Efficient Enantio- and Diastereo-divergent Synthesis of Poison-frog Alkaloids 251O and trans-223B

Abstract

An efficient and flexible synthesis of poison-frog alkaloids 251O and trans-223B has been achieved using for both alkaloids an enantiodivergent process starting from the common lactam 1. The relative stereochemistry of 251O and trans-223B was determined to be 7 (R = n- C₇H₁₅, R’ = n-Pr) and 14 by the present enantioselective synthesis.

Introduction

A variety of lipophilic alkaloids have been detected in skin extracts of neotropical poison-frogs and over 800 alkaloids from 24 classes have been detected to date.¹ These alkaloids serve as a chemical defense against predation and some of them also exhibit significant inhibitory effects on nicotinic acetylcholine receptors (nAChRs).²

Very interestingly, most of these alkaloids appear to be sequestered from dietary arthropods.³ Thus, the 3,5-disubstituted pyrrolizidine 251O, detected in the poison-frogs Mantella haraldmeieri, M. bernhardi and M. baroni of Madagascar, has also been found in Malagasy ants of the genus Anochetus grandidieri.⁴ So far, several syntheses of trans, trans-type of 3,5-disubstituted pyrrolizidines such as xenovenine have been reported,⁵ whereas no synthesis of the trans, cis-type of 3,5-disubstituted pyrrolizidine alkaloids has been reported. Natural xenovenine is found in frogs as cis-223H. It has the 3R, 5S, 8S absolute configuration as shown in Figure 1 (unpublished work, HMG, TFS and JWD). Alkaloid 251O has a trans, cis-type of pyrrolizidine ring system; however, both the relative and absolute stereochemistry are still unknown (Figure 1). As part of a program directed at studying the synthesis of biologically active alkaloids,⁶ we report herein, the efficient enantio- and diastereo-divergent synthesis of 251O starting from a common lactam, 1.⁷

Figure 1.

Structure of xenovenine and 251O

Results and Discussion

The known olefin 2,⁸ derived from 1, was converted to a Boc-imide, which was treated with n-Pr or n-C₇H₁₅ magnesium bromide according to Martin’s reaction conditions⁹ to provide the ketones 3 (R = n-Pr or n-C₇H₁₅) in high yield. Both ketones 3 were subjected to cyclization and subsequent reduction of the resulting iminium ion with Ph₃SiH⁹ to give rise to the cis-substituted pyrrolidines 4 (R = n-Pr or n-C₇H₁₅). The cross-metathesis reaction of 4 (R = n-Pr or n-C₇H₁₅) with ethyl acrylate using Grubbs’ second-generation catalyst¹⁰ afforded the unsaturated esters 5 (R = n-Pr or n-C₇H₁₅). The key pyrrolizidine ring-closure reaction of 5 (R = n-Pr or n-C₇H₁₅) resulted after treatment with 2 equivalents of AlCl₃ in CH₂Cl₂ followed by K₂CO₃ in the desired pyrrolizidines 6 (R = Et or n-C₆H₁₃) in excellent yield with high diastereoselectivity (>30:1). The stereochemistry of 6 (R = Et) was determined to be as shown based on an NOE experiment. In a difference NOE experiment, an NOE enhancement (ca. 2.3%) was observed on one of the methylene protons of the side chain at C-5 upon irradiation of the methine proton at C-3.

The highly selective formation of the desired 6 (R = Et or n-C₆H₁₃) is explained by invoking kinetic control as shown in Figure 2.¹¹ Finally, half-reduction of the ester moiety with diisobutylaluminum hydride, Wittig olefination of the resulting aldehyde followed by hydrogenation of the corresponding olefin furnished 7 (R = n-Pr, R’ = n-C₇H₁₅ or R = n-C₇H₁₅, R’ = n-Pr). (Scheme 1)

Figure 2.

Kinetic control on pyrrolizidine formation

Scheme 1.

