a concise synthesis of (−)-indolizidines 209d and 209b

Chinese Journal of Chemistry, 2009, 27, 183—188 Full Paper

* E-mail: [email protected]; Tel.: 0086-021-54925182; Fax: 0086-021-64166128 Received November 5, 2008; revised December 8, 2008; accepted December 22, 2008. Project supported by the National Natural Science Foundation of China (No. 20672135). † Dedicated to Professor Qingyun Chen on the occasion of his 80th birthday.

© 2009 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

A Concise Synthesis of (－)-Indolizidines 209D and 209B†

WU, Hao(武豪) YU, Menglong(俞梦龙) ZHANG, Yazhu(张亚竹) ZHAO, Gang*(赵刚)

Laboratory of Modern Synthetic Organic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China

A general stereoselective synthetic route to 5-substituted and 5,8-disubstituted indolizidine alkaloids has been developed starting from commercially available L-proline. (－)-Indolizidines 209D and 209B were efficiently syn-thesized in 9.8% and 14.8% overall yields in seven and five-step reactions from readily available aldehyde 3 and ketone 10, respectively. The key steps of this synthesis involve a substrate-induced asymmetric addition of ethyl lithiopropiolate to aldehyde 3 or methyl ketone 10, and a two-step one-pot hydrogenation/cyclization sequence to construct the bicyclic skeleton.

Keywords synthesis, indolizidine, alkaloid

Introduction

The neotropical frogs of the Dendrobatidae family have been a rich source of biologically active alkaloids with varied structure prototypes.1 Among them, alka-loids of the indolizidine family are the most important class of compounds known for their wide range of in-teresting pharmaceutical properties. For example, some of them are found to function as noncompetitive block-ers of neuromuscular transmission and some others could effectively promote the discharge of Ca2＋, height-ening the contraction of cardiac muscles and skeletal muscles.1b The scarcity of natural material, coupled with their intriguing biological activity, makes these alkaloids ideal targets for total synthesis. Two typical compounds of this family are the highly toxic indolizidines 209D (1) and 209B (2) (Figure 1). Despite their seemingly simple structures, these two alkaloids are not easy to prepare in enantiomerically pure forms due to multi-stereocenter existing, especially for the construction of the bicyclic entity with the desired con-figuration at the C(5) and C(8) positions. In the past decades, a number of total syntheses of these two alka-loids have been reported.2,3 However, many of these syntheses resorted to the use of chiral auxiliaries, which usually required multiple steps and, with few exceptions, were characterized by low yields, especially in the case of (－)-indolizidine 209B. Herein, we report a short and efficient stereoselective synthesis of (－)-indolizidines 209D and 209B, which utilized the addition reaction of ethyl lithiopropiolate to the aldehyde 3 or ketone 104 to construct the azabicyclic ring skeleton followed by the construction of the C(5) and C(8) chiral centers. The advantage of this approach lies in its flexibility and ver-

satility for the synthesis of a series of 5-substituted and 5,8-disubstituted indolizidine alkaloids.

Figure 1 Structures of (－)-indolizidines 209D and 209B.

Results and discussion

As depicted in Scheme 1, our synthesis started with (2S)-N-Cbz-pyrrolidine-2-carboxaldehyde (3), which was prepared according to the published method.5 The addition of ethyl propiolate to aldehyde 3 using LiHMDS (lithium hexamethyldisilazide) as base in THF at －78 ℃ afforded 4 in 89% yield as a mixture of isomers which could not be separated by column chro-matography. Silylation of the alcohol 4 with TBSCl/ imidazole (TBS＝tert-butyldimethylsilyl) in CH2Cl2 led to TBS-ether 5 in 70.5% yield. Subsequently, removal of the Cbz group, hydrogenation of the C—C triple bond and lactamization of 5 were achieved in one step by hydrogenation using 10% Pd/C as catalyst under 101.325 kPa pressure of H2 at room temperature, pro-viding the desired azabicyclic ring skeletons 6a and 6b in 83% combined yield with a molar ratio of 1.3∶1 (Scheme 1).4b It is worthy mentioning that lactams 6a and 6b could be very useful building blocks in the syn-thesis of indolizidine alkaloids.

