a concise account of various approaches for ...download.xuebalib.com/31iqt0chzpoh.pdf · synthesis...

A Concise Account of Various Approaches for StereoselectiveConstruction of the C‑20(H) Stereogenic Center in Steroid Side ChainBapurao B. Shingate*,†,‡ and Braja G. Hazra*,‡

†Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431 004, India‡Division of Organic Chemistry, National Chemical Laboratory, Pune 411 008, India

CONTENTS

1. Introduction and Scope A1.1. Steroids with C-20 Natural Configuration B1.2. Steroids with C-20 Unnatural Configuration C1.3. Other Compounds with Sterol-like Side

Chains D2. Spectroscopic Method for Determining the

Configuration of C-21 Methyl Group in theSteroid Side Chain D

3. X-ray Crystallographic Analysis for Determiningthe Configuration at C-20 D

4. Methods for Stereoselective Generation of C-20(H) Stereogenic Center in Steroid Side Chain E4.1. Catalytic Hydrogenation of Steroidal C-20

Double Bonds E4.2. Ionic Hydrogenation G4.3. C-20 Alkylation H

4.3.1. Alkylation of Steroidal C-21 Esters H4.3.2. Alkylation of Unsaturated Steroidal C-21

Esters I4.3.3. Alkylation of C-20 Cyano Steroid I4.3.4. Alkylation of Des-AB Steroids I

4.4. Ring-Opening of Steroidal C-20,22-Oxirane J4.5. Ene Reaction K

4.5.1. Ene Reaction with Propiolate Esters K4.5.2. Ene Reaction with Acrylates L4.5.3. Carbonyl−Ene Reaction L

4.6. Aldol Reaction O4.7. Michael Addition Reaction P4.8. Mukaiyama−Michael Conjugate Addition

Reaction P4.9. Chirality Transmission Approach Q4.10. Claisen and Claisen-type Rearrangements R4.11. Wittig Rearrangement T4.12. Organopalladium Reagents V

4.13. Organoboron Reagents W4.14. Organocopper Reagents X

4.14.1. Alkylidene Oxiranes X4.14.2. C-17(20)-en-16-keto Steroids Y4.14.3. C-17(20)-en-16-Pivalates/Carbamates Z

4.15. Organozirconocene Reagents Z4.16. Hydrovinylation Reaction AB4.17. Miscellaneous AB

5. Conclusions ACAuthor Information AD

Corresponding Authors ADNotes ADBiographies AD

Acknowledgments ADDedication AEAbbreviations AEReferences AE

1. INTRODUCTION AND SCOPE

Sterols are compounds containing a perhydro-1,2-cyclo-pentenophenanthrene ring system and are found in a varietyof different marine, terrestrial, and synthetic sources. The vastdiversity of natural and synthetic members of this class dependson variation in side-chain substitution (primarily at C-17),degree of unsaturation, degree and nature of oxidation, andstereochemical relationship at the ring junctions.1 The mostfrequently encountered sterol of animal origin is the highlylipophilic compound cholesterol, 1, which is metabolized to bileacids in the liver and also serves as starting material for thesynthesis of steroid hormones. A wide variety of sterols havebeen reported2 to possess modified iso-octyl (cholesterol-type)side chains and the unit being attached to the polycyclicnucleus at C-17 with (R) or (S) stereochemistry at C-20.3

During the early and middle years of sterol and relatedterpenoid chemistry, synthetic efforts were focused primarily onthe ring system and some of the more simple functional sidechains. Comparatively, little attention was paid to the side chainexcept for two carbon units present in corticosteroids and otherpregnane derivatives and interconversions between the sidechains of cholesterol, plant sterols, and bile acids. The last fewdecades have witnessed intensive research on side-chainsynthesis, yielded many imaginative syntheses of generalinterest, and contributed to a great extent to the developmentof stereospecific chiral carbon formation.4,5 The biologicalsignificance of both the C-20 epimers of naturally occurring

Received: July 29, 2013

Review

pubs.acs.org/CR

© XXXX American Chemical Society A dx.doi.org/10.1021/cr4004083 | Chem. Rev. XXXX, XXX, XXX−XXX

pubs.acs.org/CR

and/or synthetic sterol molecules provided not only steroidchemists but also natural product chemists an opportunity topursue new syntheses of sterols or compounds with similarchain structures. This review is limited to sequencescommencing upon generation of both epimers at C-20. Theaim of this review is to survey the synthesis of sterols, terpenes,and vitamin side chains with natural and unnatural config-urations at C-20 (Figure 1).

1.1. Steroids with C-20 Natural Configuration

There are many classes of natural and synthetic sterols, bestknown for their wide array of biological activity.1 Representa-tive members of the naturally occurring sterols such ascholesterol 1, β-sitosterol 2, stigmasterol 3, ergosterol 4, andecdysone 5 have the C-20 natural stereochemistry (Figure 2).

These sterols 1−5 are widely distributed in the animal andvegetable kingdoms and are used in the pharmaceutical industryas raw materials for obtaining drugs by chemical, enzymatic,and microbiological methods.Sterols with additional methyl groups on the ring skeleton

are found in many plants and fungi and abundantly in the woolfat of sheep. The best examples are lanosterol 6, agnosterol 7,and 4,4′-dimethyl-5α-cholesta-8,14,24-trien-3β-ol 8 [FF-MAS(follicular fluid meiosis-activating sterol)], a naturally occurringsterol isolated6 from human follicular fluid (Figure 3).Bile acids, derivatives of cholesterol, are found predominantly

in the bile of mammals. The two major bile acids are cholic acid9 and deoxycholic acid 10 (Figure 4). Other bile acidderivatives such as lithocholic acid 11, conjugates of taurocholicacid 12, and glycocholic acid 13 are all found in humanintestinal bile with C-20 natural stereochemistry.

Vitamin D refers to a group of seco-steroids that possess acommon conjugated triene system of double bonds.5 VitaminD3 (cholecalciferol) 14 and vitamin D2 (ergocalciferol) 15 arewell-known examples with C-20 natural stereochemistry(Figure 5). Vitamin D3 is a prohormone that is convertedinto physiologically active form, primarily 1,25-dihydroxyvita-min D3 16, by successive hydroxylations in the liver and kidney.

Naturally occurring and commercially important sapogenins,particularly diosgenin 17, hecogenin 18, and tigogenin 19, alsopossess the natural configuration at C-20 (Figure 6). These

sapogenins are important source of starting materials for thecommercial steroid industry, owing to their relative abundancein easily cultivated plants and their ease of isolation.1

Commercially important plant growth-promoting steroidbrassinolide7 20, recently isolated sterol polyamine conjugate8

squalamine 21, saponin9 OSW-1 22, and contignasterol10 23have natural C-20 stereochemistry (Figure 7). The bioactivitiesof these naturally occurring steroids and their syntheticanalogues have been exploited in the development of steroidaldrugs. Certonardosterol D2 24, a polyhydroxysterol isolatedfrom the starfish Certonardoa semiregularis, has exceptionallypotent antitumor activity.11 Agosterol A 25, isolated frommarine sponges of Spongia sp., is a reversing substance tomultidrug resistance (MDR) in human carcinogenic cell linesand also has been synthesized by Kobayashi and co-workers.12

Furthermore, physanolide A 26, a new steroid skeletonisolated from Physalis angulata;13 amaranzole A 27, a 24-N-imidazolyl steroid alkaloid from Phorbas amaranthus;14 and

Figure 1. (A) Natural configuration at C-20; (B) unnaturalconfiguration at C-20.

Figure 2. Cholesterol 1, β-sitosterol 2, stigmasterol 3, ergosterol 4, andecdysone 5.

Figure 3. Lanosterol 6, agnosterol 7, and FF-MAS 8.

Figure 4. Cholic acid 9, deoxycholic acid 10, lithocholic acid 11,taurocholic acid 12, and glycocholic acid 13.

Figure 5. Vitamin D3 (cholecalciferol) 14, vitamin D2 (ergocalciferol)15, and 1,25-dihydroxyvitamin D3 16.

Figure 6. Diosgenin 17, hecogenin 18, and tigogenin 19.

Chemical Reviews Review

dx.doi.org/10.1021/cr4004083 | Chem. Rev. XXXX, XXX, XXX−XXXB

withaferin A 28, a cytotoxic steroid isolated15 from Vassobiabreviflora, all have C-20 natural configuration (Figure 8).

Li et al.16 described the chemistry, bioactivity, and geo-graphical diversity of steroidal alkaloids isolated from Veratrumand Fritillaria sp. of the Liliaceae family, which containderivatives of pyridine/piperidine heterocycle attached to theC-20 position of steroid backbone with C-20(H) natural/unnatural stereogenic center. Similarly, Atta-ur-Rahman andChoudhary17 have also reviewed the isolation of varioussteroidal alkaloids. Introduction of a heteroatom in the steroidalring or side chain could have a biological impact; there has beenprogress in the field of thia- and azasteroids.18 A new cytotoxicsteroidal alkaloid, plakinamine I 29 (Figure 9), with anunprecedented 3α-amino-19-acetoxy nucleus, and other similartype of compounds were isolated19 from a Corticium sp. sponge.1.2. Steroids with C-20 Unnatural Configuration

Sterols/steroids with unnatural configuration at C-20 or C-20epimers are attracting attention because of interesting biologicalactivities, and hence methods for their stereoselective synthesisare highly desirable. Sargasterol has been isolated from

Sargassum ringgoldianum and its structure was proposed as(20S)-fucosterol 30 (Figure 10) on the basis of degradation

products by Tsuda et al.20 Idler et al.21 reported the presence of20-epi-cholesta-5,22-dien-3β-ol 31 in the scallop Placopectenmagellanicus. Koreeda and co-workers22 reported that 20-epi-cholesterol 32 with C(20S) stereochemistry showed significantin vitro inhibitory activity for the conversion of cholesterol to3β-hydroxypregn-5-en-20-one (pregnenolone). Similarly, thenaturally occurring halosterol 33, in which the side chain hasbeen shortened by one methylene (CH2) group, possessesunnatural configuration at C-20.23

Vanderah and Djerassi24 described the isolation of foursterols 34−37 (Figure 11), having the unnatural C(20S)

stereochemistry, from a sea pen, Ptilosarcus gurneyi and alsodevised methods for their synthesis. Methyl (20S,22E)-3-oxochola-1,4,22-trien-24-oate 38, isolated from Alcyoniumgracillimum and Dendronephthya sp. of the order Alcyonacea,showed no antifouling activity against barnacle (Balanusamphitrite) larvae but lethality to barnacle larvae at aconcentration of 100 μg/mL (LD100).

25

20-epi-1α,25-Dihydroxyvitamin D3 (20-epi-calcitriol) 39 ismore potent26 in regulating cell growth and cell differentiationthan the corresponding natural C-20 stereoisomer (Figure 12).Analogue 39 exhibits immunosuppressive properties27 and 1α-fluoro-16,23-diene-20-epi hybrid deltanoid (Ro 26-9228) 40 isundergoing human clinical trials for the treatment ofosteoporosis.28

Figure 7. Brassinolide 20, squalamine 21, saponin OSW-1 22,contignasterol 23, certonardosterol D2 24, and agosterol A 25.

Figure 8. Physanolide A 26, amaranzole A 27, and withaferin A 28.

Figure 9. Plakinamine I 29.

Figure 10. (20S)-Fucosterol 30, 20-epi-cholesta-5,22-dien-3β-ol 31,20-epi-cholesterol 32, and 20-epi-halosterol 33.

Figure 11. 20-epi-Cholanic acid derivatives 34−37 and methyl(20S,22E)-3-oxochola-1,4,22-trien-24-oate 38.


dx.doi.org/10.1021/cr4004083 | Chem. Rev. XXXX, XXX, XXX−XXXC

1.3. Other Compounds with Sterol-like Side Chains

Sesterterpenoids such as gascardic acid 41, (+)-ophiobolin A42, (+)-ophiobolin C 43, (+)-ceroplastol I 44, (+)-ceroplastolII 45, and (+)- albolic acid 46 bearing sterol-like iso-octyl sidechains on C ring skeleton were also reported29 (Figure 13).

Shi and co-workers30 reported incisterols 47−49, possessinga highly degraded 1−5,10,19-heptanorergosterane skeletonisolated from Phellinus igniarius (Figure 14). DemethylincisterolA3 50 and chaxine A 51 (Figure 14) were isolated from theChinese mushroom Agrocybe chaxingu and are potentosteoclast-forming suppressing agents.31

2. SPECTROSCOPIC METHOD FOR DETERMINING THECONFIGURATION OF C-21 METHYL GROUP IN THESTEROID SIDE CHAIN

Information on the spectral properties of steroidal C-20epimers is now available and permits us to make somegeneralizations. The spectra are influenced by several factors;therefore the generalizations may not be always directlyapplicable to new compounds. Possibly, the most informativemethod for stereochemical assignment has been the use ofNMR spectroscopy. For elucidating C-20 stereochemistry insterol/steroid, the C-21 methyl protons give the best diagnosticsignal.4a,32 The 20β-isomer (natural C-20 epimer, according to

steroid nomenclature system) generally has its signal moredownfield in proton NMR than the 20α-isomer (unnatural C-20 epimer). In ambiguity to this, for steroids bearing/possessing a double bond at C-16(17), the 20α-isomer showsmore downfield than 20β-isomer. Representative values for C-21 methyl protons of C-20 epimers are shown in Table 1.

3. X-RAY CRYSTALLOGRAPHIC ANALYSIS FORDETERMINING THE CONFIGURATION AT C-20

Crystal structure data33,43 of sterols with natural configurationat C-20 show that the conformation about 17(20) bond in theusual view of the molecule is to the right, meaning the sidechain is to the right side of the steroid skeleton. The right-handed rotational isomer probably derives from its having thesmallest of the groups on C-20 (the H atom) in front andtherefore, adjacent to C-18 in a pseudo 1,3-diaxial fashion. In

Figure 12. 20-epi-Calcitriol 39 and deltanoid (Ro 26-9228) 40.

Figure 13. Gascardic acid 41, (+)-ophiobolin A 42, (+)-ophiobolin C43, (+)-ceroplastol I 44, (+)-ceroplastol II 45, and (+)- albolic acid 46.

Figure 14. Incisterols 47−49, demethylincisterol A3 50, and chaxine A51.

Table 1. Representative Values for C-21 Methyl Protons ofC-20 Epimers


dx.doi.org/10.1021/cr4004083 | Chem. Rev. XXXX, XXX, XXX−XXXD

the case of C-20 unnatural configuration, the left-handedconformer is skew and possesses the least steric compression,that is, an opposite conformational preference compared to thenatural one.Linker et al. described the syntheses44a and crystal

structures44b,c of methyl (20S,22E)-3-oxochola-1,4,22-trien-24-oate 38 and methyl (20R,22E)-3-oxochola-1,4,22-trien-24-oate52 (Figure 15).

All bond lengths and angles of the steroidal skeleton arewithin normal range and in accordance with the epimericproduct. For 38, the D ring adopts a conformation between13β,14α-half chair [Δ = 12.84°, ψm = 47.1°). The substituentsat C-20 are staggered with respect to those at C-17, but in thiscase C-22 is anti to C-16. The side chain is oriented toward thering system44b (Figure 16A). For 52, the calculated values of Δ

= 20.15°, ψm = 45.2° indicate a D ring conformation midwaybetween a 13β-envelope and a 13β,14α-half chair. Thesubstituents at C-20 are staggered with respect to those at C-17, with the methyl C-21 anti to C-16. The remainder of theside chain extends away from the steroid rings44c (Figure 16B).Significant differences between the two epimers in the side-

chain torsion angles44b,c are as shown in Table 2.

4. METHODS FOR STEREOSELECTIVE GENERATIONOF C-20(H) STEREOGENIC CENTER IN STEROIDSIDE CHAIN

The total synthesis of sterols/steroids has represented one ofthe great challenges to synthetic chemists and culminated inestablishing elegant and practical approaches to this ring

system.4,5,7,45 Introduction of the properly functionalized sidechains onto tetracyclic steroidal starting materials has been thesubject matter of several investigations. An important aspect orproblem that arises in this approach is the stereoselectivecontrol of C-20 stereochemistry; formation of the C-20stereogenic center with hydrogen (H) at that position is ofgreat interest. Various stereoselective methods used forgeneration of both the C-20 natural and unnatural epimers(Figure 1) are discussed.4.1. Catalytic Hydrogenation of Steroidal C-20 DoubleBonds

Uskokovic and co-workers46 reported catalytic hydrogenationof a mixture of E- and Z-olefins 53 and 54 over platinum oxidecatalyst in 95% ethanol to furnish approximately 1.5:1 mixtureof saturated ketones 55 (C-20 natural configuration) and 56(C-20 unnatural configuration) (Scheme 1). Similarly, catalytic

hydrogenation of a mixture of 57 and 58 over platinum oxidecatalyst led to 20(R)-ketone 60 (50% yield), which was readilyseparated from the 20(S)-isomer 59 by crystallization with 95%ethanol. A similar selective hydrogenation of a C-20(22) doublebond was also reported by Ikan et al.47 in their synthesis of β-sitosteryl acetate.Synthesis of (22R)-22,25-dihydroxysterol and its 6-oxo

derivatives has been achieved48 from 63. Compound 62,obtained from 3β-acetoxypregn-5-en-20-one (pregnenoloneacetate) 61, upon chemoselective catalytic hydrogenationwith Pd/C furnished the 20S-63 in quantitative yield (Scheme2).Compounds 65 and 68 have been used49 for efficient

syntheses of 3β-hydroxy-5α-cholanic acid 66 and 3β-hydroxy-5-en-cholanic acid 69, respectively. Catalytic hydrogenation of C-20(22)-olefinic compounds 64 and 67 (both obtained fromcorresponding C-20 tert-alcohols followed by dehydration withPOCl3−pyridine) with PtO2 in ethanol resulted into thecorresponding saturated compounds 65 and 68 in 97% yields49

Figure 15. Methyl (20S,22E)-3-oxochola-1,4,22-trien-24-oate 38 andmethyl (20R,22E)-3- oxochola-1,4,22-trien-24-oate 52.