Synthesis of 7 (R = n-Pr, R' = n-C₇H₁₅ or R = n-C₇H₁₅, R' = n-Pr)

Reagents and conditions

(a) Boc₂O, DMAP, MeCN, rt (95%); (b) n-C₃H₇MgBr or n-C₇H₁₅MgBr, TMEDA, THF, −78 °C (88% for R = n-Pr, 78% for R = n-C₇H₁₅); (c) B(C₆F₅)₃, Ph₃SiH, CH₂Cl₂, −78 ° C to rt (85% for R = n-Pr, 89% for R = n-C₇H₁₅); (d) ethyl acrylate, Grubbs' 2nd catalyst, CH₂Cl₂, reflux (96% for R = n-C₃H₇, 96% for R = n-C₇H₁₅); (e) AlCl₃, CH₂Cl₂, rt then K₂CO₃, CH₂Cl₂, rt (93% for R = Et, 88% for R = n-C₆H₁₃); (f) DIBAL, CH₂Cl₂, −78 °C; (g) n-C₅H₁₁P⁺Ph₃Br⁻ , n-BuLi or MeP⁺Ph₃I⁻ , n-BuLi, THF, 0 °C to rt (46% for R = n-Pr, R' = C₇H₁₃, 49% for R = n-C₇H₁₅, R' = allyl); (h) 10% Pd/C, H₂, EtOAc, 1 atm (quant for R = n-Pr, R' = n-C₇H₁₅, 95% for R = n-C₇H₁₅, R' = n-Pr)

Ent-7 (R = n-Pr, R’ = n-C₇H₁₅ or R = n-C₇H₁₅, R’ = n-Pr) was synthesized from 1 in a similar way as shown in Scheme 2.

Scheme 2.

Synthesis of ent-7 (R = n-Pr, R' = n-C₇H₁₅ or R = n-C₇H₁₅, R' = n-Pr)

Reagents and conditions

(a) EtMgBr or n-C₆H₁₃MgBr, THF, −35 °C (52% for R = n-Pr, 50% for R = n-C₇H₁₅); (b) Boc₂O, DMAP, MeCN, rt (94% for R = n-Pr, 93% for R = n-C₇H₁₅); (c) 4-butenylMgBr, TMEDA, THF, −78 °C (95% for R = n-Pr, 98% for R = n-C₇H₁₅); (d) B(C₆F₅)₃, Ph₃SiH, CH₂Cl₂, −78 ° C to rt (73% for R = n-Pr, 86% for R = n-C₇H₁₅); (e) ethyl acrylate, Grubbs' 2nd catalyst, CH₂Cl₂, reflux (96% for R = n-Pr, 95% for R = n-C₇H₁₅); (f) AlCl₃, CH₂Cl₂, rt then K₂CO₃, CH₂Cl₂, rt (93% for R = n-Pr, 91% for R = n-C₇H₁₅); (g) DIBAL, CH₂Cl₂, −50 °C; (h) n-C₅H₁₁P⁺Ph₃Br⁻ , n-BuLi or MeP⁺Ph₃I⁻ , n-BuLi, THF, 0 °C to rt (48% for R = n-Pr, R' = C₇H₁₃, 52% for R = n-C₇H₁₅, R' = allyl); (h) 10% Pd/C, H₂, EtOAc, 1 atm (96% for R = n-Pr, R' = n-C₇H₁₅, quant for R = n-C₇H₁₅, R' = n-Pr).

The enantiodivergent synthesis of trans-223B was also achieved starting from common lactam 2 as shown in Scheme 3

Scheme 3.

