bornmann, W. G.; Danishefsky, S. J. Tetrahedron Lett. 1993, 34, 7253. (14) Nicolaou, K. C.; Yang, Z.; Sorensen, E.; Nakada, M. J . Chem. Soc.,

Chem. Commun. 1993, 1024. (15) Mundy, B. P.; Theodore, J. J. J . Am. Chem. SOC. 1980, 102, 2005. (16) Sharpless, K. B.; Michaelson, R. C. J . Am. Chem. SOC. 1973, 95,

6136. Sharpless, K. B.; Verhoeven, T. R. Aldrichimica Acta 1979, 12,63. Rao, A. S. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Ley, S. V., FRS, Eds.; Pergamon Press: New York, 1991; Vol. 7, p 376. (17) Mwai, S.; Mwai, T.; Kato, S. In Comprehensive Organic Synthesis;

Trost, B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 8, p 871.

(18)McMurry, J. E. Chem. Rev. 1989, 89, 1513. McMurry, J. E. Acc. Chem. Res. 1983, 16, 405. McMurry, J. E.; Lectka, T.; Rico, J. G. J . Org. Chem. 1989,54, 3748. McMuny, J. E.; Rico, J. G. Tetrahedron Lett. 1989, 30, 1169; Lenoir, D. Synthesis 1989, 883. (19) Evans, M. E.; Parrish, F. W.; Long, L., Jr. Carbohydr. Res. 1967,

3, 453. Lipshutz, B. H.; Barton, J. C. J . Org. Chem. 1988, 53, 4495. (20) Griffith, W. P.; Ley, S . V. Aldrichimica Acta 1990, 23, 13. (21) Kende, A. S.; Johnson, S.; Sanfilippo, P.; Hodges, J. C.; Jungheim,

L. N. J . Am. Chem. SOC. 1986, 108, 3513.


Scheme 3. Synthesis of the Acetonide Model System 25 by the Shapiro Reaction'

HO HO '". .. E t O , C n a 'p b -P - EtOzC

HO HO 17 18 10

Nicolaou et al.

Scheme 4. Synthesis of the ABC Taxoid Systems 33 and 35 by the McMuny Reaction"

BnO 1 OMEM

c-

HO

21 20

el

22 23

g1

25 24

(I Reagents and conditions: (a) 5.0 equiv of i-BuzAlH, CHKlz, -78 - 25 "C, 10 h, 95%; (b) Hz, 0.2 equiv of PdC, EtOAc, 3 h, 100%; (c) 1.0 equiv of KH, 1.0 equiv of PhCHZBr, THF, 0 - 25 "C, 1.5 h, 85%; (d) 2.0 equiv of pyridinium dichromate (PDC), molecular sieves, CHzC12,O - 25 "C, 4 h, 90%; (e) 16, 2.1 equiv of n-BuLi, THF, -78 OC, 0.5 h, then 0 "C, 10 min, 1.3 equiv of 21, THF, 0 - 25 "C, 5 h, 83% (cu. 2:l diastereomeric mixture); (f) 1.1 equiv of r-BuOOH, 0.014 equiv of VO(acac)z, PhH, 25 OC, 2 h, 91%; (g) 2.0 equiv of LiAla, EtzO, 0 "C, 20 min, 25 "C, 6 h, 96%; (h) 2 equiv of 2,2-dimethoxypropane, 0.2 equiv of camphorsulfonic acid (CSA), CHzC12, 25 OC, 12 h, 85%. MEM = (methoxyethoxy)ethyl, Bn = CHzPh, acac = acetylacetonate.

as a mixture of two diastereoisomers (stereochemistry unassigned). This reaction produced no A C9-C10 olefin, although the C9-Cl2 coupled byproduct 32 was formed (25% yield) as also observed by Kende.21 The mechanistic aspects of this reaction will be discussed in a subsequent paper in this series. Oxidation of the mixture of diols 31 with Mn0222 gave the dienediol 33 in 90% yield, and acetylation of 31 followed by PCC oxidation23 led to enone 35 via diacetate 34. The work presented in Schemes 3 and 4 demonstrated the viability of our Shapiro-McMuny strategy toward Taxol (1) and placed us in the position of facing the challenge of Taxol (1) itself.

Construction of C Ring Systems a. The Diels-Alder Reaction. In contrast to the achiral

ring A system, ring C of Taxol, with its numerous stereocenters (22) Fatiadi, A. J. Synthesis 1976, 65. (23) Parish, E. J.; Wei, T. Y. Synrh. Commun. 1987,17, 1227. Rathore,

R.; Saxena, N.; Chadrasekaran Synth. Commun. 1986, 16, 1493.

30

33 35

Reagents and conditions: (a) H2,20% Pd(OH)2 on C, EtOH, 25 OC, 2 h, 100%; (b) 1.2 equiv of Ac20, 1.3 equiv of 4-(dimethylamino)pyridine (DMAP), CHzClz, 0 - 25 "C, 2.5 h, 97%; (c) 1.0 equiv of TiCL, CHzC12, -78 OC, 10 min, then -20 "C, 10 min, 65%; (d) 0.1 equiv of KzC03, MeOH, 25 "C, 4 h, 91%; (e) 0.05 equiv of tetrapropylammonium permthenate (TPAP), 3.0 equiv of 4-methylmorpholine N-oxide (NMO), 4-A sieves, CH2C12,25 OC, 10 min, 87%; (f) 8.0 equiv of TiCls-(DME)1.5, 15 equiv of Zn-Cu, DME, 50 "C, 5 h, 40% of 31,25% of 32; (g) excess MnOz, CH2C12, 25 "C, 20 min, 90%; (h) excess AczO, excess pyridine, CHzClz, 25 "C, 0.5 h, 98%; (i) 30 equiv of pyridinium chlorochromate (PCC), 30 equiv of NaOAc, Celite, benzene reflux, 2 h, 71%. MEM = (methoxyeth0xy)ethyl.

and high degree of oxygenation, presented a more serious challenge to the Diels-Alder approach. Early approaches examined the reaction of dienophile 40 (prepared from l-hydroxy-2-propene (36) according to Scheme 5) and 3-car- bomethoxy-2-pyrone (43) (Scheme 6). According to previous work by CoreyZ4 and BrysonZ5 with the latter compound, and considering the substitution pattem of dienophile 40, we expected this reaction to proceed regio- and stereoselectively to afford product 45 via intermediate 44. Diene 45 was then expected to serve as a precursor to a fully functionalized ring C for coupling with ring A. In the event, however, this Diels- Alder reaction (155 "C, 24 h, 81% yield based on 51% conversion) proceeded with the opposite regiochemistry from that expected, furnishing product 47, via presumed intermediate 46, the latter undergoing a facile decarboxylation under the reaction conditions. A series of regio- and stereochemically controlled reactions, as shown in Scheme 6, converted cyclo- hexadiene system 47 into crystalline diol 51. X-ray crystallographic analysis of 51 (see ORTEP drawing, Figure 2)

(24) Corey, D. I.; Watt, D. S. J. Am. Chem. SOC. 1973, 95, 2303. (25) Bryson, T. A.; Donelson, D. M. J. Org. Chem. 1977, 42, 2930.

Total Synthesis of Taxol. 2 J. Am. Chem. SOC., Vol. 117, No. 2, 1995 637

Q: CI 7

30

HO OH

51

HO OH

'"OTBS

60

a7

Scheme 5. Synthesis of Dienophiles 40-42"

37 4 0 R = TPS 41:R=THP 42: R = H zd

a Reagents and conditions: (a) 1.1 equiv of TPSC1, 1.15 equiv of imidazole, DMF, 0 "C, 1 h, then 0 3 , CH2C12, -78 "C, 1 h, then 2.2 equiv of Ph3P. -78 "C - 25 "C; (b) 2.1 equiv of dihydropyran, 0.005 equiv of p-TsOH, CH2C12, 25 "C, 0.5 h, then 0 3 , CH2C12, -78 T, 5 h, then 1.0 equiv of Ph3P, -78 "C - 25 "C, 98%; (c) for 40, 1.4 equiv of Ph3P=C(CH3)C02Et, CH2C12,25 "C, 20 h, 91% from 36; for 41, 1.03 equiv of Ph3P=CHC02Et, CH2C12, 0 "C, 4 h, then 25 "C, 18 h, 90%; (d) 0.05 equiv of p-TsOH, MeOH, 25 "C, 18 h, 92%. TPS = Si-t-BuPh2, THP = tetrahydropyranyl.

Scheme 6. Early Diels-Alder Attemptsa 0

C02Me OTPS

40 43 46

Y -IC021 1 TPSO

TPSO TPSO C02Me C02Me

44 45 47

bl RO OH TPSO OH TPSO

I""' p,p HO E102C\"" Po C02Me

HO A0 50: R = TPS 49 4a ' C S I : R = H

Reagents and conditions: (a) 1.0 equiv of 40, 2.0 equiv of 43, neat, 155 OC, 24 h, 81% based on 51% conversion; (b) 4.0 equiv of m-CPBA, CH2C12, 25 'C, 4 h, 71% plus 19% of a epoxide; (c) excess i-Bu?AlH, EtzO, 0 "C, 2 h, 91%; (d) excess 2,2-dimethoxypropane, 0.05 equiv of camphorsulphonic acid (CSA), CH2C12, 25 "C, 1 h, 90%; (e) 1.0 equiv of n-BWNF (TBAF), THF, 25 "C, 1 h, 95%. TPS = Si-t-BuPh2.

confirmed its structure and those of its precursors and revealed the undesired regioselectivity of the Diels- Alder reaction.

Faced with this unfortunate regiochemical outcome, we then focused our attention on 3-hydroxy-2-pyrone (52, Scheme 7 ) as a diene in the Diels-Alder reaction. Although Corey26 has demonstrated that this system would give the opposite regiochemical pathway from that required for our purposes, the pioneering work of Narasaka*' afforded us the possibility for success in this endeavor. Scheme 7 demonstrates Narasaka's

(26) Corey, E. J.; Kozikowski, A. P. Tetrahedron Len. 1975, 2389. (27) Narasaka, K.; Shimada, S.; Osoka, K.; Iwasawa, N. Synthesis 1991,

Figure 2. ORTEP drawings for intermediates 7, 30, 51, 60, 87, 103. 1171.


Scheme 7. Synthesis of Common C-Ring Intermediate 55

+Et

OH

52 0

OH - a

EtOzC I 42 53

55 54

"Reagents and conditions: 1.4 equiv of 52, 1.4 equiv of PhB(OH)z, PhH, reflux (Dean-Stark trap), 48 h, then 1.4 equiv of 2,2-dimethyl-1,3- propanediol, 25 "C, 1 h, 79% based on 77% conversion of 42.

principle of temporarily tethering the two reaction partners in order to dictate the regiochemistry of the Diels-Alder reaction. Thus, reaction of dienophile 42 (prepared from 1,3-dihydroxy- cis-2- butene (37), Scheme 6) with 2-hydroxy-2-pyrone (52) in the presence of phenylboronic acid under dehydrating conditions led, after decomplexation with excess 2,2-dimethyl- 1,3-propanediol, to compound 55. Evidently, the initially formed Diels-Alder product 54 promptly rearranges under the reaction conditions via intramolecular acyl transfer from the secondary to the primary hydroxyl group to afford the observed product in 79% yield based on 77% conversion of 42.28 Relief of strain in going from the [2.2.2] cycloaddition product 54 to the [3.4.0] bicyclic system 55 may be the primary reason for this facile rearrangement.

Scheme 8 demonstrates a number of useful transformations of compound 55 that led not only to confiiation of its structure but also to more advanced intermediates as required for our plans. Exhaustive acetylation of 55 led to diacetate 56 which exhibited significant downfield shifts in its proton NMR spectrum (CDC13, 6 Ha, 4.59 -+ 5.84 and Hb, 3.10 - 3.90). Pyridinium dichromate (PDC) oxidationz9 of 55 furnished enone 57 in accord with the assigned structure (55), whereas persily- lation of the same compound with TBSOTf3O gave the bis(sily1 ether) 58 isolated as a C20 hydrate. The latter compound underwent selective reduction with LAH in Et20 at 0 - 25 "C to afford primary alcohol 59 (97% yield) which was monode- silylated with camphorsulfonic acid (CSA) in Me0H:CHzClz to afford the crystalline lactone diol 60 in 94% yield. X-ray crystallographic analysis of 60 (see ORTEP drawing, Figure 2) confirmed its structure and those of its progenitors. An NMR experiment (500 MHz, CDCl3) conf i i ed that neither acid (CSA) nor base (DMAP) causes any skeletal rearrangement of 55, serving as a control for the reactions summarized in Scheme 8.

b. The First Attempt at a CD Ring System. Oxetane Is Formed but Interferes with Subsequent Chemistry. One of our early plans was to construct a CD ring system with the oxetane ring already in place before coupling with a ring A

(28) For obvious practical reasons, large-scale reactions are performed with 1.0 equiv of diene and dienophile each and 0.95 equiv of PhB(0H)z; diol 55 is typically obtained in ca. 60% yield based on ca. 50% conversion. The crude starting material mixture is recycled in the same process.

(29) Corey, E. J.; Boger, D. L. Tetrahedron Lett. 1978, 2461. (30) Corey, E. J.; Cho, H.; Rucker, C.; Hua, D. H. Tetrahedron Lett.

1981, 22, 3455.

Scheme 8. Structural Confirmation of 55"

55: R = H % : R = A c

'I 57

HO OH

e

OH '0

50: R E C02Et L 59: R = CH2OH 60

"Reagents and conditions: (a) 5.0 equiv of AczO, 2.5 equiv of 4-(dimethylamino)pyridine (DMAP), CHZC12, 25 "C, 10 min, 100%; (b) 1.2 equiv of pyridinium dichromate (PDC), 4-A molecular sieves, CHZClz, 25 OC, 1 h, 81%; (c) 4.0 equiv of t-BuMezSiOTf, 4.0 equiv of 2,6-lutidine, 0.1 equiv of DMAP, CHzClz, 0 "C, 4 h, 92%; (d) 1.1 equiv of LiAW, Etz0,O - 25 "C, 0.5 h, 97%; (e) 0.05 equiv of camphorsulfonic acid (CSA), CHzClz, MeOH, 25 "C, 1 h, 94%. TBS = Si-t-BuMez, Tf = S02CFs.

hydrazone. To this end, diol 55 (Scheme 9) was dibenzylated using excess KH and benzyl bromide31 to afford compound 61 which was then reduced with excess LAH in ether at 0 "C to give hydroxy lactol 62 as a 1:l mixture of diastereoisomers (71% yield from 55). Selective monoprotection of the primary alcohol using fert-butyldiphenylsilyl chloride (TPSCl) and imidazole in DMF3z followed by further reduction of the lactol with LAH in THF at 25 "C furnished diol 64 in 78% yield. Reaction of 64 with pivaloyl chloride (1.05 equiv) under basic conditions led to a 1:3.2 mixture of the two pivaloate esters 65 and 66 which were chromatographically separated.

The next task was the introduction of an alcohol at C5. Even though a previous had shown that the primary hydroxyl group in a similar system could be used to direct the hydroboration of the cyclohexene double bond, the feasibility of using a mesylate (SOzCH3) as a possible directing group in this hydr~borat ion~~ was explored. Such a method would more efficiently lead to the targeted oxetane system. Indeed hydroboration of 68, prepared from 65 by standard mesylation, with borane in THF (0-25 "C) followed by oxidative workup, led to the formation of the C5 alcohol 69 as the major product and in 53% yield. Treatment of the latter compound with NaH in THF at 45 "C resulted in the formation of oxetane 70 in 86% yield, confirming the stereochemical orientation of the newly generated alcohol in 69. Attempts to reach the targeted C2 aldehyde were, however, thwarted by failure to cleanly remove the pivaloate group from 70, presumably due to interference from the oxetane ring under the reductive or basic conditions employed in these attempts. Nevertheless, this sequence confirmed the potential feasibility of constructing the oxetane ring by this method and rendered the aldehyde 67

(31) Evans, M. E.; Parrish, F. W.; Long, L., Jr. Carbohydr. Res. 1967, 3, 453. Lipshutz, B. H.; Barton, J. C. J . Org. Chem. 1988, 53, 4495.

(32) Hanessian, S.; Lavallb, P. Can. J . Chem. 1975,53,2975. Hanessian, S . ; Lavalike, P. Can. J . Chem. 1977, 55, 562.

(33) Nicolaou, K. C.; Liu, J.-J.; Hwang, C.-K.; Dai, W.-M.; Guy, R. K. J . Chem. SOC., Chem. Commun. 1992, 1118.

(34) Smith, K.; Pelter, A. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 8, p 703.


Scheme 9. Synthesis of Oxetane-Containing C-ring 70" 0 OR RO OBn TPSO QBn


55: R = H 6 2 : R = H 64 a 6 6 1 : R = Bn c C 6 y R = T P S "1

+ TPSO OBn

67 66 65

g l t

Tps'Qo TPSO @' OBn h TPSO '@ OBn - - OH

' b B n OPiv

" b B n OMS

Opiv OBn OPiv

70 69 68 Reagents and conditions: (a) 3.5 equiv of PhCHzBr, 3.5 equiv of KH,

0.05 equiv of n - B N 0 "C - 25 "C, 2 h, 75%; (b) 2.0 equiv of LiAlH4, Et20, 0 "C, 1 h, 94%; (c) 1.4 equiv of TPSC1, 1.5 equiv of imidazole, DMF, 0 "C, 2 h, 25 "C, 4 h, then excess n-BWF, THF, 10 h, 82% based on 54% conversion; (d) 1.3 equiv of LiAIh, THF, 0 "C - 25 "C, 0.5 h, 96%; (e) 1.05 equiv of PivC1, 1.5 equiv of 4-(dimethylamino)pyndine (DMAP), CH2C12, 0 "C, 0.5 h, 55% of 66, plus 17% of 65, plus 24% of C2-C20 dipivalate, based on 84% conversion; (0 0.05 equiv of tetrapropylammonium permthenate (TPAP), 1.5 equiv of 4-methylmorpholine N-oxide (NMO), CH3CN, 25 'C, 1.5 h, 91%; (g) 1.5 equiv of MsCl, 2.0 equiv of DMAP, CHZClz, 0 "C - 25 "C, 1.5 h, 95%; (h) 10 equiv of BHqTHF, THF, 25 "C, 10 h, then excess H202, aqueous NaHC03, 53%; (i) 5.0 equiv of NaH, THF, 45 "C, 3 h, 86%. Bn = CHzPh, TPS = Si-t- BuPh2, Piv = CO-t-Bu, Ms = S02CH3.

available through oxidation of 66 using the TPAP-NMO method.*O The latter compound was utilized in a subsequent attempt to construct the ABC ring skeleton of Taxol (1) as will be discussed in a later section of this paper.

c. A Second Attempt at the CD Ring System. Success but the Oxetane Ring Interferes Again after the Shapiro Coupling. After our first attempt to construct a suitable CD aldehyde failed, we quickly redesigned our approach, choosing new protecting groups and targeting aldehyde 79 as a potential electrophile for the Shapiro coupling. Scheme 10 outlines the chemistry involved in this second approach. Thus, upon treatment with KH and TBSCl, intermediate 55 underwent skeletal rearrangement involving acyl migration from the primary to the secondary hydroxyl group, presumably driven by trapping of the primary hydroxyl as a silyl ether, to afford 71. Protection of the tertiary alcohol as a methoxymethyl (MOM) ether7 led to 72. Reduction of the ester and lactone functionalities in 72 using excess LAH in THF formed triol 73. Introduction of the benzylidene group35 protected the C7- C9 diol system in the latter compound, furnishing 74 in 72% yield from 72. The possibility of generating a C7 benzyl, C9 hydroxy derivative directly from the ben~y l idene~~ dictated the choice of this protecting group. Directed hydroboration of olefin

(35) Albert, R.; Dax, K.; Pleschko, R.; Stutz, K. Carbohydr. Res. 1985, 137, 282. Yamanoi, T.; Akiyama, E.; Inazu, T. Chem. Lett. 1989, 335. Crimmins, M. T.; Hollis, W. G., Jr.; Lever, J. G. Tefrahedron Left. 1987, 28, 3647.

Scheme 10. Synthesis of ACD Ring System 81"

TBSO b R

7 1 : R = H 7 3 : R = H 55 c 7 2 : R = MOM 6 7 4 : R = CHPh

Ph

OH

RO MOM OR

79

I-Pr i

15 Ph

R = TBS R = H

75: R = H ' K 7 6 : R = Ts

Ph

80 81 Reagents and conditions: (a) 2.0 equiv of KH, 1.2 equiv of TBSC1,

THF, 25 OC, 0.5 h, 61%; (b) 2.0 equiv of MOMC1, 1.5 equiv of KH, CH2C12, 25 "C, 12 h, 92%; (c) 5.0 equiv of LiAlb, THF, 25 "C, 1 h; (d) 3.8 equiv of PhCH(OMe)Z, 0.05 equiv of camphorsulfonic acid (CSA), CH2C12, 25 "C, 72% from 72; (e) 3.0 equiv of BHyTHF, THF, 25 "C, 10 h, then excess Hz02, aqueous NaHCO3, 37%; (f) 1.6 equiv of TsCl, 3.0 equiv of 4-(dimethy1amino)pyridine (DMAP), CHzC12, 25 "C, 5 h; (g) 2.2 equiv of NaH, THF, 45 "C, 10 h, 78% from 75; (h) excess n-BuflF, THF, 25 "C, 2 h, 95%; (i) 3.0 equiv of Dess-Martin periodinane, CH2Cl2, 25 "C, 2 h, 91%; Q) 1.2 equiv of 15, 2.4 equiv of n-BuLi, THF, -78 'C, 0.5 h, 80%. then 0 "C; 1.0 equiv of 79, THF, 0 "C, 0.5 h, 85% (ca. 5:3 mixture); (k) excess t-BuOOH, 0.05 equiv of VO(acac)z, PhH, 25 "C, 2 h. MOM = methoxymethyl, TBS = Si-t-BuMez, Ts = S02-p-Tol. acac = acetylacetonate. 74 resulted in the formation of the C5 ,8-hydroxy compound 75 in 37% yield. Tosylation (80%) of the latter followed by exposure to NaH in THF at 45 "C led to oxetane 77 (78%) via tosylate 76. Finally, desilylation of 77 using TBAF,37 followed by Dess-Martin ~ x i d a t i o n , ~ ~ furnished aldehyde 79 via 78 in 86% overall yield. The Shapiro reaction proceeded well in combining hydrazone 15 and aldehyde 79 to produce alcohol 80 (85%, mixture of diastereoisomers, Scheme 10). Epoxide 81 could not, however, be cleanly obtained from the major isomer 80 using the vanadium-catalyzed procedure.

Due to the problems encountered in the two approaches discussed above, the strategy of having the oxetane installed in the molecule prior to the coupling reactions was abandoned in favor of schemes involving oxetane construction at a later stage.

d. Successful Progression to the McMurry Cyclization Stage. Having just experienced the complications of the highly

(36) Takano, S.; Akiyama, M.; Sato, S.; Ogasawara, K. Chem. Lett. 1983, 1593. Hatakeyama, S.; Sakurai, K.; Saijo, K.; Takano, S. Tetrahedron Lett. 1985, 26, 1333. Schreiber, S. L.; Wang, Z . ; Schulte, G. Tetrahedron Lett. 1988, 29, 4085. Adam, G.; Seebach, D. Synthesis 1988, 373. (37) Corey, E. J.; Venkateswarlu, A. J . Am. Chem. SOC. 1972, 94, 6190. (38) Dess, D. B.; Martin, J. C. J . Org. Chem. 1983,48,4155. Dess, D.

B.; Martin, J. C. J . Am. Chem. SOC. 1991, 113, 7277. Ireland, R. E.; Liu, L. J . Org. Chem. 1993, 58, 2899.