Figure 16. Views of (A) 3844b and (B) 52.44c

Table 2. Selected Torsion Angles for Compounds 38 and 52

38 52

C(17)−C(13)−C(14)−C(15), deg 46.8 (2) 45.9 (2)C(13)−C(14)−C(15)−C(16), deg −34.7 (3) −32.3 (3)C(14)−C(15)−C(16)−C(17), deg 9.0 (3) 5.7 (3)C(14)−C(13)−C(17)−C(16), deg −40.3 (2) −41.0 (2)C(15)−C(16)−C(17)−C(13), deg 19.6 (3) 22.1 (3)C(13)−C(17)−C(20)−C(21), deg 174.6 (2) −66.0 (3)C(16)−C(17)−C(20)−C(21), deg 54.3 (3) 172.8 (2)C(17)−C(20)−C(22)−C(23), deg 143.4 (3) −132.3 (3)C(21)−C(20)−C(22)−C(23), deg −92.8 (4) 103.0 (3)

Scheme 1


dx.doi.org/10.1021/cr4004083 | Chem. Rev. XXXX, XXX, XXX−XXXE

with C-20R natural configuration (Scheme 3). Kametani et al.50

reported the first asymmetric total synthesis of (+)-chenodeox-

ycholic acid 72 via hydrogenation of the 20(22)-dehydrocompound 70 with Pt in methanol, resulting in 71 in 97% yieldwith C-20 natural configuration (Scheme 3). The obtained 71was converted to chenodeoxycholic acid 72 after somesynthetic manipulations.Catalytic hydrogenation of 73 with Rh−Al2O3 gave 74 in

90% yield as a mixture of C-20 epimers (20S:20R 4:3).51 In thesame report,51 catalytic hydrogenation of 75 with Pd/C gave amixture of C-20 hydrogenated product 76 in 56% yield(mixture at C-20) and deoxygenated product 77 in 34% yield(also mixture at C-20) (Scheme 4).

Stereoselective and catalytic reduction of steroidal 5-ylidenetetronate derivative to control the stereochemistry ofthe contiguous four acyclic chiral centers has been described.52

The steroidal Z-isomer 78, upon catalytic hydrogenation overrhodium−alumina, afforded52 the saturated lactone 79 as thesole product (90% yield) (Scheme 5). Again, the steroidal E-isomer 80, upon catalytic hydrogenation over rhodium−alumina, resulted in lactone 81 in 92% yield. Similarly, catalytic

hydrogenation of steroidal olefin 82 to lactone 83 occurred in92% yield.53

Similar type of catalytic hydrogenation of olefin 84 over 5%Rh−Al2O3 in ethyl acetate afforded54 lactone 85 with C-20natural configuration in 92% yield (Scheme 6). Again,

reduction of steroidal C-20(21)-ene 86 over 5% Rh−Al2O3 inethyl acetate afforded tetraacetylcastasterone 87 (naturalconfiguration at C-20) and its C-20 epimer 88 in 92% yieldin the ratio 1:1. This indicates that the position of double bondin the present substrate 86 under similar reaction conditionsmay profoundly affect the configuration of the product.Honda et al.55 described catalytic hydrogenation of a mixture

of olefins 89 and 90 over Pd/C in ethyl acetate, resulting in 91as a C-20 epimeric mixture in 89% yield (Scheme 7).

Scheme 2

Scheme 3

Scheme 4

Scheme 5

Scheme 6

Scheme 7


dx.doi.org/10.1021/cr4004083 | Chem. Rev. XXXX, XXX, XXX−XXXF

The reaction condition/method played an important role inthe stereoselective hydrogenation of double bonds. Catalytichydrogenation56 of all three olefinic double bonds at C-16, C-20, and C-24 in 92 with Pd/C in EtOAc−EtOH provided C-20epimeric compound 93 in 98% yield [diastereomeric ratio (dr)2.5:1 20S:20R] (Scheme 8).

Stereoselective and chemoselective reduction57 of dienol 94by use of Raney nickel in ethanol at 50 °C provided 95a as amajor product (20R:20S ≈ 4:1), which upon cleavage oftetrahydropyranyl (THP) ether by p-toluenesulfonic acid(PTSA)−MeOH afforded 95b in 52% yield over two steps(Scheme 9).

Chemoselective transfer hydrogenation58 of 96, with acatalytic amount of 10% Pd/C and excess triethylsilane inmethanol, afforded 97 and 98 as a C-20 epimeric mixture(Scheme 10).

Zhang and Danishefsky59 reported the total synthesis of(±)-aplykurodinone 1 (101), in which stereoselective installa-tion of the C-13 methyl group through hydrogenation withhomogeneous catalyst is the key step. Upon hydrogenation inthe presence of Crabtree catalyst in dichloromethane, thetrisubstituted olefin 99 was reduced in diastereoselectivefashion (>5:1) to afford 100 in 50% yield (Scheme 11).Compound 100 bears all the stereocenters of aplykurodinone 1101. In the same report,59 stereoselective and chemoselectivereduction of disubstituted olefin 102 by Wilkinson’s catalystunder atmospheric hydrogen in benzene resulted 13-epi-aplykurodinone 1 103 (>6:1) in 67% yield.4.2. Ionic Hydrogenation

Ionic hydrogenation of the steroidal C-20,22-ketene dithioace-tal 104, obtained from commercially available60 16-dehydro-pregnenolone acetate (3β-acetoxypregna-5,16-dien-21-one), byuse of triethylsilane (Et3SiH) and trifluoroacetic acid(CF3COOH) in dichloromethane afforded61 the C(20R)

saturated compound 105 in 89% yield with 100% stereo-selectivity (Scheme 12).

Ionic hydrogenation reaction involves a carbocation−silanehydride transfer reaction. Ionic hydrogenation of olefinsgenerates the carbocation at the more substituted carbon,followed by hydride transfer reaction.62a In the present case,there is formation of carbocation at C-22 to give the sulfur-stabilized intermediate62b 104A (Figure 17). Protonation hy

trifluoroacetic acid at C-20 position in 104 from the lesshindered α-face of the steroid backbone leads to formation ofcarbocation at C-22, followed by transfer of hydride (fromEt3SiH) at C-22, resulting in the exclusive formation ofC(20R)-methyl product 105.Ionic hydrogenation63 is an effective method for the removal

of steroidal tertiary alcohols. Ionic hydrogenation of steroidalC-20 tert-alcohol 108 by use of triethylsilane and trifluoroaceticacid64 gave the deoxygenated product 105, with unnaturalC(20R) stereochemistry, in low yield (41%). The same reactionwith Et3SiH and boron trifluoride etherate (BF3·OEt2) in placeof trifluoroacetic acid gave the C-20 deoxygenated product10565,66 in 94% yield (Scheme 13). Similarly, 106, uponexposure to similar reaction conditions (Et3SiH, BF3·OEt2)leading to deoxygenation of the C-20 tert-alcohol along with

Scheme 8

Scheme 9

Scheme 10

Scheme 11

Scheme 12

Figure 17. Mechanism of ionic hydrogenation of the C-20,22-ketenedithioacetal 104.


dx.doi.org/10.1021/cr4004083 | Chem. Rev. XXXX, XXX, XXX−XXXG

deprotection of the 3β-tert-butyldimethylsilyl (TBDMS) group,gives 109 in 90% yield. The same product 109 was obtainedunder identical reaction conditions on 3,20-diol 107 inexcellent yield (92%). Compound 111, upon ionic hydro-genation with Et3SiH and BF3·OEt2 in dichloromethane,afforded 112 in 94% yield (Scheme 13). The obtainedintermediates 105 and 112 were transformed to thecorresponding unnatural steroidal C(20R) aldehydes 110 and113, respectively. The steroidal unnatural C(20R) aldehydes110 and 113 are ideal starting materials66 for the synthesis oflarge number of naturally occurring steroids with unnaturalstereocenter at C-20.4.3. C-20 Alkylation

4.3.1. Alkylation of Steroidal C-21 Esters. Wicha andBal67 reported stereoselective C-20 alkylation of steroidal ester115 [obtained from 3β-acetoxyandrost-5-en-20-one 114 viaReformatsky reaction followed by dehydration, selectivehydrogenation of C-17(20) double bond, and exchange ofprotecting group] with bromo compound 116 in the presenceof LDA (lithium diisopropylamide) and HMPA (hexamethylphosphorotriamide), affording 117 in 66% yield (Scheme 14).Alkylation68 of steroidal ester 115 with methyl iodide intetrahydrofuran (THF), with slight excess of LDA in HMPA,gave 118 in 91% yield (Scheme 14). Similarly, alkylation ofester 115 with 1-bromo-4-methylpentane (isohexyl bromide)

gave methyl ester 119 in 86% yield. The intermediatepregnenoic acid ester 115 was synthesized by Wittig−Hornerreaction69 on steroidal C-20 ketone 114, followed by Mg−MeOH reduction.70 Stereoselective synthesis of (20S)-cholest-5-en-3β-ol from 3β-(tetrahydropyran-2-yloxy)androst-5-en-17-one via ethyl (20R)-3β-(tetrahydropyran-2-yloxy)-23,24-bis-norchol-5-en-22-oate in high yield has been described byJarzebski and Wicha.71 In this report,71 methylation of ethylester of 115 with LDA/MeI furnished the (20R)-methylderivative as the sole product.The stereoselective synthesis of 25(R),26- and 25(S),26-

dihydroxycholesterols were accomplished72,73 by the C-20alkylation−reduction method. Steroidal ester 115 was alkylatedwith iodide 120 in the presence of LDA to affordmonoalkylated ester 121 in 80% yield (Scheme 15). Similarly,when esters 115 and 124 were alkylated with 122 and 120,monoalkylated esters 123, 125, and 126 were obtained in 84%,85%, and 85% yield, respectively (Scheme 15).

An epimer of natural hormone 17-epi-calcitriol wassynthesized via 17-epi-cholesterol as described.74 One of thekey steps in this synthesis was C-20 alkylation of steroidal ester130. The C-17-epi-steroidal ester 130 was synthesized from127. Compound 127, upon reaction with methyl diazoacetatein the presence of palladium(II) acetate, afforded epimers 128aand 128b in 92% yield (7:1) (Scheme 16). Treatment of 128awith lithium in liquid ammonia in the presence of THF as acosolvent and tert-butyl alcohol as a proton donor gave amixture of alcohol and aldehyde. The crude product wasreduced with LiAlH4 to give 129 in 90% yield. Compound 129was oxidized with dimethyl sulfoxide (DMSO)−PySO3, furtheroxidized with KMnO4 in tert-butanol, and then treated withdiazomethane to afford 130. C-20 alkylation74 of 17-epi ester130 by use of LDA−methyl iodide−HMPA gave diastereomeri-cally pure product 131 in almost quantitative yield (Scheme16). In this case, the orientation of C-17 hydrogen plays a rolein stereoselective generation of the C-20 chiral center from 130to 131. Similarly, diastereoselective alkylation of pregnanoicacid ester 132 afforded product 133 in 98% yield.Alkylation75 of steroidal ester 134 with (Z)-1-bromo-3-

trimethyl-4-methylpent-2-ene 135 afforded stereoselective

Scheme 13

Scheme 14

Scheme 15


dx.doi.org/10.1021/cr4004083 | Chem. Rev. XXXX, XXX, XXX−XXXH

product 136 in 75% yield (Scheme 17). Similarly, alkylation ofester 134 with (Z)-1,3-dibromo-4-methylpent-2-ene 137produced 138 in 80% yield.

Guo and co-workers76 reported stereoselective alkylation ofsteroidal ester 139 with LDA and isohexyl bromide in thepresence of HMPA at −78 °C, resulting in (20R) ester 140 in75% yield (Scheme 18).

4.3.2. Alkylation of Unsaturated Steroidal C-21 Esters.Stereoselective synthesis of 20S and 20R steroidal side chainsvia a facile alkylation process starting from unsaturated esterprecursor was reported.40,77 Reaction of (E)-ethyl 3β-(tert-butyldimethylsiloxy)pregna-5,17(20)-dien-21-oate 141, withexcess LDA, followed by alkylation with methyl iodide in thepresence of HMPA, furnished methylated products 142a and

142b (ratio 94:6) in 94% combined yield (Scheme 19).Similarly, when 141 was alkylated with LDA and isohexyl

iodide, products 143a and 143b (ratio 94:6) were obtained in98% yield. Analogously, when enoates (E)-ethyl 3β-(tert-butyldimethylsiloxy)-5α-pregn-17(20)-en-21-oate 144 and(E)-ethyl 6β-methoxy-3α,5-cyclo-5α-pregn-17(20)-en-21-oate146 are reacted with LDA followed by methyl iodide, formationof (20S) alkylated products 145 and 147 takes place in 89%and 94% yield, respectively (Scheme 19).

4.3.3. Alkylation of C-20 Cyano Steroid. C-20 cyanosteroid 148 was prepared from 3β-hydroxyandrost-5-en-20-onevia Wittig reaction followed by reduction of α,β-unsaturatednitrile with Mg−MeOH in quantitative yield.78 C-20 cyanosteroid 148, upon condensation/alkylation with (S)-benzyl 2,3-epoxypropyl ether or (R)-benzyl 2,3-epoxypropyl ether in thepresence of lithium hexamethyldisilazide [LiN(SiMe3)2] inTHF, gave78 a C-20 epimeric mixture of cyano alcohols 149aand 149b (Scheme 20).

4.3.4. Alkylation of Des-AB Steroids. Interest in steroidsynthesis has been characterized by the development ofimaginative new ways of synthesizing hydrindanone andhydrindenone derivatives, which represent the C,D-ring systemand side-chain unit of the steroids. The alkylation methodshown for the steroid skeleton is also applicable for des-ABsteroids having cis or trans ring junctions. The obtainedproducts are useful starting materials for the synthesis ofvitamins.Clase and Money79 have described stereoselective alkylation

of ketal ester 151 (synthesized from 150 via Wittig reactionfollowed by Mg−MeOH reduction) with 5-iodo-2-methylpent-2-ene 152 to afford 153 in 95% yield (Scheme 21). Similarly,ester 151 was alkylated80 with isohexyl iodide 154 to give 155in 71% yield. Treatment of 156 with LDA in HMPA−THF,followed by addition of side-chain synthon 157, resulted in the

Scheme 16

Scheme 17

Scheme 18

Scheme 19

Scheme 20


dx.doi.org/10.1021/cr4004083 | Chem. Rev. XXXX, XXX, XXX−XXXI

efficient formation of alkylated ester 158 in 87% yield81

(Scheme 21).Van Gool et al.82 reported the alkylation of cis-fused isomer

162 (obtained from Hajos−Wiechert ketone 159 via asequence of reactions) with LDA and MeI to furnish 163 in92% yield with complete diastereoselectivity (Scheme 22).

Stereoselective alkylation83 of ester 164 and cyanocompound 165 with bromo derivative 166 in the presence ofLDA afforded 167 and 168 in 70% and 95% yield, respectively,with different configurations (Scheme 23).

Alkylation of ketal ester 169 with LDA/THF, followed bymethyl bromoacetate and a catalytic amount of tetrabutylam-monium iodide, afforded84 ketal diester 170 in 93% yield with>99% diastereoselectivity (Scheme 24).Selective alkylation of 173 (obtained from 171 via Wittig

reaction followed by catalytic hydrogenation) at the α-positionof carboethoxy group, by use of LDA, isohexyl iodide, andHMPA, gave 174 in 75% yield85 (Scheme 25). Alkylation of173 with MeI and bromoderivative 176 under analogousconditions afforded 175 and 177 in 75% and 76% yield,respectively.85 1α,25-Dihydroxyvitamin D3 diastereomer, differ-ing from the parent compound in configuration at four

asymmetric carbon atoms in rings C/D and side chain (C-13,C-14, C-17, and C-20), was synthesized from intermediates174, 175, and 177 and was shown to have a significant affinityfor the vitamin D receptor.85

Michalak and Wicha86 reported stereoselective alkylation ofdes-AB 17-epi-steroid, used for the synthesis of 17-epi-calcitriolderivatives. Cyclopropane carboxylic ester 178 was reducedwith lithium in liquid ammonia−THF in the presence of tert-butanol, followed by oxidation with Jones reagent andtreatment with diazomethane, afforded ester 179. Treatmentof 179 with LDA in THF at −78 °C, followed by MeI, affordedmethyl derivative 180 in 95% yield (Scheme 26)

4.4. Ring-Opening of Steroidal C-20,22-Oxirane

Koreeda and Koizumi22a described the reaction of iso-amylmagnesium bromide in THF with epoxide 182, derivedfrom pregnenolone derivative 181. The rearranged alcohol 183was produced with unnatural configuration at C-20, and 100%stereoselective hydride shift occurred during the transformation(Scheme 27).

Scheme 21

Scheme 22

Scheme 23

Scheme 24

Scheme 25

Scheme 26

Scheme 27


dx.doi.org/10.1021/cr4004083 | Chem. Rev. XXXX, XXX, XXX−XXXJ

Schauder and Krief87 described the stereoselective hemisyn-thesis of 20S-isolanosterol (20-epi-lanosterol) via a sequence ofreactions. The stereoselective hydride shift during the reactionbetween an epoxide and the Grignard reagent (derived fromethoxyacetylene) have been discussed. Epoxide 186 wasobtained from C-20 ketone 184 via a sequence of reactions.Reaction of epoxide 186 and ethoxyacetylene magnesiumbromide in ether−benzene afforded 187 via C-22 aldehydeformed in situ in 67% yield with unnatural configuration at C-20 (Scheme 28).