Synthesis of both enantiomers of trans-223B

Reagents and conditions

(a) Boc₂O, DMAP, MeCN, rt (95%); (b) n-BuMgBr, TMEDA, THF, −78 °C (98%); (c) B(C₆F₅)₃, Ph₃SiH, CH₂Cl₂, −78 °C to rt (73%); (d) ethyl acrylate, Grubbs' 2nd catalyst, CH₂Cl₂, reflux (96%); (e) AlCl₃, CH₂Cl₂, rt then K₂CO₃, CH₂Cl₂, rt (92%); (f) DIBAL, CH₂Cl₂, −50 °C; (g) EtP⁺Ph₃Br⁻ , n-BuLi, THF, 0 °C to rt (50%); (h) 10% Pd/C, H₂, EtOAc, 1 atm (quant); (i) Boc₂O, DMAP, MeCN, rt (95%); (j) 10% Pd/C, H₂, EtOAc, 1 atm, then 4-butenylMgBr, TMEDA, THF, −78 °C (96%); (k) B(C₆F₅)₃, Ph₃SiH, CH₂Cl₂, −78 °C to rt (72%); (l) ethyl acrylate, Grubbs' 2nd catalyst, CH₂Cl₂, reflux (84%); (m) AlCl₃, CH₂Cl₂, rt then K₂CO₃, CH₂Cl₂, rt (92%); (n) DIBAL, CH₂Cl₂, −50 °C; (o) EtP⁺Ph₃Br⁻ , n-BuLi, THF, 0 °C to rt (53%); (p) 10% Pd/C, H₂, EtOAc, 1 atm (quant).

The GC-MS and GC-FTIR spectra of synthetic 7 (R = n- C₇H₁₅, R’ = _n-Pr) were identical with those for natural 251O present in skin extracts of three Madagascan frogs (Mantella haraldmeieri collected in 2004, M. bernhardi collected in 1997, and M. baroni collected in 2004, unpublished results; see supporting information). Furthermore, the GC-MS and GC-FTIR spectra of synthetic 14 were also identical with those for natural trans-223B present in a skin extract of the Argentinean frog Melanophryniscus stelzneri.¹² The mass spec evidence, with a strong loss of propyl from the molecular ion at m/z 208 (251-43) indicates a pseudo-axial position for the propyl group: a group that is trans-antiparallel to the radical ion on the N atom should cleave preferentially, all other things being equal. The heptyl group, being larger cleaves better, but the comparison of the MS on the Supplemental Information, between trans-stereoisomers with a Pr-group pseudo-axial or a Pr-group pseudo-equatorial, clearly indicates a bigger fragmentation of the propyl group for the one in the pseudo-axial position. This MS evidence indicates that natural 251O is (3S, 5S, 8R) or the enantiomer (3R, 5R, 8S) same as 7 (R = n- C₇H₁₅, R’ = n-Pr) or ent-7 (R = n-C₇H₁₅, R’ = n-Pr). Unfortunately, we could not achieve the separation of both enantiomers of synthetic 7 by GC analysis using two different columns. For the enantiomers of synthetic 14, we anticipate even more difficulty in the separation since the two side-chains are identical; however, this separation was not attempted.

In conclusion, we have achieved the first synthesis of alkaloids 251O and trans-223B in enantio- and diastereo-divergent fashion in 8 or 9 steps in 25~29% overall yield from the known lactam 1, respectively. Furthermore, the relative stereochemistries of natural 251O and trans-223B were determined to be 7 (R = n- C₇H₁₅ R’ = n-Pr) and 14, respectively, by the present efficient syntheses and comparisons with the natural compounds. It is difficult to separate the enantiomers of 7 and 14, but further work on the GC separation of the enantiomers of 7 and 14 for the determination of the absolute stereochemistry of natural 251O and trans-223B is in progress.¹³

Experimental Section

(2R)-(−)-2-(But-3-enyl)-5-oxopyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred solution of 2⁸ (337 mg, 2.42 mmol) in MeCN (20 mL) was added DMAP (326 mg, 2.67 mmol) at 0 °C, and the reaction mixture was stirred at 0 °C for 30 min. To the reaction mixture was added Boc₂O (633 mg, 2.90 mmol) at 0 °C, and the resulting mixture was stirred at room temperature for 45 h. The volatiles were evaporated, and the residue was chromatographed on silica gel (20 g, hexane/acetone=15:1) to give the Boc-imide (550 mg, 95%) as a colorless oil.