640 J. Am. Chem. Soc., Vol. I 17, No. 2, 1995 Nicolaou et al.

Scheme 11. Synthesis of A-C Ring System 87" HO oen

1%

QB" a OH

62

86

i-Pr. 15, Ar =*i-pr

i-Pr

82: X = 0 6 8 3 : X = (OMe)*

TBSO

07

a Reagents and conditions: (a) 3.0 equiv of Dess-Martin periodinane, CH2C12, 0 "C - 25 "C, 12 h; (b) excess of HC(OMe)3, 0.05 equiv of camphorsulfonic acid (CSA), MeOH, CH2C12, 25 "C, 12 h, 81% from 62; (c) 1.2 equiv of LiAl&, THF, reflux, 1 h; (d) 1.5 equiv of PivC1,5.0 equiv of 4-(dimethylamino)pyridine (DMAP), CH2C12, 0 "C, 15 min, 70% from 83; (e) 1.7 equiv of Dess-Martin periodinane, CH2C12, 25 "C, 1.5 h, 83%; (f) 15, 2.2 equiv of n-BuLi, THF, -78 "C, 0.5 h, then 0 "C; 1.2 equiv of 86, THF, -40 "C, 5 min, 74%. Bn = CH2Ph, Piv = CO-t-Bu, TBS = Si-t-BuMe2. oxygenated intermediates of the previous schemes, we decided to minimize such problems by targeting aldehyde 86 (Scheme 11). Oxidation of intermediate 62, readily available as described in Scheme 10, with De~s-Mar t in~~ reagent afforded aldehyde lactone 82. Protection of the aldehyde as a methoxy acetal39 produced compound 83 (81% yield from 62) which was then reduced with LAH in THF at reflux to give diol 84. Treatment of the latter compound with pivaloyl chloride in the presence of DMAPO selectively protected the C20 alcohol as a pivaloate ester, leading to intermediate 85 in 70% yield from 83. Molecular models revealed the C2 hydroxyl group of 84 to be more crowded [interference from bis(methoxy) group] than the C20 hydroxyl group (pseudo axial position) and thus the selectivity observed. Finally, oxidation with either TPAP- NM020 or Dess -Martin reagent38 easily converted compound 85 to aldehyde 86 (83% yield).

With the aldehyde 86 in hand, we then proceeded to the Shapiro reaction utilizing hydrazone 15 as the precursor to the vinyllithium reagent. This coupling reaction furnished alcohol 87 as a single diastereoisomer in 74% yield. X-ray crystallographic analysis allowed the assignment of the stereochemistry of this intermediate (see ORTEP drawing, Figure 2). The stereoselectivity of this reaction can be explained by invoking 6-membered ring chelate intermediate 88, as shown in Figure 3. In this model, the re face of the aldehyde is more accessible to nucleophilic attack than the si face due to shielding by the C8 methyl and C20 pivaloyl groups.

(Re face)

Nu'

88: Li+ chelate derived from aldehyde 86

Figure 3. Stereoselectivity of the Shapiro reaction. The model was generated with Chem3d, most hydrogens are omitted for clarity.

Early attempts to unblock the aldehyde group of 87 under acidic conditions failed due to formation of a cyclic hemiacetal with the C2 hydroxyl group. Epoxidation of the allylic system in 87 proved rather slow and, therefore, the C20 hydroxyl group was called upon to assist in this reaction. Treatment of 87 with LAH in ether resulted in the formation of diol 89 (88% yield) which underwent smooth epoxidation with tBuOOH in the presence of VO(acac)2 catalyst to afford epoxide 90 in 82% yield (Scheme 12).

At this point our plan involved engaging the two hydroxyl groups of our latest intermediate (90) in a cyclic system in order to both prevent the undesired hemiacetal formation and to preorganize the substrate prior to the construction of ring B. To this end, diol 90 was treated with phosgene in the presence of pyridine41 in an attempt to produce the 7-membered ring carbonate. These conditions, however, produced exclusively the tetrahydrofuran derivative 91, presumably via nucleophilic attack by the C2 hydroxyl group on the activated C20 chloro- formyl intermediate. To circumvent this problem, both alcohols were engaged in a cyclic lactone by exposure of diol 90 to Dess-Martin reagent,38 giving the y-lactone 92 in 61% yield.

Removal of the silyl group from compound 92, followed by oxidation with Dess-Martin reagent,38 afforded aldehyde 94, via intermediate alcohol 93, in 71% overall yield. Revealing the C9 aldehyde by exposure to trifluoroacetic acid42 (TFA) at 0 OC, produced, in addition to dialdehyde 95 (51% yield), the conjugated system 96 (24%) (Scheme 13), presumably arising from 95 via acid-induced epoxide opening.

Several attempts to cyclize dialdehyde 95 using the McMurry reaction under a variety of conditions were unsuccessful. The only detectable product was the diol 97, apparently produced by reduction of both aldehyde groups. It became clear that this particular design did not favor the required ring closure and that we had to design yet another synthetic sequence.

e. First Attempt with the C1-CZCarbonate Approach. Aiming to enforce a different conformation in the McMuny substrate, we decided to introduce a C1 -C2-carbonate ring.

(39) Wenkert, E.; Goodwin, T. E. Synth. Commun. 1977, 7, 409. (40) Hofle, G.; Steglich, W.; Vorbriiggen, H. Angew. Chem., Znt. Ed.

Engl. 1978, 17, 569.

(41) Haworth, W. N.; Porter, C. R. J. Chem. SOC. 1930, 151. (42) Ellison, R. A.; Lukenbach, E. R.; Chiu, C.-W. Tetrahedron Lett.

1975, 499.


Scheme 12. Synthesis of Lactone 93a TBSO


Scheme 13. First Attempt at the McMurry Cyclization"

8 7 R = PN a L : R = ti

01

04

b - TBSO

94

/ O5

97 96 02

a Reagents and conditions: (a) trifluoroacetic acid neat, 0 "C, 15 min, 51%; (b) 10 equiv of TiC13*(DME)1,5, 15 equiv of Zn-Cu, DME, 60 "C, 4 h, 95 added over 5 h (syringe pump), then 55 "C, 3 h, 34% based on 43% conversion. Bn = CHZPh.

probably responsible for this relative unreactivity. The carbonate 104 was then desilylated with fluoride ion and oxidized with TPAP-NMOZo to afford dialdehyde 106 via the corresponding diol (105) in 80% overall yield.

With the requisite dialdehyde 106 in hand, we proceeded to

l

03

Reagents and conditions: (a) 2.0 equiv of LiAlb, EtzO, -10 "C, 5 min, 88%; (b) 2.0 equiv of r-BuOOH, 0.25 equiv of VO(acac)z, PhH, 25 "C, 0.5 h, 82%; (c) 5.0 equiv of phosgene, pyridine, 75 "C, 2.5 h, 35%; (d) 10 equiv of Dess-Martin periodinane, CHzC12,50 "C, 1 h, 61%; (e) excess n-B-, THF, 25 "C, 2 h; (f) 5.0 equiv of Dess-Martin periodinane, CHzClz, 25 "C, 0.5 h, 71% from 92. TBS = Si-t-BuMez, Bn = CHZPh, Piv = CO-t-Bu, acac = acetylacetonate.

Molecular modeling (S ybyl) indicated that this functionality would preorganize the expected intermediate geometry by bringing the two aldehydes to the same face of the molecule. Learning from our previous experience with protecting groups, we decided to utilize aldehyde 67 (prepared as described in Scheme 9, above) and hydrazone 15 as partners for the Shapiro reaction. Thus (as shown in Scheme 14) the Shapiro reaction produced compound 98, as a single isomer (stereochemistry confirmed by X-ray crystallographic analysis of subsequent intermediate 103) in 82% yield. Deprotection with LAH afforded diol 99 (87% yield). Vanadium-catalyzed epoxidation of 99 with 'BuOOH led stereoselectively to epoxide 100 in 95% yield. Regioselective epoxide opening with LAH gave triol 101 in 78% yield based on 81% conversion. Selective protection of the primary alcohol in 101 as a MOM ether proceeded smoothly under standard conditions to afford compound 102 in almost quantitative yield. Diacetate 103 was prepared using acetic anhydride and DMAP (83% yield). X-ray crystallographic analysis of the latter compound confirmed the previously proposed stereochemistry (see ORTEP drawing, Figure 2).

By this time both our model studies and degradation work' pointed to a carbonate protecting group at Cl-C2 as the most suitable device for our synthetic scheme. In order to install the latter into our intermediate (102), it was necessary to use rather strong conditions (excess KH, phosgene, ether:HMPA, 1:1, 25 "C, 88% yield based on 57% conversion) as compared to those used in making the taxoid carbonate II.' The flexibility of the 1,2-diol 102 as compared to the rigidity of the corresponding taxoid diol employed in the degradation studies is

investigate its-conversion to a cyclic taxoid system through McMurry coupling. In traversing the temperature range from 0 to 70 "C, no cyclic coupling products were observed; at 85 "C, however, a 15% yield of the cyclic olefin 107 (Scheme 14) was isolated, suggesting that the desired cyclic diol might remain elusive even with these rigid precursors. The conclusion was that further preorganization was needed in order to lower the activation energy to avoid deoxygenation of carbons 9 and 10 during the McMurry cyclization.

Conclusion In this paper we described the evolution of the chemistry that

eventually led to a successful construction of a taxoid system containing the ABC ring framework of Taxol (1). While the construction of a suitable ring A fragment proceeded smoothly via a Diels-Alder approach, that of a suitable ring C fragment presented more difficulties. Although the highly functionalized and stereochemically defined ring C intermediate was easily produced via a boron template controlled reaction, the finetuning of the functional groups for proper elaboration required considerable experimentation. Through the process of design, experimentation, and redesign, however, enough knowledge was gathered that made the final push toward a suitable ABC taxoid ring system possible. This final and successful approach is discussed in the following paper.

Experimental Section General Techniques. For a description of general technique, see

the Fist paper in this series.' Experimental techniques and data for compounds 10-14, 16, 18-35, 47-51, 57, 58, 61-80, 82-87, and 89-107 can be found in the supplementary material.

Diene 3. A solution of ketone 2 (245.0 g, 1.44 mol) in Et20 (1500 mL) at 0 "C was treated with methylmagnesium bromide (576 mL of a 3.0 M solution in EtzO, 1.73 mol). The reaction mixture was allowed to warm to 25 OC and stirred for 8 h. After cooling to 0 "C, the reaction was quenched with aqueous NI&C1(600 mL). The organic layer was separated and washed with H20 (2 x 400 mL) and brine (400 mL).


Scheme 14. Formation of the ABC taxoid system 107 by a McMuny cyclizationa

TBSO

Nicolaou et al.

98: R = Piv bCe0: R = H

I TBSO TBSO "1

101

0 - j &

" 1 - O I

0 vu "'OBn

'OMOM Yo 0

H OBn C M O M

107 108

a Reagents and conditions: (a) 1.3 equiv of 15, 2.6 equiv of n-BuLi, THF, -78 "C, 0.5 h, then 0 "C, 1.0 equiv of 67, THF, -78 "C, 20 min, 82%; (b) 2.0 equiv of LiAW, EtzO, 25 "C, 0.5 h, 87%; (c) 2.0 equiv of t-BuOOH, 0.05 equiv of VO(acac)z, PhH, 25 "C, 0.5 h, 95%; (d) 15 equiv of LiAl&, EtzO, 25 "C, 3 h, 78% based on 81% conversion; (e) 10 equiv of MOMCl, 12 equiv of i-PrWt, CHZClZ, 25 "C, 10 h, 99%; ( f ) excess n-Bu$rTF (TBAF), THF, 25 "C, 2 h, then 4.0 equiv of AczO, 6.0 equiv of 4-(dimethylamino)pyridine (DMAP), CHZC12,25 "C, 2 h, 83%; (g) 5.0 equiv of phosgene, 5.0 equiv of KH, EtzO, HMPA, 25 "C, 1 h, 88% based on 57% conversion; (h) excess TBAF, THF, 25 "C, 1 h, 88%; (i) 0.05 equiv of tetrapropylammonium permthenate (TPAP), 3 .O equiv of 4-methylmorpholine N-oxide (NMO), CH~CN-CH~C~Z (1:l). 25 "C, 0.5 h, 91%; (j) 10 equiv of TiCly(DME)1.5,20 equiv of Zn-Cu, DME, reflux, 3 h, 106 added over 1 h, then 1.5 h, 15%. Piv = CO-t-Bu, TBS = Si-t-BuMez, Bn = CHzPh, TPS = Si-t-BuPhz, MOM = methoxymethyl.

The combined aqueous layer was extracted with Et20 (2 x 200 mL). The combined organic layer was dried (MgS04) and concentrated to give the corresponding alcohol which was taken in the next step without further purification.

A solution of the previous alcohol in benzene (600 mL) was treated with p-toluenesulfonic acid (54 g, 276 "01) and heated to 65 "C for 3 h. After being cooled to 25 "C, the reaction mixture was treated with Et3N (39 mL, 280 mmol), diluted with Et20 (600 mL), washed with H20 (400 mL), aqueous NaHC03 (400 mL), and brine (400 mL), dried (MgS04), concentrated (bath temperature <30 "C), and distilled

(40-45 "C, 0.05 " H g ) to give 3 (169 g, 70%) as a colorless liquid Rf = 0.35 (silica, 2% Et20 in petroleum ether); 'H NMR (300 MHz, CDC13) 6 5.05 (d, J = 1.0 Hz, 1 H, HC=C), 4.74 (d, J = 1.0 Hz, 1 H, HC-), 4.14 (q, J = 7.0 Hz, 2 H, C02CH2CH3), 1.97 (s, 3 H, CH~C-CHZ), 1.80 (s, 3 H, CH~CSC), 1.78 (s, 3 H, CH3C%), 1.24 (t, J = 7.0 Hz, 2 H, C02CHzCH3).

Alcohol 4. A solution of ester 3 (169 g, 1.01 mol) in CH2C12 (1000 mL) at -78 "C was treated with diisobutylaluminum hydride (2220 mL of a 1.0 M solution in CHzC12, 2.22 mol) and stirred at -78 "C for 0.5 h. The reaction mixture was allowed to warm to 25 "C and stirred for 12 h. The reaction mixture was slowly poured into a mixture of ice (600 mL) and glacial acetic acid (300 mL), and the resulting mixture was stirred for 3.5 h. The aqueous layer was separated and extracted with CHzClz (2 x 500 mL). The combined organic layer was washed with brine (2 x 500 mL), dried (MgSOd), concentrated (bath temperature <25 "C), and purified by flash chromatography (silica, 20% Et20 in petroleum ether) to give 4 (117.4 g, 92%) as a pale yellow oil: Rf = 0.26 (silica, 20% Et20 in petroleum ether); 'H NMR (300 MHz, CDCl3) 6 5.08 (b d, J = 1.0 Hz, 2 H, C-CHz), 4.71 (b d, J = 1.0 Hz, 2 H, C=CHz), 4.16 (s, 2 H, CHzOH), 1.82 (t, J = 1.0 Hz, 3 H, (CH3)C+Hz), 1.76 (s, 3 H, Ce(CH3)z), 1.71 (s, 3 H, C=(CH3)2).

Acetate 5. A solution of alcohol 4 (113.6 g, 0.9 mol) in CHzClz (lo00 mL) at 0 "C was treated with Et3N (150.5 mL, 1.08 mol), 4-(dimethylamino)pyridine (DMAP, 22 g, 0.18 mol), and Ac20 (94.3 mL, 1.0 mol). The reaction mixture was allowed to warm to 25 "C and stirred for 1 h. The reaction mixture was washed with HzO (2 x 300 mL) and brine (300 mL), and the combined aqueous layer was extracted with CH2C12 (2 x 300 mL). The combined organic layer was dried (Mgsod), concentrated, and purified by flash chromatography (silica, 5% Et20 in petroleum ether) to give 5 (145.4 g, 96%) as a pale yellow oil: Rf = 0.66 (silica, 20% Et20 in petroleum ether); 'H NMR (300 MHz, CDCls) 6 4.96 (s, 1 H, C=CH2), 4.64 (s, 3 H, CsCH2 and CHZOAC), 2.02 (s, 3 H, COCH3), 1.77 (s, 3 H, CH,C=C), 1.75 (s, 3 H, CHsC=C), 1.71 (s, 3 H, CHsC=C).

Chloro Nitrile 7. A mixture of diene 5 (90.3 g, 537 "01) and freshly distilled 2-chloroacrylonitrile (65 mL, 806 "01, purchased from Tokyo-Kasei) was stirred at 130 "C in a sealed tube for 72 h. During the course of the reaction, the reaction mixture turned dark brown. The reaction mixture was allowed to cool to 25 "C and purified by flash chromatography (silica, 10% Et20 in petroleum ether) to give 7 (110 g, 80%) as clear crystals: mp 86-88 "C, from EtzO; Rf = 0.25 (silica, 10% Et20 in petroleum ether); IR (thin film) v,, 2979, 2938, 1730, 1436, 1370, 1240 cm-'; 'H NMR (300 MHz, CDC13) 6 4.63 (s,

3 H, COCHj), 1.75 (s, 3 H, l8-CH3), 1.39 (s, 3 H, 16-CH3), 1.28 (s, 3 H, 17-CH3); FAB HRMS (NBNCsI) d e 388.0080, M + Cs+ calcd for C13H&102N 388.0080.

Hydroxy Ketone 8. A solution of chloro nitrile 7 (15 g, 58.7 "01) and KOH (19.8 g, 352 "01) in t-BuOH (293 mL) was heated to 70 "C and stirred for 4 h. After being cooled to 25 "C, the reaction mixture was diluted with EtOAc (lo00 mL) and washed with H20 (2 x 300 mL) and brine (300 mL). The combined aqueous layer was extracted with EtOAc (4 x 200 mL), and the combined organic layer was dried (MgS04), concentrated, and purified by flash chromatography (silica, 25 - 30% EtOAc in benzene) to give 7 (4.5 g, 30%) and 8 (6.2 g, 90% based on 70% conversion) as a pale orange oil: Rj = 0.30 (silica, 30% EtOAc in benzene); IR (thin film) v,, 3410, 2980, 2930, 1710, 991 cm-l; IH NMR (500 MHz, CDC13) 6 4.26 (s, 2 H, CHZOH), 2.53

2 H, CH~OAC), 2.48-2.29 (band, 4 H, 13-CH2 and 14-CH2), 2.07 (s,

(t, J = 8.5 Hz, 2 H, 13-CHz), 2.38 (t, J = 8.5 Hz, 2 H, 14-CHz), 1.84 (s, 3 H, 18-CH3), 1.44 (b S, 1 H, OH), 1.19 (s, 6 H, 16-CH3 and 17-

Cl&IlaOz 191.1050. CH3); FAB HRMS (NBA/NaI) d e 191.1048, M + Naf calcd for

TBS Ether 9. A solution of alcohol 8 (4.00 g, 23.8 "01) and imidazole (1.95 g, 28.6 m o l ) in CHzClz (40 mL) at 0 "C was treated with tert-butyldimethylsilyl chloride (TBSCl, 3.96 g, 26.2 mmol), allowed to warm to 25 "C, and stirred for 2 h. After dilution with Et20 (300 mL), the reaction mixture was washed with HzO (100 mL) and brine (100 mL), dried (MgSOd), concentrated, and purified by flash chromatography (silica, 5 - 10% Et20 in petroleum ether) to give 9 (5.71 g, 85%) as a pale yellow oil: Rj = 0.48 (silica, 10% Et20 in petroleum ether); IR (thin film) v,, 2929, 2857, 1716, 1462, 1377, 1253 cm-'; 'H NMR (500 MHz, CDC13) 6 4.12 (s, 2 H, lO-CHZ), 2.51


(t, J = 7.0 Hz, 2 H, 13-CHz), 2.36 (t, J = 7.0 Hz, 2 H, 14-CHz), 1.74 (s, 3 H, 18-CH3), 1.18 (s, 6 H, 16-CH3 and 17-CH3), 0.87 (s, 9 H,

CDC13) 6 215.2, 135.6, 131.8, 59.2, 41.2, 35.7, 30.5, 25.8, 24.6, 22.5, SiC(CH3)3(CH3)2), 0.05 (s, 6 H, SiC(CH3)3(CH3)2); I3C NMR (125 MHz,

18.2, -5.5; FAB HRMS (NBNCsI) d e 697.3056, M + Cs+ calcd for C 1&002Si 697.3085.

TBS Hydrazone 15. A solution of ketone 9 (2.79 g, 9.88 "01) in THF (33 mL) at 25 "C was treated with (2,4,6-triisopropylbenze- nesulfony1)hydrazine (2.95 g, 9.88 "01) and stirred for 24 h. The reaction mixture was concentrated, and the solid residue was dissolved in a minimum amount of Et20 (10 mL). The solution was diluted with petroleum ether (50 mL) and cooled to -20 "C to induce crystallization. After removal of the mother liquor by filtration, the crystalline material was washed with petroleum ether (30 mL) and dried in vacuo to give 15 (4.89 g, 88%) as colorless crystals: mp 135-137 "C, from EtzO- petroleum ether; Rf = 0.24 (silica, 20% Et20 in petroleum ether); IR (thin film) v,, 3250,2957, 1600 cm-I; IH NMR (500 MHz, CDC13) 6 7.68 (b s, 1 H, NH), 7.21 (s, 2 H, Ar), 4.28 (septet, J = 7.0 Hz, 2 H, o-CH(CH&), 4.14 (s, 2 H, lO-CH;?), 2.95 (septet, J = 7.0 Hz, 1 H, p-CH(CH3)2), 2.44 (t, J = 7.0 Hz, 2 H, 13-CH2), 2.21 (t, J = 7.0 Hz, 2 H, 14-CH2), 1.75 (s, 3 H, 18-CH3), 1.33 (d, J = 7.0 Hz, 12 H, O-CH- (cH3)2), 1.32 (d, J = 7.0 Hz, 6 H, p-CH(CH3)2), 1.13 (s, 6 H, 16-CH3 and 17-C&), 0.92 (s, 9 H, SiC(CH3)3(CH3)2), 0.10 (s, 6 H, SiC(CH3)3- (CH3)2); I3C NMR (125 MHz, CDC13) 6 164.0, 152.9, 151.1, 136.0, 131.5, 131.4, 124.0, 123.4,59.0,42.2, 34.1,30.6,29.8, 26.0,26.0,25.9, 25.9, 25.8, 24.9, 24.8, 24.7, 24.6, 23.5, 21.4, 19.5, 18.3, -5.4; FAB HRMS (NBA) d e 563.3716, M + H+ calcd for C31H5403N2SSi 563.3703.

Aldehyde 39. A solution of 1,4-dihydroxy-cis-2-butene (137 g, 1.56 mol) and p-toluenesulfonic acid (1.35 g, 7 "01) in CH2C12 (2000 mL) at 25 "C was treated with dihydropyran (300 mL, 3.29 mol), dropwise, over the period of 0.5 h. After being stirred for 10 min, the mixture was treated with Et3N (2.0 mL, 14 mmol), reduced in volume to a total of 2 L, treated with decolorizing carbon, filtered through a pad of silica gel, and concentrated to give a yellow oil that was taken to the next step without further purification: Rf = 0.30 (silica, 25% EtOAc in hexanes); IR (thin film) v,, 2950,2800, 1200, 1050 cm-I;

s, 2 H, OCHO), 4.19 (m. 2 H, CH2CH20), 4.03 (m, 2 H, CHZCHZO), 3.77 (m, 2 H, CHCHzO), 3.42 (m, 2 H, OCHzCH), 1.75-1.43 (band,

25.3, 19.2; FAB HRMS (NBA/NaI) d e 279.1572, M + Na+ calcd for

A solution of the previous alkene (200 g, 0.78 mol) in CHZClz (600 mL) was treated with ozone at -78 "C until the solution tumed blue. The reaction was quenched by the careful addition of triphenylphosphine (205 g, 0.78 mol) in portions. The mixture was allowed to warm to 25 "C over the period of 8 h, concentrated, washed with Et20 (3 x 500 mL), and filtered. The combined washes were concentrated and purified by flash chromatography (silica, 25% EtOAc in hexanes) to give aldehyde 39 (220 g, 98%) as a clear oil: Rf = 0.20 (silica, 25% EtOAc in hexanes); IR (thin film) vmax 2944,2889, 1739, 1136, 1078,

'H NMR (500 MHz, CDC13) 6 5.65 (t, J = 5.0 Hz, 2 H, CH), 4.55 (b

12 H, CH2); I3C NMR (125 Hz, CDC13) 6 129.0,97.7,62.6, 61.9.30.4,

Cl4H2404 279.1572.