4.5. Ene Reaction

The Lewis acid-mediated/catalyzed ene reaction represents animportant alternative method for the addition of an allyl groupto a carbonyl group. The resulting secondary homoallylicalcohols are amenable to a number of structural modificationsand constitute useful synthetic building blocks. Thesehomoallylic alcohols are formally the synthetic equivalent ofaldol addition products, because the olefin of the products canbe a surrogate for carbonyl functionality. The configuration atC-20 in the product of the ene reaction depends on the 17(20)-olefin. The Z-olefin, upon ene reaction with a variety ofenophiles, usually gives the natural configuration, and E-olefingives the unnatural configuration. Another major difference isthat the yield of the product derived from Z-olefin is greater ascompared to E-olefin.4.5.1. Ene Reaction with Propiolate Esters. Lewis acid-

induced reactions of acetylenic esters with alkenes provide aversatile method for formation of new carbon−carbon doublebonds with a great deal of stereo- and regiocontrol. Snider etal.88 described ene reaction of nonsteroidal substrates withacetylenic esters and also proposed the mechanism.Diethylaluminum chloride (Et2AlCl) catalyzed89 the ene

reaction of steroidal 17(20)-(Z)-enes 188a and 188b withmethyl propiolate in benzene to afford trienes 189a and 189b,respectively, in 95% yield (Scheme 29). The same reactionconditions were employed to convert the ethylidene derivativeof estrone methyl ether 190 via ene reaction to ester 191 in90% yield.The 17(Z)-ethylidene steroids 188a, 193, and 196 were

synthesized via Wittig reaction of corresponding C-17-ketones114, 192, and 195, followed by acetylation.41a The ene reactionof (17Z)-ethylidene steroids 188a, 193, and 196 with methyl

propiolate in the presence of EtAlCl2 afforded41a ene products

189a, 194, and 197, respectively, in excellent yields with C-20natural configuration (Scheme 30).

(17E)-3β-Acetoxy-5,17(20)-pregnadiene 199 was synthe-sized from 114 via Wittig−Horner reaction followed byreduction−bromination−reduction and acetylation.41b Daubenand Brookhart41b reported that the EtAlCl2-catalyzed enereaction between (17E)-3β-acetoxy-5,17(20)-pregnadiene 199and methyl propiolate proceeded stereospecifically from the α-face to yield methyl (20S)-3β-acetoxy-5,16,22-trienoate 200with unnatural configuration at C-20 (Scheme 31). The ene

reaction with the steroidal E-olefin proceeds at least an order ofmagnitude less rapidly than with the Z-isomer, but the reactionproceeds in a stereospecific manner. In this case, configurationof the steroidal olefin describes the stereochemical outcome ofthe reaction.The unnatural enantiomer of desmosterol (ent-desmosterol)

was synthesized by Westover and Covey90 via ene reaction is

Scheme 28

Scheme 29

Scheme 30

Scheme 31


dx.doi.org/10.1021/cr4004083 | Chem. Rev. XXXX, XXX, XXX−XXXK

the key step. The C-17(20)-Z-olefin 202 was synthesized byWittig reaction of 201, followed by acetylation. The enereaction90 of olefin 202 with methyl propiolate in the presenceof Et2AlCl afforded 203 with C(20R) configuration (Scheme32). Synthesis of enantiomeric deoxycholic acid, lithiocholic

acid, and chenodeoxycholic acid was reported by Katona et al.91

In their synthesis, ene reaction of 205 and 208 was the key step.The C-17(20)-Z-olefins 205, 208a, and 208b was prepared byWittig reaction of 204, 207a, and 207b followed by acetylation.The ene reaction of steroidal olefin 205 with methyl propiolatein the presence of MeAlCl2 gave 206, which is the precursor ofent-deoxycholic acid, in good yield (Scheme 32). Again,steroidal olefins 208a and 208b, upon reaction with methylpropiolate catalyzed by Et2AlCl, lead to 209a and 209b,respectively.91 In all cases, the configuration at C-20 was thesame.Acetylated compound 210, upon ene reaction with ethyl

propiolate in the presence of EtAlCl2, produced92 211 in 96%

yield (Scheme 33).

4.5.2. Ene Reaction with Acrylates. Acid-mediated enereaction of steroidal Z-ene with acrylate-type dienophiles is alsowell documented.93 Acetate 188a, upon treatment with methylacrylate and EtAlCl2 in dichloromethane at room temperature,afforded93 212 in 85% yield (Scheme 34). The use of α-substituted acrylic esters, namely, methyl 2-chloroacrylate in theene reaction, was also demonstrated for the introduction of twochiral centers in steroid side chain. Accordingly, 213 and 214were obtained from acetate 188a and methyl 2-chloroacrylatein the ratio 6:1 (Scheme 34).4.5.3. Carbonyl−Ene Reaction. Uskokovic and co-work-

ers93 described a simple and efficient method for highlystereoselective introduction of steroid side chains (at C-17 andC-20), which are suitably functionalized for further elaboration.The ene reaction of (17Z)-ethylidene steroids with variousenophiles, such as formaldehyde leads93 to useful intermediates

that contain the natural steroid configuration at C-20.Treatment of (Z)-3-acetoxypregna-5,17(20)-diene 188a withparaformaldehyde (CH2O)n in the presence of boron trifluorideetherate (BF3·Et2O) in acetic anhydride (Ac2O)/dichloro-methane at room temperature afforded diacetate 215a in 59%yield (Scheme 35).

Hazra et al.94 described the application of cation-exchangeresins as catalysts for the ene reaction. Ene reaction of 188cwith (CH2O)n in the presence of Ac2O, with various cation-exchange resins as catalyst, stereospecifically afforded the C-22acetate 215d (Scheme 35) in excellent yields. Again, the 22-acetate 215d was obtained in 82% yield by ene reaction oftosylate 188c with (CH2O)n, Ac2O, and titanium triisopropoxychloride as a Lewis acid in dichloromethane.95 Me3SiCl and t-BuMe2SiCl have also yielded the same acetate in 81% and 74%yields, respectively, under similar reaction conditions.95 In allcases, the configuration at C-20 is natural.Nakai and co-workers96 reported Lewis acid-catalyzed ene

reaction with glyoxylate. The ene reaction of steroidal olefin216 with methyl glyoxylate in the presence of Me2AlCl afforded(20S,22R)-erythro product 217 as a single stereoisomer in 67%yield (Scheme 36). Similarly, ene reaction of 216 with α-haloaldehyde was shown to exhibit a high anti-diastereofacialselection or syn-diastereoselection to afford an efficient methodfor preparing stereochemically defined β-haloalcohols includingthe 22R-hydroxy side chain unit in steroids.97 The ene reactionof 216 and chloroacetaldehyde with Me2AlCl gave 20S,22R-synproduct 218 as a single natural C-20 epimer in 73% yield(Scheme 36).Again, Me2AlCl-promoted ene approach to either (22S)- or

(22R)-hydroxy steroid side chain has been described by thesame group.98 In this case, the ene reaction was based on theconcept of chelation versus nonchelation control of thecarbonyl−ene reaction; the choice of Lewis acid and protectinggroup of α-alkoxyaldehyde enophiles allows control of thereaction. Ene reaction of steroidal olefin 216 with α-

Scheme 32

Scheme 33

Scheme 34

Scheme 35


dx.doi.org/10.1021/cr4004083 | Chem. Rev. XXXX, XXX, XXX−XXXL

silyloxyaldehyde 219 and Me2AlCl afforded (22R)-hydroxyproduct 220 with C-20 natural configuration as a singlestereoisomer in 90% yield (Scheme 37). Ene reaction of 221

with α-benzyloxyaldehyde 222 and SnCl4 gave the correspond-ing product (22S)-223 in 91% yield with >99% diastereose-lectivity without cleavage of the silyl protecting group.Brassinosteroids have a 22R-hydroxy group in the side chain,

and attention has been focused on the development ofmethodologies/routes for the stereocontrolled generation ofsteroidal side chain. Nakai and co-workers99 reported the enereaction approach for concurrent control over the chiral centersat C-20 and C-22 of steroid side chain. Ene reactions of (Z)-steroidal olefin 216 with acetylenic aldehydes 224 (having silyland alkyl parts) in the presence of Me2AlCl produce (20S,22R)-erythro-22-hydroxy-23,24-acetylenic steroid side chain 225 withhigh diastereofacial selectivity (Scheme 38, Table 3).Ene reaction of 221,100 229a,101a 229b,101b and 231102 with

paraformaldehyde in the presence of catalytic amounts of BF3·Et2O leads to the corresponding alcohols 227, 230a, 230b, and

232, respectively, in good yields (Scheme 39). Matsuya et al.103

reported the ene reaction of 221 and 226 with (CH2O)n in the

presence of Me2AlCl to the corresponding alcohols 227 and228 (Scheme 39). Similarly, stereospecific ene reaction104 ofketone 233 with (CH2O)n in the presence of BF3·Et2O afforded5α-23,24-bisnorchol-16-en-22-ol-3-one 234 in 98% yield(Scheme 39). All products are obtained with C-20 naturalconfiguration.(Z)-17-Ethylidene steroid 196 was subjected105 to stereo-

selective ene reaction with paraformaldehyde in the presence ofboron trifluoride etherate to give C-22 alcohol 235 as a singleproduct in 80% yield (Scheme 40).Synthesis of C2-symmetric bis(20S)-5α-23,24-bisnorchol-16-

en-3β,6α,7β-triol-22-terephthaloate, active as a Na+-transport-ing transmembrane channel, was reported106 from 3β-hydroxyandrost-5-en-17-one 236 via stereospecific functional-

Scheme 36

Scheme 37

Scheme 38

Table 3. Ene Reactions of Steroidal Olefin 216 withAldehydes 224a−d99

entry aldehyde yield (%) 22R:22S

1 224a 02 224b quant >95:53 224c 90 90:104 224d quant 90:10

Scheme 39

Scheme 40


dx.doi.org/10.1021/cr4004083 | Chem. Rev. XXXX, XXX, XXX−XXXM

ization of the side chain by ene reaction. The starting steroidalmaterial 239 was synthesized from 3β-hydroxyandrost-5-en-17-one 236 via a sequence of reactions in which Wittig reaction isa key step. Transformation of (Z)-17(20)-ethylidene 239 to the(20S)-22-hydroxy side-chain compound 240 with (CH2O)n inthe presence of BF3·Et2O in 79% yield was the key step in theirsynthesis (Scheme 41).

Compound 188c was subjected107 to ene reaction with(CH2O)n in the presence of Et2AlCl as catalyst, and 22-hydroxyderivative 241 was obtained in 74% yield (Scheme 42). In

addition, 3β-chloro-17-ethylidene steroid 242 was isolated asbyproduct; the latter was formed as a result of partialtransformation only at the C-3 center. Ene reaction of olefin243 with (CH2O)n in the presence of Et2AlCl in CH2Cl2afforded 22-hydroxy compound 244 in 68% yield (Scheme 42).Dimethylaluminum chloride-mediated ene reaction of

aldehydes with (Z)-3β-acetoxy-5,17(20)-pregnadiene 188a atlow temperatures, followed by acetylation of the resultingalcohols, has been shown to produce108 stereoselectively 22-acetoxylated steroid derivatives 245 in good to excellent yields(Scheme 43, Table 4). Stereochemical outcome of these enereactions depends on the size of the aldehyde employed; theless sterically hindered aldehydes, such as 4-methylpentanal andcyclohexane carboxaldehyde, afforded (20S,22R)-22-acetoxyproducts stereoselectively, whereas benzaldehyde and other

aromatic aldehydes produced predominantly (20S,22S)-22-acetates.Lewis acid-mediated carbonyl−ene reaction has been used109

for the synthesis of 6-deoxoteasterone, a brassinolidebiosynthetic intermediate, and its 20-epimer from steroidal C-17(20)-olefin and chiral α-alkoxyaldehyde. The carbonyl−enereaction between aldehyde 246 and (Z)-3β-acetoxypregna-5,17-diene 188a with MeAlCl2, furnished ene adduct 247 in65% yield, with C-20 unnatural configuration (Scheme 44).

This stereochemical outcome was unusual compared withhitherto-known ene reactions between (Z)-ethylidene steroidand various enophiles, which gave only 20-natural steroid. Tothis comparison, the ene reaction between 246 and (E)-3β-acetoxypregna-5,17-diene 199 was reported to proceedsmoothly under the same conditions as those for (Z)-isomer,and ene adduct 248 with natural configuration at C-20 wasobtained in 52% yield. Similarly, ene reaction of 188a and (R)-2-benzyloxy-3-methylbutanal 249 in the presence of EtAlCl2,followed by hydrolysis, gave 250 in 53% yield for two steps.110

Scheme 41

Scheme 42

Scheme 43

Table 4. Me2AlCl-Mediated Ene Reactions of Pregnadiene188a with Various Aldehydes108

Scheme 44


dx.doi.org/10.1021/cr4004083 | Chem. Rev. XXXX, XXX, XXX−XXXN

The four models of contignasterol’s side chains have beenstereospecifically synthesized by the Me2AlCl-mediated enereaction between steroidal derivative 231 and pseudo-enantiomeric aldehydes 251 and 254111 (Scheme 45). Reaction

with aldehyde 251 led to formation of 252 and 253 in 80% and16% yield, respectively, as an epimeric mixture at C-22, with C-20 natural configuration. Again, reaction with aldehyde 254gave 255 and 256 in 50% and 10% yield, respectively. Similartype of Me2AlCl-mediated ene reaction on 257 with aldehyde258 gave112 (22S,24R) adduct 259 (72%) and epimer(22R,24R) adduct 260 (18%) (Scheme 45).Kumar and Covey113 reported an efficient total synthesis of

the enantiomer of cholesterol from ent-testosterone. TheMe2AlCl-mediated ene reaction of Z-olefin 261 with 4-methyl-1-pentanal gave a quantitative yield of the inseparableepimeric 22-hydroxy steroid 262 (Scheme 46). As observed

previously for steroids of naturally occurring absoluteconfiguration, stereocontrol at C-20 was achieved due to thepresence of the methyl group at C-13, which in this caseprecludes the reaction taking place from the α-face of thesteroid.Nemoto and co-workers114a reported the synthesis of estrane

analogues of OSW-1 from estrone 263. The 17(20)-ene 265was synthesized from estrone derivative 264 via Wittig reaction(Scheme 47). Hydroxymethylation accompanied by theformation of a new chiral center was achieved throughstereoselective ene reaction of 265 with (CH2O)n and Me2AlCl,which approaches from the less congested α-side to afford thealcohol 266 in 61% yield.114 Reaction time and temperaturewere important for satisfactory results in this reaction, asaromatic hydroxymethylation on the A-ring competed with the

ene reaction if the experiment was carried out for prolongedtime or at over −60 °C.The carbonyl−ene reaction is also applicable for not only

A,B,C-ring-containing compound but also des-AB steroids. Enereaction of (Z)-ethylidene derivative 267 with (CH2O)n in thepresence of Me2AlCl proceeded

115 stereoselectively to afford268 in 86% yield (Scheme 48).

Ene reaction of 210, 269, and 271 with (CH2O)n, catalyzedby BF3·Et2O/Me2AlCl and BF3·Et2O, gave 270116a−c and272116d stereospecifically (Scheme 49). Similarly, ene reactionof 274 (obtained from 273 via reduction) with (CH2O)n andBF3·Et2O lead exclusively117 to alcohol 275 in 82% overall yield(Scheme 49).4.6. Aldol Reaction

Shi et al.118 described a novel and efficient approach toconstruction of the 16β,17α-dihydroxycholest-22-one steroidalarchitecture characteristic of the saponin OSW-1 (22, Figure 7)

Scheme 45

Scheme 46

Scheme 47

Scheme 48

Scheme 49


dx.doi.org/10.1021/cr4004083 | Chem. Rev. XXXX, XXX, XXX−XXXO

family in which aldol condensation was the key reaction. Aldolcondensation of ketones 276−278 (Scheme 50), with lithium

E-enolate of ethyl propionate predominantly led to the desiredproduct with 20(S) configuration. The 17α-hydroxy(silyloxy)-20S-products 279a, 280a, and 281a were formed in 41%, 63%,and 43% yield, respectively (method A, Table 5). Without

control of the exclusive generation of E-enolate of ethylpropionate, reaction of ketone 276 provided the natural 20Sproduct 279a in a comparable 41% yield, but its 20R isomer279b was also obtained in 29% yield (method B).However, reaction of ketone 277 under similar conditions in

the absence of HMPA (method C) afforded the desired 280a ina 75% yield, with its 20R-isomer 280b in 12% yield.Condensation of 277 with isobutyl and dodecyl propionate(method C) provided the desired 17α-hydroxy-20(S) adducts282a and 283a in good yields (78% and 81%, respectively).Aldol condensation119 of 3β-hydroxyandrost-5-en-17-one

236 with propionitrile and LDA at −78 °C afforded 284 asepimeric mixture in excellent yield (Scheme 51).

4.7. Michael Addition Reaction

A stereospecific protocol for the steroid side chain constructionbased on Michael addition of nitroalkanes to steroidal 17(20)-en-16-ones has been developed120 for the synthesis ofsapogenin, steroidal alkaloid, and cholesterol also. Michael

addition of nitroacetate 286 to α,β-unsaturated ketone 285 (E-enone) afforded 287 in 40% yield, which was utilized for thesynthesis of diosgenin (Scheme 52).

Synthesis of solanidine was achieved via Michael addition ofmethyl 5-nitro-2S-methyl pentanoate 288 with α,β-unsaturatedketone 285, resulting121 in intermediates 289 and 290 in 20%and 26% yield, respectively (Scheme 53).

Michael addition of nitromethane or sodium cyanide onketones 285 and 292 (Z-enone) provided122 the correspondingcompounds 291, with C-20 natural configuration, and 293,with unnatural configuration at C-20 (Scheme 54). Thestereochemical outcome of the Michael addition depends onthe starting steroidal enone.