IR (neat) 3078, 1785, 1750, 1714, 1308, 1153 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 1.52 (9H, s), 1.59 (1H, m), 1.78 (1H, m), 1.90 (1H, m), 2.03–2.19 (3H, br m), 2.43 (1H, ddd, J = 9.0, 8.5, 2.1 Hz), 2.57 (1H, dd, J = 9.0, 8.5 Hz), 4.12 (1H, m), 5.01 (1H, d, J = 10.7 Hz), 5.04 (1H, d, J = 15.0 Hz), 5.80 (1H, m); ¹³C NMR (75 MHz, CDCl₃) δ 21.9 (t), 27.7 (q), 29.6 (t), 31.0 (t), 32.4 (t), 57.1 (d), 82.2 (s), 115.0 (t), 136.7 (d), 149.3 (s), 173.7 (s); MS 182 (M⁺-57), 84 (100); HRMS Calcd for C₉H₁₂O₃N 182.0817, Found 182.0830; [α]_D ²⁶ −56.68 (c 2.34, CHCl₃).

(1R)-(+)-[1-(3-Oxohexyl)pent-4-enyl]carbamic acid tert-butyl ester (3, R = n-Pr)

To a stirred solution of above Boc-imide (239 mg, 1.00 mmol) in THF (5 mL) was added a solution of n-PrMgBr, prepared from n-PrBr (0.27 mL, 3.00 mmol) and Mg (72 mg, 3.00 mmol) in THF (10 mL) at reflux, and TMEDA (0.48 mL, 3.00 mmol) at −78 °C, and the resulting mixture was stirred at the same temperature for 1.5 h. The reaction was quenched with i-PrOH (5 mL), and the reaction mixture was diluted with Et₂O. The organic layer was washed with 10% HCl (aq) solution, dried over MgSO₄, and evaporated to give pale yellow oil, which was chromatographed on silica gel (20 g, hexane/acetone=50:1−30:1) to give 3 (R = n-Pr, 250 mg, 88%) as a colorless solid (mp 41~43 °C). IR (KBr) 3349, 3081, 1708, 1689, 1528, 1175 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.90 (3H, t, J = 7.2 Hz), 1.42 (9H, s), 1.48–1.63 (5H, br m), 1.79 (1H, m), 2.08 (2H, q-like, J = 7.2 Hz), 2.37 (2H, t, J = 7.2 Hz), 2.46 (2H, t, J = 7.2 Hz), 3.53 (1H, br), 4.25 (1H, br d, J = 10.2 Hz), 4.95 (1H, d, J = 9.4 Hz), 5.01 (1H, d, J = 14.8 Hz), 5.78 (1H, m); ¹³C NMR (75 MHz, CDCl₃) δ 13.6 (q), 17.1 (t), 28.2 (q), 29.0 (t), 30.1 (t), 35.1 (t), 39.1 (t), 44.6 (t), 49.9 (d), 78.5 (s), 114.5 (t), 137.6 (d), 155.4 (s), 210.3 (s); MS 226 (M⁺-57), 57 (100); HRMS Calcd for C₁₂H₂₀O₃N 226.1443, Found 226.1457; [α]_D ²⁶ +1.17 (c 1.21, CHCl₃).

(1R)-(−)-[1-(3-Oxodecyl)pent-4-enyl]carbamic acid tert-butyl ester (3, R = n-C₇H₁₅)