1033; 'H NMR (500 MHz, CDC13) 6 9.72 (s, 1 H, HCO), 4.63 (t, J = 4.0 Hz, 1 H, OCHO), 4.22 (d, J = 18.0 Hz, A of AB, COCHzO), 4.16 (d, J = 18.0 Hz, B of AB, COCHZO), 3.83 (m, 2 H, CHZCHZO), 3.50 (m, 2 H, CHZCH~O), 2.00 - 1.50 (band, 4 H, CHI); 13C NMR (125

(NBADJaI) d e 167.0684, M + Na+ calcd for C7H1203 167.0684. Silyl Ether 40. Aldehyde 38 from 36. To a solution of allylic

alcohol 36 (11.6 g, 200.0 "01) and imidazole (15.7 g, 230.9 m o l ) in DMF (200 mL) was added tert-butylchlorodiphenylsilane (58.4 mL, 220.0 mmol) dropwise at 0 OC. The solution was stirred at 0 OC for 1 h. After dilution with Et20 (500 mL), the solution was washed with aqueous NH4Cl (100 mL), H20 (3 x 50 mL), and brine (100 mL). The organic layer was dried (MgS04) and concentrated to give the corresponding crude silyl ether (66.2 g) which was taken to the next step without further purification.

A fraction of the crude silyl ether (13.0 g) was dissolved in CHZC12 (300 mL) and treated with 03 at -78 "C for 1 h. The reaction was quenched with Ph3P (25.0 g, 96.0 mmol) at -78 OC, and the resulting mixture was allowed to warm to 25 "C. After being stirred at 25 "C for 0.5 h, the reaction mixture was diluted with toluene (100 mL) and

Hz, CDC13) 6 201.2, 99.4, 72.9, 62.5, 30.2, 25.1, 19.6; FAB HRMS

J. Am. Chem. SOC., Vol. 117, No. 2, I995 643

concentrated to give crude aldehyde 38 as a yellowish solid (40.7 g) which was taken to the next step without further purification.

Aldehyde 38: Rf = 0.60 (silica, 50% Et20 in petroleum ether); 'H NMR (300 MHz, CDC13) 6 9.72 (s, 1 H, CHO), 7.67-7.37 (band, 10

Conversion of 38 to 40. To a solution of the crude aldehyde 38 (13.2 g) in CHzClz (200 mL) was added (carbethoxyethy1idene)- triphenylphosphorane (22.3 g, 62.0 m o l ) in one portion. The reaction mixture was stirred at 25 "C for 20 h, concentrated, and purified by flash chromatography (silica, 5 - 10% Et20 in petroleum ether) to give 40 (13.7 g, 91% from 36) as an oil: Rf = 0.80 (silica, 20% Et20 in petroleum ether); 'H NMR (300 MHz, CDC13) 6 7.70-7.36 (band,

4.20 (q, J = 7.2 Hz, 2 H, COOCHz), 1.64 (s, 3 H, Me), 1.30 (t, J =

Ester 41. A solution of aldehyde 39 (159 g, 1.10 mol) in CHzClz (600 mL) at 0 "C was treated with a solution of (carbethoxymethy1ene)- triphenylphosphorane (408 g, 1.13 mol) in CHZC12 (1200 mL) over the period of 4 h. The solution was allowed to warm to 25 "C and stirred for 18 h. The mixture was concentrated, suspended in 30% Et20 in hexanes, and filtered through a pad of silica gel to give 41 (222 g, 90%) as an oil: Rf = 0.40 (silica, 30% EtOAc in hexanes); 'H NMR (500 MHz, CDC13) 6 6.78 (m, 1 H, %H), 4.59 (m, 1 H, OCHO), 4.37 (m, 1 H, A of AB, CH~CHZO), 4.13 (band, 3 H, =CCH20 and CH~CHZO), 3.80 (m, 1 H, B of AB, CHZCH~O), 3.47 (m, 1 H, B of AB, =CCHzO), 1.79 (s, 3 H, CH3), 1.76-1.47 (band, 6 H, CHz), 1.23,

Alcohol 42. A solution of ether 41 (222 g, 0.97 mol) in MeOH (2500 mL) at 25 "C was treated with p-toluenesulfonic acid (1 g) and stirred at 25 "C for 18 h. The mixture was treated with Et3N (2 mL), concentrated, redissolved in EtOAc (1500 mL), washed with aqueous NaHC03 (2 x 100 mL), HzO (2 x 100 mL), and brine (2 x 100 mL), dried (MgS04). filtered, and concentrated to give a clear oil that was purified by flash chromatography (silica, 40% ethyl acetate in hexanes) to give 42 (128 g, 92%) as a colorless oil: Rf = 0.20 (silica, 30% EtOAc in hexanes); IR (thin film) vm, 3434,2983,2934, 1713, 1650,

H, Ar), 4.21 (s, 2 H, CHz), 1.09 (s, 9 H, t-Bu).

lOH,Ar),6.87(t,J=5.6H~,CH=),4.36(d,J=5.6H~,2H,CHz),

7.2 Hz, 3 H, COOCHZCH~), 1.05 (s, 9 H, t-Bu).

(t, J = 7.0 Hz, 3 H, CH3CH2).

1446, 1368, 1261, 1132, 1031, 731; 'H NMR (500 MHz, CDC13) 6 6.62 (b S , 1 H, =CH), 4.11 (d, J = 6.0 Hz, 2 H, OCHzCH), 3.98 (q, J = 7.0 Hz, 2 H, CHZCH~), 3.90 (s, 1 H, OH), 1.61 (s, 3 H, CH3C), 1.09 (t, J = 7.0 Hz, 3 H, CH2CH3); 13C NMR (125 Hz, CDC13) 6 167.5, 140.6, 127.5, 60.4, 58.8, 13.7, 12.0; FAB HRMS (NBNCsI) d e 276.9841, M + Cs+ calcd for C7H1203 276.9846.

Diol 55. A. Small-Scale Procedure. A mixture of dienophile 42 (1.44 g, 10 mmol), diene 52 (1.52 g, 13.6 mmol), and PhB(OH)2 (1.7 g, 13.9 "01) in benzene (30 mL) was stirred at reflux with azeotropic removal of water (Dean-Stark trap) for 48 h. After the solution was cooled to 25 "C, the reaction was quenched with 2,2-dimethyl-1,3- propanediol(l.45 g, 13.9 m o l ) and the resulting mixture was stirred at 25 "C for 1 h, concentrated, and purified by flash chromatography (silica, 10 - 50% EtOAc in hexanes) to give dienophile 42 (0.33 g, 23%), diene 52 (0.51 g, 34%), and diol 55 (1.56 g, 79% based on 77% conversion) as a yellow oil.

B. Large-Scale Procedure. A mixture of dienophile 42 (70.0 g, 0.49 mol), diene 52 (54.4 g, 0.49 mol), and PhB(0H)z (56.3 g, 0.45 mol) in benzene (lo00 mL) was stirred at reflux with azeotropic removal of water (Dean-Stark trap) for 144 h. After the solution was cooled to 25 "C, the reaction was quenched with 1,3-propanediol (36.8 mL, 0.51 mol) and the resulting mixture was stirred at 25 OC for 2.5 h, concentrated, and purified by flash chromatography (silica, 10 - 50% EtOAc in hexanes) to give dienophile 42 and diene 52 (64.7 g, 52%, 1:l mixture), plus diol 55 (34.88 g, 58% based on 48% conversion) as a yellow oil: Rf = 0.13 (silica, 50% EtOAc in hexanes); IR (thin film) vmax 3423,2987, 1766, 1715, 1257, 1202, 1021 cm-I; 'H NMR (500 MHz, CDC13) 6 6.06 (dd, J = 10.0, 4.0 Hz, 1 H, 6-H), 5.78 (b d, J = 10.0 Hz, 1 H, 5-H), 4.57 (dd, J = 9.5, 7.5 Hz, 1 H, 2-H), 4.57-4.55 (band, 1 H, 7-H), 4.42 (dd, J = 9.5, 8.5 Hz, 1 H, 2-H), 4.15 (q, J = 7.0 Hz, 2 H, COZCH~CH~), 4.18-4.12 (band, 1 H, 4-OH), 3.07 (b t, J = 8.5 Hz, 1 H, 3-H), 3.04 (b d, J = 5.0 Hz, 1 H, 7-OH), 1.25 ( s , 3 H, 19-CH3), 1.94 (t, J = 7.0 Hz, 3 H, C02CHzCH3); I3C NMR (125 MHz, CDC13) 6 176.5, 175.6, 133.0, 124.9,71.6, 66.8, 62.4,47.3,46.6,42.0, 15.4, 13.8; FAB HRMS (NBA/NaI) mle 279.0859, M + Na+ calcd for C&1606 279.0845.

644 J. Am. Chem. SOC., Vol. 1 17, No. 2, I995

Bis(sily1 ether) 58. A solution of diol 55 (28.5 g, 11 1 mmol), 2,6- lutidine (102 mL, 445 mmol), and 4-(dimethylamino)pyridine (DMAP, 1.50 g, 12.2 "01) in CHzClz (250 mL) was treated with teri- butyldimethylsilyl trifluoromethanesulfonate (TBSOW, 52.0 mL, 445 "01) and stirred at 0 "C for 4 h. The reaction mixture was added to aqueous NaHCo3 (100 mL), extracted with Et20 (2 x 150 mL), washed with aqueous CuSO4 (2 x 100 mL), dried (NazSOh), concentrated, and purified by flash chromatography (silica, 5 - 15% Et20 in petroleum ether) to give 58 (49.6 g, 92%) as a white solid: Rf = 0.62 (silica, 15% Et20 in petroleum ether); IR (thin film) vmm 2960, 2936, 2857, 1746, 1256 cm-'; 'H NMR (500 MHz, C&) 6 6.19 (dd, J = 8.5, 5.0 Hz, 1 H, 6-H), 6.10 (dd, J = 8.5, 1.0 Hz, 1 H, 5-H), 4.12 (dd, J = 8.5, 4.5 Hz, 1 H, 2-H), 4.11 (dd, J = 5.0, 1.0 Hz, 1 H, 7-H), 3.83-3.70 (band, 2 H, CO~CHZCH~), 3.40 (d, J = 8.5 Hz, 1 H, 2-H), 2.83 (d, J = 4.5 Hz, 1 H, 3-H), 1.22 (s, 3 H, 19-C&), 1.02 (s, 9 H, Si(C(CH3)3)- (CH3)Zh 0.97 (s, 9 H, S~(C(CH~)S)(CH~)Z), 0.32 (s, 3 H, Si(C(CH3M- (cH3)2), 0.30 (s, 3 H, S~(C(CH~M(CH~)Z), 0.21 (s, 3 H, Si(C(CHsh)-

6 174.0, 133.5, 132.4, 119.0, 80.0, 70.9, 62.8, 60.6, 53.0, 45.9, 26.0, 25.9, 20.5, 18.4, 14.0; FAB HRMS (NBA/NaI) mle 617.1731, M + Na+ calcd for C2&06Si2 617.1731.

Alcohol 59. A solution of ester 58 (49.6 g, 102 "01) in Et20 (500 mL) at 0 "C was treated with LiAEb (1 10 mL of a 1 M solution, 110 mmol), allowed to warm to 25 "C, and stirred at 25 "C for 0.5 h. After the solution was cooled to -78 "C, the reaction was quenched with EtOAc (25 mL) and aqueous NH&1 (150 mL). The reaction mixture was allowed to warm to 25 "C and stirred for 1 h. The organic layer was separated, and the aqueous layer was extracted with Et20 (3 x 200 mL). The combined organic layer was dried (Na2S04), concentrated, and purified by flash chromatography (silica, 20 - 45% Et20 in petroleum ether) to give 59 (43.9 g, 97%) as a white solid: Rj

= 0.22 (silica, 30% Et20 in petroleum ether); IR (thin film) vman 2955, 2931, 2857, 1471, 1280, 1253 cm-'; lH NMR (500 MHz, CDC13) 6

(CH3)2), 0.15 (S, 3 H, Si(C(CH&)(CH3)2); 13C NMR (125 MHz, CD.5)

6.43 (dd, J = 8.5, 5.3 Hz, 1 H, 6-H), 6.20 (dd, J = 8.5, 1.7 Hz, 1 H, 5-H), 4.10 (dd, J = 8.0, 4.1 Hz, 1 H, 2-H), 3.95 (dd, J = 5.3, 1.7 Hz, 1 H, 7-H), 3.58 (d, J = 8.0 Hz, 1 H, 2-H), 3.25 (dd, J = 10.4, 4.3 Hz, 1 H, 9-H), 3.15 (dd , J= 10.4,4.3 Hz, 1 H, 9-H), 1.60 (b t, J = 4 . 3 Hz, 1 H, 9-OH), 1.47 (d, J = 4.1 Hz, 1 H, 3-H), 1.22 ( s , 3 H, Ig-CH,), 0.92 (s, 9 H, Si(C(CH3)3)(CH3)d7 0.86 (s, 9 H, S~(C(CH~)~)(CH~)Z), 0.17 (s, 3 H, Si(C(CH3)3)(CH3)2). 0.15 (s, 3 H, S~(C(CH~)~)(CH~)Z), 0.12 (s, 3 H, Si(C(CHMCH3M, 0.10 (s, 3 H, Si(C(CH3)3)(CH3)2); I3C NMR (125 MHz, C a s ) 6 132.8, 131.7, 119.0, 80.0, 72.0, 69.6, 63.1, 46.0,44.7, 26.0, 25.7, 18.9, 18.2, 18.0, -2.9, -3.0, -3.1, -3.2; FAB HRMS (NBA/CsI) mle 575.1636, M + Cs+ calcd for CzzH4205- Si2 575.1625.

Nicolaou et al.

Diol 60. A solution of alcohol 59 (43.9 g, 99 "01) in CHzClz (250 mL) and MeOH (20 mL) was treated with camphorsulfonic acid (CSA, 0.52 g, 5 "01) and stirred at 25 OC for 1 h. After dilution with CHzClz (300 mL), the reaction was quenched with aqueous

(150 mL). The organic layer was separated, and the aqueous layer was extracted with Et20 (2 x 200 mL). The combined organic layer was dried (NazS04), concentrated, and purified by flash chromatography (silica, 50% Et20 in petroleum ether) to give diol 60 (32.6 g, 94%) as white crystals: mp 109-1 11 "C, from EtOAc-hexanes; Rf = 0.38 (silica, EtzO); IR (thin film) vmm 3433,2932,2859,1766,1469, 1384, 1081, 1023; 'H NMR (500 MHz, CDCl3) 6 5.99 (ddd, J = 18.0, 3.0, 1.5 Hz, 1 H, 5-H), 5.82 (dd, J = 18.0, 1.5 Hz, 1 H, 6-H), 4.38 (A of ABX, dd, J = 9.5, 7.5 Hz, 1 H, 2-H), 4.33 (B of ABX, ddd, J = 9.5, 5.0, 1.0 Hz, 1 H, 2-H), 4.24 (b S, 1 H, 7-H), 3.57 (A' of A'B', d b, J = 11.0 Hz, 1 H, 9-H), 3.39 (B' of A'B', b d, J = 11.0 Hz, 1 H,

7.5,S.O Hz, 1 H, 3-H), 0.88 (s, 3 H, 19-c&), 0.83 (s, 9 H, Si(C(CH3)3)- (CH3)2), 0.16 (s, 6 H, Si(C(CH3)3)(CH3)2); 13C NMR (125 MHz, CDC13) 6 175.7, 135.1, 124.4, 74.5, 68.7, 67.7, 66.4, 47.5, 41.9, 25.6, 18.1, 12.9, -2.7, -3.1; FAB HRMS ( M A ) d e 329.1772, M + H+ calcd for C 1 & ~ 0 ~ S i 329.1784.

9-H), 2.70-2.33 (band, 2 H, 9-OH and 7-OH), 2.55 (X of ABX, dd,

Acknowledgment. We thank Drs. Dee H. Huang, Gary Siuzdak, and Raj Chadha for NMR, mass spectroscopic, and X-ray crystallographic assistance, respectively. This work was financially supported by NM, The Scripps Research Institute, fellowships from Mitsubishi Kasei Corporation (H.U.), R.W. Johnson-ACS Division of Organic Chemistry (E.J.S.), The Office of Naval Research (R. K. G.), Glaxo, Inc. (C.F.C.), Mr. Richard Staley (C.F.C.), RhBne-Poulenc Rorer (P.G.N.), and grants from Merck Sharp & Dohme, Pfizer, Inc., Schering Plough, and the ALSAM Foundation.

Supplementary Material Available: Experimental techniques and data for compounds 10-14,16,18-35,47-51,57, 58, 61-80, 82-87, and 89-107 (44 pages). This material is contained in many libraries on microfiche, immediately follows this article in the microfilm version of the journal, and can be ordered from the ACS. See any current masthead page for ordering information.

JA942 193U

J. Am. Chem. SOC. 1995,117, 645-652 645

Total Synthesis of Taxol. 3. Formation of Taxol's ABC Ring Skeleton

K. C. Nicolaou,* Z. Yang, J.-J. Liu, P. G. Nantermet, C. F. Claiborne, J. Renaud, R. K. Guy, and K. Shibayama

Contribution from the Department of Chemistry, The Scripps Research Institute, 10666 North Torrey Pines Road, La Jolla, Califomia 92037, and Department of Chemistry and Biochemistry, University of Califomia, San Diego, 9500 Gilman Drive, La Jolla, Califomia 92093 Received July 7, 1994@

Abstract: The synthesis of Taxol's ABC ring system has been achieved. The Shapiro coupling of an aldehydic C ring synthon (8) with an anionic A ring synthon derived from hydrazone 9 gave, diastereoselectively, A-B conjugate 10. Functional group manipulations and McMuny ring closure produced the highly functionalized ABC ring system 17. Extensive attempts to optimize the McMuny reaction revealed a single predominant side reaction leading to byproducts 19 and 20. Resolution of the C9,ClO-diol (f)-17 via its camphanyl esters provided the ABC ring system as its natural isomer (+)17.

Introduction

In the preceding two papers1-* in this series, we described our degradation and reconstruction studies with Taxol (1, Figure l), preliminary investigations with rings A and C, and possible schemes for their elaboration to an appropriately functionalized ABC taxoid framework. Armed with the knowledge gained in these studies, we were now ready to attempt the final drive toward Taxol's ABC ring skeleton. As already discussed, the starting materials were defined as hydrazone 92 (Scheme 2) and aldehyde 8 (Scheme l), the synthesis of which is detailed below. The C4-C20 five-membered acetonide group was chosen as a means to protect the vicinal diol system of the intermediate and to introduce additional rigidity in the system prior to cyclization to form the 8-membered ring.

Construction of Taxol's ABC Ring Skeleton

a. Synthesis of the C Ring Aldehyde 8. Scheme 1 summarizes the preparation of the targeted aldehyde 8 from the previously described intermediate 2.* Thus, treatment of diol 2 with tert-butyldiphenylsilyl chloride (TPSC1) and imidazole3 resulted in monosilylation of the primary alcohol, providing the C7 hydroxyl, C9 silyl ether 3 in 92% yield. Benzylation of the C7 hydroxyl group using KH and benzyl bromide4 afforded benzyl ether 4 in 88% yield. Exhaustive reduction of the lactone ring in 4, accompanied by removal of the C4 TBS group, resulted in the formation of triol 5 (80% yield). The crucial 5-membered ring acetonide was then installed using 2,2- dimethoxypropane in the presence of a catalytic amount of CSA5 in methylene chloride:ether (98:2) at ambient temperature. Under these conditions, the reaction was found to be quite rapid

* Address correspondence to this author at The Scripps Research Institute or the University of California.

@ Abstract published in Advance ACS Abstracts, December 15, 1994. (1) Nicolaou, K. C.; Nantennet, P. G.; Ueno, H.; Guy, R. K.; Coula-

douros, E. A.; Sorensen, E. J. J . Am. Chem. SOC. 1995, 117, 624. (2) Nicolaou, K. C.; Liu, J.-J.; Yang, Z.; Ueno, H.; Sorensen, E. J.;

Claibome, C. F.; Guy, R. K.; Hwang, C.-K.; Nakada, M.; Nantermet, P. G. J . Am. Chem. SOC. 1995, 117, 634.

(3) Hanessian, S.; Lavallk, P. Can. J . Chem. 1975,53,2975. Hanessian, S. : LavallBe. P. Can. J . Chem. 1977. 55. 562.

(4) Kand;, K.; Sakamoto, I.; Ogawa, S:; Suami, T. Bull. Chem. SOC. Jpn. 1987, 60, 1529.

(5) Lipshutz, B. H.; Barton, J. C. J. Org. Chem. 1988, 53, 4495.

0002-786319511517-0645$09.0010

1 : Taxol


Scheme 1. Synthesis of C Ring Aldehyde 8" HO OH TPSO OR TPSO 08

C - )TBS

2

8 7 6

Reagents and conditions: (a) 1.3 equiv of TPSCl, 1.35 equiv of imidazole, DMF, 25 "C, 12 h, 92%; (b) 1.2 equiv of KH, 1.2 equiv of PhCHZBr, 0.04 equiv of n - B N , EtzO, 25 OC, 1 h, 88%; (c) 3.0 equiv of LiAlH4, EtzO, 25 OC, 12 h, 80%; (d) 5.0 equiv of 2,2-dimethoxypropane, 0.05 equiv of camphorsulfonic acid (CSA), CHzC1Z:EtzO (98: 2), 25 OC, 7 h, 82%; (e) 0.05 equiv of tetrapropylammonium permthenate (PAP), 1.5 equiv of 4-methylmorpholine N-oxide WO), CH3CN, 25 "C, 2 h, 97%. TBS = Si-t-BuMez, Bn = CHZPh, TPS = Si-t-BuPhz.

with the initially formed 7-membered ring acetonide 6 rear- ranging slowly and essentially completely to the desired, and thermodynamically more stable, 5-membered ring isomer 7 (82%). Finally, PAP-NMO oxidation6 of the remaining hydroxyl group in 7 furnished the targeted aldehyde 8 in 97%



12

qn 0 -

k" 0% 20

(Re face) Nu'

16: L? chelate derived from aldehyde 8

Figure 3. Stereoselectivity of the Shapiro reaction. The model was generated with Chem3d. Most hydrogens are omitted for clarity.

Scheme 2 to afford allylic alcohol 10 as a single diastereoisomer and in 82% yield. X-ray crystallographic analysis of a subsequent intermediate confirmed the stereochemical structure of 10 (vide infra). The stereoselectivity of this reaction can be explained by invoking the chelated intermediate 16, depicted in Figure 3, in which the acetonide plays a crucial role. As seen in this model, the aldehyde group is fixed by the lithium template in a conformation in which nucleophilic attack can freely proceed from only one side, the re face, with the si face being blocked by the C8 methyl group.