4.8. Mukaiyama−Michael Conjugate Addition Reaction

Sterol C/D side-chain fragments were synthesized from keteneacetal derived from 6-methylheptanoic acid, 2-methylcyclopent-2-en-1-one, and allyl methyl carbonate, with Mukaiyama−Michael conjugate addition and Tsuji alkylation as the keysteps.123,124 Reaction of enone 294 with ketene acetal 295 inthe presence of trityl hexachloroantimonate (TrSbCl6),followed by quenching with pyridine-2-methanol, afforded amixture of O-trimethylsilyl enol ether 296 and correspondingketone 297 in 76% yield (Scheme 55).The carbon framework of des-AB cholestane was obtained by

the one-pot three-component reaction of ketene acetal,unsaturated ketone, and ketal previously described.125 Reactionof ketene acetal 298 with α,β-unsaturated ketone 294 in the

Scheme 50a

aReagents and conditions: Method A, (i) i-Pr2NH, n-BuLi, −78 °C, 15min; (ii) −78 °C, HMPA, THF, propionate, 0.5 h; (iii) 276−278, −78°C. Method B, (i) i-Pr2NH, n-BuLi, −78 °C, 15 min; (ii) propionate,HMPA, THF, −78 °C, 0.5 h; (iii) 276−278, −78 °C. Method C,similar to method B but without addition of HMPA.

Table 5. Aldol Condensation with Propionate Enolates118

entry ketone propionate method product (yield, %)

1 276 ethyl A 279a (41),279b (0)2 277 ethyl A 280a (63), 280b (0)3 278 ethyl A 281a (43), 281b (0)4 277 ethyl B 279a (41), 279b (29)5 277 ethyl C 280a (75), 280b (12)6 277 isobutyl C 282a (78), 282b (0)7 277 dodecyl C 283a (81), 283b (0)

Scheme 51

Scheme 52

Scheme 53

Scheme 54


dx.doi.org/10.1021/cr4004083 | Chem. Rev. XXXX, XXX, XXX−XXXP

presence of TrSbCl6 gave adduct 299 in 46% yield125 (Scheme56). Similarly, reaction of 300 and 294 in the presence ofTrSbCl6 gave the adduct, which upon reaction with 301 and amixture of TiCl4−Ti(OiPr)4 gave the product 302 in 68% yield.

Ketene acetal 298, upon treatment with enone 294 in thepresence of a catalytic amount of TrSbCl6 and then addition ofthe reaction mixture to 1-thiophenylbut-3-en-2-one 303 as thesecond Michael acceptor, gave diketone 304 in 72% yield126

(Scheme 57).

Wicha and co-workers127 described the diastereoselectiveMukaiyama−Michael addition reaction of selected opticallyactive ketene acetals with 2-methylcyclopent-2-en-1-one.Reaction of 294 with 305 in the presence of TrSbCl6, followedby 303, gave 306 in 55% yield. Similarly, reaction of 294 with307 and 303 afforded 308 in 75% yield (Scheme 58). Products306 and 308 are precursors for synthesis of 1α,25-dihydroxyvitamin D3 and its enantiomer.127

4.9. Chirality Transmission Approach

Radical cyclization has been one of the most productiveapplications of the temporary silicon connection. Thetemporary silicon connection transforms a potential intermo-lecular one by transiently connecting both partners through asilicon linkage. Generally, these temporary connections areethers. Temporary connectivity endows the reaction withentropic advantages as well as regiospecificity, and oftenstereoselectivity.128 The silicon-based protocol, first applied in

radical cyclizations, was extended to many types of reactions.C−C bond formation via free-radical-mediated cyclizationreactions now has a firmly established role in synthetic organicchemistry as a highly versatile and often indispensable methodof skeleton construction.128

Koreeda and George129 described the synthesis of 22-hydroxylated steroid side chain in which the regio- andstereocontrolled synthesis lies in the generation of the twostereocenters, C-17 and C-20 in a single, radical cyclization stepas a result of chirality transmission from the stereodirecting 16-hydroxy derivative. Both 309 (17E,16α) and 312 (17E,16β)underwent exclusively 6-endo cyclization that furnished, afterdesilylation, diols 311 and 314, respectively, as singlediastereomers (Scheme 59). This mode of cyclization could

result from conformational rigidity and a lower degree ofsubstitution at C-20 versus C-17. Chirality at C-16 was cleanlytransmitted to C-20. Also, a remarkable feature is the exclusiveformation of 17-α-H for both 310 and 311. Treatment of 309with (n-Bu)3SnH in the presence of a catalytic amount ofazobisisobutyronitrile (AIBN) induced cyclization of theresulting radical to give 310. Oxidation of 310 with H2O2resulted into the C-16,22-diol 311 with natural configuration atC-20. Similarly, C-16β,α-bromosilyl ether 312 produced thecyclized product 313 in 65% yield, and a similar protocol ofoxidation resulted in 314 with unnatural configuration at C-20.

Scheme 55

Scheme 56

Scheme 57

Scheme 58

Scheme 59


dx.doi.org/10.1021/cr4004083 | Chem. Rev. XXXX, XXX, XXX−XXXQ

This suggests that the chirality at C-16 determines thestereochemical outcome of the product.Again, radical cyclization of bromide 315 with Bu3SnH and

AIBN provides cyclic 316, with natural configuration at C-20and chair conformation, and its C-22 epimer 317 in a ratio of4:1 in 65% yield130 (Scheme 60). Treatment of the major

compound 316 with KOH in DMSO was found to substitute amethyl by a hydroxy group, generating silanol 318 (65% yield)as well as the protiodesilylation product 16α-hydroxycholester-ol 319 (10−20% yield). The obtained silanol 318 understandard Tamao oxidation conditions afforded diol 320 in 75%yield.The silyl connector at the C-22 hydroxyl represents another

approach to the stereoselective construction of steroid sidechains. Wicha and co-workers131 described the radicalcyclizations of 17(E) 321 and 17(Z) 325: they were virtuallynonstereoselective at C-20, with the ratio of protiodesilylationproducts 323 (with natural configuration at C-20) to 324 (withunnatural configuration at C-20) being nearly 1:1 (Scheme 61).The approach from the β-face of the Z-double bond of 325 ispoorly reflected in this product distribution. In contrast to 321and 325, the cyclizations of isopentyl derivatives 326 and 327were totally stereoselective, yielding products 328 and 329(natural configuration at C-20). This can be viewed as theminimization of allylic interactions between C-16 and C-22substituents. The use of diastereomeric silafuran mixture 322(derived from 321 and 325) produced oxetane 330. Reactionof 330 with lithium acetylide derivative 331 in the presence ofBF3·Et2O led to highly selective ring-opening and only onediastereomer, 332, in 83% yield (Scheme 61).4.10. Claisen and Claisen-type Rearrangements

Claisen rearrangement reaction, with a highly ordered six-membered transition state in the concerted cyclic process, leadsto high stereoselectivity.132 Stereospecific control of the C-20configuration in cholesterol and other sterols/steroids ispossible. From analysis of the respective transition states ofrearrangement of both possible allyl alcohols, it can be deducedthat C-17(E)-isomer 333 will produce the natural configuration(20R) at C-20 in 334, whereas the C-17(Z)-isomer 335produces steroidal unnatural C-20 isomer 336 (Scheme 62).

Carroll rearrangement of allylic ester 337 in boiling xyleneafforded132 a single rearranged material 338 (90% yield) withnatural configuration at C-20 (Scheme 63). Similarly, isomericZ-allylic keto acetate 339, upon Carroll reaction, afforded 340(62% yield) with C-20 unnatural configuration.Nakai and co-workers133 reported the synthesis of 20-epi-

cholesterol, which relies on the unprecedented β-face Claisenrearrangement of an E-vinyloxy steroid, leading exclusively to

Scheme 60

Scheme 61

Scheme 62

Scheme 63


dx.doi.org/10.1021/cr4004083 | Chem. Rev. XXXX, XXX, XXX−XXXR

the unnatural 20S chirality. The allylic alcohol 341 was treatedwith ethyl vinyl ether, in the presence of mercuric(II) acetate,and the rearranged C(20S) aldehyde 342 was obtained in 84%yield as a single unnatural C-20 stereoisomer. Aldehyde 342,after some synthetic manipulations, was converted to 20-epi-cholesterol133 (Scheme 64).

Claisen−Ireland sigmatropic rearrangement of 343 withLDA and trimethylsilyl chloride, followed by methylation withCH2N2, afforded

134 (22R)-erythro product 344 as a singlestereoisomer in 88% yield with natural configuration at C-20(Scheme 65).

Steroidal allylic alcohol 345, subjected to the conditions oforthoester Claisen rearrangement (triethyl orthoacetate,propionic acid, heating in xylene), afforded135 rearrangedester 346 as a single isomer in 98% yield with naturalconfiguration at C-20 (Scheme 66).

Xestobergsterol A 349, a potent inhibitor of histaminerelease, was synthesized from dehydroepiandrosterone (an-drostenolone) via the orthoester Claisen rearrangement.136

Compound 347 was subjected to orthoester Claisen rearrange-ment with triethyl orthoacetate and propionic acid to give therearranged ester 348 with natural configuration at C-20 as asingle isomer in 88% yield (Scheme 67).

Allylic alcohol 350 was subjected to Johnson−Claisenrearrangement and afforded137 ester 351 as a single isomer in87% yield with natural configuration at C-20 (Scheme 68).Product 351 is utilized for the synthesis of candicanoside A352, a potent antitumor saponin.

Enantioselective syntheses of both (20R)- and (20S)-des-AB-cholest-8(14),22-dien-9-one, which are potential intermediatesleading to vitamin D3, steroids and their analogues, wereachieved.138,139 Claisen rearrangement of vinyl ether 353 gavethe single product 354 in quantitative yield (Scheme 69).Similarly, epimer 355 gave a single product, 356.

Enantiomerically pure C,D-ring allylic alcohol 357 stereo-specifically undergoes [3,4]-sigmatropic rearrangements togive140 C-23-functionalized 16-ene vitamin D3 side-chainunits with natural C-20(S) configuration (Scheme 70).Reaction of allylic alcohol 357 with ethyl vinyl ether andmercury diacetate afforded the desired enol ether 358, whichunderwent thermal rearrangement in situ to give aldehyde 359in 97% yield, with only one diastereomer (Scheme 70).Johnson orthoester rearrangement of alcohol 357 withtrimethyl orthoacetate, in the presence of a catalytic amountof 2,4,6-trimethylbenzoic acid, afforded methyl ester 361 in83% yield via 360 (Scheme 70). An anion-assisted Carrollreaction, performed via the β-keto ester 362, resulted in 94%yield from the reaction of 357 with diketene. This β-keto ester362, upon reaction with 2 equiv of sodium hydride, smoothlyunderwent rearrangement and in situ decarboxylation at 140 °Cto give the 16-ene-23-methyl ketone 363 in 96% yield.Conversion of allylic alcohol 357 into an α-sulfide ester 364

Scheme 64

Scheme 65

Scheme 66

Scheme 67

Scheme 68

Scheme 69


dx.doi.org/10.1021/cr4004083 | Chem. Rev. XXXX, XXX, XXX−XXXS

by use of (phenylthio)acetyl chloride proceeded in 95% yield.This ester 364 was then methenylated by use of Tebbe’sreagent to form the corresponding allylic vinyl ether 365, whichthermally rearranged into β-keto phenyl sulfide 366 in 89%yield.4.11. Wittig Rearrangement

The concept of stereochemical transmission via [2,3]-Wittigrearrangement has several applications in steroid side-chainsynthesis.141,142 One general and simple application is toemploy the [2,3]-Wittig strategy for specifically transferring aconfigurationally defined chirality on the steroidal side chain toanother center within the side-chain framework, analogous tosimple acyclic counterparts.141,142 [2,3]-Wittig rearrangementcan also be used for specifically transmitting an epimericallydefined chirality at C-16 of the steroidal nucleus to the newchiral centers at C-20 and C-22 of the side chain (Figure 18).

Its significant feature is that it allows concurrent control ofabsolute and relative configurations at C-20 and C-22 throughthe proper combination of exo-olefin geometry, configuration(α or β) at C-16, and the key G group.141,142

Nakai and co-workers143 successfully demonstrated theutility of this approach in the stereocontrolled synthesis ofeither 22(S)- or 22(R)-hydroxy-23-acetylenic side chains fromthe single precursor with natural 20(S) configuration in bothcases. The most significant feature in this example is dianionrearrangement of 367 to afford the (20S,22S)-threo product

369 as a single stereoisomer in 75% yield (Scheme 71), whereasintroduction of the silyl group in 368 induced the reversal of

distereoselection to give the (20S,22R)-erythro product 225b asa single stereoisomer. Products 369 and 225b serve as keyintermediates for the synthesis of many important side-chain-modified steroids, such as insect hormone ecdysones and plant-growth-promoting brassinosteroids, respectively.Upon reaction with n-BuLi, the sterically congested β-face in

steroid 370 exhibits the usual erythro selection to afford 225bas a single stereoisomer144 (Scheme 72).

Castedo et al.145 reported the stereocontrolled synthesis ofsteroidal C-20 epimers via [2,3]-Wittig sigmatropic rearrange-ment under mild conditions. An efficient and closely relatedalternative relies on a primary α-oxycarbanion-induced [2,3]-Wittig sigmatropic rearrangement as the key step for stereo-specific synthesis of three-carbon side chain, suitably function-alized for further elaborations. Treatment of steroidal stannylderivative 371 at −78 °C with n-BuLi resulted in homoallylic20S alcohol 372 in 83% yield (Scheme 73). Under similarreaction conditions, n-butyllithium-induced rearrangement ofsteroidal stannyl derivative 373 afforded homoallylic 20Ralcohol 374 in 70% yield.145 The stereochemical outcome atC-20 position depends on the configuration of starting steroidalolefin.Again, Castedo et al.146 reported the steroidal β-face [2,3]-

sigmatropic rearrangement of alkoxy-organolithium intermedi-ate to stereospecific construction of the unnatural configurationat C-20 in steroid. The α-alkoxy organostannane steroidcompound 375, upon treatment with t-BuLi in refluxing THF,gave 374 in 89% yield (Scheme 74).Stereoselective [2,3]-Wittig rearrangement on 17(20)-ethyl-

idene-16α-(carbomethyl)oxy steroid 376 with LDA in THF at

Scheme 70

Figure 18. Wittig rearrangement.

Scheme 71

Scheme 72


dx.doi.org/10.1021/cr4004083 | Chem. Rev. XXXX, XXX, XXX−XXXT

−56 °C, followed by esterification with CH2N2, afforded147 α-

hydroxy ester 377 in 85% overall yield (Scheme 75).

One-step introduction148 of both the steroidal double bondat C-16 and a side chain with the natural 20R stereocenter andthe 25-hydroxy group of the principal metabolites of vitamin Din 379 was achieved via [2,3]-Wittig sigmatropic rearrangementof steroid 378 in better yield (Scheme 76).

Tsubuki et al.149 reported Wittig rearrangement of 17(20)-ethylidene-16-furfuryloxy steroids in the stereoselective con-struction of the steroid side chain. Reaction of 17E(20)-ethylidene-16α-(2-furyl)methoxy steroid 380 with t-BuLi inTHF afforded (20S,22S)- and (20S,22R)-22-hydroxy steroids381 and 382 and 17Z(20)-ethylidene-16α-(2-furyl)-hydroxymethyl steroid 383 in 61%, 28%, and 9% yields,respectively (Scheme 77). Similarly, treatment of 17E(20)-ethylidene-16β-(2-furyl)methoxy steroid 384 with base gave(20R,22R)-22-hydroxy steroid 385 and 17Z(20)-ethylidene-16β-(2-furyl)hydroxymethyl steroid 386 in 60% and 17%

yields, respectively. In disparity to this, 17Z(20)-ethylidene-16-(2-furyl)methoxy steroids 387 and 389 led to the correspond-ing 2,3-rearranged products in low yields [25% for (20R,22S)-22-hydroxy steroid 388; 31% for (20S,22R)-22-hydroxy steroid382].Tsubuki et al.150 utilized Wittig rearrangement of 17E(20)-

ethylidene-16α-(4′-methyl-2′-thienyl)methyloxy steroid forconstruction of saponin OSW-1 and its analogues. Treat-ment150 of steroid 391 with n-BuLi (10 equiv) in THF at −78°C, followed by warming to 0 °C, gave [2,3]-rearrangedproducts 382, 393, and [1,2]-rearranged 394 in a ratio of23:23:54, respectively, in 97% total yield (Scheme 78) (Table 6,entry 1). Again, reaction of 391 with s-BuLi (3 equiv) in THFat −78 °C produced 392−394 in a ratio of 19:34:47 in

Scheme 73

Scheme 74

Scheme 75

Scheme 76

Scheme 77

Scheme 78


dx.doi.org/10.1021/cr4004083 | Chem. Rev. XXXX, XXX, XXX−XXXU

moderate yield (62%) (Table 6, entry 2). Use of t-BuLi for the[2,3]-rearrangement gives better results (Table 6, entry 3).Similarly, treatment of 395 with t-BuLi (5 equiv) in THF at−78 °C gave [2,3]-rearranged product 396 (22α:22β alcoholsin a ratio of 78:22) in 59% yield (Scheme 78).4.12. Organopalladium Reagents