To a stirred solution of above Boc-imide (239 mg, 1.00 mmol) in THF (5 mL) was added a solution of n-C₇H₁₅MgBr, prepared from n-C₇H₁₅Br (0.47 mL, 3.00 mmol) and Mg (72 mg, 3.00 mmol) in THF (10 mL) at reflux, and TMEDA (0.48 mL, 3.00 mmol) at −78 °C, and the resulting mixture was stirred at the same temperature for 1.5 h. The reaction was quenched with i-PrOH (5 mL), and the reaction mixture was diluted with Et₂O. The organic layer was washed with 10% HCl (aq) solution, dried over MgSO₄, and evaporated to give a pale yellow oil, which was chromatographed on silica gel (20 g, hexane/acetone=50:1−30:1) to give 3 (R = n-C₇H₁₅, 265 mg, 78%) as a colorless solid (mp 60~62 °C). IR (KBr) 3347, 3080, 1709, 1684, 1525, 1173 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.85 (3H, t, J = 7.2 Hz), 1.26 (8H, br), 1.43 (9H, s), 1.46–1.61 (5H, br m), 1.81 (1H, m), 2.13 (2H, m), 2.39 (2H, t, J = 7.2 Hz), 2.47 (2H, t, J = 7.2 Hz), 3.53 (1H, br), 4.24 (1H, br d, J = 9.6 Hz), 4.95 (1H, d, J = 9.6 Hz), 5.01 (1H, d, J = 15.0 Hz), 5.78 (1H, m); ¹³C NMR (75 MHz, CDCl₃) δ 14.0 (q), 22.5 (t), 23.7 (t), 28.3 (q), 29.0 (t), 29.1 (t), 30.1 (t), 31.6 (t), 35.2 (t), 39.2 (t), 42.9 (t), 50.0 (d), 78.7 (s), 114.6 (t), 137.7 (d), 155.4 (s), 210.6 (s); MS 282 (M⁺-57), 57 (100); HRMS Calcd for C₁₆H₂₈O₃N 282.2069, Found 282.2091; [α]_D ²⁶ −1.56 (c 0.74, CHCl₃).

(2R,5S)-(−)-2-But-3-enyl-5-propylpyrrolidine-1-carboxylic acid tert-butyl ester (4, R = n-Pr)

To a stirred solution of 3 (R = n-Pr, 226 mg, 0.80 mmol) in CH₂Cl₂ (5 mL) was added a solution of (C₆F₅)₃B (82 mg, 0.16 mmol) and Ph₃SiH (415 mg, 1.59 mmol) in CH₂Cl₂ (5 mL) at −78 °C, and the reaction mixture was stirred at −78 °C for 30 min, and then at room temperature for 20 h. The reaction was quenched with Et₃N (0.6 mL), and the resulting mixture was stirred at room temperature for 20 min. The mixture was diluted with Et₂O, and the organic layer was washed successively with 10% AcOH (aq) solution and satd. NaHCO₃ (aq) solution, dried over MgSO₄, and evaporated to give a pale yellow oil, which was chromatographed on silica gel (20 g, hexane/acetone=200:1−150:1) to give 4 (R = n-Pr, 182 mg, 85%) as a colorless oil.

IR (neat) 3073, 1694, 1389 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.92 (3H, t, J = 7.2 Hz), 1.28 (6H, br m), 1.46 (9H, s), 1.61 (2H, m), 1.90 (2H, m), 2.04 (2H, m), 3,76 (2H, br), 4.94 (1H, d, J = 9.6 Hz), 5.03 (1H, d, J = 15.6 Hz), 5.81 (1H, m); ¹³C NMR (75 MHz, CDCl₃) δ 14.2 (q), 19.6 (t), 28.5 (q), 29.4 (t), 30.7 (t), 35.1 (t), 38.2 (t), 57.8 (d), 58.1 (d), 78.7 (s), 114.2 (t), 138.3 (d), 154.7 (s); MS 267 (M⁺), 57 (100); HRMS Calcd for C₁₆H₂₉O₂N 267.2198, Found 267.2215; [α]_D ²⁶ −3.23 (c 1.10, CHCl₃).

(2R,5S)-(−)-2-But-3-enyl-5-heptylpyrrolidine-1-carboxylic acid tert-butyl ester (4, R = n-C₇H₁₅)

To a stirred solution of 3 (R = n-C₇H₁₅, 250 mg, 0.77 mmol) in CH₂Cl₂ (5 mL) was added a solution of (C₆F₅)₃B (78 mg, 0.15 mmol) and Ph₃SiH (401 mg, 1.54 mmol) in CH₂Cl₂ (5 mL) at −78 °C, and the reaction mixture was stirred at −78 °C for 30 min, and then at room temperature for 20 h. The reaction was quenched with Et₃N (0.6 mL), and the resulting mixture was stirred at room temperature for 20 min. The mixture was diluted with Et₂O, and the organic layer was washed successively with 10% AcOH (aq) solution and satd. NaHCO₃ (aq) solution, dried over MgSO₄, and evaporated to give a pale yellow oil, which was chromatographed on silica gel (20 g, hexane/acetone=200:1−150:1) to give 4 (R = n-C₇H₁₅, 222 mg, 89%) as a colorless oil.