Treatment of 6a (or 6b) with C6H13MgBr followed by acidification afforded an iminium ion intermediate,

184 Chin. J. Chem., 2009, Vol. 27, No. 1 WU et al.


Scheme 1 Synthesis of lactams 6a and 6b

Reagents and conditions: (a) ethyl propiolate, LiHMDS, THF, －78

℃, 89%; (b) TBSCl, imidazole, CH2Cl2, r.t., 24 h, 70.5%; (c) H2, Pd/C,

MeOH, 83%.

which was in situ reduced with NaBH4 2g to give a sin-

gle amine product 7a (or 7b) with excellent stereoselec-tivity attributable to the stereoinducing effect of the stereochemistry of the five-membered pyrrolidine ring, which drived the reduction of the iminium ion to occur from the less bulkier face occupied by the hydrogen atom. Thus the C(5) stereocenter was constructed via a sub-strate-induced asymmetric addition and reduction reac-tion sequence. Subsequent desilylation of 7a (or 7b) with 4.0 mol/L HCl/MeOH solution afforded compound 8a (or 8b) in 92% (or 93%) yield. Then the synthesis of (－)-indolizidine 209D (1) from 8 required the conver-sion of the C(8)-hydroxyl group to a hydrogen atom. Failing to displace the corresponding sulfonates of the C(8)-hydroxyl group with a hydride reagent (Li(Et)3BH), we turned to radical deoxygenation reactions, in which the alcohol 8a (8b) was firstly converted to thiocarbon-ate ester 9a (9b) by reaction with CS2 and MeI. React-ing the thiocarbonate ester 9a (9b) under standard Bar-ton-McCombie deoxygenation conditions6 with tribu-tyltin hydride successfully furnished the target molecule (－)-indolizidine 209D (1) in 60% yield. The physical and spectral data as well as the optical rotation value of the synthetic sample were consistent with those previ-ously reported. 20.6

D[α] －82.0 (c 0.55, CH2Cl2) [lit. 24D[α] －77.7 (c 0.7, CH2Cl2)

3j, 25D[α] －78.1 (c 0.98,

CH2Cl2)3m] (Scheme 2).

Following a similar strategy described above, (－)- indolizidine 209B bearing a methyl group at the 8-position was also efficiently synthesized by choosing (2S)-2-aceto-N-(Cbz)-pyrrolidine 104a instead of alde-hyde 3 as the starting material (Scheme 3). Firstly, a separable mixture of 11a and 11b were prepared in a combined yield of 87% by using n-BuLi as base in THF at －78 ℃. The molar ratio of 11a to 11b was ap-proximately 2.5∶1, which was determined by the iso-lated yields of the addition products after purification by column chromatography on silica gel. Hydrogenation of the mixture 11a and 11b in MeOH at room tempera-ture under 101.325 kPa of H2 in the presence of 10%

Scheme 2 Synthesis of (－)-indolizidine 209D (1)

Reagents and conditions: (a) i) C6H13MgBr; ii) AcOH, NaBH4, 63% of

7a, 62% of 7b; (b) 4 mol/L HCl/MeOH, 50 ℃, 92% of 8a, 93% of 8b; (c)

NaH, CS2, MeI, r.t. 53% of 9a, 55% of 9b; (d) Bu3SnH, AIBN, toluene,

reflux, 60%.

Scheme 3 Synthesis of (－)-indolizidine 209B

Reagents and conditions: (a) ethyl propiolate, n-BuLi, THF, －78 ℃,

87%; (b) H2, 10% Pd/C, MeOH, 77% of 12a, 77% of 12b; (c) SOCl2,

Et3N, CH2Cl2, －78 ℃, 75%; (d) 506.625 kPa H2, 10% Pd/C, MeOH,

70%; (e) i) C5H11MgBr; ii) AcOH, NaBH4, 42% of 2 in two steps.

Pd/C provided the desired lactams 12a and 12b4a. De-hydroxylation of the mixture 12a and 12b using SOCl2/Et3N afforded 13 in 75% yield.7 In contrast to the high stereoselectivity obtained in the epoxidation or

Indolizidine Chin. J. Chem., 2009 Vol. 27 No. 1 185


dihydroxylation of 13,8 the ensuing hydrogenation of 13 in MeOH under 506.625 kPa of H2 in the presence of 10% Pd/C gave an inseparable mixture of (8R,9S)-(－)- hexahydro-8-methyl-5-indolizinone 14 and its diastereo- mer 8-epi-14 with a molar ratio of approximately 3∶1 (determined by 1H NMR analysis). Treatment of the mixture 14 with C5H11MgBr followed by AcOH/ NaBH4 afforded the pure target compound (－)-indolizidine 209B 2 after column chromatography. ( 25

D[α] －89.7 (c 0.34, CH3OH) [lit.2h 24

D[α] －90.1 (c 1.38, MeOH)]. The physical and spectral data agreed well with those previously reported.2h

Conclusion

In conclusion, we have completed a new efficient synthesis of two indolizidine alkaloids 209D and 209B through seven and five steps in overall yields of 9.8% and 14.8% from 3 and 10, respectively. The key step of this synthesis involved a substrate-induced asymmetric addition and reduction reaction sequence to stereoselec-tively construct the bicyclic skeleton. The procedure is simple to perform and amenable to the synthesis of other 5-alkyl and 5,8-dialkylindolizidines.