Directed epoxidation9 of the C1-C14 double bond in 10, although slow, proceeded smoothly to afford the single epoxide 11 in 87% yield. Regioselective openinglo of the epoxide group in 11 with LiAl& resulted in the formation of diol 12 in 76% yield. The crystalline diol 12 was subjected to X-ray crystallographic analysis (see ORTEP drawing, Figure 2) confirming the assigned stereochemistry of all intermediates in Scheme 2. Exposure of 12 to excess KH and phosgene in ether:HMPA (3: 1) resulted in the formation of carbonate 13 (86% yield, 58% conversion). Desilylation of 13 with fluoride ion3 furnished diol 14 (80% yield), which was oxidized smoothly with TPAP- NM06 to afford the dialdehyde 15 (92% yield)- preorganized in a conformation favorable for the upcoming McMurry cyclization.

c. The McMurry Cyclization and Synthesis of the ABC Ring Skeleton 17. The search for the conditions required to yield the requisite cyclized product using the McMurry pinacol

(6) Griffith, W. P.; Ley, S. V. Aldrichimica Acta 1990, 23, 13. (7) Shapiro, R. H. Org. React. 1976,23,405. Chamberlin, A. R.; Bloom,

S. H. Org. React. 1990, 39, 1. Martin, S. F.; Daniel, D.; Cherney, R. J.; Liras, S. J. Org. Chem. 1992, 57, 2523.

(8) This strategy was later used by others to accomplish similar couplings: Di Grandi, M. J.; Jung, D. K.; Krol, W. J.; Danishefsky, S. J. J. Org. Chem. 1993, 58, 4989. Masters, J. J.; Jung, D. K.; Bornmann, W. G.; Danishefsky, S. J. Tetrahedron Lett. 1993, 34, 7253.

(9) Sharpless, K. E.; Michaelson, R. C. J. Am. Chem. SOC. 1973, 95, 6136. Sharpless, K. B.; Verhoeven, T. R. Aldrichimica Acta 1979, 12, 63. Rao, A. S . In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Ley, S. V., FRS, Eds.; Pergamon Press: New York, 1991; Vol. 7, p 376.

(10) Murai, S.; Murai, T.; Kato, S. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 8,

wo, 0

Po O 0

30

Figure 2. ORTEP drawings for compounds 12, 19, 20, and 30.

Yield. Thus a rapid and efficient Pathway to key in te rmdate 8 was established. p 871.

(11) McMuny, J. E. Chem. Rev. 1989, 89, 1513. McMurry J. E. Acc. Chem. Res. 1983,16,405. McMurry, J. E.; Lectka, T.; Rico, J. G. J . Org. Chem. 1989,54,3748. McMurry, J. E.; Rico, J. G. Tetrahedron Lett. 1989, 30, 1169. Lenoir, D. Synthesis 1989, 883.

The Reaction and Synthesis Of Dialdehyde 15* The Shapiro 9 with aldehyde 8 proceeded under the conditions specified in

reacti0n7'8 Of

Total Synthesis of Taxol. 3 J. Am. Chem. SOC., Vol. 117, No. 2, 1995 647

Scheme 2. Shapiro Coupling of 8 with 9 and Synthesis of Dialdehyde 15"

TBSO

&OTBS+ N NHS02Ar

i- Pr.

TPSO OBn - OHC

9, Ar = e i - P r a i- Pr

- \ 10

f TBSO

TBSO

Scheme 3. McMurry Cyclization and Synthesis of Diol 17" n

12 11

0

f

15

a Reagents and conditions: (a) 1.1 equiv of 9,2.3 equiv of n-BuLi, THF, -78 - 0 "C, 1.0 equiv of 8, THF, -78 "C, 0.5 h, 82%; (b) 0.03 equiv of VO(acac)z, 3.0 equiv of t-BuOOH, PhH, 4 8, molecular sieves, 25 "C, 14 h, 87%; (c) 5.0 equiv of LiAlh, 25 "C, Et20,7 h, 76%; (d) 3.0 equiv of KH, Et20:HMPA (3:1), 1.6 equiv of phosgene (20% in toluene), 25 "C, 0.5 h, 86% based on 58% conversion; (e) 3.8 equiv of n - B u m (TBAF), THF, 25 O C , 14 h, 80%; (f) 0.05 equiv of tetrapropylammonium permthenate (TPAF'), 3 .O equiv of 4-methylmorpholine N-oxide (NMO), CH3CN, CH2Cl2, (2:1), 25 "C, 2 h, 92%. TBS = Si-t-BuMez, TPS = Si-t-BuPh2, Bn = CHzPh.

coupling methodology included varying the temperature (0 - 100 "C), solvent (e.g. THF, DME, ether) and stoichiometry, as well as the use of various bases as additives. It was finally determined that 11 equiv of TiC13*(DME)1.5 and 26 equiv of Zn-Cu couple in DME at 70 "C provided the optimum yield of diol 17 (25%, Scheme 3). In addition to diol 17, whose stereochemistry was assigned on the basis of a subsequent intermediate (vide infia), a number of other products were obtained including olefin 18 (10% yield), lactoll9 (40% yield), and formate ester 20 (15% yield). The structures of 17 and 18 were based solely upon spectroscopic evidence (except for the stereochemistry of 17 at C9 and C10 which was later confirmed, vide infra), whereas those of 19 and 20 were secured from both spectroscopic and X-ray crystallographic data (see ORTEP drawings, Figure 2).

Analysis of molecular models for dialdehyde 15 indicated a possible ground state conformation in which the two aldehyde moieties of 15 are in close proximity (Figure 4), thus requiring only small conformational changes to reach the geometry necessary for cyclization. Rotation around the C2-C3 carbon- carbon bond would either bring the two aldehyde groups in very close proximity, as desired, or induce strong steric interactions between ring A and the acetonide group. In contrast, dialdehyde 21 (see Figure 5 and previous paper2 in this series, Scheme 13,

V 17 (23-25%) 18 (10%)

19 (40%) 20 (1 5%)

a Reagents and conditions: 11 equiv of TiCl3*(DME)1.5,26 equiv of Zn-Cu, DME, reflux, 3.5 h, then 70 "C, then 15 added over 1 h, then 70 "C, 0.5 h. Bn = CH2Ph.

6 Oxo 0 ' 0 3 O

15

Figure 4. Possible ground state conformation of 15. The model was generated with Chem3d. The C7 benzyl protecting group and all hydrogens are omitted for clarity. Bn = CH9h.

structure 95) offers much higher conformational freedom via rotation around the Cl-C2 carbon-carbon bond. Analysis of molecular models indicated a possible ground state conformation (21) (Figure 5) for this compound in which the two aldehyde functionalities are far apart. Failure to cyclize to such a system


Ph

\ Scheme 4. Postulated Mechanism of the McMurry Cyclization and Formation of Products 17 and 18

0 Tio -

21

Figure 5. Possible ground state conformation of 21. The model was generated with Chem3d. All hydrogens are omitted for clarity.

in the McMurry reaction may reflect the large entropic and enthalpic cost for the conformational change necessary for reaction to take place.

Mechanistic rationales for the formation of products 17-28 are shown in Schemes 4 and 5. The pathways leading to 17- 19 are in accord with previous proposals by McMurryl' and Kende.12 The formation of the keto formate 20, however, requires an additional oxygen atom which may, presumably, come from molecular oxygen introduced during workup. A speculative mechanism for its formation is proposed in Schemes 4 (15 - 22 - 24) and 5 (24 - 25 - 27 - 28 - 20).

Attempts at masking the C11-Cl2 double bond in order to avoid the formation of byproducts 19 and 20 were abandoned after unsuccessful early trials. Further studies along this line, however, may prove useful in controlling product formation in this reaction.

d. Resolution of ABC Ring System Diol 17. To secure enantiomerically pure intermediates for the synthesis of Taxol (l), we decided to attempt a resolution of the racemic diol 17 obtained from the McMurry cyclization as described above. Encouraged by a successful resolution of a similar taxoid13 via camphanate esters,14 we applied the sequence shown in Scheme 6 to our system. Treatment of diol (f)-17 with an excess of (18-(-)-camphanic chloride in methylene chloride in the presence of Et3N resulted in the formation of two diastereomeric monoesters 29 and 30 in 36% total yield (1:l ratio). Chro- matographic separation of the mixture allowed the more polar isomer (30, Rf= 0.21, silica, 15% EtOAc in PhH; [ a ] 2 2 ~ -133 (c 0.49, CHC13)) to crystallize. X-ray crystallographic analysis (see ORTEP drawing, Figure 2) revealed the absolute stereochemistry of the latter diastereoisomer and thus allowed identification of the requisite isomer for the synthesis of Taxol as the less polar diastereoisomer (29; Rf = 0.26, silica, 15% EtOAc in PhH; +117 (c 0.54, CHC13)). Hydrolysis of this isomer (29) under basic conditions (K2CO3, MeOH) regenerated diol (+)-17 (90% yield; [o!]22D +187 (c 0.5, CHC13)), now in its enantiomerically pure form.

(12) Kende, A. S.; Johnson, S.; Sanfilippo, P.; Hodges, J. C.; Jungheim,

(13) Nicolaou, K. C.; Claiborne, C. F.; Nantermet, P. G.; Couladouros,

(14) Gerlach, H. Helv. Chim. Acta 1978, 61, 2773.

L. N. J. Am. Chem. SOC. 1986, 108, 3513.

E. A.; Sorensen, E. J. J . Am. Chem. SOC. 1994, 116, 1591.

23 i 24

17 18

The appearance of the chiral auxiliary on the C9 hydroxyl group of these esters (29 and 30) was at first surprising, particularly in view of the fact that monoacetylation of diol 17 leads selectively to the C10 acetate (see following paper).15 Inspection of molecular models revealed rather similar steric environments for these two positions, and therefore, predictions or rationalizations were not easy to make. Apparently, the more reactive allylic C10 hydroxyl group attracts the smaller acetate group, whereas only the C9 hydroxyl can accommodate the bulkier camphanate ester functionality.

Conclusion

In this paper we describe the successful construction of a suitable ring C aldehyde (8) and its stereoselective coupling with the ring A hydrazone (9) through a Shapiro reaction. Elaboration of the A-C-coupled product (10) led to a dialdehyde (15) which entered into a successful McMurry cyclization to afford ring B with retention of the C9 and C10 oxygens. Resolution of the resulting racemic ABC taxoid diol 17 through its diastereomeric camphanate esters (29 and 30) set the stage for an enantioselective synthesis of Taxol(1). The final stages of the total synthesis of this target molecule are described in the following paper.15


the first paper in this series.l Silyl Ether 3. A solution of diol 2 (9.20 g, 28.0 m o l ) in DMF

(50 mL) was treated with imidazole (2.58 g, 37.9 m o l ) and

(15) Nicolaou, K. C.; Ueno, H.; Liu, J.-J.; Nantermet, P. G.; Yang, Z.; Renaud, J.; Paulvannan, K.; Chadha, R. J. Am. Chem. Soc. 1995,117,653.

J. Am. Chem. SOC., Vol. I 17, No. 2, 1995 649 Total Synthesis of Tmol. 3

Scheme 5. Postulated Mechanism for the Formation of Products 19 and 20

a - Tio /

25

H+ 1

26

1

19

0 2

Ti0

27

Ti 1 /I

28

9 1

&p li "0 o y

20

tea-butylchlorodiphenylsilane (9.46 mL, 36.0 m o l ) and stirred at 25 "C for 12 h. After dilution with Et20 (400 mL), the reaction was quenched with aqueous NaHCO3 (100 mL). The organic layer was separated, and the aqueous layer was extracted with Et20 (2 x 50 mL). The combined organic layer was washed with brine (50 mL), dried (Na2S04), concentrated, and purified by flash chromatography (silica, 30% Et20 in petroleum ether) to give 3 (14.6 g, 92%) as a pale yellow oil: Rj = 0.41 (silica, 50% Et20 in petroleum ether); IR (thin film) vmax 3460,2954,2931,2857, 1770, 1471, 1110, 1086 cm-'; 'HNMR (500 MHz, CDCl3) 6 7.65-7.55 (band, 4 H, Ar), 7.48-7.35 (band, 6

Hz, 1 H, 5-H), 4.58 (m, 1 H, 7-H), 4.19 (dd, J = 10.0, 6.5 Hz, 1 H, H, Ar), 5.91 (dd, J = 10.5, 2.0 Hz, 1 H, 6-H), 5.84 (dd, J = 10.5, 2.5

2-H), 3.95 (dd, J = 10.0, 2.0 Hz, 1 H, 2-H), 3.61 (d, J = 10.6 Hz, 1 H, 9-H), 3.41 (d, J = 10.6 Hz, 1 H, 9-H), 2.59 (dd, J = 6.5, 2 Hz, 1 H, 3-H), 2.05 (d, J = 5.5 Hz, 1 H, 7-OH), 1.07 (s, 9 H, SiC(CH3)s- Phz), 0.80 (s, 9 H, SiC(CH3)3(CH&), 0.69 (s, 3 H, 19-C&), 0.11 (s, 6 H, SiC(CH&(CH&); 13C NMR (125 MHz, CDC13) 6 175.3, 136.1, 135.6, 135.5, 132.6, 132.5, 130.1, 127.9, 124.6, 74.5, 68.7, 66.6, 65.6, 47.2,44.1,26.9,25.4, 19.2, 18.0, 11.0, -2.8, -3.1; FAB HRMS (NBN NaI) mle 589.2795, M + Na+ calcd for C3zH4605Si~ 589.2782.

Benzyl Ether 4. A solution of alcohol 3 (21.5 g, 37.9 mmol), benzyl bromide (5.4 mL, 45.4 mmol), and n - B W (0.5 g, 1.35 mmol) in Et20 (300 mL) was treated with KH (6 g of a 30% suspension in mineral oil, 44.8 mmol, prewashed with dry EtzO) and stirred at 25 "C for 1 h. After the reaction was quenched with MeOH (5 mL), the reaction mixture was stirred at 25 "C for 15 min. After dilution with Et20 (200 mL), the resulting solution was washed with brine (100 mL), dried (Na2S04), concentrated, and purified by flash chromatography (silica, 10 - 30% Et20 in petroleum ether) to give 4 (21.9 g, 88%) as a yellowish oil: Rj = 0.57 (silica, 25% Et20 in petroleum ether); IR (thin film) vmax 2956, 2925,2849, 1773, 1467, 1101 cm-I; 'H NMR (500 MHz, CDC13) 6 7.65-7.55 (band, 4 H, Ar), 7.45-7.25 (band, 11 H, Ar), 6.04 (dd, J = 10.0, 2.5 Hz, 1 H, 6-H), 5.82 (dd, J = 10.0, 2.5

Scheme 6. Resolution of Diol 17"

O% x

(f)-l7 I

"I 0

It 0

29 [a]"~ +117 (c 0.54, CHC13)

(+)-17

OReagents and conditions: (a) 5.0 equiv of (18-(-)-camphanic chloride, 20 equiv of EtsN, 0.05 equiv of 4-(dimethy1amino)pyridine (DMAP), CHzC12, 25 "C, 1 h, 86%; (b) 7.0 equiv of K2C03, MeOH, 25 "C, 0.5 h, 90%. Bn = CHgh.

Hz, 1 H, 5-H), 4.72 (d, J = 11.5 Hz, 1 H, OCHzPh), 4.58 (d, J = 11.5 Hz, 1 H, OCH2Ph). 4.36 (dd, J = 2.5, 2.0 Hz, 1 H, 7-H), 4.08 (dd, J = 9.5, 7.0 Hz, 1 H, 2-H), 3.96 (dd, J = 9.5, 3.5 Hz, 1 H, 2-H), 3.69 (d, J = 10.6 Hz, 1 H, 9-H), 3.39 (d, J = 10.6 Hz, 1 H, 9-H), 2.66 (dd, J = 7.0, 3.5 Hz, 1 H, 3-H), 1.08 (s, 9 H, SiC(CH3)3Ph2), 0.78 (s, 9 H, SiC(CH3)3(CH3)2), 0.77 (s, 3 H, 19-C&), 0.12 (s, 3 H, SiC(CH3)3- (cH3)2), 0.11 (s, 3 H, SiC(CHs)s(CH3)2); 13C NMR (125 MHz, CDCl3) 6 175.6, 138.3, 135.6, 132.9, 132.9, 132.8, 130.0, 129.8, 128.4, 127.8, 127.7, 127.6, 127.4, 124.7,74.5,74.4,72.6,65.7,65.6,47.5,43.9,27.0, 25.5, 19.3, 18.0, 12.8, -2.8, -3.1; FAB HRMS (NBNCsI) mle 789.2395, M + Cs+ calcd for C39H5205Si~ 789.2408.

Triol 5. A solution of lactone 4 (14.7 g, 22.4 m o l ) in Et20 (150 mL) was treated with LiAlH4 (66 mL of a 1 M solution in EtzO, 66.0 mmol) and stirred at 25 "C for 12 h. After dilution with Et20 (200 mL), the reaction mixture was cooled to -78 "C, and the reaction was quenched with aqueous W C 1 (100 mL). After the solution was w m e d to 25 OC, the organic layer was separated, washed with brine (100 mL), dried (NazSOd), concentrated, and purified by flash chromatography (silica, 60% EtOAc in petroleum ether) to give 5 (9.8 g, 80%) as a colorless oil: Rj = 0.23 (silica, 50% EtOAc in hexanes); IR (thin film) vmar 3374, 2927, 2851, 1463, 1422, 1387, 1105 cm-'; 'H NMR (500 MHz, CDC13) 6 7.65-7.55 (band, 4 H, Ar), 7.45-7.15 (band, 11 H, Ar), 5.85 (dd, J = 10.0,2.5 Hz, 1 H, 6-H), 5.69 (dd, J = 10.0, 1.5 Hz, 1 H, 5-H), 4.55 (d, J = 11.5 Hz, 1 H, OCHzPh), 4.27 (d, J = 11.5 Hz, 1 H, OCHzPh), 4.01 (b S, 1 H, 7-H), 3.96-3.89 (band, 3 H, 20-CH2 and 2-H), 3.72 (d, J = 10.5 Hz, 1 H, 9-H), 3.70 (s, 1 H, 4-OH), 3.58 (m, 1 H, 2-H), 3.51 (d, J = 10.5 Hz, 1 H, 9-H), 3.45- 3.35 (band, 2 H, 2-OH and 20-OH), 2.15 (dd, J = 6.5, 3.5 Hz, 1 H, 3-H), 1.09 (s, 9 H, SiC(CH3)3Phz), 0.89 (s, 3 H, 19-CI-h); 13C NMR

128.3, 128.2, 127.7, 127.5, 127.3, 76.2, 73.1, 71.6, 67.1, 66.7, 59.4, 48.0, 43.4, 27.0, 25.8, 19.3, 15.3; FAB HRMS (NBNCsI) mle 679.1871, M + Cs+ calcd for C33H4205Si 679.1856.

Acetonide 7. A solution of triol 5 (16.2 g, 29.6 mmol) and 2,2- dimethoxypropane (18.2 mL, 148 mmol) in CH2Cl2 (98 mL) and Et20 (2 mL) was treated with camphorsulfonic acid (350 mg, 1.5 m o l ) and stirred at 25 "C for 7 h. After the reaction was quenched with

(125 MHz, CDC13) 6 138.1, 135.8, 135.7, 132.9, 131.2, 129.9, 129.8,


aqueous NaHC03 (50 mL), the organic layer was separated, dried (Naz- concentrated, and purified by flash chromatography (silica, 50%

Et20 in petroleum ether) to give 7 (14.25 g, 82%) as a colorless oil: Rf = 0.51 (silica, 50% Et20 in petroleum ether); IR (thin film) vmax 3467,2932,2858, 1462, 1373, 1210, 1106, 1054 cm-'; 'H NMR (500

Ar), 7.15-7.05 (band, 2 H, Ar), 5.79 (dd, J = 10.0, 1.5 Hz, 1 H, 6-H), MHz, CDC13) 6 7.66-7.60 (band, 4 H, Ar), 7.45-7.20 (band, 9 H,

5.72 (dd, J = 10.0, 2.5 Hz, 1 H, 5-H), 4.45 (d, J = 11.5 Hz, 1 H, OCHZPh), 4.16 (d, 9.0 Hz, 1 H, 20-H), 4.11 (d, J = 11.5 Hz, 1 H, OCHzPh), 3.99 (b S, 1 H, 7-H), 3.97-3.89 (band, 2 H, 2-CH2), 3.81 (d, 9.0 Hz, 1 H, 20-H), 3.76 (A of AB, d, J = 10.5 Hz, 1 H, 9-H), 3.73 (B of AB, d, J = 10.5 Hz, 1 H, 9-H), 3.42 (b t, J = 6.0 Hz, 1 H, 2-OH), 2.14 (t, J = 4.0 Hz, 1 H, 3-H), 1.44 (s, 3 H, C(CH3)2), 1.42 (s, 3 H, C(CH&), 1.09 (s, 9 H, SiC(CH&Phz), 0.87 (s, 3 H, 19-CH3); 13C

129.9, 129.8, 128.2, 127.7, 127.4, 127.2, 126.6, 107.9, 81.9,75.9,71.3, 70.0, 67.1, 58.8, 48.1, 44.2, 27.3, 27.0, 26.4, 19.3, 14.1; FAB HRMS (NBA/NaI) m/e 609.3028, M + Na+ calcd for C36H4605si 609.3012.

Aldehyde 8. A solution of alcohol 7 (9.7 g, 16.5 m o l ) in CH3CN (100 mL) was treated with tetrapropylammonium penuthenate (TPAP, 290 mg, 0.83 "01) and 4-methylmorpholine N-oxide (NMO, 2.91 g, 24.8 "01) and stirred at 25 "C for 2 h. After dilution with CHzCl2 (400 mL), the reaction mixture was filtered through silica gel. The resulting solution was concentrated and purified by flash chromatography (silica, 30% Et20 in petroleum ether) to give 8 (9.37 g, 97%) as a white foam: Rf = 0.45 (silica, 30% Et20 in petroleum ether); IR (thin film) vmax 2931, 2857, 1720, 1472, 1428, 1371, 1111 cm-'; 'H

(band, 4 H, Ar), 7.47-7.22 (band, 9 H, Ar), 7.17-7.10 (band, 2 H,

NMR (125 MHz, CDCl3) 6 138.1, 135.9, 135.8, 132.9, 132.7, 132.5,

NMR (500 MHz, CDCls) 6 9.98 (d, J = 3.5 Hz, 1 H, 2-H), 7.65-7.55

Ar), 5.84 (dd, J = 10.5, 1.5 Hz, 1 H, 6-H), 5.71 (dd, J = 10.5, 2.0 Hz, 1H,5-H),4.50(d,J~11.5H~,1H,OCH~Ph),4.22(d,J~11.5H~, 1 H, OCHzPh), 4.20 (d, 9.5 Hz, 1 H, 20-H), 4.10 (dd, J = 2.0, 1.5 Hz, 1 H, 7-H), 3.84 (d, 9.5 Hz, 1 H, 20-H), 3.72 (A of AB, d, J = 10.0 Hz, 1 H, 9-H), 3.70 (B of AB, d, J = 10.0 Hz, 1 H, 9-H), 3.18 (d, J = 3.5 Hz, 1 H, 3-H), 1.42 (s, 3 H, C(CH3)z). 1.39 (s, 3 H, C(CH3)z). 1.09 (s,

CDC13)G 202.3, 138.1, 135.8, 135.8, 135.7, 135.6, 133.0, 132.9, 131.1, 9 H, SiC(CH&Phz), 1.04 (s, 3 H, 19-CH3); 13C NMR (125 MHz,

129.7, 129.7, 129.5, 128.8, 128.2, 128.2, 127.6, 127.4, 127.4, 127.2, 127.2, 127.1, 108.6, 80.7.75.4, 71.8,70.0,65.7, 57.6,44.9, 26.9, 26.5, 19.3, 13.6; FAB HRMS (NBA/NaI) mle 607.2865, M + Na+ calcd for

Alcohol 10. To a solution of hydrazone 9 (28.2 g, 50.1 "01) in THF (400 mL) at -78 OC was added dropwise n-BuLi (65.5 mL of a 1.6 M solution in hexanes, 105 "01). After the reaction mixture was stirred at -78 "C for 20 min, it was allowed to warm to 0 OC, resulting in Nz gas evolution. The resulting bright orange solution was cooled to -78 "C, and a solution of the aldehyde 8 (26.4 g, 45.1 mmol) in THF (100 mL) was slowly added via canula. The reaction mixture was stirred at -78 "C for 0.5 h, and then the reaction was quenched with aqueous N&Cl (50 mL). After being warmed to 25 "C, the reaction mixture was extracted with Et20 (2 x 200 mL). The organic layer was dried (Na2S04), concentrated, and purified by flash chromatography (silica, 15% Et20 in petroleum ether) to give 10 (31.7 g, 82%) as a colorless oil: Rf = 0.25 (silica, 10% Et20 in petroleum ether); IR (thin film) v,, 3445, 2935, 2852, 1251, 1464, 1429, 1370, 1049 cm-'; 'H NMR (500 MHz, CDC13) 6 7.73-7.65 (band, 4 H, Ar), 7.48- 7.25 (band, 11 H, Ar), 5.98 (b s, 1 H, 14-H), 5.97 (d, J = 10.0 Hz, 1

C36Hu05Si 607.2856.