IR (neat) 3075, 1695, 1390, 1174, 1107 cm₋₁; ₁H NMR (500 MHz, CDCl₃) δ 0.88 (3H, t, J = 7.2 Hz), 1.27 (14H, br), 1.46 (9H, s), 1.62 (2H, m), 1.90 (2H, m), 2.07 (2H, br), 3.75 (2H, br), 4.95 (1H, d, J = 10.2 Hz), 5.02 (1H, d, J = 15.8 Hz), 5.84 (1H, m); ¹³C NMR (75 MHz, CDCl₃) δ 14.1 (q), 22.7 (t), 26.4 (t), 28.5 (q), 29.3 (t), 29.6 (t), 30.8 (t), 31.8 (t), 35.1 (t), 35.9 (t), 57.8 (d), 58.4 (d), 78.7 (s), 114.2 (t), 138.3 (d), 154.7 (s); MS 323 (M⁺), 168 (100); HRMS Calcd for C₂₀H₃₇O₂N 323.2824, Found 323.2847; [α]_D ²⁶ −0.97 (c 0.55, CHCl₃).

(2R,5S)-(−)-2-(4-Ethoxycarbonylbut-3-enyl)-5-propylpyrrolidine-1-carboxylic acid tert-butyl ester (5, R = n-Pr)

To a stirred solution of 4 (R = n-Pr, 117 mg, 0.44 mmol) in CH₂Cl₂ (8 mL) were added Grubbs 2^nd catalyst (15 mg, 0.018 mmol) and ethyl acrylate (0.24 mL, 2.20 mmol), and the resulting mixture was refluxed for 5.5 h. After cooling, the solvent was removed under reduced pressure, and the residue was chromatographed on silica gel (20 g, hexane/acetone=100:1−60:1) to give 5 (R = n-Pr, 143 mg, 96%) as a pale yellow oil.

IR (neat) 1721, 1693, 1390, 1174 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.91 (3H, t, J = 7.2 Hz), 1.20–1.30 (8H, br, including at δ 1.27, 3H, t, J = 7.2 Hz), 1.45 (9H, s), 1.61 (2H, m), 1.90 (3H, m), 2.19 (2H, br), 3.76 (2H, br), 4.16 (2H, q, J = 7.2 Hz), 5.85 (1H, d, J = 15.8 Hz), 6.96 (1H, dt, J = 15.8, 6.8 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 14.1 (q), 14.2 (q), 19.5 (t), 28.5 (q), 29.1 (t), 29.5 (t), 34.2 (t), 38.2 (t), 57.6 (d), 58.1 (d), 60.0 (t), 78.8 (s), 121.1 (d), 148.4 (d), 154.6 (s), 166.2 (s); MS 339 (M⁺), 196 (100); HRMS Calcd for C₁₉H₃₃O₄N 339.2410, Found 339.2392; [α]_D ²⁶ −6.81 (c 0.66, CHCl₃).

(2R,5S)-(−)-2-(4-Ethoxycarbonylbut-3-enyl)-5-heptylpyrrolidine-1-carboxylic acid tert-butyl ester (5, R = n-C₇H₁₅)

To a stirred solution of 4 (R = n-C₇H₁₅, 134 mg, 0.41 mmol) in CH₂Cl₂ (7 mL) were added Grubbs 2_nd catalyst (14 mg, 0.016 mmol) and ethyl acrylate (0.23 mL, 2.07 mmol), and the resulting mixture was refluxed for 5.5 h. After cooling, the solvent was removed under reduced pressure, and the residue was chromatographed on silica gel (20 g, hexane/acetone=100:1−60:1) to give 5 (R = n-C₇H₁₅, 157 mg, 96%) as a pale yellow oil.