Experimental

General remarks

All reactions were conducted under Ar atmosphere unless stated otherwise and monitored by TLC on pre-coated silica gel HSGF254 plates (Yantai Chemical Co. Ltd). Column chromatography was performed on silica gel 300—400 mesh (Yantai Chemical Co. Ltd) and the columns were eluted with petroleum ether (60—90

℃). Solvents were refluxed and distilled under nitrogen from sodium benzophenone ketyl (THF, Et2O) or CaH2 (CH2Cl2). NMR spectra were recorded on a Bruker AMX-300 spectrometer and are reported in δ units in parts per million and J values in Hz with Me4Si as an internal standard. Mass spectra (MS) and high-resolu- tion mass spectra (HRMS) were measured on a Bruker APEXⅢ 7.0 TESLA FTMS and an IonSpec 4.7 Tesla FTMS spectrometers. Infrared (IR) spectra were re-corded on a Digital FTIR spectrometer and are reported in wave- numbers (cm－1). Optical rotations were meas-ured on a Perkin-Elmer 241 Autopol polarimeter. [α]D values are reported in units of 10－ 1 deg•cm2•g－ 1. (2S)-N-Cbz-pyrrolidine-2-carboxaldehyde (3)5 and (2S)- 2-acetyl-N-(Cbz)-pyrrolidine (10)4a were prepared ac-cording to known procedures.

(S)-Benzyl 2-(1-(tert-butyldimethylsilyloxy)-4- ethoxy-4-oxobut-2-ynyl)pyrrolidine-1-carboxylate (5): TBSCl (11.0 g, 73.0 mmol) was added to a solution of alcohol 4 (16.2 g, 49 mmol) and imidazole (10.2 g, 150 mmol) in CH2Cl2 (300 mL) at 0 ℃. The resulting mix-ture was warmed to 25 ℃ and stirred for 24 h. The reaction mixture was diluted with CH2Cl2 (100 mL) and washed with saturated aqueous NaHCO3 (50 mL) and brine (50 mL). The organic layer was dried (Na2SO4)

and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (sil-ica gel. V(hexane)/V(EtOAc)＝10/1) to give 5 (15.4 g, 70.5%) as a colorless oil. 24.8

D[α] －78 (c 1.20, CHCl3); IR (film) ν: 2956, 2931, 2885, 2858, 2234, 1713, 1412, 1361, 1248, 1116 cm－1; 1H NMR (CDCl3, 300 MHz) δ: 0.08—0.18 (m, 6H), 0.83—0.91 (m, 9H), 1.30 (t, J＝7.2 Hz, 3H), 1.76—1.83 (m, 1H), 1.96—2.25 (m, 3H), 3.34—3.60 (m, 2H), 3.86—4.00 (m, 1H), 4.22 (q, J＝7.2 Hz, 2H), 4.84—4.85 (m, 0.5H), 5.07—5.23 (m, 2.5H), 7.36 (s, 5H, aromatic); MS (ESI) m/z: 446.2 [M＋H]＋, 468.1 [M＋Na]＋. HRMS (ESI) calcd for C24H35NNaO5Si＋1

[M＋Na]＋468.2177, found 468.2186. (8aS)-8-(tert-Butyldimethylsilyloxy)-hexahydroin-

dolizin-5(1H)-one (6a and 6b respectively): To a solu-tion of 5 (603 mg, 1.35 mmol) in absolute MeOH (20 mL) was added 10% Pd/C (100 mg). The reaction mix-ture was stirred under H2 (101.325 kPa) for 24 h, then filtered through celite and concentrated in vacuo to give a slightly yellow crude product, which was purified by flash chromatography (silica gel. V(EtOAc)/V(MeOH)＝15/1) to provide 6a (170 mg) and 6b (131 mg) in a combined yield of 83%.

(8S,8aS)-8-(tert-Butyldimethylsilyloxy)-hexahydr-oindolizin-5(1H)-one (6a): m.p. (54.6±0.5) ℃, 20

D[α] －18.9 (c 1.0, MeOH); 1H NMR (300 MHz, CDCl3) δ: 0.07—0.08 (2s, 6H), 0.88 (s, 9H) 1.79—2.00 (m, 6H), 2.28—2.36 (m, 1H), 2.43—2.56 (m, 1H), 3.46—3.51 (m, 3H), 4.08—4.11 (m, 1H); 13C NMR (75 MHz, CDCl3) δ: 168.9, 64.6, 63.1, 45.2, 29.0, 28.0, 26.3, 25.7, 22.1, 18.1, －4.6, －5.0; IR (KBr) ν: 2955, 2881, 1632, 1460 cm－1; MS (ESI) m/z: 270.1 [M＋H]＋. HRMS (ESI) calcd for C14H27NaNO2Si＋1 [M＋Na]＋292.1715, found 292.1703.