Trost and co-workers151−153 extensively studied the stereo-controlled introduction of side chains at C-20 by use ofsteroidal (Z)-C-17(20)-olefin compounds and palladiumchemistry. 17(20)Z-3-Methoxy-19-norpregna-1,3,5(10),17-(20)-tetraene 190, obtained from estrone methyl ether by theWittig reaction, was converted to its π-allylpalladium complex397 (Scheme 79). Complex 397 underwent C-20 alkylation by

dimethyl malonate and methyl phenylsulfonyl acetate nucleo-philes, separately in the presence of a phosphine, preferably 1,2-bis(diphenylphosphino)ethane (dppe), which proceeded highlyregio- and stereoselectively to 398 and 399 with unnaturalstereochemistry at C-20 in 81% and 82% yields, respectively.The reaction was carried out151−153 catalytically, starting

from allylic acetates 400, 402, and 404, to afford 401, 403, and405 in 83%, 86%, and 85% yield, respectively, with overallretention and natural configuration at C-20 (Scheme 80). Thetwo pathways, using stoichiometric and catalytic amounts ofpalladium, led to products with opposite stereochemistry at C-20.Palladium-catalyzed 1,4-addition of carbon nucleophiles was

applied to the regio- and stereoselective introduction of 15β-hydroxy group and side chain to steroid moiety. Upon reactionof steroidal C-15(16)-epoxy compound 406 with the dimethylmalonate nucleophile, the 1,4-adducts 407 and 408 wereobtained154,155 in 83% yield with 95:5 ratio (Scheme 81).Similarly, exposure of steroid 409 to β-keto ester 410 furnishedC-22 epimeric compound 411 in 86% yield with unnaturalconfiguration at C-20.Palladium-catalyzed regioselective hydrogenolysis of allylic

carbonates with triethylammonium formate was applied to theintroduction of steroidal C-20 side chains.37,156 The steroid sidechain with C-20 natural configuration was generated stereo-specifically by palladium-catalyzed hydrogenolysis of C-20 (Z)-

allylic carbonates with triethylammonium formate. The steroidside chain with C-20 unnatural configuration was generatedfrom C-20 (E)-allylic carbonates.37,156 Palladium-catalyzedhydrogenolysis of C-23 allylic formate 412 afforded terminalolefin 413 regioselectively (Scheme 82). The reaction was notstereoselective and shows that the product 413 is a 1:1 mixtureof stereoisomers at C-20. The intermediate π-allylpalladiumcomplex 414 can rotate freely, and hydride transfer takes placefrom both α and β sides to give both isomers.Steroidal (E)-carbonate 415 and (Z)-carbonate 416 were

subjected to palladium catalysis with an excess of formic acid

Table 6. Wittig Rearrangement150 of ThiophenemethylEther 391

entry base yield (%) ratio of 392/393/394

1 n-BuLi 97 23:23:542 s-BuLi 62 19:34:473 t-BuLi 90 40:18:42

Scheme 79

Scheme 80

Scheme 81

Scheme 82


dx.doi.org/10.1021/cr4004083 | Chem. Rev. XXXX, XXX, XXX−XXXV

and triethylamine to give the unnatural C-20 isomer 417 andnatural C-20 isomer 418, respectively,37,156 in 92% and 91%yield (Scheme 83). Similarly, (E)-carbonate 419 and (Z)-

carbonate 420, upon palladium-catalyzed hydrogenolysis,afforded the corresponding compounds 421 with unnaturalstereochemistry at C-20 and 422 with C-20 naturalconfiguration in excellent yields (Scheme 83).4.13. Organoboron Reagents

Bottin and Fetizon157 studied the hydroboration of C-20(21)steroidal olefins that leads to (20S)-21-hydroxy steroids in goodyields. Tetrahydropyranyl steroidal derivative 423, upontreatment with an excess (1:5) of disiamylborane and thenhydrogen peroxide, afforded (20S)-alcohol 424 in 45% yield(Scheme 84). Use of the calculated amount of diborane leads to

a 40:60 mixture of 20R and 20S isomers. Furthermore, Trivediand co-workers158 also reported the hydroboration of 423 with9-borabicyclo[3.3.1]nonane (9-BBN), followed by oxidationwith H2O2/NaOH, which gave 424 in 78% yield.The use of stereoselectively formed organoboron inter-

mediates as blocking groups for carbon−carbon bond-formingreactions has been developed.159 An efficient approach for theconstruction of steroid backbones via hydroboration of steroidwith 9-BBN, followed by carbon−carbon bond-formingreactions, was developed.159 The approach of borane fromthe β-face is apparently blocked by the angular methyl group.Hydroboration of 17(20)-(Z)-ethylidene steroid 188a (Scheme85) with 9-BBN proceeds in a highly selective manner from theα-face of the steroid.159 The resulting 9-BBN derivative 425,

upon treatment with chloroacetonitrile and base 426, producescyano steroid 427 possessing the natural configuration at C-17and C-20. Furthermore, 17(20)-E-ethylidene isomer 199undergoes hydroboration to produce 429 with the unnaturalconfiguration at C-20.Midland and Kwon160 studied the hydroboration reaction for

steroidal olefins. Predominantly, hydroboration occurs from thetop (si) face to provide the 20S product (Scheme 86).

Hydroboration of 430 with borane (Table 7, entry 1) affordedproducts 431 and 432 unselectively (dr = 1:1), whereas use ofreagents such as 9-BBN (Table 7, entry 3) and dicyclohex-ylborane (Table 7, entry 5) furnished 431 as the major productwith 14:1 and 26:1 diastereomeric ratio, respectively. With ahindered borane such as bis(trans-2-methylcyclohexyl)borane,greater than 98% purity of 431 was obtained.Pregnenolone is readily converted into E-trisubstituted olefin

433 by the Wittig reaction, followed by hydroboration of 433with 9-BBN, which proceeds in a highly chemoselective andstereoselective manner to produce 434 in excellent yield.160

Although deprotection of acetate took place, the 5(6) doublebond remains intact. The 20S,22R isomer is essentially the onlyproduct (20S,22R:20R:22S = 300:1) (Scheme 87).Stereoselective and chemoselective hydroboration161 of 435

with dicyclohexylborane provided alcohol 436 with 20S

Scheme 83

Scheme 84

Scheme 85

Scheme 86

Table 7. Hydroboration160 of 430

entry reducing agent 431:432

1 BMS 1:12 thexylborane 4:13 9-BBN 14:14 disiamylborane 22:15 dicyclohexylborane 26:16 bis(trans-2-methylcyclohexyl)borane 54:1


dx.doi.org/10.1021/cr4004083 | Chem. Rev. XXXX, XXX, XXX−XXXW

configuration as the predominant product (dr 26:1) (Scheme88).

Pregnenolone (3β-hydroxypregn-5-en-20-one) 437 wasstereoselectively converted into (25R)-26-hydroxycholesterol441 via stereoselective hydroboration, asymmetric reduction,and stereospecific [2,3] sigmatropic rearrangement (Scheme89).162 Stereoselective and chemoselective hydroboration ofthe steroidal 20(22)-double bond in 438 with 9-BBN providedalcohol 442 in 95:5 ratio (20R:20S) (Scheme 89).

The stereochemistry at C-17 and C-20 in ent-steroids was setby hydroboration163 of steroidal C-17(20)-ene with 9-BBN,which enters from the top face of alkene 261. Coupling of theresulting hindered trialkylborane with chloroacetonitrile in thepresence of hindered base gave nitrile 443 as a single isomer in47% yield (Scheme 90). This product, 443, was further utilizedfor the synthesis of ent-cholesterol.163

Vandewalle and co-workers164 reported the total synthesis of1α,25-dihydroxy-18-norvitamin D3, in which the constructionof C-20 stereocenter was achieved by the hydroboration

reaction. Compound 444, upon treatment with 9-BBN in THFfollowed by H2O2 and NaOH, gave 445 in 70% yield withlower stereoselectivity (66% diastereomeric excess, de)(Scheme 91). This can be attributed due to the absence ofthe 18-angular methyl group substituent in 444.

4.14. Organocopper Reagents

4.14.1. Alkylidene Oxiranes. Marino and co-workers165

reported the regiospecific and stereospecific 1,4-addition ofalkyl cyanocuprates to cyclic vinyl oxiranes to give thecorresponding alcohols. This strategy was utilized for thestereospecific construction of side chains from substituted exo-methylene epoxycycloalkanes: mixed cyanocuprates canselectively generate trans-4-alkylcyclohex-2-enols. The method-ology is greatly extended to a chiral alkylideneoxirane of knownconfiguration, where there exists the possibility for a 1,4-chirality transfer in which two asymmetric centers are generatedin a 1,4-relationship165 (Figure 19).

1,4-Trans additions of alkyl cyanocuprates to alkylideneox-iranes of sterols provide the stereospecific methodology forconcomitant introduction of the C-20 asymmetric center andthe 15β-hydroxyl group. Stereospecific conversions of dehy-droepiandrosterone to cholesterol, isocholesterol, and their15β-hydroxy derivatives were described via 1,4-trans-additionreaction by Marino and Abe.166 Steroidal oxirane 409, uponreaction with excess lithium isohexylcyanocuprate in ether at−78 °C, produced isomerically pure 1,4-adduct 446 with C-20natural configuration in 82% yield (Scheme 92). Steroidaloxirane 406, upon addition of lithium methylcyanocuprate,formed equal amounts of 1,4- and 1,2-adducts 447 and 448,

Scheme 87

Scheme 88

Scheme 89

Scheme 90

Scheme 91

Figure 19. 1,4-Chirality transfer.

Scheme 92


dx.doi.org/10.1021/cr4004083 | Chem. Rev. XXXX, XXX, XXX−XXXX

respectively (Scheme 92). Intermediate 447 was utilized forsynthesis of 20-epi-cholesterol (32, Figure 10).Treatment of 449 with magnesium cyanocuprate of 2-(2-

bromoethyl)-isopropyl-1,3-dioxolane 450 gave 1,4-adduct 451in excellent yield167 (Scheme 93). Stereochemistry at C-20 in

451 results from attack of the mixed cuprate on the α-face ofthe E-17(20)-alkene. Similarly, organocuprate 452, upontreatment with 449, gave exclusively the 1,4-addition product453. Highly efficient168 conjugate 1,4-addition of organo-cuprate 455 to steroidal 15β,16β-epoxy-17(20)(E)-ethylidene454 gave 456 in 93% yield (Scheme 93).McMorris and co-workers169 reported the synthesis of 15β-

hydroxy-24-oxocholesterol 457 from 3β-acetoxyandrost-5-ene-17-one 114, with 1,4-conjugate addition reaction as the keystep (Scheme 94). Reaction of (17E)-3β-(dimethyl-tert-

butylsilyloxy)-15β,16β-epoxypregna-5,17(20)-diene 409 withmagnesium cyanocuprate derivatives of 3-(1,3-dioxolan-2-yl)-4-methylpentyl bromide 458 gave (20R)-3β-(dimethyl-tert-butylsilyloxy)-15β-hydroxy-24-oxocholesta-5,16-diene-24-ethyl-ene acetal 459 in 80% yield (Scheme 94). Similarly, 409, uponreaction with 460 in the presence of CuCN, furnished 461 in82% yield.4.14.2. C-17(20)-en-16-keto Steroids. Reactions of

organocuprates with various C-17(20)-unsaturated steroid

substrates lead to stereocontrolled introduction of the sidechain with either of the C-20 epimers.35 Reaction of C-17(20)-en-16-keto steroid 462 with lithium isoamylcuprate 463 andlithium diisohexylcuprate 465 leads to α-face attack, givingexclusively corresponding products 464 and 466, having the C-20 natural configuration (Scheme 95).

The α-alkoxy vinyl cuprate 469, upon 1,4-addition reactionto Z-enone 468 (synthesized from 467 via Dess−Martinperiodinane oxidation) in the presence of TMSCl, afforded170

silyl enol ether 470 with the C-20 unnatural configuration in92% yield (Scheme 96). Similarly, TMSCl-activated 1,4-

addition of α-alkoxy vinyl cuprate 469 to E-enone 471(synthesized from 221 via allylic hydroxylation followed bySwern oxidation) gave silyl enol ether intermediate 472 in goodyield (having the C-20 natural configuration), which wasfurther utilized for synthesis of OSW-1.Danishefsky and co-workers171 reported the first total

synthesis of neurotrophic compound NGA0187 (476) viastereoselective conjugate addition of vinyl cuprate to enone.Stereoselective addition of vinyl cuprate 474 from the si face ofthe steroidal C-17(20)-en-16-one 473a,b, followed by kineticprotonation of the resultant enolate from the same face,furnished steroid 475a,b, respectively, with the desiredstereochemistry at C-17 and C-20 (Scheme 97).Conjugate addition5c of lithium dimethyl cuprate to enones

477 and 478 resulted in natural C-20 isomer 479 (67%) andunnatural C-20 isomer 480 (37%), respectively (Scheme 98).

Scheme 93

Scheme 94

Scheme 95

Scheme 96


dx.doi.org/10.1021/cr4004083 | Chem. Rev. XXXX, XXX, XXX−XXXY

4.14.3. C-17(20)-en-16-Pivalates/Carbamates. Reactionof C-17(20)-en-16α-pivaloyloxy steroid 481 and 16β-pivaloy-loxy steroid 484 separately with lithium isohexylcyanocuprate482 in ether proceeded35 in a regio- and stereocontrolledmanner. The former 16α-compound 481 gave exclusively theunnatural 20S-isomer 483, while the latter 16β-compound 484gave exclusively the natural 20R-isomer 485 (Scheme 99).

Mourino and co-workers26a developed two efficient syntheticroutes to 1α,25-dihydroxy-16-dehydrovitamin D3 and their C-20 analogues. The salient feature common to both routes is theintroduction of side chains functionalized at the C-20 position.In the first route, C,D side-chain fragments were prepared bySN2′ syn displacement of allylic carbamates by Li2Cu3R5. In thesecond route, SN2′ syn displacement of the carbamate moiety

by Li2Cu3R5 is carried out. Carbamate 486 is used forpreparation of vitamin D analogues with the unnaturalconfiguration at C-20. Compounds 487a−e were obtained inhigh yields by reaction of 486 with Li2Cu3R5 (Scheme 100).

Treatment of carbamate 488 with different higher-ordercuprates (Li2Cu3R5) gave compounds 489a−d, with the naturalconfiguration at C-20, as a single isomer in high yields. Whencarbamate 490 was treated with Li2Cu3R5, an inseparable 1:1mixture of the protected vitamin D3 491 and its 5,6-transisomer 492 was obtained. Again, reaction of 493 with thehigher-order cuprates Li2Cu3R5 (R = Me, n-Bu, Ph) proceededcleanly to give vitamin D analogues 494a−c with unnaturalconfiguration at C-20. Carbamate 495 was subjected withLi2Cu3R5 to produce 496a,b vitamin D analogues with thenatural configuration at C-20 by SN2′ syn displacement of thecarbamoyl moiety. Both routes gave the desired allyl productsin high yields.4.15. Organozirconocene Reagents

Organozirconocenes have emerged as a useful classes oftransition metal derivatives, used in organic synthesis. A widerange of zirconocene-mediated organic transformations and therelative ease of preparation of alkenyl- and alkyl chlorozirco-nocenes contribute to the broad appeal of this chemistry.Schwartz and co-workers172,173 have studied the coupling of

steroidal (π-allylic)palladium complexes with organozirconiumspecies as a new route for steroid synthesis. The regiochemistryof the coupling product could be controlled with the use of

Scheme 97

Scheme 98

Scheme 99

Scheme 100


dx.doi.org/10.1021/cr4004083 | Chem. Rev. XXXX, XXX, XXX−XXXZ

exogeneous olefins. Coupling of palladium complex 497 andzirconium complex 498 is slow and is inhibited172 by theaddition of PPh3 at room temperature (Scheme 101). However,

in the presence of maleic anhydride, the reaction proceeds tocompletion within 5 min, even at −78 °C. The regiochemistryof this coupling is affected by the olefins. In absence of ligands,coupling products 499 and 500 were obtained in the absence ofligands and formed by reaction at the C(20) and C(16)carbons, respectively, in a 2:3 ratio (51% yield). The C(20)coupling product was obtained in the presence of maleicanhydride with greater than 7:1 selectivity of 499 to 500 (96%yield).Similar work was described173 for the construction of

unnatural stereochemistry at C-20 from the E-17(20)-isomerof steroidal backbone. The coupling reaction of steroidal (E)-isomer 501 with zirconocene complex 502 in the presence ofmaleic anhydride, predominantly at C(20) over the temper-ature range −78 to 25 °C, resulted in formation of 503 in 85%yield with unnatural configuration at C-20 (Scheme 102).

Synthesis of 25-hydroxycholesterol and 25-hydroxy-20-epi-cholesterol were described by use of a dimetalated couplingreagent via (η3-allyl)palladium-based systems by Riediker andSchwartz.42 Steroidal (Z)-17(20)-isomer 504, upon reactionwith organozirconocene 505 in the presence of maleicanhydride, yielded 506 in 70% yield with C(20R) naturalconfiguration and side product 507 in 18% yield (Scheme 103).A similar coupling reaction, using the steroidal (E)-17(20)-isomer 508 with 505, yielded 509 with C(20S) unnaturalconfiguration in 82% and 510 in 11% yield.Selective coupling between allylic acetates and alkenylzirco-

nium complexes via (π-allylic)Pd(II) complex can serve as acatalyst precursor.174 Reaction between C-20 acetate com-pound 402 and zirconocene 502, in the presence of Pd(PPh3)4and Ph3P as a ligand, resulted a mixture of C-20-alkylated 503and C-16-alkylated 511 in 35:65 ratio.174 Furthermore, C-20

acetate 402, upon reaction with zirconocene 502 in thepresence of maleic anhydride and PdCl2, leads to 503 and 511in 5:1 ratio (Scheme 104).

Regioselective opening of vinyl cyclopropane ring-containingsubstrates via complexation with a stoichiometric amount ofCp2Zr was established.175 This strategy was utilized in thestereocontrolled preparation of steroidal side chain in naturaland/or unnatural forms and showed a high possibility ofconstructing the new analogues.175 Steroidal vinyl cyclo-propanes 512 and 514 were prepared via a sequence ofreactions including Simon−Smith reaction. Cp2Zr complex-ation of 512, followed by addition of acetone and deprotectionof TBDMS group, gave C-20-epi-steroid 513 in 60% yield(Scheme 105). Similarly, 514 gave the C-20 naturallyconfigured steroid 515 in 47% yield.