IR (neat) 1716, 1696, 1387, 1174 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.87 (3H, t, J = 7.2 Hz), 1.17–1.33 (13H, br, including at δ 1.27, 3H, t, J = 7.2 Hz), 1.45 (9H, s), 1.60 (2H, m), 1.92 (2H, m), 2.20 (2H, m), 3.76 (2H, br), 4.16 (2H, q, J = 7.2 Hz), 5.81 (1H, d, J = 15.6 Hz), 6.97 (1H, dt, J = 15.6, 6.8 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 13.9 (q), 14.1 (q), 22.4 (t), 26.2 (t), 28.3 (q), 29.0 (t), 29.1 (t), 29.4 (t), 31.6 (t), 34.1 (t), 35.8 (t), 57.4 (d), 58.2 (d), 59.7 (t), 78.6 (s), 121.0 (d), 148.2 (d), 154.4 (s), 165.9 (s); MS 338 (M⁺-57), 57 (100); HRMS Calcd for C₁₉H₃₂O₄N 338.2331, Found 338.2338; [α]_D ²⁶ −1.75 (c 0.88, CHCl₃).

(3R,5S,8S)-(+)-(5-Propylhexahydropyrrolizin-3-yl)acetic acid ethyl ester (6, R = Et)

To a stirred solution of 5 (R = n-Pr, 123 mg, 0.36 mmol) in CH₂Cl₂ (10 mL) was added AlCl₃ (106 mg, 0.80 mmol) at 0 °C, and the resulting suspension was stirred at room temperature for 24 h. The reaction was quenched with satd. NaHCO₃ (aq) solution, and the organic layer was separated. The aqueous layer was extracted with CHCl₃ (10 mL×5), and the organic layer and extracts were combined, dried over K₂CO₃, and evaporated to give the residue. To a stirred solution of this residue in CH₂Cl₂ (10 mL) was added K₂CO₃ (100 mg, 0.72 mmol), and the resulting suspension was stirred at room temperature for 48 h. The insoluble material was filtered off, and washed with CH₂Cl₂. The filtrate was evaporated to afford the residue, which was chromatographed on silica gel (20 g, hexane/acetone=20:1−12:1) to give 6 (R = Et, 80 mg, 93%) as a pale yellow oil, and the stereoisomer at the 3-position (all cis-pyrrolizidine, 2.5 mg, 3%) also as a pale yellow oil.

IR (neat) 1732, 1178 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.94 (3H, t, J = 7.2 Hz), 1.26 (3H, t, J = 7.2 Hz), 1.31 (1H, m), 1.33–1.44 (4H, br m), 1.52 (1H, m), 1.74–1.81 (4H, br m), 2.03 (2H, m), 2.28 (1H, dd, J = 15.1, 9.8 Hz), 2.57 (1H, dd, J = 15.1, 3.9 Hz), 3.01 (1H, br), 3.40 (1H, m), 3.57 (1H, br), 4.12 (2H, q, J = 7.2 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 14.2 (q), 14.4 (q), 21.4 (t), 30.1 (t), 30.8 (t), 31.3 (t), 32.4 (t), 33.5 (t), 43.2 (t), 54.2 (d), 60.0 (t), 63.5 (d), 65.6 (d), 172.1 (s); MS 239 (M⁺), 196 (100); HRMS Calcd for C₁₄H₂₅O₂N 239.1885, Found 239.1869; [α]_D ²⁶ +25.94 (c 1.95, CHCl₃).

Stereoisomer at the 3-position: IR (neat) 1736, 1174 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.90 (3H, t, J 7.2 Hz), 1.26 (3H, t, J = 7.2 Hz), 1.22–1.37 (2H, m), 1.38–1.52 (5H, m), 1.91–1.98 (2H, m), 2.01–2.04 (2H, m), 2.28 (1H, dd, J = 15.0, 8.6 Hz), 2.53 (1H, dd, J = 15.0, 3.6 Hz), 2.67 (1H, m), 3.15 (1H, m), 3.57 (1H, br), 4.12 (2H, q, J = 7.2 Hz); MS 239 (M⁺), 83 (100).