(8R,8aS)-8-(tert-Butyldimethylsilyloxy)-hexahydr-oindolizin-5(1H)-one (6b): 20

D[α] －44 (c 1, CHCl3); 1H NMR (300 MHz, CDCl3) δ: 0.00 (s, 6H), 0.81 (s, 9H), 1.30—1.45 (m, 1H), 1.60—1.80 (m, 2H), 1.82—1.95 (m, 2H), 2.10—2.37 (m, 2H), 2.41—2.55 (m, 1H), 3.15—3.23 (m, 1H), 3.40—3.49 (m, 3H); IR (film) ν: 2953, 2930, 2885, 2857, 1650 cm－1; MS (ESI) m/z: 270.1 [M＋H]＋, 292.2 [M＋Na]＋.

(5R,8S,8aS)-8-(tert-Butyldimethylsilyloxy)-5-hexyl- octahydroindolizine (7a): Lactam 6a (146 mg, 0.54 mmol) was dissolved in dry ether (10 mL) and the solu-tion was placed in an ice bath. A solution of n-hexylmagnesium bromide (1.35 mL of 2.0 mol/L so-lution in ether, 2.71 mmol) was added and the ice bath was then removed. After being stirred for 12 h, the mixture was chilled in an ice bath and acetic acid (5.0 mL) was added, followed by NaBH4 (41 mg, 1.08 mmol). The ice bath was removed and the mixture was stirred for 3 h at r.t. Ether (10 mL) was added and the solution was washed with 7.5% KOH (40 mL). The aqueous layer was extracted with ether (20 mL×3) and the combined organic layers were washed with brine, dried over Na2SO4 and concentrated to an oil. The crude product was purified by flash chromatography (silica



gel, V(hexane)/V(EtOAc)＝5/1) to provide 7a (115 mg, 63%) as a colorless oil. 24

D[α] －41 (c 0.92, CHCl3); 1H

NMR (300 MHz, CDCl3) δ: 0.04 (s, 3H), 0.06 (s, 3H), 0.87—0.90 (m, 12H), 1.25—2.00 (m, 22H), 3.28 (t, J＝6.3 Hz, 1H), 3.36—3.39 (m, 1H); 13C NMR (75 MHz, CDCl3) δ: 67.5, 66.4, 63.3, 50.8, 33.9, 32.4, 31.3, 29.2, 25.6, 25.5, 25.1, 24.4, 22.1, 19.7, 18.0, 13.6, －5.1; IR (neat) ν: 2954, 2929, 2857, 2776, 1463, 1253, 835 cm－1; MS (MALDI) m/z: 340.3 [M＋H]＋; HRMS (MALDI) calcd for C20H42NOSi ＋ 1 [M＋H] ＋ 340.3030, found 340.3021±0.003.

(5R,8R,8aS)-8-(tert-Butyldimethylsilyloxy)-5-hexyl- octahydroindolizine (7b): Under similar reaction con-ditions as described above, 6b was converted to 7b in 62% yield as a colorless oil. 22

D[α] －59.7 (c 0.78, CHCl3);

1H NMR (300 MHz, CDCl3) δ: 0.04 (s, 6H), 0.86 (s, 12H), 1.25—2.08 (m, 22H), 3.23 (td, J＝8.1, 2.4 Hz, 1H), 3.34—3.42 (m, 1H); 13C NMR (75 MHz, CDCl3) δ: 76.0, 72.5, 64.6, 53.6, 46.5, 36.5, 36.2, 33.6, 32.0, 31.5, 30.9, 27.6, 24.4, 22.3, 19.8, 15.9, －2.3, －2.8; IR (neat) ν: 2955, 2930, 2858, 2783, 1462, 1251, 1097, 836 cm－1; MS (MALDI) m/z: 340.3 [M＋H]＋; HRMS (MALDI) calcd. for C20H42NSiO＋1 [M＋H]＋

340.3030, found 340.3031±0.003. (5R,8S,8aS)-5-Hexyl-octahydroindolizin-8-ol (8a):

7a (180 mg, 0.53 mmol) was dissolved in MeOH (10 mL) and the solution was stirred in an ice bath. Acetyl chloride (1.3 mL) was added and then the ice bath was removed. The reaction mixture was warmed to 50 ℃ and stirred for 8 h. The reaction mixture was concen-trated, diluted with 10% NaOH (15 mL) and then ex-tracted with CH2Cl2 (15 mL×3). The combined organic layers were dried with Na2SO4. The filtrate was concen-trated in vacuo followed by flash chromatography (sil-ica gel. V(CH2Cl2)/V(MeOH)＝10/1) to give 8a (109 mg, 92%) as a pale yellow solid. 21

D[α] －61.2 (c 0.93, CHCl3);