H, 5-H), 5.79 (dd, J = 10.0, 5.0 Hz, 1 H, 6-H), 4.88 (b S, 1 H, 2-H), 4.73 (d, J = 11.5 Hz, 1 H, OCHzPh), 4.59 (d, J = 11.5 Hz, 1 H, OCH2- Ph), 4.45 (d, 9.5 Hz, 1 H, 20-H), 4.33 (d, J = 10.5 Hz, 1 H, 10-H), 4.29 (d, J = 3.5 Hz, 1 H, 2-OH), 4.24 (d, J = 10.5 Hz, 1 H, 10-H), 3.96 (d, 9.5 Hz, 1 H, 20-H), 3.79 (d, J = 10.0 Hz, 1 H, 9-H), 3.72 (d, J = 10.0 Hz, 1 H, 9-H), 3.70 (d, J = 5.0 Hz, 1 H, 7-H), 2.80-2.65 (band, 3 H, 3-H and 13-CH2), 1.81 (s, 3 H, 18-CH3), 1.43 (s, 3 H,

17-CH3), 1.25 (s, 3 H, 19-C&), 1.11 (s, 9 H, SiC(CH&Ph2), 0.98 (s, 9 H, SiC(CH&(CH3)2), 0.15 (s, 6 H, SiC(CH3)3(CH3)2); 13C NMR (125

129.4, 129.4, 129.0, 128.4, 127.8, 127.7, 127.4, 127.4, 122.6, 120.7, 106.7, 80.2, 74.1, 72.4, 71.4, 70.9, 68.4, 59.1, 46.9, 43.3, 39.2, 33.6,

C(CH3)2), 1.41 (s, 3 H, C(CH3)z). 1.35 (s, 3 H, 16-CH3), 1.32 (s, 3 H,

MHz, CDC13) 6 145.1, 137.5, 137.0, 135.7, 135.7, 135.1, 133.9, 133.7,

28.6, 26.9, 26.7, 26.1, 26.0, 24.6, 19.4, 19.3, 19.2, 18.3, -5.3; FAB HRMS (NBNCsI) d e 983.4050 M + Cs+ calcd for C52H7406Si~ 983.4078.

Epoxide 11. A solution of allylic alcohol 10 (18.7 g, 22.0 "01) in benzene (500 mL) was treated with 4-A molecular sieves (2 g), VO- (acac)~ (175 mg, 0.66 mmol), and t-BuOOH (22 mL of a 3 M solution in decane, 66.0 "01) and stirred at 25 "C for 14 h. After the reaction was quenched with MezS (5 mL) and aqueous N&Cl (300 mL), the reaction mixture was extracted with Et20 (200 mL). The organic layer was dried (Na~S04), concentrated, and purified by flash chromatography (silica, 15% Et20 in petroleum ether) to give 11 (16.6 g, 87%) as a colorless oil: Rf= 0.47 (silica, 15% EtzO in petroleum ether); IR (thin film) Y- 3490, 2935, 2852, 1471, 1257, 1049 cm-'; 'H NMR (500 MHz, CDC13) 6 7.65-7.55 (band, 4 H, Ar), 7.50-7.28 (band, 11 H, Ar), 5.82 (d, J = 10.0 Hz, 1 H, 5-H), 5.74 (dd, J = 10.0, 5.0 Hz, 1 H, 6-H), 4.82 (d, J = 4.5 Hz, 1 H, 2-H), 4.70 (d, J = 11.5 Hz, 1 H, OCHzPh), 4.56 (d, J = 10.0 Hz, 1 H, 20-H), 4.54 (d, J = 11.5 Hz, 1 H, OCHzPh), 4.14 (A of AB, d, J = 11.5 Hz, 1 H, 10-H), 4.1 1 (B of AB, d, J = 11.5 Hz, 1 H, 10-H), 4.06 (d, J = 10.0 Hz, 1 H, 20-H), 3.85 (d, J = 10.0 Hz, 1 H, 9-H), 3.71 (d, J = 5.0 Hz, 1 H, 7-H), 3.54 (d, J = 10.0 Hz, 1 H, 9-H), 3.35 (d, J = 4.5 Hz, 1 H, 2-OH), 2.93 (s, 1 H, 14-H), 2.49 (b S, 2 H, 13-CH2), 1.80 (s, 1 H, 3-H), 1.70 (s, 3 H, 18-CH3), 1.41 (s, 3 H, Ig-CHs), 1.30 (s, 3 H, C(CH3)2), 1.29 (s, 3 H, C(CH3)2), 1.25 (s, 3 H, C(CH3)2), 1.24 (s, 3 H, C(CH3)2), 1.06 (s, 9 H, SiC(CH3)3Ph2), 0.90 (s, 9 H, SiC(CH3)3(CH3)2), 0.08 (s, 3 H, SiC(CH3)3- (cH3)2), 0.07 (s, 3 H, SiC(CH3)3(CH3)2); 13C NMR (125 MHz, CDCl3) 6 137.8, 135.9, 135.6, 135.6, 135.4, 134.1, 133.7, 129.4, 129.3, 128.3, 127.7, 127.4, 127.2, 123.9, 122.0, 107.1, 79.6, 74.3, 72.3, 70.8, 69.2, 64.1, 58.8, 53.4, 44.9, 42.3, 39.6, 31.7, 28.3, 26.9, 26.1, 25.9, 25.9,

CsI) d e 999.4050, M + Cs' calcd for C52H7407Si2 999.4027. Diol 12. A solution of epoxide 11 (20.06 g, 23.1 "01) in Et20

(100 mL) was treated with LiA1I-b (1 15 mL of a 1 M solution in EtzO, 115 "01) and stirred at 25 OC for 7 h. After dilution with Et20 (200 mL), the reaction mixture was cooled to -78 "C, and the reaction was quenched with EtOAc (25 mL) followed by aqueous NI&Cl(100 mL). After warming to 25 "C, the organic layer was separated and the aqueous layer was extracted with Et20 (2 x 100 mL). The combined organic layers were dried (NazSOd), concentrated, and purified by flash chromatography (silica, 30% Et20 in petroleum ether) to give 12 (15.3 g, 76%) as colorless crystals: mp 115-1 17 "C, from CHzCl2-hexanes; Rf = 0.58 (silica, 30% Et20 in petroleum ether); IR (thin film) Y,,

3468,2955,2857, 1471, 1367, 1254, 1052 cm-'; IH NMR (500 MHz,

25.8, 23.2, 21.9, 19.4, 19.3, 16.8, -5.5, -5.6; FAB HRMS (NBN

CDC13) 6 7.65-7.61 (band, 4 H, Ar), 7.42-7.28 (band, 11 H, Ar), 5.85(d,J=10.5H~, lH,5-H) ,5 .67(dd,J=10.5 ,5 .0Hz, 1H,6-H), 4.63 (d, J = 11.0 Hz, 1 H, OCHZPh), 4.55 (d, J = 10.0 Hz, 1 H, 20- H), 4.54 (d, J = 11.0 Hz, 1 H, OCHZPh), 4.18 (d, J = 4.5 Hz, 2-H), 4.16 (d, J = 11.0 Hz, 1 H, 10-H), 4.07 (d, J = 10.0 Hz, 1 H, 10-H), 3.97 (d, J = 4.5 Hz, 1 H, 2-OH), 3.87 (d, J = 11.0 Hz, 1 H, 20-H), 3.79 (d, J = 10.0 Hz, 1 H, 9-H), 3.64 (d, J = 5.0 Hz, 1 H, 7-H), 3.57 (d, J = 10.0 Hz, 1 H, 9-H), 3.22 (b S, 1 H, 1-OH), 2.23-2.04 (band, 2 H, 13-CHz), 2.15 (s, 1 H, 3-H), 1.77-1.59 (band, 2 H, 14-CH2), 1.67 (s, 3 H, 18-CH3), 1.23 (s, 6 H, C(CH3)2), 1.19 (s, 3 H, 19-CH3), 1.07 (s, 3 H, C(CH&), 1.06 (s, 9 H, SiC(CH&Phz), 0.98 (s, 3 H, C(CH&), 0.92 (s, 9 H, SiC(CH3)3(CH3)2), 0.09 (s, 3 H, SiC(CH3)3- (CH3)2), 0.08 (s, 3 H, SiC(CH3)3(CH3)2); I3C NMR (125 MHz, CDC13) 6 137.5, 136.3, 135.7, 135.6, 135.0, 133.9, 133.7, 129.9, 129.4, 129.3, 128.3, 127.9, 127.7, 127.3, 122.6, 107.2, 79.5, 74.5, 74.3, 72.7, 72.6, 71.1, 68.8, 59.5, 47.2, 44.3, 43.6, 29.9, 28.5, 27.8, 26.9, 26.7, 25.9, 20.9, 19.3, 19.1, 19.0, 18.3, -5.4, -5.5; FAB HRMS (NBNCsI) m/e 1001.4170, M cs+ calcd for C52H7607Si~ 1001.4184.

Carbonate 13. A solution of diol 12 (9.67 g, 11.1 "01) in Et20 (150 mL) and hexamethylphosphoramide (HMPA, 50 mL) was treated with KH (4.41 g of a 30% suspension in mineral oil, 33.0 "01, prewashed with dry Et20) and stirred at 25 OC for 20 min, after which phosgene (10 mL of a 20% solution in toluene, 17.5 "01) was added. The reaction mixture was stirred at 25 OC for 0.5 h. After dilution with Et20 (300 mL), the reaction mixture was added to a half saturated solution of tartaric acid. The organic layer was separated, washed with brine (150 mL), dried (NazSOd), concentrated, and purified by flash chromatography (silica, 2% MeOH in CH2C12) to give diol 12 (4.06 g, 42%) and carbonate 13 (4.72 g, 86% based on 58% conversion) as a

Total Synthesis of Tarol. 3

yellow solid Rf = 0.64 (silica, 2% MeOH in CHZC12); IR (thin film) v,, 2932, 2857, 1800, 1472, 1254, lo00 cm-'; 'H NMR (500 MHz, cDc13) 6 7.63-7.58 (band, 5 H, Ar), 7.42-7.28 (band, 10 H, Ar), 5.85(dd,J~10.0,5.0Hz,1H,6-H),5.79(d,J~10.0Hz,1H,5-H), 5.32 (s, 1 H, 2-H), 4.66 (d, J = 11.5 Hz, 1 H, OCHZPh), 4.36 (d, J = 11.5 Hz, 1 H, OCHzPh), 4.09 (A of AB, d, J = 11.5 Hz, 1 H, 20-H), 4.06(BofAB,d,J=11.5Hz,lH,20-H),4.04(d,J=9.0Hz,lH, lO-H), 3.97 (d, J = 9.0 Hz, 1 H, 10-H), 3.73 (d, J = 10.5 Hz, 1 H, 9-H), 3.62 (d, J = 5.0 Hz, 1 H, 7-H), 3.60 (d, J = 10.5 Hz, 1 H, 9-H), 2.42-2.02 (band, 4 H, 13-CHz and 14-CH2), 2.26 (s, 1 H, 3-H), 1.65 (s, 3 H, 18-CH3), 1.25 (s, 3 H, C(CH3)2), 1.24 (s, 3 H, C(CH&), 1.14 (s, 3 H, 19-CH3), 1.09 (s, 3 H, C(CH&), 1.07 (s, 9 H, SiC(CH3)3Ph2), 1.03 (s, 3 H, C(CH3)2), 0.88 (s, 9 H, SiC(CH3)3(CH3)2), 0.05 (s, 3 H, S~C(CH~)~(CH~)Z), 0.03 (s, 3 H, SiC(CH3)3(CH&); NMR (125 MHz, CDC13) 6 154.7, 138.7, 135.7, 135.6, 134.0, 133.7, 133.5, 132.5, 130.5, 129.5, 129.4, 128.0, 127.6, 127.4, 127.3, 125.2, 107.3, 88.2,79.7,78.9, 73.1, 71.2, 71.2, 70.4, 59.4, 46.5, 44.2, 43.4, 29.3, 27.9, 27.0, 26.6, 25.8, 25.2, 19.3, 19.1, -5.6; FAB HRMS (NBNCsI) mle 1027.3950, M 4- cs+ calcd for C53H7408Si~ 1027.3977.

Diol 14. A solution of carbonate 13 (4.72 g, 5.27 m o l ) in THF (20 mL) was treated with n - B W (TBAF, 20 mL of a 1.0 M solution in THF, 20.0 m o l ) and stirred at 25 "C for 14 h. After dilution with EtzO (50 mL), HzO (50 mL) was added. The organic layer was separated, washed with brine (30 mL), dried (NaZSOd), concentrated, and purified by flash chromatography (silica, 80% Et20 in petroleum ether) to give 14 (2.29 g, 80%) as a white solid: Rf = 0.49 (silica, EtzO); IR (thin film) v,, 3438,2980,2879, 1778, 1371, 1061 cm-'; 'H NMR (500 MHz, CDCl3) 6 7.33-7.27 (band, 5 H, Ar), 5.99 (dd, J = 10.0, 3.5 Hz, 1 H, 6-H), 5.89 (d, J = 10.0 Hz, 1 H, 5-H), 5.23 (s, lH ,2 -H) ,4 .72 (d ,J= l l .OHz, IH,OCHzPh),4.42(d,J=ll .OHz, 1 H, OCHzPh), 4.27 (b d, J = 9.0 Hz, 1 H, 10-H), 4.11 (b S, 2 H, 20-CHz), 4.02 (d, J = 9.0 Hz, 1 H, 10-H), 3.69 (dd, J = 9.5, 5.0 Hz, 1 H, 9-H), 3.49 (d, J = 3.5 Hz, 1 H, 7-H), 3.25 (dd, J = 9.5, 9.0 Hz, 1 H, 9-H), 2.77 (dd, J = 9.0, 5.0 Hz, 1 H, 9-OH), 2.40-2.18 (band, 4

1.47 (s, 3 H, C(CH3)2), 1.44 (s, 3 H, C(CH3)2), 1.08 (s, 3 H, 19-C&), 1.05 (s, 3 H, C(CH&), 1.03 (s, 3 H, C(CH3)z); 13C NMR (125 MHz, CDCls) 6 154.6, 136.8, 133.9, 133.5, 132.8, 128.2, 127.8, 127.6, 126.2, 106.7, 88.4, 80.5, 78.8, 74.5, 71.6, 71.2, 67.9, 58.6, 44.3, 44.2, 43.5, 29.2, 27.2, 26.2, 24.5, 23.7, 20.2, 19.1, 18.5; FAB HRMS (NBNCsI) mle 675.1942, M + Cs+ calcd for C31b208 675.1934.

Dialdehyde 15. A solution of diol 14 (0.66 g, 1.22 "01) and 4-methylmorpholine N-oxide (NMO, 0.43 g, 3.67 "01) in CH3CN (40 mL) and CHzClz (20 mL) was treated with 4-A molecular sieves (50 mg) and stirred at 25 "C for 10 min. Tetrapropylammonium permthenate ("PAP, 22 mg, 0.062 "01) was added, and the reaction mixture was stirred at 25 "C for 2 h. After dilution with CHzClz (100 mL), the reaction mixture was filtered through silica gel. The resulting solution was concentrated to give dialdehyde 15 (0.611 g, 92%) as a white solid: Rf = 0.70 (silica, 50% EtOAc in hexanes); IR (thin film) vmax 2919,1793, 1724, 1669,1063 cm-'; 'H NMR (500 MHz, (CD3)2-

H, 13-CHz and 14-CHz), 2.37 (s, 1 H, 349, 1.72 (s, 3 H, 18-CH3),

CO) 6 10.98 (S, 1 H, 10-H), 9.40 (s, 1 H, 9-H), 7.39-7.29 (band, 5 H, Ar), 6.25 (dd, J = 10.0, 4.5 Hz, 1 H, 6-H), 5.84 (d, J = 10.0 Hz, 1 H, 5-H), 5.35 (d, J = 2.5 Hz, 1 H, 2-H), 4.81 (d, J = 11.0 Hz, 1 H, OCHzPh), 4.56 (d, J = 11.0 Hz, 1 H, OCHzPh), 4.28 (d, J = 4.5 Hz, 1 H, 7-H), 3.97 (s, 2 H, 20-CHz). 2.91 (d, J = 2.5 Hz, 1 H, 3-H), 2.65 (m, 1 H, 13-H), 2.52-2.46 (band, 2 H, 13-H and 14-H), 2.23 (m, 1 H, 14-H), 2.16 (s, 3 H, 18-CH3), 1.41 (s, 3 H, Ig-CHs), 1.29 (s, 3 H, C(CH3)z), 1.25 (s, 3 H, C(CH3)2), 1.21 (s, 3 H, C(CH3)z), 1.15 (s, 3 H, C(CH3)z); 13C NMR (125 MHz, (CD3)zCO)) 6 198.9, 192.2, 155.2, 154.2, 139.5, 137.5, 133.3, 129.0, 128.4, 128.4, 109.3, 89.9,80.4,77.0, 72.6, 72.5, 72.2, 53.8, 46.4, 43.4, 32.4, 27.3, 26.8, 25.2, 24.1, 18.8, 18.6, 17.7; FAB HRMS (NBNCsI) mle 671.1630, M + Cs+ calcd for

8-Membered Ring Intermediates 17-20. TiC13.(DME)l.5 (1.53 g, 5.3 "01) and ZdCu couple (1.66 g, 12.7 m o l ) were transferred to a dry flask under argon (glovebag). The mixture was further dried at 140 "C, under vacuum for 10 min. Freshly distilled DME (70 mL) was then added, and the suspension was stirred at reflux for 3.5 h. After the mixture was cooled to 70 "C, a solution of dialdehyde 15 (260 mg, 0.48 "01) in DME (25 mL) was added via syringe pump over 1 h. The reaction mixture was stirred at 70 "C for an additional

C31H3808 671.1621.


0.5 h. After cooling to 25 "C, the reaction mixture was added to a saturated solution of NaHC03 (100 mL), and the resulting mixture was stirred at 25 "C for 2 h. The organic layer was separated, and the aqueous phase was extracted with EtOAc (3 x 75 mL). The combined organic layer was dried (NaZSOd), concentrated, and purified by flash chromatography (silica, 20 -. 40% EtOAc in petroleum ether) to give products 17 (65.3 mg, 25%), 18 (24.6 mg, lo%), 19 (104.4 mg, 40%), and 20 (40.5 mg, 15%).

Diol 17: Rf = 0.41 (silica, 50% EtOAc in hexanes); IR (thin film) Y- 3490,2970,1789,1456,1100 cm-1; 'H NMR (500 MHz, CDc13) 6 7.42-7.31 (band, 5 H, Ar), 5.97 (dd, J = 10.0, 1.5 Hz, 1 H, 5-H), 5.63 (dd, J = 10.0, 1.5 Hz, 1 H, 6-H), 5.46 (d, J = 5.0 Hz, 1 H, 2-H), 4.77 (d, J = 12.0 Hz, 1 H, OCHZPh), 4.49 (d, J = 8.5 Hz, 1 H, 20-H), 4.39 (d, J = 12.0 Hz, 1 H, OCHZPh), 4.29 (b t, J = 6.0 Hz, 1 H, lO-H), 4.24 (dd, J = 6.0, 3.0 Hz, 1 H, 9-H), 3.80 (d, J = 8.5 Hz, 1 H, 20-H), 3.58 (b S, 1 H, 7-H), 2.87 (d, J = 3.0 Hz, 1 H, 9-OH), 2.70 (ddd, J = 15.0, 10.5, 3.0 Hz, 1 H, 14-H), 2.54 (ddd, J = 20, 12.0, 3.0 Hz, 1 H, 13-H), 2.31 (d, J = 5.0 Hz, 1 H, 3-H), 2.18 (d, J = 6.0 Hz, 1 H, lO-OH), 1.93 (ddd, J = 20.0, 10.5, 3.0 Hz, 1 H, 13-H), 1.78 (ddd, J = 15.0, 12.0, 3.0 Hz, 1 H, 14-H), 1.56 (s, 3 H, 18-CH3), 1.42 (S, 3 H, 19-CH3), 1.39 (s, 3 H, 16-CH3), 1.38 (s, 3 H, 17-CH3), 1.16 (s, 3 H, C(CHJ)Z), 1.05 (s, 3 H, C(CH3)z); 13C NMR (125 MHz, CDC13) 6 153.9, 139.4, 137.3, 136.1, 135.6, 128.7, 128.5, 128.3, 122.0, 108.2, 93.5, 82.4, 77.9, 75.7, 74.2, 71.2, 70.4, 69.3, 46.3, 44.3, 40.0, 31.2, 28.9, 27.9, 26.8, 23.6, 21.7, 21.3, 16.0; FAB HRMS (NBNCsI) d e 673.1782, M -I- Cs+ calcd for c31bo8 673.1778.

Alkene 18: Rf = 0.95 (silica, 50% EtOAc in hexanes); IR (thin film) Vmax 2971,1726 cm-'; 'H NMR (500 MHz, CDC13) 6 7.35-7.27 (band, 5 H, Ar), 5.93 (dd, J = 10.5, 2.5 Hz, 1 H, 6-H), 5.86 (b d, J = 12.0 Hz, 1 H, lO-H), 5.56 (dd, J = 10.5, 1.5 Hz, 1 H, 5-H), 5.48 (d, J = 12.0 Hz, 1 H, 9-H), 4.67 (d, J = 7.0 Hz, 1 H, 2-H), 4.65 (d, J = 10.5 Hz, 1 H, OCHZPh), 4.49 (d, J = 8.0 Hz, 1 H, 20-H), 4.44 (d, J = 10.5 Hz, 1 H, OCHzPh), 3.80 (d, J = 8.0 Hz, 1 H, 20-H), 3.68 (b S, 1 H, 7-H), 2.86 (d, J = 7.0 Hz, 1 H, 3-H), 2.35-2.22 (band, 3 H, 13- CHZ and 14-H), 1.96 (m, 1 H, 14-H), 1.54 (s, 6 H, 18-CH3 and 19- CH3), 1.45 (s, 3 H, C(CH&), 1.39 (s, 3 H, C(CH&), 1.37 (s, 3 H, C(CH&), 1.07 (s, 3 H, C(CH3)z); I3C NMR (125 M H z , cW13) 6 149.4, 143.2, 137.6, 137.3, 133.4, 128.7, 128.2, 128.1, 127.7, 125.3, 122.0, 108.4, 90.6, 81.7, 75.7, 72.0, 71.0, 62.3, 47.5, 43.7, 36.3, 29.7, 29.1, 26.8, 26.6, 26.4, 24.4, 16.1, 14.4; FAB HRMS (NBNCsI) mle 639.1736, M + Cs+ calcd for C31H3806 639.1723.