Scheme 101

Scheme 102

Scheme 103

Scheme 104

Scheme 105


dx.doi.org/10.1021/cr4004083 | Chem. Rev. XXXX, XXX, XXX−XXXAA

4.16. Hydrovinylation Reaction

Addition of vinyl group and hydrogen across a double bond isknown as a hydrovinylation reaction, a promising method insynthetic organic chemistry. Transition-metal-catalyzed hydro-vinylation holds tremendous potential as a generally useful C−C bond forming reaction, because a cheap feedstock (ethylene)is used and the reaction proceeds in an atom-economicalfashion. Donaldson and co-workers176 described hydrovinyla-tion of steroidal diene 516 with excess ethylene in the presenceof catalyst 517 to give a single diastereomer 518 in 88% yieldwith unnatural 20(S) configuration (Scheme 106). The

stereochemistry in the neighborhood of the diene moietydetermined the stereochemistry of the newly constructed chiralcenter at C-20. Intermediate 518 was utilized for synthesis ofthe Roche vitamin D3 analogue Ro 26-9228, which wasreported to increase bone mineral density in rats.A similar method was also used by Rajanbabu and co-

workers177 with various chiral ligands. Ni(II)-catalyzed hydro-vinylation of 1,3-dienes by use of finely tuned phosphoramiditeligands lead to exclusively C-20(R) or C-20(S) steroids withoutmutual contamination, depending on the type of enantiomericligands. Steroidal 1,3-dienes 516 and 520 were subjected tohydrovinylation with [(allyl)2NiBr]2 and sodium salt of borate,in the presence of ligand 523 along with atmospheric pressureof ethylene, to give the corresponding 20(S)-hydrovinylationadducts 518 and 521, respectively. In place of ligand 523, otherligands 524 and 525 gave 20(R) adducts 519 and 522,respectively, with C-20 natural configuration (Scheme 107).4.17. Miscellaneous

Stereospecific nucleophilic displacement (SN2) of secondarytosylate 526 with the carbanion derived from 527 resulted inproduct 528 in 70% yield (Scheme 108).178 Tosylate 529,obtained from pregnenolone, underwent inversion of config-uration at C-20 when it was treated179 with the anion of theprotected cyanohydrin 530, which gave intermediate 531 withnatural configuration at C-20 (Scheme 108). Intermediate 531,upon treatment with PTSA−MeOH followed by base treat-ment of the resulting cyanohydrin with NaOH, gavecorresponding enone 532 in 83% overall yield without C-20epimerization.Application of the anionic oxy-Cope rearrangement in

steroid synthesis was documented by Koreeda et al.180 (Scheme109). Treatment of steroidal C-16 tert-alcohol 533 withpotassium hydride in refluxing dioxane produced therearranged (20R)-keto olefin 534 as a single stereoisomer atC-17 and C-20 in 94% yield. Product 534 provided a versatileintermediate for synthesis of vitamin D metabolite and steroidsincorporating modified side chains.A similar type of anionic oxy-Cope rearrangement on steroid

substrate has been reported by Voss and co-workers.181

Compound 535, upon reaction with KH in 1,2-dimethoxy-ethane under reflux conditions followed by quenching withwater at −10 °C, gave 17R,20R-keto olefin 536 as a single

diastereomer in 91% yield (Scheme 110). Analogously, undersimilar conditions followed by quenching of the intermediate at0−25 °C, the 17S-epimer 537 was obtained in 20−40% yield.The sterol/steroid-type side chain can be achieved via

oxidative cleavage of diol 538 with sodium metaperiodate(NaIO4) followed by sodium borohydride reduction, which

Scheme 106

Scheme 107

Scheme 108

Scheme 109


dx.doi.org/10.1021/cr4004083 | Chem. Rev. XXXX, XXX, XXX−XXXAB

afforded182 monocyclic diol 539 in 87% overall yield (Scheme111).

Baeyer−Villiger oxidation of 540 with H2O2, followed bytreatment with TsOH in benzene, gave rearranged lactone 541in 79% yield.183 Lactone 541, upon reduction with LiAlH4 andselective protection of the primary alcohol with TBDMSCl,gave 542 in 95% overall yield (Scheme 112). The criticalcenters corresponding to C-13 and C-20 have been createdwith the correct relative configuration.183

Bicyclic ketone 543, upon Baeyer−Villiger oxidation withbasic hydrogen peroxide in aqueous methanol−THF, gave184the sensitive hydroxy acid 544, which upon treatment with BF3·Et2O gave the rearranged intermediate 545 (85% overall yield)with the transfer of chirality from C-14 to C-16 (steroidnumbering) (Scheme 113).

Keto acid 547 was obtained by ozonolysis of 546, followedby hydrolysis of the resulting acid anhydride, and thenconverted into acetal carboxylic acid 548 (by use of ethyleneglycol and camphorsulfonic acid, CSA) in 70% overall yield185

(Scheme 114).

β-Hydroxy ketone 549, upon exposure to sodium hydride inTHF, proceeded smoothly in retro-aldol condensation followedby isomerization of the ring methyl group, giving (2R,3R)-2-methyl-3-[(R)-1-methyl-3-oxobutyl)]-cyclopentanone 550 in75% yield186 (Scheme 115). The absolute (R) configurationof both methyl groups present in 550 are in agreement withthose at C-17 and C-20 of steroidal substrates.

Vandewalle and co-workers187 described the synthesis of avitamin D analogue with a six-membered D-ring and theabsence of C-ring. In their synthesis, construction of the C-20side chain was achieved from spirolactones 551 and 552, whichupon reduction with LiAlH4 followed by silylation gave 553and 554, respectively, in 85% over two steps (Scheme 116).

5. CONCLUSIONSThis review presents a collection of highly interesting anduseful methods for stereoselective construction of the C-20(H)stereogenic center in steroid side chain. These methods may beuseful for synthesis of newly isolated sterols/steroids withnatural and unnatural configuration at C-20. The variousmethods for construction of the steroidal C-20 stereogeniccenter, by use of named/unnamed reactions/rearrangements,organometallic compounds, and others, are also shown inFigure 20 to illustrate the importance and scope of future work.These methods are useful for the synthesis of naturally

Scheme 110

Scheme 111

Scheme 112

Scheme 113

Scheme 114

Scheme 115

Scheme 116


dx.doi.org/10.1021/cr4004083 | Chem. Rev. XXXX, XXX, XXX−XXXAC

occurring steroids such as cholesterol, bile acids, cortico-steroids, ecdysones, brassinosteroids, squalamine, and manymore that have natural C-20 configuration, as well ascompounds with the unnatural C-20 configuration such as20-epi-sterols/steroids, epi-cholesterol (different activity thannatural cholesterol), 20-epi-cholanic acid derivatives, other 20-epi-steroids (whose biological activity has not been exploredyet), and 20-epi-vitamin D3, particularly 20-epi-calcitriol, whichis is more active than the natural enantiomer.

AUTHOR INFORMATIONCorresponding Authors

*Telephone 91-240-2403311-313; fax 91-240-2403113; [email protected].*E-mail [email protected]

The authors declare no competing financial interest.

Biographies

Bapurao B. Shingate was born in Salagara (Divati), OsmanabadDistrict of Maharashtra State, India, in 1975. He obtained his B.Sc. andM.Sc. degrees from Dr. Babasaheb Ambedkar Marathwada University,Aurangabad (MS), India. He earned his Ph.D. degree from Universityof Pune, Pune (MS), under the supervision of Dr. Braja G. Hazra atthe Division of Organic Chemistry, National Chemical Laboratory(CSIR), Pune. His Ph.D. work focused on the stereoselective

syntheses of steroidal unnatural C(20R) aldehydes by ionic hydro-genation and their elaboration to naturally occurring 20-epi-cholanicacid derivatives. In addition to this, he has carried out stereoselectivesyntheses and ionic hydrogenation of steroidal C-20 tertiary alcoholswith aliphatic, vinylic, aromatic, 5- and 6-membered heterocyclic sidechains, and also synthesized various oxygenated lanosterol derivatives.His current research interests include asymmetric synthesis, totalsynthesis of natural products, multicomponent reactions, heterocyclicsynthesis, and green chemistry. In 2008, he joined as an AssistantProfessor in the Department of Chemistry, Dr. Babasaheb AmbedkarMarathwada University, Aurangabad. He has published about 50research articles in journals of international repute and contributed achapter of a book. He is a recipient of prestigious Indo-U.S. ResearchFellowship 2013 award for carrying out advanced research in chemicalsciences at the University of California, Irvine, CA.

Braja Gopal Hazra was born in Bankura District of West Bengal in1943. He received an M.Sc. degree in chemistry from CalcuttaUniversity (1965) followed by a Ph.D. from Jadavpur University(1971). Subsequently he worked as a postdoctoral research associate atSheehan Research Institute, Cambridge, MA (1974−1975); atBrandeis University, Waltham, MA (1975−1976; and as a JSPSVisiting Scientist at University of Tokyo, Japan (Host ScientistProfessor Kenji Mori) (1984−1985). He was an elected fellow of theMaharashtra Academy of Sciences. He retired from National ChemicalLaboratory, Pune (CSIR) as a senior scientist in 2003 and was anemeritus scientist at National Chemical Laboratory until 2008. He hasmore than 4 decades of research experience in synthetic organicchemistry, particularly synthesis of natural products and analogueshaving biological and commercial importance. He developed andcommercialized technology of (22S,23S)-homobrassinolide, (a highlypotent plant growth promoter). He has trained and supervised morethan 25 M.Sc. students in chemistry for their project work andsupervised 8 Ph.D. students in synthetic organic chemistry. More than70 research publications in international journals, four U.S. patents,and 31 Indian patents are to his credit.

ACKNOWLEDGMENTSWe sincerely acknowledge many colleagues and friends for thereprints or preprints that they furnished and also for theirvaluable/critical suggestions and helpful discussions. We thankDrs. V. S. Pore, N. P. Argade, D. B. Salunke, N. S. Vatmurge, S.N. Bavikar, N. G. Aher, P. S. Sagar, A. P. Thakur, H. V.Thulasiram, M. S. Shingare, R. A. Mane, and B. R. Sathe fortheir timely help and co-operation during the preparation ofthis review. We thank the University Grants Commission, andCouncil of Scientific and Industrial Research, New Delhi, forfinancial assistance in the form of fellowships. B.B.S. thanks toIndo-US Science and Technology Forum, New Delhi, for the

Figure 20. Various methods for construction of the steroidal C-20stereogenic center.


dx.doi.org/10.1021/cr4004083 | Chem. Rev. XXXX, XXX, XXX−XXXAD

mailto:[email protected]

mailto:[email protected]

award of Indo-US Research Fellowship to carry out advancedresearch in chemical sciences.

DEDICATION

We dedicate this review to all the researchers that havecontributed to this field of steroids, terpenoids, vitamins, andnatural products, and we hope that it will inspire current andfuture chemists to utilize and expand the field of constructionof steroidal C-20(H) stereogenic center.

ABBREVIATIONS

Ac acetylAIBN azobis(isobutyronitrile)aq aqueousAr aryl9-BBN 9-borabicyclo[3.3.1]nonaneBMS borane-methyl sulfideBn benzyl(CH2O)n paraformaldehydeCp cyclopentadienylCSA camphorsulfonic acidDCM dichloromethaneDMAP 4-(dimethylamino)pyridineDMF dimethylformamideDMSO dimethyl sulfoxidedppe 1,2-diphenylphosphinoethanedr diastereomeric ratioE entgegen in IUPAC nomenclatureEE ethoxyethylent enantiomericepi epimericEtOAc ethyl acetateHMPA hexamethylphosphoramideHMPT hexamethylphosphorous triamideiso isomericLD lethal doseLDA lithium diisopropylamideLiHMDS lithium hexamethyldisilazide or lithium bis-

(trimethylsilyl) amideMEM β-methoxyethoxymethylMOM methoxymethylNaN(SiMe3)2 sodium bis(trimethylsilyl)amidePd(acac)2 palladium acetylacetonePd3(TBAA)3 tris(tribenzylideneacetyl acetone)tripalladiumppm parts per millionPTSA p-toluenesulfonic acidPy pyridinequant quantitativert room temperatureSN

2 bimolecular nucleophilic substitutionsp speciesSt steroidTBS tert-butyldimethylsilylTBDMS tert-butyldimethylsilylTBDPS tert-butyldiphenylsilylTES triethylsilylTHF tetrahydrofuranTHP tetrahydropyranylTMBA 2,4,6-trimethyl benzoic acidTMSCl trimethylsilyl chlorideTMS trimethylsilylTs p-toluenesulfonyl

TsCl p-toluenesulfonyl chlorideTsOH p-toluenesulfonic acidTrSbCl6 trityl hexachloroantimonateZ zusammen in IUPAC nomenclature

REFERENCES(1) Morgan, B. P.; Moynihan, M. S. In Kirk−Othmer Encyclopedia ofChemical Technology, 4th ed.; Kroschwitz, J. I., Howe-Grant, M., Eds.;John Wiley & Sons: New York, 1997; pp 851−921.(2) (a) Zeelen, F. J. Medicinal Chemistry of Steroids; Elsevier ScienceB.V.: New York, 1990. (b) Blickenstaff, R. T. Antitumor Steroids;Academic Press: San Diego, CA, 1992. (c) D’Auria, M. V.; Minale, L.;Riccio, R. Chem. Rev. 1993, 93, 1839. (d) Stonik, V. A. Russ. Chem. Rev.2001, 70, 673. (e) Sarma, N. S.; Krishna, M. S.; Pasha, S. G.; Rao, T. S.P.; Venkateswarlu, Y.; Parmeswaran, P. S. Chem. Rev. 2009, 109, 2803.(f) Nes, W. D. Chem. Rev. 2011, 111, 6423. (g) Blunt, J. W.; Copp, B.R.; Keyzers, R. A.; Munro, M. H. G.; Pinsep, M. R. Nat. Prod. Rep.2013, 30, 237. (h) Salvodor, J. A. R.; Carvalho, J. F. S.; Neves, M. A.C.; Silvestre, S. M.; Leitao, A. J.; Silva, M. M. C.; Melo, M. L. S. Nat.Prod. Rep. 2013, 30, 324.(3) (a) Moss, G. P. Pure Appl. Chem. 1989, 61, 1783. (b) Moss, G. P.Eur. J. Biochem. 1989, 186, 429. (c) Kasal, A. Structure andNomenclature of Steroids. In Steroid Analysis, 2nd ed.; SpringerScience+Business Media B.V.: Dordrecht, The Netherlands, 2010, 1−25.(4) (a) Piatak, D. M.; Wicha, J. Chem. Rev. 1978, 78, 199.(b) Redpath, J.; Zeelen, F. J. Chem. Soc. Rev. 1983, 75. (c) Kameritskii,A. V.; Reshetova, I. G.; Chernoburova, E. I. Chem. Nat. Compd. 1988,24, 1. (d) Zhabinskii, V. N.; Ol’khovik, V. K.; Khripach, V. A. Russ. J.Org. Chem. 1996, 32, 305. (e) Kovganko, N. V. Chem. Nat. Compd.1997, 33, 506. (f) Kovganko, N. V.; Kashkan, Z. N.; Chernov, Y. G.;Ananich, S. K.; Sokolov, S. N.; Survilo, V. L. Chem. Nat. Compd. 2003,39, 411. (g) Chapelon, A.-S.; Moraleda, D.; Rodriguez, R.; Ollivier, C.;Santelli, M. Tetrahedron 2007, 63, 11511.(5) (a) Georghiou, P. E. Chem. Soc. Rev. 1977, 83. (b) Zhu, G.-D.;Okamura, W. H. Chem. Rev. 1995, 95, 1877. (c) Taber, D. F.; Jiang,Q.; Chen, B.; Zhang, W.; Campbell, C. L. J. Org. Chem. 2002, 67, 4821.(d) Gorobets, E.; Stepanenko, V.; Wicha, J. Eur. J. Org. Chem. 2004,783.(6) Blume, T.; Guttzeit, M.; Kuhnke, J.; Zom, L. Org. Lett. 2003, 5,1837.(7) (a) Adam, G.; Marquardt, V. Phytochemistry 1986, 25, 1787.(b) Khripach, V. A. Pure Appl. Chem. 1990, 62, 1319. (c) Lokhvich, F.A.; Khripach, V. A.; Zhabinskii, V. N. Russ. Chem. Rev. 1991, 60, 658.(d) Kovganko, N. V.; Ananich, S. K. Chem. Nat. Compd. 1997, 33, 389.(e) Kovganko, N. V.; Ananich, S. K. Chem. Nat. Compd. 2002, 38, 122.(f) Massey, A. P.; Pore, V. S.; Hazra, B. G. Synthesis 2003, 426.(g) Ramirez, J. A.; Brosa, C.; Galagovsky, L. R. Phytochemistry 2005,66, 581.(8) (a) Brunel, J. M.; Letourneux, Y. Eur. J. Org. Chem. 2003, 3897and references cited therein. (b) Zhang, D. H.; Cai, F.; Zhou, X.-D.;Zhou, W.-S. Org. Lett. 2003, 5, 3257. (c) Okumura, K.; Nakamura, Y.;Takeuchi, S.; Kato, I.; Fujimoto, Y.; Ikekawa, N. Chem. Pharm. Bull.2003, 51, 1177. (d) Zhang, D.-H.; Cai, F.; Zhou, X.-D.; Zhou, W.-S.Chin. J. Chem. 2005, 23, 176.(9) Morzycki, J. W.; Wojtkielewicz, A. Phytochem. Rev. 2005, 4, 259and references cited therein..(10) Burgoyne, D. L.; Andersen, R. J.; Allen, T. M. J. Org. Chem.1992, 57, 525.(11) Jiang, B.; Shi, H.-P.; Tian, W.-S.; Zhou, W.-S. Tetrahedron 2008,64, 469 and references cited therein.(12) (a) Aoki, S.; Setiawan, A.; Yoshioka, Y.; Higuchi, K.; Fudetani,R.; Chen, Z.-S.; Sumizawa, T.; Akiyama, S.-c.; Kobayashi, M.Tetrahedron 1999, 55, 13965. (b) Murakami, N.; Sugimoto, M.;Morita, M.; Kobayashi, M. Chem.Eur. J. 2001, 7, 2663.(13) Kuo, P.-C.; Kuo, T.-S.; Damu, A.-G.; Su, C.-R.; Jee, E.-J.; Wu,T.-S.; Shu, R.; Chen, C.-M.; Bastow, K.-F.; Chen, T.-H.; Lee, K.-H.Org. Lett. 2006, 8, 2953.