1H NMR (300 MHz, CDCl3) δ: 0.87 (t, J＝6.6 Hz, 3H), 1.26—2.11 (m, 21H), 2.57 (s, br, 1H), 3.15—3.21 (m, 1H), 3.74 (s, 1H); 13C NMR (75 MHz, CDCl3) δ: 67.7, 65.5, 63.4, 51.6, 34.5, 31.9, 31.8, 29.7, 25.3, 25.0, 24.9, 22.6, 20.7, 14.1; IR (neat) ν: 3502, 2929, 2857, 2786, 1461, 1376, 1126 cm－1; MS (MALDI) m/z: 226.2 [M＋H]＋; HRMS (MALDI) calcd for C14H28NO＋1

[M＋H]＋ 226.2165, found 226.2174±0.003. (5R,8R,8aS)-5-Hexyl-octahydroindolizin-8-ol (8b):

Under similar reaction conditions as described above, 7b was converted to 8b in 93% yield. 19.7

D[α] －89.9 (c 0.84, CHCl3);

1H NMR (300 MHz, CDCl3) δ: 0.88 (t, J＝6.9 Hz, 3H), 1.23—1.34 (m, 12H), 1.56—1.92 (m, 6H), 2.00—2.12 (m, 3H), 2.51 (brs, 1H), 3.26 (td, J＝8.4, 2.1 Hz, 1H), 3.38—3.46 (m, 1H); 13C NMR (75 MHz, CDCl3) δ: 73.1, 70.6, 62.7, 51.6, 34.2, 34.0, 31.8, 30.0, 29.6, 28.3, 25.8, 22.6, 20.6, 14.0; IR (neat) ν: 3372, 2930, 2858, 2783, 1459, 1376, 1070 cm－1; MS (MALDI) m/z: 226.2 [M＋H]＋; HRMS (MALDI) m/z: calcd. for C14H28NO＋ 1 [M＋H]＋ 226.2165, found 226.2175±0.003.

O-(5R,8S,8aS)-5-Hexyl-octahydroindolizin-8-yl S-

methyl carbonodithioate (9a): To a solution of 8a (140 mg, 0.62 mmol) in THF (20 mL) were added sodium hydride (60% suspension in mineral oil, 120 mg, 3 mmol) and carbon disulfide (0.18 mL, 3 mmol) at 0 ℃. The mixture was stirred at room temperature for 2 h, and then iodomethane (0.18 mL, 3 mmol) was added. After being stirred for 12 h, the reaction was quenched by slow addition to brine (20 mL). The mixture was separated, and the aqueous layer was washed with CH2Cl2 (20 mL×3). The combined organic extracts were dried (Na2SO4), concentrated and purified (silica gel, V(hexane)/V(EtOAc)＝30/1) to afford 9a (103 mg, 53%) as a yellow oil. 21

D[α] －51.4 (c 0.67, CHCl3); 1H

NMR (300 MHz, CDCl3) δ: 0.89 (t, J＝6.6 Hz, 3H), 1.25—1.43 (m, 11H), 1.65—1.72 (m, 6H), 1.95—1.98 (m, 2H), 2.19—2.23 (m, 2H), 2.56 (s, 3H), 3.31 (t, J＝7.2 Hz, 1H), 5.87—5.88 (m, 1H); 13C NMR (75 MHz, CDCl3) δ: 216.7, 78.2, 66.3, 63.2, 51.1, 34.3, 31.8, 29.7, 28.5, 25.9, 25.5, 25.4, 22.6, 20.1, 19.0, 14.1; IR (neat) ν: 2926, 2856, 2781, 1225, 1067, 1049 cm－1; MS (MALDI) m/z: 316.2 [M＋H] ＋ ; HRMS (MALDI) calcd for C16H30NOS2

＋1 [M＋H]＋ 316.1763, found 316.1771±0.003.

O-(5R,8R,8aS)-5-Hexyl-octahydroindolizin-8-yl S- methyl carbonodithioate (9b): Under similar reaction conditions as described above, 8b was converted to 9b in 55% yield as a yellow oil. 20

D[α] －66.2 (c 1.3, CHCl3);

1H NMR (300 MHz, CDCl3) δ: 0.87 (t, J＝6.6 Hz, 3H), 1.24—1.41 (m, 11H), 1.60—2.34 (m, 10H), 2.52 (s, 3H), 3.23 (t, J＝8.4 Hz, 1H), 5.39—5.47 (m, 1H); 13C NMR (75 MHz, CDCl3) δ: 215.1, 84.6, 67.3, 62.4, 51.3, 34.1, 31.8, 29.7, 29.7, 29.6, 28.3, 25.6, 22.6, 20.7, 18.9, 14.0; IR (neat) ν: 2955, 2926, 2856, 2785, 1231, 1058 cm－1; MS (MALDI) m/z: 316.2 [M＋H]＋. HRMS (MALDI) calcd for C16H30NOS2

＋1 [M＋H]＋

316.1763, found 316.1770±0.003.