Hemiacetal 19: mp 170-174 "C, 195-200 "C (corresponding aldehyde), from CHzClz-hexanes; Rf = 0.51 (silica, 50% EtOAc in hexanes ); IR (thin film) vm, 3422, 2924, 1797, 1454, 1381, 1216, 1052 cm-l; 'H NMR (500 MHz, CDCl3) 6 7.35-7.30 (band, 5 H, Ar), 6.05 (dd, J = 10.5, 1.0 Hz, 1 H, 5-H), 5.71 (dd, J = 10.5, 1.0 Hz, 1 H, 6-H), 5.57 (d, J = 2.0 Hz, 1 H, 10-H), 5.20 (d, J = 8.5 Hz, 1 H, 2-H), 4.67 (d, J = 11.5 Hz, 1 H, OCHzPh). 4.45 (d, J = 11.5 Hz, 1 H, OCHz- Ph), 4.27 (d, J = 8.5 Hz, 1 H, 20-H), 4.26 (s, 1 H, 9-H), 3.97 (b S, 1 H, 7-H), 3.90 (d, J = 8.5 Hz, 1 H, 20-H), 3.19 (d, J = 8.5 Hz, 1 H, 3-H), 2.42 (d, J = 2.0 Hz, 1 H, 11-H), 2.30-1.85 (band, 4 H, 13-CHz and 14-CHz), 1.51 (s, 3 H, 16-CH3), 1.49 (s, 3 H, I7-CH3), 1.32 (s, 3 H, C(CH~)Z), 1.24 (s, 3 H, C(CH3)2), 1.11 (s, 3 H, 18-CH3), 1.07 (s, 3 H, NMR (125 MHz, CDC13) 6 153.2, 137.2, 134.0, 128.4, 128.0, 127.9, 124.0, 108.0,98.4,89.6,82.5,77.9,74.8,71.6,69.6,62.6, 45.3, 43.9, 42.2, 38.5, 38.1, 30.2, 29.0, 27.1, 26.4, 25.9, 20.3, 15.7; FAB HRMS (NBNCsI) d e 673.1760, M + Cs+ calcd for c31bo8

673.1778. Formate Ester 20: mp 222-224 "C, from CHzClz-hexanes; Rf =

0.59 (silica, 50% EtOAc in hexanes); IR (thin f i ) vmax 2986, 1799, 1728, 1383, 1139, 1058, cm-l; *H NMR (500 MHz, CDCl3) 6 7.89 (s, 1 H, 9-CHO), 7.41-7.32 (band, 5 H, Ar), 6.11 (dd, J = 10.0, 1.5 Hz, 1 H, 5-H), 5.71 (dd, J = 10.0, 1.0 Hz, 1 H, 6-H), 5.54 (s, 1 H, 9-H), 5.16(d,J=9.0Hz,lH,2-H),4.73(d,J=11.5H~,lH,OCH2Ph), 4.52 (d, J = 11.5 Hz, 1 H, OCHzPh), 4.30 (d, J = 8.5 Hz, 1 H, 20-H), 4.09 (b S, 1 H, 7-H), 3.89 (d, J = 8.5 Hz, 1 H, 20-H), 3.42 (d, J = 9.0 Hz, 1 H, 3-H), 2.42-2.22 (band, 4 H, 13-CHz and 14-CHz), 1.52 (s, 3 H, C(CH3)2), 1.50 (s, 3 H, C(CH3)2), 1.37 (s, 3 H, 16-CH3), 1.28 (s, 3 H, 17-CH3), 0.99 (s, 3 H, 18-CH3), 0.89 (s, 3 H, 19-CH3); NMR (125 MHz, CDCl3) 6 211.4, 158.4, 152.3, 136.6, 134.3, 128.6, 128.5, 128.2, 123.6, 108.4, 98.5, 88.1, 82.2,77.6,77.5, 75.5, 71.5,69.5, 52.0,


50.6, 47.0, 43.6, 29.5, 28.9, 27.1, 25.4, 24.6, 24.6, 18.9, 15.4; FAB HRMS (NBNCsI) mle 687.1570, M + Cs+ calcd for C31H3809 687.1570.

Camphanate Esters 29 and 30. A solution of diol 17 (42 mg, 0.077 mmol) and Et3N (0.217 mL, 1.5 "01) in CHzClz (3.5 mL) was treated with a catalytic amount of 4-(dimethylamino)pyridhe (DMAP, 0.5 mg, 0.004 mmol) and (19-(-)-camphanic chloride (84 mg, 0.388 mmol) at 25 "C for 1 h. After dilution with Et20 (10 mL), the reaction was quenched with aqueous NaHC03 (5 mL), and the resulting mixture was stirred at 25 "C for 15 min. The organic layer was separated, and the aqueous layer was extracted with CHzClz (3 x 10 mL). The combined organic layer was washed with brine (10 mL), dried (MgSOd), concentrated, and purified by preparative TLC (silica, 20% EtOAc in benzene) to give camphanic esters 29 and 30 (23 and 25 mg, respectively, 86% combined yield) as white solids.

+117 (c 0.54, CHC13); IR (thin film) vmax 3500, 2970, 2930, 1792, 1744, 1458, 1103, 1058, 914 cm-'; IH NMR (500 MHz, CDC13) 6 7.33-

Ester 29: Rf = 0.26 (silica, 15% EtOAc in benzene);

7.24 (band, 5 H, Ar), 5.94 (dd, J 10.5, 1.5 Hz, 1 H, 6-H), 5.74 (d, J = 5.0 Hz, 1 H, 9-H), 5.63 (dd, J = 10.5, 1.0 Hz, 1 H, 5-H), 5.51 (d, J = 4.5 Hz, 1 H, 2-H), 4.70 (d, J = 12.0 Hz, 1 H, OCHzPh), 4.64 (d, J = 8.5 Hz, 1 H, 20-H), 4.45 (d, J = 12.0 Hz, 1 H, OCHzPh), 4.36 (dd, J = 5.0,3.0 Hz, 1 H, 10-H), 3.78 (d, J = 8.5 Hz, 1 H, 20-H), 3.70 (b S, 1 H, 7-H), 2.72 (ddd, J = 14.0, 10.0, 3.5 Hz, 1 H, 13-H), 2.63- 2.53 (band, 1 H, 14-H), 2.56 (d, J = 3.0 Hz, 10-OH), 2.38 (ddd, J = 14.0, 11.0,4.0 Hz, 1 H, CH(H)CHz camph.), 2.33 (d, J = 4.5 Hz, 1 H, 3-H), 2.12-1.88 (band, 3 H, 13-H and CH(H)CH(H) Camph.), 1.81 (ddd, J = 14.5, 12.0, 2.5 Hz, 1 H, 14-H), 1.71 (ddd, J = 13.5,9.0, 4.0 Hz, 1 H, CH(H)CH2 camph.), 1.62 ( s , 3 H, 18-CH3), 1.57 (s, 3 H, OC(O)C(CHd), 1.41 ( s , 3 H, (O)zC(CH3)z), 1.40 (s, 3 H, (0)zC(CH3Mr 1.12 (s, 6 H, C(CH& camph.), 1.10 (s, 3 H, 16-CH3), 1.06 (s, 3 H,

166.2, 153.8, 143.6, 137.1, 135.5, 132.7, 128.7, 128.5, 128.3, 122.1, 108.4, 93.4, 90.8, 82.5, 78.0, 74.9, 74.0, 74.0, 71.2, 70.9, 54.8, 54.3, 47.2, 44.8, 39.8, 31.5, 30.9, 29.0, 28.8, 28.0, 26.9, 23.6, 21.7, 21.7, 16.8, 16.8, 16.2,9.6; FAB HRMS (NBNCsI) mle 853.2545, M + Cs+ calcd for C~IHSZOII 853.2564. Ester 30. colorless crystals, mp 240 "C, dec, from CH2Cl~-hexanes;

Rj = 0.21 (silica, 15% EtOAc in benzene); [aIz2~ 133 (c 0.49, CHC13); IR (thin film) vmax 3498,2976,1793,1742,1457,1378,1265,

17-CH3). 1.00 (s, 3 H, 19-CH3); NMR (125 MHz, CDC13) 6 178.0,

1059 cm-'; 'H NMR (500 MHz, CDC13) 6 7.35-7.30 (band, 5 H, Ar), 5.96 (dd, J = 10.0, 1.5 Hz, 1 H, 6-H), 5.85 (d, J = 5.5 Hz, 1 H, 9-H), 5.63 (dd, J = 10.0, 1.0 Hz, 1 H, 5-H), 5.53 (d, J = 4.5 Hz, 1 H, 2-H), 4.71 (d, J = 12.0 Hz, 1 H, OCHZPh), 4.48 (d, J = 8.0 Hz, 1 H, 20-H), 4.46 (d, J = 12.0 Hz, 1 H, OCH2Ph). 4.33 (dd, J = 5.5, 3.0 Hz, 1 H, lO-H), 3.79 (d, J = 8.0 Hz, 1 H, 20-H), 3.74 (b S, 1 H, 7-H), 2.77 (ddd, J = 14.0, 10.5, 3.0 Hz, 1 H, 13-H), 2.68-2.55 (band, 1 H, 14- H), 2.58 (d, J = 3.0 Hz, 10-OH), 2.48 (ddd, J = 13.5, 10.5, 4.0 Hz, 1 H, CH(H)CHz camph.), 2.36 (d, J = 4.5 Hz, 1 H, 3-H), 2.15-1.92 (band, 3 H, 13-H and CH(H)CH(H) camph.), 1.90-1.65 (band, 2 H, 14-H and CH(H)CHz camph.), 1.72 (s, 3 H, 18-CH3), 1.57 (s, 3 H, OC(O)C(CH3)), 1.44 (s, 3 H, (O)ZC(CH~)Z), 1.42 (s, 3 H, (O)zC(CH3)z), 1.14 (s, 6 H, C(CH3)z cmph.), 1.1 1 (s, 3 H, 16-CH3), 1.08 (s, 3 H, 17-CHs), 0.98 (s, 3 H, 19-CH3); 13C NMR (125 MHz, CDCl3) 6 177.8, 166.2, 153.8, 143.6, 137.1, 135.4, 132.8, 128.6, 128.3, 128.2, 122.3, 108.3, 93.4, 91.5, 82.4, 77.9, 75.2, 74.1, 73.6, 71.2, 71.1, 54.8, 54.4, 47.1, 44.7, 39.7, 31.4, 31.1, 29.0, 28.8, 27.8, 26.9, 23.5, 21.7, 21.5, 17.1, 16.8, 16.1, 9.6; FAB HRMS (NBNCsI) mle 853.2543, M + Cs+ calcd for C41HSZOll 853.2564.

Diol (+)-17. A solution of ester 29 (23 mg, 0.032 "01) in MeOH (3.5 mL) was treated with KzCO3 (3.0 mg, 0.22 mmol) and stirred at 25 "C for 0.5 h. After dilution with CHzClz (15 mL), the reaction was quenched with aqueous m C 1 (10 mL). The organic layer was separated, and the aqueous layer was extracted with CHzCl2 (3 x 10 mL). The combined organic layer was dried (MgSOd), concentrated, and purified by flash chromatography (silica, 25 - 50% EtOAc in petroleum ether) to give diol (+)-17 (15.5 mg, 90%) as a white solid: [alzZ~ +187 (c 0.5, CHC13).

Acknowledgment. We thank Drs. Dee H. Huang, Raj Chadha, and Gary Siuzdak for the NMR, X-ray crystallographic analyses, and mass spectroscopy, respectively. This work was supported by the NIH, The Scripps Research Institute, fellowships from RhBne-Poulenc Rorer (P.G.N.), The Office of Naval Research (R.K.G.), Glaxo, Inc. (C.F.C.), Mr. Richard Staley (C.F.C.), NSERC (J.R.), and grants from Merck Sharp and Dohme, Pfizer, Inc., Schering Plough, and the ALSAM Foundation.

JA942194M

J. Am. Chem. SOC. 1995,117, 653-659 653

Total Synthesis of Taxol. 4. The Final Stages and Completion of the Synthesis

K. C. Nicolaou,* H. Ueno, J.-J. Liu, P. G. Nantermet, Z. Yang, J. Renaud, K. Paulvannan, and R. Chadha

Contribution from the Department of Chemistry, The Scripps Research Institute, 10666 North Torrey Pines Road, La Jolla, Califomia 92037, and Department of Chemistry and Biochemistry, University of Califomia, San Diego, 9500 Gilman Drive, La Jolla, Califomia 92093

Received July 7, I994@

Abstract: The total synthesis of (-)-Tax01 has been achieved. Functional group manipulation of diol 2 provided the ABC ring system with the correct C9-keto, C10-acetyloxy functionality. Careful optimization allowed the oxidation of the C5-C6 alkene in 4 at C5 via a hydroboration reaction. Functional group manipulation of this product, 29, provided, through two routes, the oxetane D ring as 36. Following the method developed by degradative studies provided the natural enantiomer of Taxol (1).

Introduction With a route to optically active diol 2 secured,' a total

synthesis of Taxol (1, Figure 1) looked quite feasible. However, several issues still remained to be addressed before the final goal could be reached. Amongst them were the functional group adjustments at C9 and C10, the installment of an oxygen at the C5 position, oxetane construction, oxygenation at C13, and side- chain attachment. Below we describe solutions to these problems and, thus, the total synthesis of Taxol (1).

Final Stages of the Total Synthesis a. Selective Functionalization at C9 and C10. Continuing

the sequence from diol 2l (Scheme l), our strategy toward Taxol (1) next called for the adjustment of the functional groups at C9 and C10 to their final form. Arriving at the desired C9- keto, C1 0-acetate functionality required differentiating between the two hydroxyl groups of diol 2. Fortunately, the higher reactivity of the allylic C10 hydroxyl group provided high selectivity in the desired direction when compound 2 was exposed to 1.5 equiv of AczO and DMAP in methylene chloride. The resulting monoacetate 3 (Scheme 1, 95% yield) was oxidized cleanly with TPAP-NM02 to afford, in 93% yield, the desired 9-keto, 10-acetate 4. The absence of a conjugated enone in 4 (as observed in the 13C NMR) and the detection of long-range coupling (J < 1.5 Hz) between the C10 proton (6 5.65, CDCl3, 500 MHz) and the C12 methyl group (6 1.68) of monoacetate 3 ('H NMR decoupling experiments) suggested the indicated regiochemistry of these intermediates. This assignment was c o n f i i e d by X-ray crystallographic analysis of benzoate 5, obtained by PCC oxidation3 of compound 4 (see Scheme 1, and ORTEP drawing in Figure 2). This regioselectivity is in contrast to that observed in the exclusive formation of the 9-camphonate ester described in the preceding paper,' in which a speculative explanation for this discrepancy is proposed. It was now time to address the introduction of an alcohol at c 5 .

* Address correspondence to this author at The Scripps Research Institute

@ Abstract published in Advance ACS Abstracts, December 15, 1994. (1) Nicolaou, K. C.; Yang, Z.; Liu, J.-J.; Nantermet, P. G.; Claibome,

C. F.; Renaud, J.; Guy, R. K.; Shibayama, K. J. Am. Chem. SOC. 1995, 117, 645.

(2) Griffith, W. P.; Ley, S. V. Aldrichimica Acta 1990, 23 (l), 13. (3) Angyal, S. J.; James, K. Carbohydr. Res. 1970, 12, 147.

or the University of California.

0002-786319511517-0653$09.00/0

1 : Taxol


Scheme 1. Functionalization of the C9 and C10 Positions of the Taxoid Frameworka

3

OI

5 4

"Reagents and conditions: (a) 1.5 equiv of AczO, 1.5 equiv of 4-(dimethylamino)pyridine (DMAP), CH*C12,25 "C, 2 h, 95%; (b) 0.1 equiv of tetrapropylammonium perruthenate (TPAP), 3.0 equiv of 4-methylmorpholine N-oxide (NMO), CH3CN, 25 "C, 2 h, 93%; (c) 30 equiv of pyridinium chlorochromate (PCC), 50 equiv of NaOAc, Celite, benzene, reflux, 1 h, 50%. Bn = CH2Ph.

b. Early Attempts to Hydroborate the C5-C6 Double Bond. Our experience with the hydroboration of ring C systems4s5 led us to adopt similar tactics for the real system. Potential differentiation of the two faces of the double bond in

(4)Nicolaou, K. C.; Liu, J.-J.; Yang, Z.; Ueno, H.; Sorensen, E. J.; Claibome, C. F.; Guy, R. K.; Hwang, C.-K.; Nakada, M.; Nantermet, P. G. J . Am. Chem. SOC. 1995, 117, 634.


654 J. Am. Chem. Soc., Vol. 117, No. 2, 1995 Nicolaou et al.

0

&I(-- p 0

0

5

& Figure 2. ORTEP diagram for benzoate 5.

ring C of intermediate 4 by an incoming reagent was not obvious by inspection of molecular models. It was, therefore, decided to initially explore the utilization of the C20 hydroxyl group as a handle to direct hydroboration from the p face of the molecule and at the C5 position as in the simple C ring case. To this end the acetonide group was removed from 4 under acid conditions to afford diol 6 (Scheme 2, 88% yield based on 53% conversion). Attempts to hydroborate6 6 under a variety of conditions failed, presumably due to the formation of a stable 5-membered ring borane complex involving the two hydroxyl groups that is both unable to reach the internal alkene and prohibitively bulky for external hydroboration.

We next considered using the 4-acetoxy, 20-hydroxy compound 7 (Scheme 2) as a possible substrate for the desired hydroboration reaction, but unfortunately, all attempts to prepare this intermediate met with failure. Under the various conditions used, the acetate group migrated facilely from the C-4 to the C20 a l ~ o h o l , ~ leading to either the primary acetate 8 or the starting diol 6 rather than the desired tertiary acetate 7. It became clear that the acetate at C4 would have to be installed after oxetane formation or in an intermediate in which the C20 hydroxy group would remain blocked until oxetane ring closure. We, therefore, turned to the C4 acetate, C20 mesylate 10, prepared from diol 6 by sequential mesylation (94% yield) and acetylation (90% yield) as detailed in Scheme 2. Hydroboration of this compound (10) with borane in THF, however, resulted not only in hydroxylation at C5 but also in concomitant reductive cleavage of the C4 acetate to afford compound 11 as the major product (67% yield) whose stereochemistry at both the C4 and C5 centers was left unassigned. Similar observations have previously been reported with simple allylic derivatives8

In order to lower the propensity of the C4 substituent toward reductive elimination, the 4-benzyloxy compounds 17 and 19 (Scheme 3) were chosen as the next potential candidates for hydroboration. Exposure to KH and benzyl bromideg failed to convert mesylate 9 to the desired benzyl ether 19, leading instead to the formation of epoxide 12 (Scheme 3). The same

( 5 ) Nicolaou, K. C.; Liu, J. J.; Hwang, C.-K.; Dai, W.-M.; Guy, R. K.

(6) Smith, K.; Pelter, A. In Comprehensive Organic Synthesis; Trost, B.

(7) Samaranavake. G.: Mah. N. F.: Jitranesri. C.: Kineston. D. G. I. J .

J . Chem. SOC., Chem. Commun. 1992, 1118.

M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 8, p 703. - . - . . - .

Org.'Chem. 1991, 56, 5114. (8) Brown, H. C.; Knights, E. F. J . Am. Chem. SOC. 1968, 90, 4439.

Pasto. D. J.: Hickman. J. 7. Am. Chem. SOC. 1968. 90, 4445. (9) Kanai, K.; Sakamoto, I.; Ogawa, S.; Suami, T. Bull. Chem. SOC. Jpn.

1987, 60, 1529.

Scheme 2. Hydroboration Studies 1"

t /

0

.i 0

8

a 0

11

a Reagents and conditions: (a) 3.0 equiv of p-toluenesulfonic acid, MeOH, 25 "C, 48 h, 88% based on 53% conversion; (b) 5.0 equiv of Dess-Martin periodinane, CHZC12,25 "C, 3 h, then 20 equiv of AczO, 25 equiv of 4-(dimethylamino)pyridine (DMAP), CH2C12, 25 "C, 3 h, then 2.0 equiv of n - B W & , THF, 25 "C, 1 h, 66% from 6; (c) 1.2 equiv of MsCl, 3.0 equiv of DMAP, CH2C12, 25 "C, 1 h, 94%; (d) 10 equiv of AczO, 15 equiv of DMAP, CH2C12, 25 "C, 5 h, 90%; (e) 10 equiv of BHs-THF, THF, 25 "C, 2 h, then excess H202, saturated aqueous NaHC03, 0.5 h, 67%. Bn = CH2Ph, Ms = S02CH3.

conditions, however, smoothly converted the corresponding acetate 8 (obtained conveniently by monoacetylation of diol 6) to the C4 benzyloxy derivative 13 (76% yield). Preparation of 17 from 13 required complete deacetylation under basic hydrolysis conditions, followed by selective silylation at C20 (triethylsilyl group), acetylation at C10, and desilylation of the C20 hydroxyl group (52% overall yield). Again, hydroboration of 17 was disappointing: the major product was the C4 deoxy compound 18. Hydroboration of the C4-benzyloxy, C20- mesylate 19, obtained through mesylation of 17, also failed: exhibiting sluggish reactivity and undesirable products.

The unwillingness of the C4-benzyloxy mesylate 19 to enter facilely into hydroboration reactions prompted us to attempt this reaction on the sterically less demanding C4-hydroxy, C20- mesylate 9 (Scheme 4). Thus, exposure of 9 to excess borane in THF followed by oxidative workup resulted in the formation of diol 20 as the major product and in 23% yield. The indicated a stereochemistry of the newly introduced C5 hydroxyl group was based on 'H NMR data and was confirmed by chemical correlation as outlined in Scheme 4. Thus, treatment of 20 with Et3N, DMAP, and AczO resulted in acetylation and intramolecular displacement of the mesylate group to give epoxide 21 (75% yield), which was debenzylated by hydrogenolysis, leading to compound 22 (95% yield). The latter compound was identical with a sample prepared from 10-deacetylbaccatin 111 (23) through intermediate 2 4 l 0 by the following short sequence: (a) exposure of 24 to Meerwein's reagent7 leading to 25 (59%) and 26 (19%); (b) mesylation of the minor product (26) to give


Scheme 3. Hydroboration Studies 2a

J. Am. Chem. SOC., Vol. 11 7, No. 2, 1995 655

0 8

0

b C 8 : R = A c S : R = H

0

0 12

18 18

Reagents and conditions: (a) 1.3 equiv of KH, 5.0 equiv of PhCHZBr, 0.05 equiv of n-BWI, EtzO, HMPA, 25 "C, 15 min, 79%; (b) 1.2 equiv of Ac20, 1.5 equiv of 4-(dimethylamino)pyridine (DMAP), CHzC12, 25 "C, 20 min, 95%; (c) 5.0 equiv of KH, 15 equiv of PhCHzBr, 0.05 equiv of n-BWI, EtzO, HMPA, 25 "C, 4 h, 76%; (d) 10 equiv of DBU, MeOH, CH2Cl2, 25 "C, 3 h, 98%; (e) 1.2 equiv of Et3SiC1, 1.5 equiv of DMAP, DMF, 25 "C, 1 h; (f) 6.0 equiv of AczO, 6.0 equiv of DMAP, CH2C12, 25 "C, 0.5 h; (g) HF-pyridine, THF, 25 "C, 1 h, 52% from 14; (h) 5.0 equiv of BH3*THF, THF, 0 "C, 0.5 h, 25 "C, 4 h, then excess H202, aqueous NaHCO3, 0.5 h; (i) 3.0 equiv of MsCl, 5.0 equiv of DMAP, CHzC11, 25 "C, 1 h, 94%. DBU = 1,s- diazabicyclo[5.4.0]undec-7-ene, Bn = CHZPh, Ms = S02CH3, TES = SiEt3.