dx.doi.org/10.1021/cr4004083 | Chem. Rev. XXXX, XXX, XXX−XXXAE

(14) Morinaka, B. I.; Masuno, M. N.; Pawlik, J. R.; Molinski, T. F.Org. Lett. 2007, 9, 5219.(15) Samadi, A. K.; Tong, X.; Mukerji, R.; Zhang, H.; Timmermann,B. N.; Cohen, M. S. J. Nat. Prod. 2010, 73, 1476.(16) Li, H.-J.; Jiang, Y.; Li, P. Nat. Prod. Rep. 2006, 23, 735.(17) (a) Atta-ur-Rahman; Choudhary, M. I. Nat. Prod. Rep. 1997, 14,191. (b) Atta-ur-Rahman; Choudhary, M. I. Nat. Prod. Rep. 1999, 16,619.(18) (a) Burbiel, J.; Bracher, F. Steroids 2003, 68, 587. (b) Ibrahim-Ouali, M.; Santelli, M. Steroids 2006, 71, 1025. (c) Ibrahim-Ouali, M.;Rocheblave, L. Steroids 2008, 73, 375.(19) (a) Marino, S. D.; Iorizzi, M.; Zollo, F.; Roussakis, C.; Debitus,C. Eur. J. Org. Chem. 1999, 697. (b) Zampella, A.; D’Orsi, R.; Sepe, V.;Marino, S. D.; Borbone, N.; Valentin, A.; Debitus, C.; Zollo, F.;D’Auria, M. V. Eur. J. Org. Chem. 2005, 4359. (c) Lu, Z.; Koch, M.;Harper, M. K.; Matainaho, T. K.; Barrows, L. R.; Wagoner, R. M. V.;Ireland, C. M. J. Nat. Prod. 2013, 76, 2150.(20) (a) Tsuda, K.; Akagi, S.; Kishida, Y.; Hayatsu, R. Chem. Pharm.Bull. 1957, 5, 85. (b) Tsuda, K.; Hayatsu, R.; Kishida, Y.; Akagi, S. J.Am. Chem. Soc. 1958, 80, 921. (c) Tsuda, K.; Sakai, K.; Ikekawa, N.Chem. Pharm. Bull. 1961, 9, 835.(21) Idler, D. R.; Khalil, M. W.; Gilbert, J. D.; Brooks, C. J. W.Steroids 1976, 27, 155.(22) (a) Koreeda, M.; Koizumi, N. Tetrahedron Lett. 1978, 19, 1641.(b) Teicher, B. A.; Koizumi, N.; Koreeda, M.; Shikita, M.; Talalay, P.Eur. J. Biochem. 1978, 91, 11.(23) Nes, W. R.; Joseph, J. M.; Landrey, J. R.; Behzadan, S.; Conner,R. L. J. Lipid Res. 1981, 22, 770 and references cited therein.(24) (a) Vanderah, D. J.; Djerassi, C. Tetrahedron Lett. 1977, 18, 683.(b) Vanderah, D. J.; Djerassi, C. J. Org. Chem. 1978, 43, 1442.(25) Tomono, Y.; Hirota, H.; Imahara, Y.; Fusetani, N. J. Nat. Prod.1999, 62, 1538.(26) (a) Rey, M. A.; Martinez-Perez, J. A.; Fernandez-Gacio, A.;Halkes, K.; Fall, Y.; Granja, J.; Mourino, A. J. Org. Chem. 1999, 64,3196. (b) Fujishima, T.; Konno, K.; Nakagawa, K.; Kurobe, M.;Okano, T.; Takayama, H. Bioorg. Med. Chem. 2000, 8, 123. (c) Sicinski,R. R.; Rotkiewicz, P.; Kolinski, A.; Sicinski, W.; Prahl, J. M.; Smith, C.M.; DeLuca, H. F. J. Med. Chem. 2002, 45, 3366. (d) Blaehr, L. K. A.;Bjorkling, F.; Calverley, M. J.; Binderup, E.; Begtrup, M. J. Org. Chem.2003, 68, 1367.(27) (a) Binderup, L.; Latini, S.; Binderup, E.; Bretting, C.; Calverley,M.; Hansen, K. Biochem. Pharmacol. 1991, 42, 1569. (b) Ryhanen, S.;Mahonen, A.; Jaaskelainen, T.; Maenpaa, P. H. Eur. J. Biochem. 1996,238, 97. (c) Selles, J.; Massheimer, V.; Santillan, G.; Marinissen, M. J.;Boland, R. Biochem. Pharmacol. 1997, 53, 1807. (d) Vaisanen, S.;Ryhanen, S.; Saarela, J. T. A.; Maenpaa, P. H. Eur. J. Biochem. 1999,261, 706. (e) Achmatowicz, B.; Przezdziecka, A.; Wicha, J. Pol. J. Chem.2005, 79, 413. (f) Fraga, R.; Lopez-Perez, B.; Sokolowska, K.; Guini,A.; Regueira, T.; Diaz, S.; Mourino, A.; Maestro, M. A. J. SteroidBiochem. Mol. Biol. 2013, 136, 14.(28) (a) Posner, G. H.; Kahraman, M. Eur. J. Org. Chem. 2003, 3889and references cited therein. (b) Begue, J.-P.; Bonnet-Delpon, D. J.Fluor. Chem. 2006, 127, 992.(29) Hog, D. T.; Webster, R.; Trauner, D. Nat. Prod. Rep. 2012, 29,752 and references cited therein.(30) Wu, X.; Lin, S.; Zhu, C.; Yue, Z.; Yu, Y.; Zhao, F.; Liu, B.; Dai,J.; Shi, J. J. Nat. Prod. 2010, 73, 1294.(31) Yajima, A.; Kagohara, Y.; Shikai, K.; Katsuta, R.; Nukada, T.Tetrahedron 2012, 68, 1729 and references cited therein.(32) Kasal, A.; Budesinsky, M.; Griffiths, W. J. SpectroscopicMethods of Steroid Analysis. In Steroid Analysis, 2nd ed.; SpringerScience+Business Media B.V.: Dordrecht, The Netherlands, 2010; pp27−161.(33) Nes, W. R.; Varkey, T. E.; Krevitz, K. J. Am. Chem. Soc. 1977, 99,260.(34) Byon, C.-Y.; Buyuktur, G.; Choay, P.; Gut, M. J. Org. Chem.1977, 42, 3619.(35) Schmuff, N. R.; Trost, B. M. J. Org. Chem. 1983, 48, 1404.

(36) Joseph, J. M.; Nes, W. R. J. Chem. Soc. Chem. Commun. 1981,367.(37) Mandai, T.; Matsumoto, T.; Kawada, M.; Tsuji, J. Tetrahedron1994, 50, 475.(38) Sato, Y.; Sonoda, Y.; Saito, H. Chem. Pharm. Bull. 1980, 28,1150.(39) Takahashi, T.; Ootake, A.; Tsuji, J. Tetrahedron Lett. 1984, 25,1921.(40) Ibuka, T.; Taga, T.; Shingu, T.; Saito, M.; Nishii, S.; Yamamoto,Y. J. Org. Chem. 1988, 53, 3947.(41) (a) Batcho, A. D.; Berger, D. E.; Uskokovic, M. R.; Snider, B. B.J. Am. Chem. Soc. 1981, 103, 1293. (b) Dauben, W. G.; Brookhart, T. J.Org. Chem. 1982, 47, 3921.(42) Riediker, M.; Schwartz, J. Tetrahedron Lett. 1981, 22, 4655.(43) Nes, W. D.; Wong, R.Y.; Benson, M.; Landrey, J. R.; Nes, W. R.Proc. Natl. Acad. Sci. U.S.A. 1984, 81, 5896.(44) (a) Linker, M.; Kreiser, W. Helv. Chim. Acta 2002, 85, 1096.(b) Linker, M.; Schurmann, M.; Preut, H.; Kreiser, W. Acta Crystallogr.2001, E57, 574. (c) Linker, M.; Schurmann, M.; Preut, H.; Kreiser, W.Acta Crystallogr. 2001, E57, 576.(45) (a) Akhrem, A. A.; Titov, Y. A. Total Steroid Synthesis. PlenumPress: New York, 1974. (b) Blickenstaff, R. T.; Ghosh, A. C.; Wolf, G.C. Total Synthesis of Steroids; Academic Press: New York, 1974.(c) Kovganko, N. V.; Ananich, S. K. Chem. Nat. Compd. 1997, 33, 133.(d) Kovganko, N. V.; Ananich, S. K. Chem. Nat. Compd. 1999, 35, 229.(e) Hanson, J. R. Nat. Prod. Rep. 2005, 22, 104 and earlier reviews ofthe series. (f) Nising, C. F.; Brase, S. Angew. Chem., Int. Ed. 2008, 47,9389. (g) Hanson, J. R. Nat. Prod. Rep. 2010, 27, 887 and earlierreviews of the series. (h) Kotora, M.; Hessler, F.; Eignerova, B. Eur. J.Org. Chem. 2012, 29.(46) Narwid, T. A.; Cooney, K. E.; Uskokovic, M. R. Helv. Chim. Acta1974, 57, 771.(47) Ikan, R.; Markus, A.; Bergmann, E. D. J. Org. Chem. 1971, 36,3944.(48) (a) Kametani, T.; Tsubuki, M.; Nemoto, H. Tetrahedron Lett.1981, 22, 2373. (b) Kametani, T.; Tsubuki, M.; Nemoto, H. J. Chem.Soc., Perkin Trans. 1 1981, 3077.(49) Fukumoto, K.; Suzuki, K.; Nemoto, H.; Kametani, T.;Furuyama, H. Tetrahedron 1982, 38, 3701.(50) (a) Kametani, T.; Suzuki, K.; Nemoto, H. J. Am. Chem. Soc.1981, 103, 2890. (b) Kametani, T.; Suzuki, K.; Nemoto, H. J. Org.Chem. 1982, 47, 2331.(51) Rahman, M. D.; Seidel, H. M.; Pascal, R. A., Jr. J. Lipid Res.1988, 29, 1543.(52) Kametani, T.; Katoh, T.; Tsubuki, M.; Honda, T. J. Am. Chem.Soc. 1986, 108, 7055.(53) Kametani, T.; Katoh, T.; Tsubuki, M.; Honda, T. Chem. Pharm.Bull. 1987, 35, 2334.(54) Kametani, T.; Katoh, T.; Fujio, J.; Nogiwa, I.; Tsubuki, M.;Honda, T. J. Org. Chem. 1988, 53, 1982.(55) Honda, T.; Katoh, M.; Yamane, S. J. Chem. Soc., Perkin Trans. 11996, 2291.(56) Jogireddy, R.; Rullkotter, J.; Christoffers, J. Synlett 2007, 2847.(57) Kyler, K. S.; Watt, D. S. J. Am. Chem. Soc. 1983, 105, 619.(58) Aher, N. G.; Gonnade, R. G.; Pore, V. S. Synlett 2009, 2005.(59) Zhang, Y.; Danishefsky, S. J. J. Am. Chem. Soc. 2010, 132, 9567.(60) The plant dioscoria, which is cultivated in many parts of India, isan abundant source of diosgenin. 16-Dehydropregnenolone acetate isprepared commercially from diosgenin following Marker’s procedure:Marker, R. E.; Wagner, R. B.; Ulshafer, P. R.; Wittbecker, E. L.;Goldsmith, D. P. J.; Rouf, C. H. J. Am. Chem. Soc. 1947, 69, 2167.(61) Shingate, B. B.; Hazra, B. G.; Pore, V. S.; Gonnade, R. G.;Bhadbhade, M. M. Chem. Commun. 2004, 10, 2194.(62) (a) Carey, F. A.; Neergaard, J. R. J. Org. Chem. 1971, 36, 2731.(b) Carey, F. A.; Court, A. J. Org. Chem. 1972, 37, 1926.(63) (a) Zheng, Y.; Li, Y. J. Org. Chem. 2003, 68, 1603 and referencescited therein. (b) Gu, Q.; Zheng, Y.-H.; Li, Y.-C. Synthesis 2006, 975.(c) Deng, G.; Li, Z.; Peng, S.-Y.; Fang, L.; Li, Y.-C. Tetrahedron 2007,63, 4630.


dx.doi.org/10.1021/cr4004083 | Chem. Rev. XXXX, XXX, XXX−XXXAF

(64) (a) Carey, F. A.; Tremper, H. S. J. Am. Chem. Soc. 1968, 90,2578. (b) Carey, F. A.; Tremper, H. S. J. Am. Chem. Soc. 1969, 91,2967.(65) Shingate, B. B.; Hazra, B. G.; Pore, V. S.; Gonnade, R. G.;Bhadbhade, M. M. Tetrahedron Lett. 2006, 47, 9343.(66) Shingate, B. B.; Hazra, B. G.; Pore, V. S.; Gonnade, R. G.;Bhadbhade, M. M. Tetrahedron 2007, 63, 5622.(67) Wicha, J.; Bal, K. J. Chem. Soc., Chem. Commun. 1975, 968.(68) Wicha, J.; Bal, K. J. Chem. Soc., Perkin Trans. 1 1978, 1282.(69) Wicha, J.; Bal, K.; Piekut, S. Synth. Commun. 1977, 7, 215.(70) Zarecki, A.; Wicha, J. Synthesis 1996, 455.(71) Jarzebski, A.; Wicha, J. Synth. Commun. 1989, 19, 63.(72) Partridge, J. J.; Shiuey, S. J.; Chadha, N. K.; Baggiolini, E. G.;Blount, J. F.; Uskokovic, M. R. J. Am. Chem. Soc. 1981, 103, 1253.(73) Partridge, J. J.; Shiuey, S. J.; Chadha, N. K.; Baggiolini, E. G.;Hennessy, B. M.; Uskokovic, M. R.; Napoli, J. L.; Reinhardt, T. A.;Horst, R. L. Helv. Chim. Acta 1981, 64, 2138.(74) (a) Kurek-Tyrlik, A.; Michalak, K.; Urbanczyk-Lipkowska, Z.;Wicha, J. Tetrahedron Lett. 2004, 45, 7479. (b) Kurek-Tyrlik, A.;Michalak, K.; Wicha, J. J. Org. Chem. 2005, 70, 8513.(75) (a) Kurek-Tyrlik, A.; Minksztym, K.; Wicha, J. J. Am. Chem. Soc.1995, 117, 1849. (b) Kurek-Tyrlik, A.; Minksztym, K.; Wicha, J. Eur. J.Org. Chem. 2000, 1027.(76) Gong, J.-X.; Miao, Z.-H.; Yao, L.-G.; Ding, J.; Kurtan, T.; Guo,Y.-W. Synlett 2010, 480.(77) Ibuka, T.; Taga, T.; Nishii, S.; Yamamoto, Y. J. Chem. Soc., Chem.Commun. 1988, 342.(78) (a) Takano, S.; Yamada, S.; Numata, H.; Ogasawara, K. J. Chem.Soc., Chem. Commun. 1983, 760. (b) Takano, S.; Numata, H.; Yamada,S.; Hatakeyama, S.; Ogasawara, K. Heterocycles 1983, 20, 2159.(79) (a) Clase, J. A.; Money, T. J. Chem. Soc., Chem. Commun. 1990,1503. (b) Clase, J. A.; Money, T. Can. J. Chem. 1992, 70, 1537.(80) Chochrek, P.; Kurek-Tyrlik, A.; Michalak, K.; Wicha, J.Tetrahedron Lett. 2006, 47, 6017.(81) Shiuey, S. J.; Partridge, J. J.; Uskokovic, M. R. J. Org. Chem.1988, 53, 1040.(82) Van Gool, M.; Zhao, X.-Y.; Sabbe, K.; Vandewalle, M. Eur. J.Org. Chem. 1999, 2241.(83) Chen, Y.-J.; Clercq, P. D.; Vandewalle, M. Tetrahedron Lett.1996, 37, 9361.(84) Money, T.; Richardson, S. R.; Wong, M. K. C. Chem. Commun.1996, 667.(85) (a) Przezdziecka, A.; Stepanenko, W.; Wicha, J. Tetrahedron:Asymmetry 1999, 10, 1589. (b) Marczak, S.; Przezdziecka, A.; Wicha,J.; Steinmeyer, A.; Zugel, U. Bioorg. Med. Chem. Lett. 2001, 11, 63.(86) Michalak, K.; Wicha, J. J. Org. Chem. 2011, 76, 6906.(87) Schauder, J. R.; Krief, A. Tetrahedron Lett. 1982, 23, 4389.(88) (a) Snider, B. B.; Roush, D. M.; Rodini, D. J.; Gonzalez, D.;Spindell, D. J. Org. Chem. 1980, 45, 2773. (b) Snider, B. B.; Ron, E. J.Am. Chem. Soc. 1985, 107, 8160.(89) Dauben, W. G.; Brookhart, T. J. Am. Chem. Soc. 1981, 103, 237.(90) Westover, E. J.; Covey, D. F. Steroids 2003, 68, 159.(91) (a) Katona, B. W.; Rath, N. P.; Anant, S.; Stenson, W. F.; Covey,D. F. J. Org. Chem. 2007, 72, 9298. (b) Katona, B. W.; Cummins, C.L.; Ferguson, A. D.; Li, T.; Schmidt, D. R.; Mangelsdorf, D. J.; Covey,D. F. J. Med. Chem. 2007, 50, 6048.(92) Baggiolini, E. G.; Iacobelli, J. A.; Hennessy, B. M.; Uskokovic,M. R. J. Am. Chem. Soc. 1982, 104, 2945.(93) Batcho, A. D.; Berger, D. E.; Davoust, S. G.; Wovkulich, P. M.;Uskokovic, M. R. Helv. Chim. Acta 1981, 64, 1682.(94) (a) Hazra, B. G.; Joshi, P. L.; Pore, V. S. Tetrahedron Lett. 1990,31, 6227. (b) Hazra, B. G.; Pore, V. S.; Joshi, P. L. J. Chem. Soc., PerkinTrans. 1 1993, 1819.(95) Hazra, B. G.; Joshi, P. L.; Bahule, B. B.; Argade, N. P.; Pore, V.S.; Chordia, M. D. Tetrahedron 1994, 50, 2523.(96) Mikami, K.; Loh, T.-P.; Nakai, T. Tetrahedron Lett. 1988, 29,6305.(97) Mikami, K.; Loh, T.-P.; Nakai, T. J. Chem. Soc., Chem. Commun.1991, 77.