(－)-Indolizidine 209D (1)

A solution of 9a (or 9b) (50 mg, 0.16 mmol), tribu-tyltin hydride (0.13 mL, 0.48 mmol), and AIBN (10 mg, 0.032 mmol) in toluene (15 mL) was heated at reflux for 3 h. The mixture was cooled, concentrated in vacuo, and purified (silica gel, V(hexane)/V(EtOAc)＝3/1) to afford 1 (24 mg, 72%) as a colorless oil. 20.6

D[α] －82 (c 0.55, CH2Cl2);

1H NMR (300 MHz, CDCl3) δ: 0.88 (t, J＝6 Hz, 3H), 1.15—2.00 (m, 23H), 3.26 (t, J＝8.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ: 65.1, 63.9, 51.6, 34.7, 31.8, 31.0, 30.9, 30.6, 29.7, 25.8, 24.7, 22.6, 20.4, 14.1.

(2S)-Benzyl 2-(5-ethoxy-2-hydroxy-5-oxopent-3- yn-2-yl)pyrrolidine-1-carboxylate (11a and 11b re-spectively): n-BuLi (9.5 mL of 1.6 mol/L solution in hexane, 15.2 mmol) was added slowly to a stirred solu-tion of ethyl propiolate (1.54 mL, 15.2 mmol) in dry THF (25 mL) at －78 ℃ under Ar. The resulting solu-tion was stirred at －78 ℃ for 1 h. Then a solution of ketone 10 (1.88 g, 7.6 mmol) in dry THF (10 mL) was added under positive Ar pressure. The resulting solution was stirred at －78 ℃ for 5 h and then the reaction

Indolizidine Chin. J. Chem., 2009 Vol. 27 No. 1 187


was monitored with TLC. Saturated aqueous NH4Cl was added at －78 ℃ to quench the reaction. The reaction mixture was warmed to room temperature and extracted with Et2O (50 mL×3). The combined organic layers were washed with brine and dried with Na2SO4. The filtrate was concentrated in vacuo. Flash chromatography (silica gel, V(hexane)/V(EtOAc)＝5/1) gave 11a (1.63 g) and 11b (0.65 g) in a combined yield of 87%.

11a: 20D[α] －120.7 (c 1.11, CHCl3).

1H NMR (300 MHz, CDCl3) δ: 1.30 (t, J＝7.2 Hz, 3H), 1.48 (s, 3H), 1.66—2.22 (m, 4H), 3.36—3.45 (m, 1H), 3.77—3.85 (m, 1H), 3.99 (t, J＝7.5 Hz, 1H), 4.21 (q, J＝7.2 Hz, 2H), 5.19 (s, 2H, OCH2Ph), 6.89 (s, 1H), 7.32—7.38 (m, 5H, aromatic); IR (neat) ν: 3288, 2984, 2890, 2240, 1711, 1668, 1498, 1454, 1420, 1359, 1245 cm－1.

11b: 20D[α] －51.3 (c 1.15, CHCl3);

1H NMR (300 MHz, CDCl3) δ: 1.29 (t, J＝7.2 Hz, 3H), 1.41 (s, 3H), 1.78—2.05 (m, 4H), 3.36—3.44 (m, 1H), 3.67—3.75 (m, 1H), 4.23 (q, J＝7.2 Hz, 2H), 4.29—4.32 (m, 1H), 5.16 (s, 2H, OCH2Ph), 6.00 (s, 1H), 7.36—7.38 (m, 5H, aromatic); IR (neat) ν: 3400, 2984, 2897, 2242, 1711, 1671, 1455, 1414, 1360, 1247 cm－1.

(8R,8aS)-8-Hydroxy-8-methyl-hexahydroindolizin- 5(1H)-one (12a): To a solution of 11a (908 mg, 2.63 mmol) in absolute MeOH (20 mL) was added 10% Pd/C (100 mg). The reaction mixture was stirred under H2 (1 atm) for 24 h, then filtered through celite and concen-trated in vacuo to give a slightly yellow crude product, which was purified by flash chromatography (silica gel, V(EtOAc)/V(MeOH)＝20/1) to provide 12a (452 mg, 77%). 20

D[α] －64 (c 0.98, CHCl3); 1H NMR (300 MHz,

CDCl3) δ: 1.18 (s, 3H), 1.60—2.12 (m, 6H), 2.27—2.40 (m, 2H), 2.48—2.58 (m, 1H), 2.95 (brs, 1H), 3.45—3.51 (m, 3H); IR (neat) ν: 3284, 2975, 2951, 2883, 1611, 1482, 1459, 1414, 1148 cm－1.