27; (c) treatment with KH in THF to form the epoxide ring; and (d) exposure to HFpyridine to remove the silyl group (81% overall yield from 26) to afford 22. This chemical correlation firmly established the regio- and stereoselectivity of the hydroboration reaction of 9. A better candidate was, however, needed to serve as a precursor to the desired oxetane system.

c. Final Hydroboration Route to a C5a-Hydroxy Inter- mediate. Having realized that the C5a-hydroxy compounds might be a more accessible series of precursors to the oxetane system, we decided at this point to examine the hydroboration of acetonide 4 (Scheme 5) . Inspection of molecular models

~~~ ~

(10) Nicolaou, K. C.; Nantermet, P. G.; Ueno, H.; Guy, R. K.; Couladouros, E. A.; Sorensen, R. J. J . Am. Chem. SOC. 1995, 11 7, 624.

Scheme 4. Chemical Corrolation Studiesu

OMS

0 0 20 24

0 21

ci I f

22 28

Reagents and conditions: (a) 10 equiv of BH3*THF, THF, 25 "C, 1.5 h, then excess H202, aqueous NaHCOs, 0.5 h, 23%; (b) 30 equiv of Ac20, excess EtsN, 0.05 equiv of 4-(dimethylamino)pyridine

1 h, 95%; (d) 2.1 equiv of EtsOBF4, CH2C12,O "C, 1 h, 59% of 25 plus 19% of 2 6 (e) 10 equiv of MsC1,20 equiv of Et3N, 2.0 equiv of DMAP, CH2C12, 25 "C, 0.5 h, 90%; (f) excess KH, THF, 25 "C, 0.5 h, 92%; (g) HFTyridine, THF, 25 "C, 1 h, 98%. Bn = CHZPh, Ms = S02CH3, TES = SiEt3.

indicated that the a face was somewhat less hindered than the p face, although the absence of a free hydroxy handle in the vicinity of the C5 position raised questions regarding the regiochemical outcome of the intended hydroboration. In the event, exposure of 4 to excess borane in THF followed by the usual oxidative workup furnished a mixture of the C5a-alcohol 29 (42% yield based on 83% conversion) and its C6 regioisomer (22% yield based on 83% conversion) (Scheme 5 ) . While the stereochemistry of the C6 regioisomer remains unassigned, that of the C5 a-isomer was confirmed by conversion to intermediate 32, previously obtained from 10-deacetylbaccatin 111 (23) via desilylation of intermediate 25 (Schemes 4 and 5) . Thus, acid- catalyzed removal of the acetonide group from 29 afforded triol 30 (80% yield based on 88% conversion). Under carefully controlled conditions, acetylation of the primary hydroxyl group

(DMAP), CHzC12,25 "C, 12 h, 75%; (c) H2, Pd(OH)dC, EtOH, 25 "C,

656 J. Am. Chem. SOC., Vol. 117, No. 2, I995

Scheme 5. Hydroboration Studies 3. Successful Hydroboration of the C5-C6 Double Bond"

Nicolaou et al.

4 20

bl

0 0 3 2 : R = H 3 0 : R = H

e r 25 : R = TES ' L 3 1 : R = A c

a Reagents and conditions: (a) 10.0 equiv of BH3*THF, THF, 0 "C, 3 h, then excess HzOz, saturated aqueous NaHC03, 25 "C, 1 h, 42% plus 22% of C6-OH regioisomer, based on 83% conversion; (b) MeOH: concd HC1 (2:l) 25 "C, 5 h, 80% based on 88% conversion; (c) 1.25 equiv of AczO, 5.0 equiv of pyridine, 0.05 equiv of 4-(dimethylamino)pyridine (DMAP), CHzC12,25 "C, 0.5 h, 95%; (d) Hz, 10% Pd(OH)2/ C, EtOAc, 25 OC, 0.5 h, 97%; (e) HFpyridine, THF, 25 "C, 2 h, 96%. Bn = CHZPh, TES = SiEt3.

in 30 proceeded selectively to afford monoacetate 31 (95% yield). Finally, hydrogenolysis of the benzyl group from 31 furnished alcohol 32, identical to material obtained from desilylation (HFpyridine, THF, 96% yield) of 25 in all respects including absolute stereochemistry (synthetic: [aIz2~ -85.2 (c 0.115, CHC13); degradative: -85.6 (c 0.43, CHCl3). With the synthesis of 32, the road to Taxol (1) was now open.

d. Installation of the Oxetane Ring and Completion of the Total Synthesis. The last remaining challenge in the total synthesis of Taxol (l), namely the construction of the oxetane ring, was accomplished following two routes which were based on work previously performed by Potier's group" on a taxoid skeleton and by Danishefsky's group12 on a C ring model system. Both sequences utilized intermediate 25 (available from total synthesis by silylation of 32 with TESC1-pyridine (85% yield) or from degradation of 10-deacetylbaccatin 1II)'O and proceeded as outlined below.

In the first approach, which was modeled after Danishefsky's work,12 the C20-acetate group was selectively removed from 25 under mildly basic conditions (KzC03-MeOH) to afford triol 33 in 97% yield (Scheme 6). The newly generated primary alcohol was then selectively silylated with TMSCl in the presence of base and exposed to triflic anhydride and base to afford the triflate silyl ether 35 via intermediate 34. The latter compound converted to oxetane 36 when exposed to mildly acidic conditions (silica gel, CH2C12) through sequential desilylation of the C20-hydroxyl group followed by internal S N ~ displacement of the triflate. The resulting hydroxy oxetane 36 was acetylated to afford the targeted oxetane system 24 in 40% overall yield from triol 33.

The second route (Scheme 6), modeled after Potier's studies," featured selective mesylation of diol 25 (73% yield) to furnish hydroxy mesylate 37 which was selectively deacetylated at C20

47, 9823.

J. J . Org. Chem. 1992, 57, 3274.

(11) Ettouati, L.; Ahond, A,; Poupat, C.; Potier, P. Tetrahedron 1991,

(12) Magee, T. V.; Bornmann, W. G.; Isaccs, R. C. A.; Danishefsky, S.

Scheme 6. Construction of the Oxetane Ring"

, 6 3 2 : R e H 25: R = TES

33

w s O M s '"OH W : O R "'OH

'Vo OAC 'k6 OTMS 0 0

37

hl 3 4 : R = H

dG 35 : R = Tf

0 0 3 6 : R r H f L 24 : R = AC

38

Reagents and conditions: (a) 25 equiv of EtsSiCl, pyridine, 25 "C, 12 h, 85%; (b) 10 equiv of KzC03, MeOH-HZ0,O "C, 15 min, 97%; (c) 10 equiv of Me3SiC1, 30 equiv of pyridine, CHZClz, 0 "C, 15 min; (d) 15 equiv of TfzO, 30 equiv of i-PrzNEt, CHzClz, 0 "C, 0.5 h; (e) 0.05 equiv of camphorsulfonic acid (CSA), MeOH, 25 "C, 15 min, then silica gel, CHZClz, 25 "C, 1 h, 40% from 33; (f) 8.0 equiv of AczO, 15 equiv of 4-(dimethylamino)pyridine (DMAP), CHzC12, 25 "C, 4 h, 94%; (g) 10 equiv of MsCl, 20 equiv of DMAP, CHZCL, 25 "C, 1 h, 73%; (h) 10 equiv of KzCO3, MeOH, HzO, 0 "C, 15 min; (i) 12 equiv of n-BWOAc, butanone, reflux, 5 h, 72% from 37. TES = SiEt3, TMS = SiMe3, Tf = SOzCF3, Ms = SOzCH3.

as before, leading to diol 38 in quantitative yield. The latter compound was heated in refluxing butanone to afford hydroxy oxetane 36 (72% yield), which was converted to acetate 24 as described above.

The final drive toward Taxol (1) from intermediate 24 was carried out as outlined in Scheme 7 and proceeded along the lines already described in paper 1 of this series.1° Synthetic Taxol (1) was identical with an authentic sample by all usual criteria, including Rf (TLC), fR (HPLC), [a]% IR, 'H and 13C NMR, HFMS, and biological assay (microtubule stabilization and cytotoxicity against a panel of eight cell lines).

Conclusion

This and the accompanying paper^',^,'^ in this series describe the studies in these laboratories which eventually culminated in the total synthesis of Taxol (1). This synthetically challenging molecule with its 11 stereocenters, four skeletal rings, and unusual steric congestion, particularly around its 8-membered ring, provided several serious obstacles and opportunities to create new strategies and to expand the scope and generality of known synthetic methods. New knowledge was gained on issues of regio-, stereo-, and chemoselectivity . Of particular interest were the applications of the Diels-Alder reaction to form rings A and C, the Shapiro and McMuny couplings to


Scheme 7. Completion of the Total Synthesis"

J. Am. Chem. SOC., Val. 117, No. 2, 1995 657

6 24 30

bl

41

a dl 40

43 :R=TES 42 1 : R = H, Taxol e

Reagents and conditions: (a) 5.0 equiv of PhLi, THF, -78 "C, 10 min, then 10 equiv of AczO, 5.0 equiv of 4-(dimethylamino)pyridine (DMAP), CH2C12, 2.5 h, 80%; (b) 30 equiv of pyridinium chlorochromate (PCC), 30 equiv of NaOAc, Celite, benzene reflux, 1 h, 75%; (c) excess N&&, MeOH, 25 "C, 3 h, 94% based on 88% conversion; (d) 3.0 equiv of NaN(SiMes)z, 3.5 equiv of B-lactam 42, THF, 0 "C, 0.5 h, 86% based on 89% conversion; (e) HF-pyridine, THF, 25 "C, 1.25 h,

construct ring B, and the regioselective opening of carbonates with organometallic reagents to form hydroxy esters.

The resulting convergent route to Taxol (1) was utilized for the construction of several new designed taxoids. A number of these compounds obtained by total synthesis13 or semisyn- t h e ~ i s ' ~ J ~ have demonstrated interesting properties and shed light on the structural requirements for Taxol's biological activity. Furthermore, water-soluble taxoids that arose from these studies are providing useful information regarding the conformation of Taxol in waterI6 and the design of prod rug^^^*^^ of this newly established chemotherapeutic agent.


the first paper in this series.1° Experimental techniques and data for compounds 5,6,8-22,27, and 28 may be found in the supplementary material.

Acetate 3. A solution of diol 2 (138 mg, 0.0256 mmol) and 4-(dimethy1amino)pyridine (DMAP, 47.0 mg, 0.0383 mmol) in CHz- Clz (10 mL) was treated with AczO (0.04 mL, 0.0383 m o l ) and stirred at 25 "C for 2 h. After dilution with Et20 (50 mL), the reaction was quenched with aqueous NH&1(50 mL), and the resulting mixture was stirred at 25 "C for 15 min. The organic layer was separated, and the aqueous layer was extracted with Et20 (3 x 20 mL). The combined

(13) Nicolaou, K. C.; Claibome, C. F.; Nantermet, P. G.; Couladouros, E. A.; Sorensen, E. J. J. Am. Chem. Soc. 1994, 116, 1591.

(14) Nicolaou, K. C.; Couladouros, E. A.; Nantermet, P. G.; Renaud, J.; Guy, R. K.; Wrasidlo, Angew. Chem., Znt. Ed. Engl. 1994,33, 1581.

(15) Nicolaou, K. C.; Renaud, J.; Guy, R. K.; Nantermet, P. G.; Couladouros, E. A.; Wrasidlo, W. Submitted.

(16) Gomez Paloma, L.; Guy, R. K.; Nicolaou, K. C. Chem. B i d 1994, I, 107.

(17) Nicolaou, K. C.; Guy, R. K.; Pitsinos, E. N.; Wrasidlo, W. Angew. Chem., Znt. Ed. Engl. 1994, 33, 1583.

80%. TES = SiEt3, BZ = COPh.

organic layer was dried (NazSOd), concentrated, and purified by flash chromatography (silica, 30% Et20 in petroleum ether) to give 3 (141 mg, 95%) as a white foam: Rf = 0.55 (silica, 60% Et20 in petroleum ether); [ a I Z Z D +181 (c 0.48, CHC13); IR (thin film) vmPx 3406, 2385, 1792, 1733, 1654, 1457, 1234, 1018 cm-I; IH NMR (500 MHz, CDC13) 6 7.35-7.27 (band, 5 H, Ar), 5.92 (dd, J = 10.0, 2.0 Hz, 1 H, 6-H), 5.62 (d, J = 5.0 Hz, 1 H, 10-H), 5.57 (dd, J = 10.0, 1.5 Hz, 1 H, 5-H), 5.49 (d, J = 4.5 Hz, 1 H, 2-H), 4.69 (d, J = 12.0 Hz, 1 H, OCH~h),4.46(d,J=8.0H~,1H,20-H),4.44(d,J=12.0Hz,lH, OCHzPh), 4.28 (b d, J = 5.0Hz, 1 H, 9-H), 3.77 (d, J = 8.0 Hz, 1 H, 20-H), 3.71 (b S, 1 H, 7-H), 2.72 (ddd, J = 14.5, 10.0, 3.5 Hz, 1 H, 13-H), 2.58 (ddd, J = 20.0, 11.5, 3.0 Hz, 1 H, 14-H), 2.42 (b S, 1 H, 9-OH), 2.36 (d, J = 4.5 Hz, 1 H, 3-H), 2.09 (s, 3 H, OAC), 2.01 (ddd, J = 20.0, 10.0, 3.5 Hz, 1 H, 14-H), 1.80 (ddd, J = 14.5, 11.5, 3.0 Hz, 1 H, 13-H), 1.68 (s, 3 H, 18-CH3), 1.53 (s, 3 H, 19-CH3), 1.42 (s, 3 H, C(CH3)2), 1.40 (s, 3 H, C(CH3)z). 1.13 (s, 3 H, 16-CH3), 1.05 (s, 3 H, 17-CH3); 13C NMR (125 MHz, C m h ) 6 169.2, 153.9, 142.5, 137.4, 135.4, 133.1, 128.5, 128.2, 122.5, 108.2, 93.3, 82.5, 78.1, 75.3, 74.1, 72.5, 71.2, 47.0, 44.7, 39.9, 31.3, 28.9, 27.8, 26.8, 23.6, 21.7, 21.2, 16.2; FAB HRMS (NBA/NaI) d e 605.2720, M + Na+ calcd for

Ketone 4. A solution of alcohol 3 (141 mg, 0.242 m o l ) in CH3- CN (10 mL) was treated with tetrapropylammonium perruthenate (PAP, 85.0 mg, 0.0242 mmol) and 4-methylmorpholine N-oxide (NMO, 85.0 mg, 0.726 mmol) and stirred at 25 "C for 2 h. After dilution with CHzClz (30 mL), the reaction mixture was filtered through silica gel. The resulting solution was concentrated to give 4 (13 1 mg, 93%) as a white solid: Rf = 0.62 (silica, 30% EtOAc in petroleum ether); [aIz2D +14 (c 0.52, CHC13); IR (thin film) vmax 2925, 1807, 1746, 1717, 1458, 1374, 1230 cm-'; lH NMR (500 MHz, CDC13) 6

c33&zog 605.2727.

7.35-7.27 (band, 5 H, Ar), 6.47 (s, 1 H, 10-H), 5.90 (dd, J = 10.5, 2.0 Hz, 1 H, 6-H), 5.67 (dd, J = 10.5, 1.5 Hz, 1 H, 5-H), 4.66 (d, J = 11.5 Hz, 1 H, OCHSh), 4.57 (d, J = 11.5 Hz, 1 H, OCHZPh), 4.40 (d,

2-H), 3.78 (d, J = 8.5 Hz, 1 H, 20-H), 2.78 (d, J = 5.5 Hz, 1 H, 3-H), J=8.5Hz,lH,20-H),4.32(m,lH,7-H),4.18(d,J=5.5Hz,lH,

2.78-2.70 (band, 2 H, 13-H and 14-H), 2.23 (m, 1 H, 14-H), 2.22 (s, 3 H, OAc), 1.93 (m, 1 H, 13-H), 1.90 (s, 3 H, 18-CH3), 1.44 (s, 3 H, C(CH3)2), 1.43 (s, 3 H, C(CH3)z), 1.26 (s, 3 H, 19-CH3), 1.27 (s, 3 H, 16-CH3), 1.15 (s, 3 H, 17-CH3); 13C NMR (125 MHz, CDC13) 6 203.2, 169.3, 152.6, 143.3, 137.1, 134.8, 128.9, 128.4, 128.3, 127.9, 123.9, 108.9, 96.5, 81.8, 80.2, 76.5, 76.2, 71.7, 71.1, 58.9, 47.5, 40.5, 29.9, 28.7, 26.8, 26.1, 23.2, 21.8, 20.8, 18.9, 12.8; FAB HRMS (NBMCsI) d e 713.1720, M + Cs+ calcd for C33&09 713.1727.

Acetate 25. Conversion of Oxetane 24 to Acetates 25 and 26. A solution of oxetane 24 (14.0 mg, 0.023 mmol) in CHzClz (2.5 mL) at 0 "C was treated with Et30BF4 (Meerwein's reagent, 1 .O M in CHI- Clz, 0.048 mL, 0.048 mmol) and stirred at 0 "C for 1 h. The reaction mixture was diluted with Et20 (IO mL), washed with aqueous m C 1 (5 mL) and brine (5 mL), dried (MgSOd), concentrated, and purified by preparative TLC (silica, 50% EtOAc in petroleum ether) to give acetate 25 (8.5 mg, 59%) and acetate 26 (2.8 mg, 19%), both as colorless fiis.

Acetate 25: Rj = 0.28 (silica, 50% EtOAc in petroleum ether); [ a I Z Z D

1461, 1373, 1232, 1120, 1014 cm-l; 'H NMR (500 MHz, CDC13) 6 -74 (C 0.75, CHC13); IR (thin film) vman 3483,2943,2884,1802,1743,

6.53 (s, 1 H, lO-H), 4.46 (d, J = 12.0 Hz, 1 H, 20-H), 4.40 (d, J = 12.0 Hz, 1 H, 20-H), 4.39 (dd, J = 11.0, 3.5 Hz, 1 H, 7-H), 4.23 (d, J=5.0Hz,lH,2-H),3.71(t,J=3.5H~,lH,5-H),3.39(d,J=5.0 Hz, 1 H, 3-H), 3.16 (s, 1 H, 4-OH), 2.82 (ddd, J = 14.0, 10.0, 3.0 Hz, 1 H, 13-H), 2.79 (s, 1 H, SOH), 2.71 (m, 1 H, 14-H), 2.25-2.05 (band,

(m, 1 H, 14-H), 1.75 (m, 1 H, 6-H), 1.20 (s, 3 H, 16-CH3), 1.18 (s, 3 H, 17-CH3), 1.14 (s, 3 H, 0.63 (t, J = 7.5 Hz, 9 H, Si(CHzCH&), 0.58-0.45 (band, 6 H, Si(CHzCH3)3); I3C NMR (125 MHz, CDC13) 6 202.8, 170.6, 169.2, 153.2, 144.7, 130.1, 93.4, 81.5, 76.0, 74.8, 70.4, 68.5, 64.8, 61.3, 43.0, 40.4, 33.8, 30.2, 26.5, 23.0, 21.1, 20.9, 20.8, 18.9, 11.9, 6.7, 5.1; FAB HRMS (NBA/NaI) d e 647.2845, M + Na+ calcd for C31&8011Si 647.2864.

Acetate 26: Rf = 0.36 (silica, 50% EtOAc in petroleum ether); IH

2 H, 6-H and 14-H), 2.14 (s, 3 H, OAC), 2.10 (s, 3 H, 18-CH3), 1.88

NMR (500 MHz, CDC13) 6 6.51 (s, 1 H, 10-H), 5.21 (t, J = 3.0 Hz, l H , 5 - H ) , 4 . 3 0 ( d d , J = l 1 . 0 , 4 . 5 H ~ , lH,7-H),4.20(d,J=4.5Hz,

(18) Nicolaou, K. C.; Riemer, C.; Ken, M. A.; Rideout, D.; Wrasidlo, W. Nature 1993, 364, 464.


(0.003 mL, 0.040 mmol), and 4-(dimethylamino)pyridine (DMAP, catalytic) and stirred at 25 "C for 0.5 h. The reaction was quenched with aqueous NaHC03 (1 mL), and the resulting mixture was extracted with Et20 (3 x 20 mL). The combined organic layer was washed with HzO (5 mL) and brine (5 mL), dried (MgSOd), concentrated, and purified by flash chromatography (silica, 50% EtOAc in petroleum ether) to give diol 8 (4.6 mg, 95%) as an amorphous solid Rr = 0.40 (silica, 50% EtOAc in petroleum ether); [alZ2~ -51 (c 0.08, CHCb); 'H NMR (500 MHz, CDC13) 6 7.40-7.20 (band, 5 H, Ar), 6.51 (s, 1 H, lO-H), 4.55 (d, J = 11.5 Hz, 1 H, OCHzPh), 4.48 (d, J = 12.0 Hz, 1 H, 20-H), 4.44 (d, J = 11.5 Hz, 1 H, OCHZPh), 4.41 (d, J = 12.0 Hz, 1 H, 20-H), 4.22 (d, J = 4.5 Hz, 1 H, 2-H), 4.06 (dd, J = 11 .O, 4.5 Hz, 1 H, 7-H), 3.74 (m, 1 H, 5-H), 3.41 (d, J = 4.5 Hz, 1 H, 3-H),

2.75 (b s, 1 H, 5-OH), 2.72 (m, 1 H, 14-H), 2.29 (ddd, J = 14.5, 4.0, 4.0 Hz, 1 H, 6-H), 2.18 (m, 1 H, 14-H), 2.17 (s, 3 H, OAc), 2.10 (s, 3 H, OAc), 2.03 (s, 3 H, 18-CH3). 1.90 (m, 1 H, 13-H), 1.69 (m, 1 H,

CH3); FAB HRMS (NBNCsI) d e 733.1633, M + Cs+ calcd for

Triol 32. Hydrogenation of 31. A solution of diol 31 (4.6 mg, 0.0077 m o l ) in EtOAc (1 mL) was treated with Pd(0H)JC (1.0 mg) under an atmospheric pressure of hydrogen and stirred at 25 OC for 0.5 h. The reaction mixture was filtered, concentrated, and purified by preparative TLC (silica, EtOAc) to give triol 32 (3.8 mg, 97%) as an amorphous solid Rf = 0.20 (silica, EtZO); [alz2~ -85.2 (c 0.115, CHC13); IR (thin film) Y,, 3492,2941,1795,1737, 1714, 1457, 1370, 1230, 1032 cm-'; 'H NMR (500 MHz, CDC13) 6 6.45 (s, 1 H, 10-H), 4.43 (s, 2 H, ~O-CHZ), 4.42 (m, 1 H, 7-H), 4.20 (d, J = 5.0 Hz, 1 H,

3.14 (S, 1 H, 4-OH), 2.83 (ddd, J = 14.5, 10.5, 4.0 Hz, 1 H, 13-H),

6-H), 1.28 (s, 3 H, Ig-CHs), 1.20 (s, 3 H, 16-CH3), 1.15 (s, 3 H, 17-