(98) Mikami, K.; Kishino, H.; Loh, T.-P. J. Chem. Soc., Chem.Commun. 1994, 495.(99) Mikami, K.; Loh, T.-P.; Nakai, T. J. Chem. Soc., Chem. Commun.1988, 1430.(100) (a) Deng, S.; Yu, B.; Lou, Y.; Hui, Y. J. Org. Chem. 1999, 64,202. (b) Deng, L.; Wu, H.; Yu, B.; Jiang, M.; Wu, J. Bioorg. Med. Chem.Lett. 2004, 14, 2781.(101) (a) Izzo, I.; Filippo, M. D.; Napolitano, R.; Riccardis, F. D. Eur.J. Org. Chem. 1999, 3505. (b) Jiang, B.; Shi, H.-P.; Xu, M.; Wang, W.-J.; Zhou, W.-S. Tetrahedron 2008, 64, 9738.(102) Deng, L.-H.; Wu, H.; Yu, B.; Jiang, M.-R.; Wu, J.-R. Chin. J.Chem. 2004, 22, 994.(103) Matsuya, Y.; Yamakawa, Y.; Tohda, C.; Teshigawara, K.;Yamada, M.; Nemoto, H. Org. Lett. 2009, 11, 3970.(104) Avallone, E.; Izzo, I.; Vuolo, G.; Costabile, M.; Garrisi, D.;Pasquato, L.; Scrimin, P.; Tecilla, P.; Riccardis, F. D. Tetrahedron Lett.2003, 44, 6121.(105) Yamamoto, K.; Shimizu, M.; Yamada, S.; Iwata, S.; Hoshino, O.J. Org. Chem. 1992, 57, 33.(106) (a) Filippo, M. D.; Izzo, I.; Savignano, L.; Tecilla, P.; Riccardis,F. D. Tetrahedron 2003, 59, 1711. (b) Izzo, I.; Avallone, E.; Monica, C.D.; Casapullo, A.; Amigo, M.; Riccardis, F. D. Tetrahedron 2004, 60,5587.(107) Litvinovskaya, R. P.; Drach, S. V.; Khripach, V. A. Russ. J. Org.Chem. 2006, 42, 27.(108) (a) Houstan, T. A.; Tanaka, Y.; Koreeda, M. J. Org. Chem.1993, 58, 4287. (b) Guo, C.; Fuchs, P. L. Tetrahedron Lett. 1998, 39,1099.(109) Watanabe, B.; Yamamoto, S.; Sasaki, K.; Nakagawa, Y.;Miyagawa, H. Tetrahedron Lett. 2004, 45, 2767.(110) Yamamoto, S.; Watanabe, B.; Otsuki, J.; Nakagawa, Y.;Akamatsu, M.; Miyagawa, H. Bioorg. Med. Chem. 2006, 14, 1761.(111) (a) Izzo, I.; Pironti, V.; Monica, C. D.; Sodano, G.; Riccardis, F.D. Tetrahedron Lett. 2001, 42, 8977. (b) Izzo, I.; Monica, C. D.;Bifulco, G.; Riccardis, F. D. Tetrahedron 2004, 60, 5577.(112) Liu, Q.; Yu, Y.; Wang, P.; Li, Y. New J. Chem. 2013, 37, 3647.(113) Kumar, A. S.; Covey, D. F. Tetrahedron Lett. 1999, 40, 823.(114) (a) Matsuya, Y.; Masuda, S.; Ohsawa, N.; Adam, S.;Tschamber, T.; Eustache, J.; Kamoshita, K.; Sukenaga, Y.; Nemoto,H. Eur. J. Org. Chem. 2005, 803. (b) Poza, J. J.; Fernandez, R.; Reyes,F.; Rodriguez, J.; Jimenez, C. J. Org. Chem. 2008, 73, 7978.(115) Matsuya, Y.; Itoh, T.; Nemoto, H. Eur. J. Org. Chem. 2003,2221.(116) (a) Johnson, W. S.; Elliot, J. D.; Hanson, G. J. J. Am. Chem. Soc.1984, 106, 1138. (b) Wovkulich, P. M.; Barcelos, F.; Batcho, A. D.;Sereno, J. F.; Baggiolini, E. G.; Hennessy, B. M.; Uskokovic, M. R.Tetrahedron 1984, 40, 2283. (c) Posner, G. H.; Lee, J. K.; Wang, Q.;Peleg, S.; Burke, M.; Brem, H.; Dolan, P.; Kensler, T. W. J. Med. Chem.1998, 41, 3008. (d) Minato, D.; Li, B.; Zhou, D.; Shigeta, Y.; Toyooka,N.; Sakurai, H.; Sugimoto, K.; Nemoto, H.; Matsuya, Y. Tetrahedron2013, 69, 8019.(117) Hatakeyama, S.; Numata, H.; Osanai, K.; Takano, S. J. Chem.Soc., Chem. Commun. 1989, 1893.(118) (a) Shi, B.; Wu, H.; Yu, B.; Wu, J. Angew. Chem., Int. Ed. 2004,43, 4324. (b) Shi, B.; Tang, P.; Hu, X.; Liu, J. O.; Yu, B. J. Org. Chem.2005, 70, 10354.(119) Xue, J.; Liu, P.; Pan, Y.; Guo, Z. J. Org. Chem. 2008, 73, 157.(120) Kessar, S. V.; Gupta, Y. P.; Rampal, A. L. Tetrahedron Lett.1966, 7, 4319.(121) Kessar, S. V.; Rampal, A. L.; Gandhi, S. S.; Mahajan, R. K.Tetrahedron 1971, 27, 2153.(122) Kessar, S. V.; Gupta, Y. P.; Mahajan, R. K.; Rampal, A. L.Tetrahedron 1968, 24, 893.(123) (a) Kobayashi, S.; Murakami, M.; Mukaiyama, T. Chem. Lett.1985, 953. (b) Kobayashi, S.; Mukaiyama, T. Chem. Lett. 1986, 221.(c) Mukaiyama, T.; Tamura, M.; Kobayashi, S. Chem. Lett. 1986, 1017.(d) Mukaiyama, T.; Tamura, M.; Kobayashi, S. Chem. Lett. 1986, 1817.(e) Mukaiyama, T.; Sagawa, Y.; Kobayashi, S. Chem. Lett. 1986, 1821.(f) Mukaiyama, T.; Tamura, M.; Kobayashi, S. Chem. Lett. 1987, 743.


dx.doi.org/10.1021/cr4004083 | Chem. Rev. XXXX, XXX, XXX−XXXAG

(124) (a) Marczak, S.; Wicha, J. Tetrahedron Lett. 1993, 34, 6627.(b) Grzywacz, P.; Marczak, S.; Wicha, J. J. Org. Chem. 1997, 62, 5293.(125) Marczak, S.; Michalak, K.; Wicha, J. Tetrahedron Lett. 1995, 36,5425.(126) (a) Michalak, K.; Stepanenko, W.; Wicha, J. Tetrahedron Lett.1996, 37, 7657. (b) Prowotorow, I.; Stepanenko, W.; Wicha, J. Eur. J.Org. Chem. 2002, 2727.(127) (a) Stepanenko, W.; Wicha, J. Tetrahedron Lett. 1998, 39, 885.(b) Gorobets, E.; Urbanczyk-Lipkowska, Z.; Stepanenko, V.; Wicha, J.Tetrahedron Lett. 2001, 42, 1135. (c) Achmatowicz, B.; Gorobets, E.;Marczak, S.; Przezdziecka, A.; Steinmeyer, A.; Wicha, J.; Zugel, U.Tetrahedron Lett. 2001, 42, 2891. (d) Gorobets, E.; Stepanenko, V.;Wicha, J. Eur. J. Org. Chem. 2004, 783.(128) Stork, G.; Sofia, M. J. J. Am. Chem. Soc. 1986, 108, 6826.(129) Koreeda, M.; George, I. A. J. Am. Chem. Soc. 1986, 108, 8098.(130) Koreeda, M.; George, I. A. Chem. Lett. 1990, 83.(131) (a) Kurek-Tyrlik, A.; Wicha, J. Tetrahedron Lett. 1988, 29,4001. (b) Kurek-Tyrlik, A.; Wicha, J.; Zarecki, A.; Snatzke, G. J. Org.Chem. 1990, 55, 3484.(132) Tanabe, M.; Hayashi, K. J. Am. Chem. Soc. 1980, 102, 862.(133) Mikami, K.; Kawamoto, K.; Nakai, T. Chem. Lett. 1985, 115.(134) Mikami, K.; Kawamoto, K.; Nakai, T. Tetrahedron Lett. 1986,27, 4899.(135) Koji, Y.; Koami, T.; Nakamura, A.; Fujimoto, Y. Chem. Pharm.Bull. 2000, 48, 1480.(136) Nakamura, A.; Kaji, Y.; Saida, K.; Ito, M.; Nagatoshi, Y.; Hara,N.; Fujimoto, Y. Tetrahedron Lett. 2005, 46, 6373.(137) (a) Tang, P.; Yu, B. Angew. Chem., Int. Ed. 2007, 46, 2527.(b) Tang, P.; Yu, B. Eur. J. Org. Chem. 2009, 259.(138) Takahashi, T.; Naito, Y.; Tsuji, J. J. Am. Chem. Soc. 1981, 103,5261.(139) Suzuki, T.; Sato, E.; Unno, K. Chem. Pharm. Bull. 1993, 41,244.(140) Hatcher, M. A.; Posner, G. H. Tetrahedron Lett. 2002, 43, 5009.(141) For reviews on [2,3]-Wittig rearrangement, see (a) Nakai, T.;Mikami, K. Chem. Rev. 1986, 86, 885. (b) Mikami, K.; Nakai, T.Synthesis 1991, 594. (c) Nakai, T.; Tomooka, K. Pure Appl. Chem.1997, 696, 595.(142) (a) Nakai, T.; Mikami, K.; Taya, S.; Fujita, Y. J. Am. Chem. Soc.1981, 103, 6492. (b) Mikami, K.; Kimura, Y.; Kishi, N.; Nakai, T. J.Org. Chem. 1983, 48, 279. (c) Mikami, K.; Azuma, K.; Nakai, T.Tetrahedron 1984, 40, 2303.(143) Mikami, K.; Kawamoto, K.; Nakai, T. Tetrahedon Lett. 1985,26, 5799.(144) Mikami, K.; Kawamoto, K.; Nakai, T. Chem. Lett. 1985, 1719.(145) Castedo, L.; Granja, J. R.; Mourino, A. Tetrahedron Lett. 1985,26, 4959.(146) Castedo, L.; Granja, J. R.; Mourino, A.; Pumar, M. C. Synth.Commun. 1987, 17, 251.(147) Koreeda, M.; Ricca, D. J. J. Org. Chem. 1986, 51, 4090.(148) Granja, J. R. Synth. Commun. 1991, 21, 2033.(149) Tsubuki, M.; Ohinata, A.; Tanaka, T.; Takahashi, K.; Honda,T. Tetrahedron 2005, 61, 1095.(150) Tsubuki, M.; Matsuo, S.; Honda, T. Tetrahedron Lett. 2008, 49,229.(151) Trost, B. M.; Verhoeven, T. R. J. Am. Chem. Soc. 1976, 98, 630.(152) Trost, B. M.; Verhoeven, T. R. J. Am. Chem. Soc. 1978, 100,3435.(153) Trost, B. M.; Matsumura, Y. J. Org. Chem. 1977, 42, 2036.(154) Takahashi, T.; Ootake, A.; Tsuji, J. Tetrahedron Lett. 1984, 25,1921.(155) Takahashi, T.; Ootake, A.; Tsuji, J.; Tachibana, K. Tetrahedron1985, 41, 5747.(156) Mandai, T.; Matsumoto, T.; Kawada, M.; Tsuji, J. J. Org. Chem.1992, 57, 6090.(157) Bottin, J.; Fetizon, M. J. Chem. Soc., Chem. Commun. 1971,1087.(158) Katoch, R.; Korde, S. S.; Deodhar, K. D.; Trivedi, G. K.Tetrahedron 1999, 55, 1741.

(159) (a) Midland, M. M.; Kwon, Y. C. J. Org. Chem. 1981, 46, 229.(b) Midland, M. M.; Kwon, Y. C. Tetrahedron Lett. 1982, 23, 2077.(160) Midland, M. M.; Kwon, Y. C. J. Am. Chem. Soc. 1983, 105,3725.(161) Midland, M. M.; Kwon, Y. C. Tetrahedron Lett. 1984, 25, 5981.(162) Midland, M. M.; Kwon, Y. C. Tetrahedron Lett. 1985, 26, 5021.(163) Rychnovsky, S. D.; Mickus, D. E. J. Org. Chem. 1992, 57, 2732.(164) Sas, B.; Clercq, P. D.; Vandewalle, M. Synlett 1997, 1167.(165) (a) Marino, J. P.; Floyd, D. M. Tetrahedron Lett. 1979, 20, 675.(b) Marino, J. P.; Hantaka, N. J. Org. Chem. 1979, 44, 4467.(166) Marino, J. P.; Abe, H. J. Am. Chem. Soc. 1981, 103, 2907.(167) (a) Moon, S.; Stuhmiller, L. M.; McMorris, T. C. J. Org. Chem.1989, 54, 26. (b) Moon, S.-S.; Stuhmiller, L. M.; Chadha, R. K.;McMorris, T. C. Tetrahedron 1990, 46, 2287.(168) Mase, T.; Ichita, J.; Marino, J. P.; Koreeda, M. Tetrahedron Lett.1989, 30, 2075.(169) Liu, D.; Stuhmiller, L. M.; McMorris, T. C. J. Chem. Soc., PerkinTrans. 1 1988, 2161.(170) (a) Yu, W.; Jin, J. J. Am. Chem. Soc. 2001, 123, 3369. (b) Yu,W.; Jin, J. J. Am. Chem. Soc. 2002, 124, 6576.(171) Hua, Z.; Carcache, D. A.; Tian, Y.; Li, Y.-M.; Danishefsky, S. J.J. Org. Chem. 2005, 70, 9849.(172) Temple, J. S.; Schwartz, J. J. Am. Chem. Soc. 1980, 102, 7381.(173) Temple, J. S.; Riediker, M.; Schwartz, J. J. Am. Chem. Soc. 1982,104, 1310.(174) Hayasi, Y.; Riediker, M.; Temple, J. S.; Schwartz, J. TetrahedronLett. 1981, 22, 2629.(175) (a) Harada, S.; Kiyono, H.; Taguchi, T.; Hanzawa, Y.; Shiro,M. Tetrahedron Lett. 1995, 36, 9489. (b) Harada, S.; Kiyono, H.;Nishio, R.; Taguchi, T.; Hanzawa, Y.; Shiro, M. J. Org. Chem. 1997, 62,3994.(176) He, Z.; Yi, C. S.; Donaldson, W. A. Org. Lett. 2003, 5, 1567.(177) (a) Saha, B.; Smith, C. R.; Rajanbabu, T. V. J. Am. Chem. Soc.2008, 130, 9000. (b) Page, J. P.; Rajanbabu, T. V. J. Am. Chem. Soc.2012, 134, 6556.(178) Takahashi, T.; Yamada, H.; Tsuji, J. J. Am. Chem. Soc. 1981,103, 5259.(179) Takahashi, T.; Ootake, A.; Yamada, H.; Tsuji, J. TetrahedronLett. 1985, 26, 69.(180) Koreeda, M.; Tanaka, Y.; Schwartz, A. J. Org. Chem. 1980, 45,1172.(181) Matovic, N. J.; Stuthe, J. M. U.; Challinor, V. L.; Bernhardt, P.V.; Lehmann, R. P.; Kitching, W.; Voss, J. J. D. Chem.Eur. J. 2011,17, 7578.(182) Nemoto, H.; Ando, M.; Fukumoto, K. Tetrahedron Lett. 1990,31, 6205.(183) Trost, B. M.; Bernstein, P. R.; Funfschilling, P. C. J. Am. Chem.Soc. 1979, 101, 4378.(184) Grieco, P. A.; Takigawa, T.; Moore, D. R. J. Am. Chem. Soc.1979, 101, 4380.(185) Nemoto, H.; Kurobe, H.; Fukumoto, K.; Kametani, T. J. Org.Chem. 1986, 51, 5311.(186) Kosugi, H.; Sugiura, J.; Kato, M. Chem. Commun. 1996, 2743.(187) Linclau, B.; De Clerca, P.; Vandewalle, M. Bioorg. Med. Chem.Lett. 1997, 7, 1465.


dx.doi.org/10.1021/cr4004083 | Chem. Rev. XXXX, XXX, XXX−XXXAH

本文献由“学霸图书馆-文献云下载”收集自网络，仅供学习交流使用。

学霸图书馆（www.xuebalib.com）是一个“整合众多图书馆数据库资源，

提供一站式文献检索和下载服务”的24 小时在线不限IP

图书馆。

图书馆致力于便利、促进学习与科研，提供最强文献下载服务。

图书馆导航：

图书馆首页文献云下载图书馆入口外文数据库大全疑难文献辅助工具

http://www.xuebalib.com/cloud/

http://www.xuebalib.com/

http://www.xuebalib.com/cloud/


http://www.xuebalib.com/vip.html

http://www.xuebalib.com/db.php

http://www.xuebalib.com/zixun/2014-08-15/44.html


a concise account of various approaches for ...download.xuebalib.com/31iqt0chzpoh.pdf · synthesis...

Documents