(8S,8aS)-8-Hydroxy-8-methyl-hexahydroindolizin- 5(1H)-one (12b): Under similar reaction conditions as described above, 11b was converted to 12b in 77% yield. 25

D[α] －41.3 (c 0.48, CHCl3); 1H NMR (300

MHz, CDCl3) δ: 1.31 (s, 3H), 1.76—2.00 (m, 7H), 2.39—2.60 (m, 2H), 3.38 (dd, J＝5.4, 10.2 Hz, 1H), 3.53 (dd, J＝4.8, 9.6 Hz, 2H); IR (neat) ν: 3371, 2968, 2927, 2877, 1618, 1474, 1411 cm－1;

(S)-8-Methyl-1,2,3,8a-tetrahydroindolizin-5(6H)- one (13): To a solution of 12a (or 12b) (247 mg, 1.46 mmol) and Et3N (3.0 mL, 14.6 mmol) in dry CH2Cl2 (20 mL) at －78 ℃ was added SOCl2 (0.53 mL, 7.3 mmol) quickly under Ar atmosphere. The reaction mixture was stirred at －78 ℃ for 30 min and then the reaction was monitored with TLC. Saturated aqueous NaHCO3 was added at －78 ℃ to quench the reaction. The reaction mixture was warmed to room temperature and extracted with CH2Cl2 (20 mL×3). The combined organic layers were washed with brine and dried with Na2SO4. The filtrate was concentrated in vacuo. Flash chromatogra-phy (silica gel, V(hexane)/V(EtOAc)＝10/1) gave 13 (165 mg, 75%) as a pale yellow oil. 26

D[α] －128.8 (c 0.5, CHCl3);

1H NMR (300 MHz, CDCl3) δ: 1.45—1.57

(m, 1H), 1.76 (s, 3H), 1.89—2.04 (m, 1H), 2.14—2.22 (m, 2H), 2.91—3.08 (m, 2H), 3.43 (t, J＝10.8 Hz, 1H), 3.74 (dd, J＝9.0, 12.0 Hz, 1H), 3.95 (brs, 1H), 5.43 (m, 1H); IR (neat) ν: 2924, 2854, 1649, 1453, 1413, 1287, 805 cm－1.

(8R,9S)-( － )-Hexahydro-8-methyl-5-indolizinone (14) and 8-epi-(14): To a solution of 13 (70 mg, 0.46 mmol) in absolute MeOH (10 mL) was added 10% Pd/C (10 mg). The reaction mixture was stirred under H2

(506.625 kPa) for 12 h, then filtered through celite and concentrated in vacuo to give a slightly yellow crude product, which was purified by flash chromatography (silica gel, V(EtOAc)/V(MeOH)＝10/1) to provide the inseparable mixture of 14 and 8-epi-14 as a pale yellow oil (49.0 mg, 70%). 20

D[α] －19 (c 0.6, CHCl3); 1H

NMR (300 MHz, CDCl3) δ: 0.85 (d, J＝7.5 Hz, 0.7H), 1.03 (d, J＝6.0 Hz, 2.1H), 1.31—1.49 (m, 2H), 1.57—2.02 (m, 4H), 2.12—2.21 (m, 1H), 2.28—2.52 (m, 2H), 2.96—3.04 (m, 1H), 3.44—3.63 (m, 2H); IR (neat) ν: 2961, 2925, 2875, 2854, 1642, 1461, 1416 cm－1.

Indolizidine-209B (2)

Lactam (14 and 8-epi-14) (48.0 mg, 0.31 mmol) was dissolved in dry ether (5.0 mL) and the solution was chilled in ice. A solution of n-pentylmagnesium bro-mide (0.78 mL of 1.0 mol/L solution in ether, 1.57 mmol) was added and then the ice bath was removed. After 12 h, the mixture was chilled in an ice bath and acetic acid (3.0 mL) was added, followed by NaBH4 (30 mg, 0.62 mmol). The ice bath was removed and the mixture was stirred for 3 h. Ether (5.0 mL) was added and the solution was washed with 7.5% KOH (20 mL). The aqueous layer was extracted with ether (10 mL×3) and the combined organic layers were washed with brine, dried (Na2SO4) and concentrated to an oil. The crude product was purified by flash chromatography (silica gel, V(hexane)/V(EtOAc) ＝ 20/1) to provide indolizidine-209B (2), 27 mg, 42%, as a pale yellow oil.

25D[α] －89.7 (c 0.34, CH3OH); 1H NMR (300 MHz,

CDCl3) δ: 0.86—1.02 (m, 7H), 1.22—1.49 (m, 11H), 1.62—2.02 (m, 8H), 3.27 (dt, J＝8.4, 2.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ: 71.4, 63.6, 51.8, 36.5, 34.5, 33.7, 32.3, 31.2, 29.1, 25.5, 22.6, 20.3, 18.8, 14.1; IR (neat) ν: 2957, 2926, 2872, 2855, 2781, 1458, 1385 cm－1.