c32&011 733.1625.

2-H), 3.77 (t, J = 3.0 Hz, 1 H, 5-H), 3.39 (d, J = 5.0 Hz, 1 H, 3-H), 3.21 (S, 1 H, 4-OH), 2.83 (s, 1 H, 5-OH), 2.86-2.71 (band, 2 H, 13-H and 14-H), 2.27-2.12 (band, 2 H, 6-H and 14-H), 2.18 (s, 3 H, OAC), 2.11 (s, 3 H, OAc), 2.08 (s, 3 H, 18-CH3), 1.91 (m, 1 H, 13-H), 1.80 (m, 1 H, 6-H), 1.23 (s, 6 H, 16-CH3 and 17-CH3), 1.10 (s, 3 H, 19-

129.2, 93.3, 81.6, 76.2, 74.8, 70.2, 68.4, 64.8, 61.1, 42.8, 40.4, 32.4, 30.4, 26.4, 22.9, 21.7, 20.9, 20.8, 18.8, 11.4; FAB HRMS (NBNCsI) d e 643.1175, M + Cs' calcd for C25H34011 643.1155.

Desilylation of 25. A solution of diol 25 (6.5 mg, 0.010 mmol) in THF (2.0 mL) at 25 "C was treated with HFTyridine (0.4 mL) and stirred for 2 h. The reaction mixture was diluted with EtOAc (10 mL), washed with 10% aqueous NaOH (5 mL) and brine (5 mL), dried (MgS04), concentrated, and purified by preparative TLC (silica, EtOAc) to give triol 32 (5.1 mg, 96%) as a colorless film.

Triol 33. A solution of acetate 25 (96.0 mg, 0.154 mmol) in MeOH (16 mL) at 0 'C was treated with a solution of K2C03 (212 mg, 1.54 "01) in HzO (4 mL). The reaction mixture was stirred at 0 "C for 15 min, and the reaction was quenched with aqueous N&C1(5 mL). The reaction mixture was extracted with CHZClz (3 x 10 mL), and the combined organic layer was washed with brine (10 mL), dried (MgSOd), concentrated, and purified by flash chromatography (silica, 25 - 50% EtOAc in petroleum ether) to give triol 33 (87.0 mg, 97%) as a white foam: Rr = 0.42 (silica, 50% EtOAc in petroleum ether); [alZzD -78 (C 0.25, CHC13); IR (thin film) vm, 3458, 2955, 1796, 1751, 1714, 1461, 1373, 1234 cm-l; IH NMR (500 MHz, CDC13) 6 6.51 (s, 1 H,

CH3); 13C NMR (125 MHz, cDcl3) 6 204.3, 170.8, 170.7, 153.1, 146.7,

10-H), 4.39 (dd, J = 11.0, 4.5 Hz, 1 H, 7-H), 4.22 (d, J = 5.0 Hz, 1 H, 2-H), 4.01 (b d, J = 9.5 Hz, 1 H, 20-H), 3.81 (s, 1 H, 4-OH), 3.70 (b S, 1 H, 5-H), 3.52 (d, J = 9.5 Hz, 1 H, 20-H), 3.33 (d, J = 5.0 Hz, 1 H, 3-H), 3.06 (s, 1 H, 20-OH), 2.95-2.85 (band, 2 H, 13-H and 5-0H), 2.71 (m, 1 H, 14-H), 2.23 (ddd, J = 19.5, 9.0, 3.0 Hz, 1 H, 14-H), 2.14 (s, 6 H, OAc and 18-CH3), 2.12 (m, 1 H, 6-H), 1.86 (ddd, J = 14.0, 12.0, 3.0 Hz, 1 H, 6-H), 1.69 (m, 1 H, 13-H), 1.18 (s, 3 H,

Hz, 9 H, Si(CHzCH&), 0.60-0.45 (band, 6 H, Si(CHzCH&); I3C NMR

76.1, 73.6, 11.7, 68.5, 62.6, 61.4, 42.7, 40.5, 33.7, 30.3, 26.4, 22.9, 21.2,20.9, 18.9, 11.9,6.7,5.1;FABHRMS(NBA/NaI)de605.2735, M + Na+ calcd for C29&010Si 605.2758.

Oxetane 36. Conversion of Triol 33 to 36. A solution of triol 33 (10.0 mg, 0.017 "01) and pyridine (0.142 mL, 0.51 "01) in CH2- Clz (2.0 mL) at 0 "C was treated with chlorotrimethylsilane (TMSC1, 0.022 mL, 0.17 m o l ) and stirred at 0 "C for 15 min. The reaction

16-CH3), 1.14 (s, 3 H, 17-CH3), 1.09 (s, 3 H, 19-CH3), 0.87 (t, J = 8.0

(125 MHz, CDCls) 6 203.3, 169.2, 153.9, 144.8, 130.2, 93.7, 81.9,

1H,2-H),4.03(d,J=11.0H~,1H,20-H),3.58(d,J=11.0Hz,1 H, 20-H), 3.34 (s, 1 H, 4-OH), 3.20 (d, J = 4.5 Hz, 1 H, 3-H), 2.94 (ddd, J = 14.0, 10.0, 3.5 Hz, 1 H, 13-H), 2.75 (m, 1 H, 14-H), 2.20 (s, 3 H, 18-CH3), 2.18 (s, 3 H, OAc), 2.16 (s, 3 H, OAc), 2.12 (m, 1 H, 14-H), 1.96 (ddd, J = 15.0, 4.5, 4.5 Hz, 1 H, 6-H), 1.90-1.84 (band, 2 H, 6-H and 13-H), 1.19 (s, 3 H, 16-CH3), 1.14 (s, 3 H, 17-CH3), 1.04 (s, 3 H, 19-C&), 0.86 (t, J = 8.0 Hz, 9 H, Si(CH2CH,),), 0.55- 0.49 (band, 6 H, S~(CHZCH~)~).

Silylation of Triol 32 to 25. A solution of triol 32 (2.0 mg, 0.0039 "01) in pyridine (0.5 mL) was treated with chlorotriethylsilane (TESC1, 0.017 mL, 0.098 "01) and stirred at 25 "C for 12 h. The reaction mixture was diluted with Et20 (10 mL), washed with aqueous CuSO4 (3 x 5 mL) and brine (5 mL), dried (MgSOd), concentrated, and purified by preparative TLC (silica, 50% EtOAc in petroleum ether) to give silyl ether 25 (2.0 mg, 85%) as a colorless film.

Alcohol 29. To a solution of acetate 4 (18.7 mg, 0.032 "01) in THF (2 mL) at 0 "C was added BHyTHF (1.0 M, 0.32 mL, 0.32 mmol), and the reaction mixture was stirred at 0 "C for 3 h. The reaction was quenched with aqueous NaHCO3 (0.5 mL) and HZOZ (0.5 mL), and the resulting solution was allowed to warm to 25 "C, stirred at 25 OC for 1 h, and extracted with Et20 (3 x 30 mL). The combined organic layer was washed with HzO (5 mL) and brine (5 mL), dried (MgSOd), concentrated, and purified by preparative TLC (silica, 10% Et20 in CHzCl2) to give acetate 4 (3.1 mg, 17%), the monoalcohol 29 (6.8 mg, 42% based on 83% conversion) as an amorphous solid, and the corresponding 6-OH regioisomer (3.3 mg, 22% based on 83% conversion) as an amorphous solid.

Alcohol 29: Rf = 0.80 (silica, 10% Et20 in CH2C12); ta1220 -58 (c 0.45, CHC13); IR (thin film) v,, 3523,2924, 1803, 1746,1716, 1459, 1372, 1230, 1064 cm-I; 'H NMR (500 MHz, CDCl3) 6 7.38-7.22 (band, 5 H, Ar), 6.50 (s, 1 H, 10-H), 5.58 (d, J = 11.5 Hz, 1 H, OCH2- Ph), 4.48 (d, J = 11.5 Hz, 1 H, OCHZPh), 4.23 (d, J = 8.5 Hz, 1 H, 20-H),4.16(d,J=4.0H~,1H,2-H),4.06(dd,J=11.0,4.5Hz,1 H, 7-H), 3.87 (t, J = 3.0 Hz, 1 H, 5-H), 3.77 (d, J = 8.5 Hz, 1 H, 20-H), 3.46 (d, J = 4.0 Hz, 1 H, 3-H), 2.81-2.68 (band, 2 H, 13-H and 14-H), 2.61 (b s, 1 H, 5-OH), 2.36 (m, 1 H, 14-H), 2.20 (m, 1 H, 13-H), 2.19 (s, 3 H, OAc), 2.03 (s, 3 H, 18-CH3), 1.92 (m, 1 H, 6-H), 1.61 (m, 1 H, 6-H), 1.45 (s, 6 H, C(CH3)2), 1.22 (s, 3 H, 16-CH3), 1.18

6 203.0, 169.2, 153.0, 144.6, 137.5, 129.8, 128.2, 127.9, 127.5, 108.8, 92.7, 84.6, 80.7, 76.1, 73.8, 71.2, 70.5, 68.8, 60.3, 40.6, 30.2, 29.7, 29.7, 29.6,26.4,26.2,23.0,21.3,20.9, 18.8, 11.5; FAB HRMS ( N E W NaI) d e 621.2658, M + Na+ calcd for C33b2010 647.2676.

Triol 30. A solution of alcohol 29 (6.8 mg, 0.01 14 "01) in MeOH (2 mL) was treated with concentrated HCl(1 mL) and stirred at 25 "C for 5 h. The reaction was quenched with aqueous NaHC03 (1 mL), and the resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with H20 (2 mL) and brine (2 mL), dried (MgSOd), concentrated, and purified by preparative TLC (silica, 75% EtOAc in petroleum ether) to give monoalcohol 29 (0.8 mg, 12%) and triol 30 (6.8 mg, 80% based on 88% conversion) as an amorphous solid: Rf = 0.30 (silica, 75% EtOAc in petroleum ether);

-71 (c 0.16, CHCls); IR (thin film) v,, 3453,2906, 1795, 1743, 1714, 1458, 1372, 1233, 1038 cm-'; 'H NMR (500 MHz, CDC13) 6

(s, 3 H, 17-CH3), 1.13 (s, 3 H, 19-CH3); NMR (125 MHz, CDCl3)

7.28-7.26 (band, 5 H, Ar), 6.49 (s, 1 H, 10-H), 4.55 (d, J = 11.0 Hz, 1 H, OCHzPh), 4.45 (d, J = 11.0 Hz, 1 H, OCHZPh), 4.20 (d, J = 4.5 Hz, 1 H, 2-H), 4.05 (dd, J 11.0, 4.5 Hz, 1 H, 7-H), 4.03 (b dd, J = 11.0, 4.5 Hz, 1 H, 20-H), 3.87 (s, 1 H, 4-OH), 3.73 (b t, J = 2.5 Hz, 1 H, 5-H), 3.52 (b dd, J = 11.0, 3.0 Hz, 1 H, 20-H), 3.35 (d, J = 4.5 Hz, 1 H, 3-H), 3.01 (b S, 1 H, 5-OH), 2.92 (ddd, J = 14.5, 10.5, 4.0 Hz, 1 H, 13-H), 2.72 (ddd, J = 20.0, 12.0, 4.0 Hz, 1 H, 14-H), 2.59 (m, 1 H, 20-OH), 2.30 (ddd, J = 14.5, 3.5, 3.0 Hz, 1 H, 6-H), 2.21

3 H, 18-CH3), 1.87 (ddd, J = 14.5, 12.0, 2.5 Hz, 1 H, 13-H), 1.61 (m, (ddd, J = 20.0, 10.5, 3.0 Hz, 1 H, 14-H), 2.17 (s, 3 H, OAC), 2.03 (s,

1 H, 6-H), 1.20 (s, 3 H, 19-cH3), 1.16 (s, 3 H, 16-CH3), 1.15 (s, 3 H, 17-CH3); 13C NMR (125 MHz, CDCls) 6 203.1, 169.2, 153.4, 144.7, 137.7, 129.8, 128.2, 127.8, 127.5, 97.9, 93.4, 81.5, 76.1, 74.5, 73.7, 72.5, 62.5, 60.0, 42.8, 30.2, 29.6, 29.4, 26.3, 22.8, 21.3, 20.9, 18.8, 12.4; FAB HRMS (NBA/NaI) d e 581.2341, M + Na+ calcd for C30H38010 581.2363.

Acetate 31. A solution of triol 30 (4.5 mg, 0.008 "01) in CHzClz (1 mL) was treated with Ac2O (0.0009 mL, 0.010 mmol), pyridine

Total Synthesis of Tanol. 4

was quenched with aqueous NaHC03 (2.0 mL). The resulting mixture was allowed to warm to 25 "C and extracted with Et20 (3 x 5 mL). The combined organic layer was washed with brine (10 mL), dried (MgSOd), and concentrated to give the crude silyl ether 34, which was taken to the next step without further purification.

A solution of silyl ether 34 and i-PratN (0.090 mL, 0.51 "01) in CHzClz (2.0 mL) at 0 "C was treated with triflic anhydride (TfzO, 0.044 mL, 0.26 mmol) and stirred at 0 "C for 0.5 h. The reaction was then quenched with aqueous NaHCO3 (1.5 mL), and the resulting mixture was allowed to warm to 25 "C and extracted with Et20 (3 x 5 mL). The combined organic layer was washed with brine (10 mL), dried (MgSOd), and concentrated to give the crude triflate 35, which was taken to the next step without further purification.

A solution of triflate 35 in MeOH (2.0 mL) was treated with camphorsulfonic acid (CSA, 0.5 mg, 0.002 "01) and stirred at 25 "C for 15 min. The reaction was quenched with aqueous NaHC03 (1.5 mL), and the mixture was extracted with CHzClz (3 x 5 mL). The combined organic layer was washed with brine (10 mL), dried (MgS04), and concentrated. The resulting residue was dissolved in CH2Clz (2.0 mL) and treated with silica gel (E. Merck, 0.1 g) at 25 "C for 1 h. The reaction mixture was filtered, concentrated, and purified by preparative TLC (silica, 50% EtOAc in petroleum ether) to give oxetane 36 (3.9 mg, 40% from 33) as a colorless film: Rj = 0.35 (silica, 33% EtOAc in petroleum ether); [ a ] 2 2 ~ -47 (c 0.42, CHC13); IR (thin film) vmax 3462,2927, 1805,1747, 1716,1595,1460,1372,1237 cm-l; 'H NMR (500 MHz, CDC13) 6 6.39 (s, 1 H, 10-H), 4.82 (dd, J = 9.5, 2.0 Hz, 1 H, 5-H), 4.66 (d, J = 9.0 Hz, 1 H, 20-H), 4.42 (d, J = 9.0 Hz, 1 H, 20-H), 4.37 (d, J = 5.5 Hz, 1 H, 2-H), 4.12 (dd, J = 10.5, 7.0 Hz, 1

1 H, 13-H), 2.48 (ddd, J = 15.0, 9.5, 7.0 Hz, 1 H, 6-H), 2.43 (s, 1 H,

CH3), 1.93 (ddd, J = 15.0, 10.5, 2.0 Hz, 1 H, 6-H), 1.89 (ddd, J = 14.5, 12.0, 2.5 Hz, 1 H, 13-H), 1.62 (s, 3 H, 19-C&), 1.19 (s, 3 H,

H, 7-H), 2.71 (m, 1 H, 14-H), 2.63 (d, J = 5.5 Hz, 1 H, 3-H), 2.62 (m,

4-OH), 2.19 (m, 1 H, 14-H), 2.15 (s, 3 H, OAc), 2.06 (s, 3 H, 18-

16-CH3), 1.18 (s, 3 H, 17-CH3), 0.87 (t, J = 8.0 Hz, 9 H, Si(CHzCH3)3), 0.54 (q, J = 8.0 Hz, 6 H, Si(CHzCH&); 13C NMR (125 MHz, CDC13) 6 203.0, 169.3, 153.4, 143.9, 131.1, 93.2, 87.5, 80.7, 80.5, 76.5, 73.8, 71.9, 59.7, 51.6, 47.1, 37.8, 30.0, 26.2, 22.9, 21.7, 20.9, 19.0, 9.8, 6.7, 5.1; FAB HRMS (NBNCsI) d e 697.1790, M + Cs+ calcd for C29hOgSi 697.1809.

Conversion of Mesylate 38 to Oxetane 36. A solution of crude diol 38 (1 1.0 mg, 0.017 mmol) in butanone (1.0 mL) was treated with n-Bu4NOAc (60.0 mg, 0.20 "01) and stirred at reflux for 5 h. The reaction mixture was allowed to cool to 25 "C and partitioned between Et20 (10 mL) and H2O (5 mL). The organic layer was washed with brine (5 mL), dried (MgS04). concentrated, and purified by flash chromatography (silica, 10 - 20% EtOAc in petroleum ether) to give oxetane 36 (6.8 mg, 72% from 37) as a colorless film.

Acetate 24. A solution of oxetane 36 (4.0 mg, 0.0091 "01) and 4-(dimethy1amino)pyridine (DMAP, 17.0 mg, 0.14 "01) in CHzCl2 (2.0 mL) was treated with acetic anhydride (0.0067 mL, 0.071 "01) and stirred at 25 OC for 4 h. The reaction mixture was diluted with Et20 (10 mL), washed with 1 N aqueous HCl (5 mL) and aqueous NaHC03 (5 mL), dried (MgSOb), concentrated, and purified by preparative TLC (silica, 33% EtOAc in petroleum ether) to give acetate 24 (4.0 mg, 94%) as a colorless film: Rf = 0.82 (silica, 50% EtOAc in hexanes); [ a l " ~ -49.4 (c 0.93, CHCl,); IR (thin film) v,, 2924, 1814, 1728, 1461, 1372, 1238 cm-l; lH NMR (500 MHz, CDC13) 6 6.40 (s, 1 H, 10-H), 4.95 (d, J = 9.0 Hz, 1 H, 5-H), 4.60 (A of AB, d, J = 9.0 Hz, 1 H, 20-H), 4.47 (B of AB, d, J = 9.0 Hz, 1 H, 20-H), 4.43 (dd, J = 10.0. 7.5 Hz, 1 H, 7-H), 4.39 (d, J = 5.5 Hz, 1 H, 2-H), 3.36 (d, J = 5.5 Hz, 1 H, 3-H), 2.71 (m, 1 H, 13-H), 2.56 (m, 1 H, 13-H), 2.17 (s, 3 H, OAc), 2.15 (s, 3 H, OAc), 2.12 (m, 1 H), 2.07 (s, 3 H, 18- CHd, 1.97 (m, 1 H), 1.88 (m, 2 H), 1.78 (s, 3 H, 19-CH3), 1.23 (s, 3

Si(CHzCH&), 0.60-0.50 (band, 6 H, Si(CHzCH3)s); I3C NMR (125 MHz, CDC13) 6 202.6, 170.3, 169.2, 153.1, 144.0, 130.7, 92.8, 84.0, 80.3, 80.0, 76.4, 76.1, 60.3, 43.5, 38.0, 29.7, 29.4, 25.5, 23.1, 21.9, 21.1, 19.1, 9.8, 6.7, 5.2; FAB HRMS (NBNCs1)de 739.1929, M + Cs+ calcd for C31II46010Si 739.1915.

Mesylate 37. A solution of alcohol 25 (46.0 mg, 0.074 mmol) and 4-(dimethylamino)pyridine (DMAP, 180 mg, 1.48 "01) in CHzClz (6.0 mL) was treated with mesyl chloride (MsC1.0.056 mL, 0.72 m o l )

H, 16-CH3), 1.17 (s, 3 H, 17-CH3), 0.88 (t, J = 7.5 Hz, 9 H,


and stirred at 25 "C for 1 h. The reaction mixture was diluted with Et20 (20 mL), washed with 1 N aqueous HCl (10 mL), aqueous NaHC03 (5 mL), and brine (5 mL), dried (MgS04), concentrated, and purified by flash chromatography (silica, 10 - 20% EtOAc in petroleum ether) to give mesylate 37 (37.0 mg, 73%) as a white solid: Rf = 0.38 (silica, 33% EtOAc in petroleum ether); [alz2~ -40 (c 0.50,

cm-I; 'H NMR (500 MHz, CDC13) 6 6.57 (s, 1 H, 10-H), 4.71 (t, J = CHC13); R (thin film) Y- 3495,2925, 1804, 1746, 1461, 1365, 1232

2.5 Hz, 1 H, 5-H), 4.53 (d, J = 12.0 Hz, 1 H, 20-H), 4.50 (d, J = 12.0 Hz, lH,20-H),4.37(dd,J=11.0,4.5H~,lH,7-H),4.26(d,J=4.5 Hz, 1 H, 2-H), 3.37 (d, J = 4.5 Hz, 1 H, 3-H), 3.15 (s, 1 H, 4-OH), 3.08 (s, 3 H, OMS), 2.87 (ddd, J = 14.5, 10.0, 3.5 Hz, 1 H, 13-H), 2.74 (ddd, J = 19.5, 12.0, 3.5 Hz, 1 H, 14-H), 2.38 (ddd, J = 19.5, 10.0, 3.0 Hz, 1 H, 14-H), 2.23 (ddd, J = 15.0, 4.5, 2.5 Hz, 1 H, 6-H), 2.19 (s, 3 H, 18-CH3), 2.18 (s, 3 H, OAC), 2.15 (s, 3 H, OAC), 2.02 (ddd,J= 15.0, 11.0, 2.5 Hz, 1 H, 6-H), 1.92 (ddd, J = 14.5, 12.0, 3.0 Hz, 1 H, 13-H), 1.27 (s, 3 H, 19-CH3), 1.22 (s, 3 H, 16-CH3), 1.17 (s, 3 H, 17-C&), 0.91 (t, J = 8.0 Hz, 9 H, Si(CHzCH&), 0.59-0.54 (band, 6 H, Si(CH2CH3)d; NMR (125 MHz, CDC13) 6 202.0, 170.9, 169.2, 152.9, 145.4, 130.0, 81.1, 80.9,75.9,73.5,68.5,64.4, 61.1,44.4,40.4, 38.9, 34.7, 30.0, 29.7, 26.5, 23.1, 21.0, 20.9, 20.7, 18.9, 12.3, 6.7, 5.0; FAB HRMS (NBNCsI) d e 835.1811, M + Csf calcd for C32H50013- SiS 835.1796.

Diol 38. A solution of acetate 37 (24.0 mg, 0.034 mmol) in MeOH (3.0 mL) at 0 "C was treated with a solution of K2CO3 (60.0 mg, 0.34 "01 in 0.5 mL of HzO) and stirred at 0 "C for 15 min. The reaction was quenched with aqueous W C l (2 mL), and the resulting mixture was extracted with CHzClz (3 x 5 mL). The organic layer was washed with brine (5 mL), dried (MgS04), and concentrated to give crude diol 38, which was taken to the next step without further purification.

Diol 38: Rf = 0.51 (silica, 50% EtOAc in petroleum ether); [a]zzD -35 (c 0.63, CHC13); IR (thin film) vmax 3742, 2925, 1800, 1749, 1716, 1461, 1363, 1234 cm-l; 'H NMR (500 MHz, CDC13) 6 6.56 (s, l H , lO-H),4.74(t,J=3.0Hz, l H , 5 - H ) , 4 . 3 8 ( d d , J = 1 1 . 0 , 4 . O H ~ , 1 H, 7-H), 4.24 (d, J = 4.5 Hz, 1 H, 2-H), 4.01 (b d, J = 11.0 Hz, 1 H, 20-H), 3.83 (s, 1 H, 4-OH), 3.61 (b d, J = 11.0 Hz, 1 H, 20- H), 3.35 (d, J = 4.5 Hz, 1 H, 3-H), 3.11 (s, 3 H, OMS), 2.96 (ddd, J

19.5, 10.0, 3.0 Hz, 1 H, 14-H), 2.26 (ddd, J = 15.0, 4.0, 3.0 Hz, 1 H, 6-H), 2.20 (s, 3 H, 18-CH3), 2.18 (s, 3 H, OAC), 1.98-1.90 (band, 2 H, 6-H and 13-H), 1.22 (s, 3 H, 1%CH3), 1.17 (s, 3 H, 16-CH3), 1.16

= 14.5, 10.0, 4.0 Hz, 1 H, 13-H), 2.74 (m, 1 H, 14-H), 2.36 (ddd, J =

(s, 3 H, 17-CHs), 0.90 (t, J = 8.0 Hz, 9 H, Si(CHzCH&), 0.59-0.53 (band, 6 H, Si(CHzCH3)3); NMR (125 MHz, CDC13) 6 202.4, 169.1, 153.6, 145.4, 130.0,82.3,81.3,76.0,72.7,68.4,62.4,53.2,43.8, 40.4, 38.5, 34.6, 30.1, 29.6, 26.4, 22.9, 21.0, 20.8, 18.8, 12.1, 6.6,4.9; FAB MS (NBA/NaI) d e 683, M + Na+ calcd for C3&8012SiS 683.

For the conversion of carbonate 24 to Tax01 (1) and physi- cal data for compounds 1, 39-41, and 43, see the fust paper in this series.'O

Acknowledgment. We thank Drs. Dee H. Huang, Gary Siuzdak, Raj Chadha, and Wolfgang Wrasidlo for NMR, mass spectroscopic, X-ray crystallographic, and biological assays assistance, respectively. We also thank Dr. Luigi Gomez- Paloma for helpful discussions regarding NMR and stereochemical issues. This work was financially supported by NIH, The Scripps Research Institute, fellowships from Mitsubishi Kasei Corporation (H.U.), Rh6ne-Poulenc Rorer (P.G.N.), NSERC (J.R.), and grants from Merck Sharp & Dohme, Pfizer, Inc., Schering Plough, and the ALSAM Foundation.

Supplementary Material Available: Experimental techniques and data for compounds 5, 6, 8-22, 27, and 28 (12 pages). This material is contained in many libraries on microfiche, immediately follows this article in the microfilm version of the journal, and can be ordered from the ACS. See any current masthead page for ordering information.

JA942195E

total synthesis of taxol. 1. retrosynthesis - researchgate

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