References

1 (a) Toyooka, N.; Tanaka, K.; Momose, T.; Daly, J. W.; Garraffo, H. M. Tetrahedron 1997, 53, 9553. (b) For a comprehensive review on occurrence, synthesis and activity of alkaloids in amphibian skins see: Daly, J. W.; Garraffo, H. M.; Spande, T. F. In Alkaloids: Chemical & Biological Perspective, Vol. 13, Ed.: Pelletier, S. W., Elsevier Science Ltd., Oxford, 1999, pp. 1—161.

2 For selected examples on syntheses of indolizidine 209B, see: (a) Foti, C. J.; Comins, D. L. J. Org. Chem. 1995, 60, 2656. (b) Simth, A. L.; Williams, S. F.; Holmes, A. B.; Hughes, L.



R.; Swithenbank, C.; Lidert, Z. J. Am. Chem. Soc. 1988, 110, 8696. (c) Momose, T.; Toyooka, N. J. Org. Chem. 1994, 59, 943. (d) Michel, P.; Rassat, A.; Daly, J. W.; Spande, T. F. J. Org. Chem. 2000, 65, 8908. (e) Back, T. G.; Nakajima, K. J. Org. Chem. 2000, 65, 4543. (f) Michael, J. P.; Gravestock, D. Synlett 1996, 981. (g) Aube, J.; Rafferty, P.; Milligen, G. L. Heterocycles 1993, 35, 1141. (h) Sataka, A.; Shimizu, I. Tetrahedron: Asymmetry 1993, 4, 1405. (i) Sato, F.; Okamoto, S.; Song, Y. C. Tetrahedron Lett. 2002, 43, 8635. (j) Davis, F. A.; Yang, B. Org. Lett. 2003, 5, 5011. (k) Toyooka, N.; Zhou, D.; Nemoto, H.; Garraffo, H. M.; Spande, T. F.; Daly, J. W. Tetrahedron Lett. 2006, 47, 577.

3 For recent examples on syntheses of indolizidine 209D, see: (a) Polniaszek, R. P.; Belmont, S. E. J. Org. Chem. 1990, 55, 4688. (b) Calter, M. A.; Liao, W. S.; Struss, J. A. J. Org. Chem. 2001, 66, 7500. (c) Ahman, J.; Somfai, P. Tetrahedron Lett. 1995, 36, 303. (d) Ahman, J.; Somfai, P. Tetrahedron 1995, 51, 9747. (e) Nukui, S.; Sodeoka, M.; Sasai, H.; Shibasaki, M. J. Org. Chem. 1995, 60, 398. (f) Jeffod, C. W.; Sienkiewicz, K.; Thornton, S. R. Helv. Chim. Acta 1995, 78, 1511. (g) Takahata, H.; Kubota, M.; Ihara, K.; Okamoto, N.;

Momose, T.; Azer, N.; Eldefrawi, A. T.; Eldefrawi, M. E. Tetrahedron: Asymmetry 1998, 9, 3289. (h) Chenevert, R.; Ziarani, G. M.; Mori, M. P.; Dasser, M. Tetrahedron: Asymmetry 1999, 10, 3117. (i) Yamazaki, N.; Ito, T.; Kibayashi, C. Org. Lett. 2000, 2, 465. (j) Kim, G.; Jung, S. D.; Kim, W. J. Org. Lett. 2001, 3, 2985. (k) Kim, G.; Lee, E. J. Tetrahedron: Asymmetry 2001, 12, 2073. (l) Hiroki, T.; Motohiro, I. Heterocycles 2006, 67, 407. (m) Patil, N. T.; Pahadi, N. K.; Yamamoto, Y. Tetrahedron Lett. 2005, 46, 2101. (n) Reddy, P. G.; Baskaram, S. J. Org. Chem. 2004, 69, 3093.

4 (a) Ni, Y. K.; Zhao, G.; Ding, Y. J. Chem. Soc., Perkin Trans. 1 2000, 19, 3264. (b) Zhang, H. L.; Ni, Y. K.; Zhao, G.; Ding, Y. Eur. J. Org. Chem. 2003, 10, 1918.

5 Thurston, D. E.; Bose, D. S.; Thompson, A. S.; Howard, P. W.; Leoni, A.; Croker, S. J.; Jenkins, T. C.; Neidle, S.; Hartley, J. A.; Hurley, L. H. J. Org. Chem. 1996, 61, 8141.

6 Barton, D. H.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1 1975, 1574.

7 Ozawa, T.; Aoyagi, S.; Kibayashi, C. Org. Lett. 2000, 2, 2955.

8 Stevenson, P. J.; O'Mahony, G.; Nieuwenhuyzen, M.; Arm-strong, P. J. Org. Chem. 2004, 69, 3968.

(E0811153 CHEN, J. X.)

a concise synthesis of (−)-indolizidines 209d and 209b

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