(3R,5S,8S)-(+)-(5-Heptylhexahydropyrrolizin-3-yl)acetic acid ethyl ester (6, R = n-C₆H₁₃)

To a stirred solution of 5 (R = n-C₇H₁₅, 270 mg, 0.68 mmol) in CH₂Cl₂ (20 mL) was added AlCl₃ (200 mg, 1.50 mmol) at 0 °C, and the resulting suspension was stirred at room temperature for 24 h. The reaction was quenched with satd. NaHCO₃ (aq) solution, and the organic layer was separated. The aqueous layer was extracted with CHCl₃ (20 mL×5), and the organic layer and extracts were combined, dried over K₂CO₃, and evaporated to give the residue. To a stirred solution of this residue in CH₂Cl₂ (20 mL) was added K₂CO₃ (189 mg, 1.37 mmol), and the resulting suspension was stirred at room temperature for 48 h. The insoluble material was filtered off, and washed with CH₂Cl₂. The filtrate was evaporated to afford the residue, which was chromatographed on silica gel (30 g, hexane/acetone=20:1−12:1) to give 6 (R = n-C₆H₁₃, 178 mg, 88%) as a pale yellow oil.

IR (neat) 1731, 1176 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.87 (3H, t, J = 7.2 Hz), 1.25 (3H, t, J = 7.2 Hz), 1.17–2.41 (14H, br m), 1.51 (1H, m), 1.76 (3H, m), 2.01 (2H, m), 2.27 (1H, dd, J = 14.8, 9.6 Hz), 2.56 (1H, dd, J = 14.8, 4.1 Hz), 2.99 (1H, br), 3.38 (1H, m), 3.56 (1H, m), 4.10 (2H, q, J = 7.2 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 13.9 (q), 14.1 (q), 22.5 (t), 28.1 (t), 29.1 (t), 29.7 (t), 30.1 (t), 30.6 (t), 31.1 (t), 31.2 (t), 31.6 (t), 32.2 (t), 43.1 (t), 54.0 (d), 59.8 (t), 63.6 (d), 65.5 (d), 171.8 (s); MS 295 (M⁺), 196 (100); HRMS Calcd for C₁₈H₃₃O₂N 295.2510, Found 295.2501; [α]_D ²⁶ +18.82 (c 1.14, CHCl₃).

(3S,5S,8S)-(+)-3-Heptyl-5-propylhexahydropyrrolizine (7, R = n-Pr, R’ = n-C₇H₁₅)

To a stirred solution of 6 (R = Et, 79 mg, 0.32 mmol) in CH₂Cl₂ (7 mL) was added a solution of DIBAL (0.98 M in hexane, 0.36 mL, 0.35 mmol) at −50 °C, and the reaction mixture was stirred at −50 °C for 30 min. The reaction was quenched with MeOH, and satd. Rochelle (aq) solution, and the organic layer was separated. The aqueous layer was extracted with CH₂Cl₂ (5 mL×3), and the organic layer and extracts were combined, dried over K₂CO₃, and evaporated to give a pale yellow oil, which was used directly in the next step.

To a stirred suspension of n-C₅H₁₁P⁺Ph₃Br^— (529 mg, 1.28 mmol) in THF (10 mL) was added a solution of n-BuLi (1.6 M in hexane, 0.7 mL, 1.12 mmol) at 0 °C, and the resulting orange suspension was stirred at 0 °C for 10 min. To the suspension was added a solution of the above aldehyde in THF (3 mL) at 0 °C, and the resulting suspension was stirred at room temperature for 22 h. The reaction was quenched with H₂O, and the aqueous mixture was extracted with Et₂O (15 mL×4). The organic extracts were combined, dried over K₂CO₃, and evaporated to give a residue, that was chromatographed on silica gel (20 g, hexane/acetone=25:1−10:1) to give the corresponding olefin (37 mg, 46%) as a mixture of E- and Z-isomers.

¹H NMR (500 MHz, CDCl₃) δ 0.89 (3H, t, J = 7.2 Hz), 0.94 (3H, t, J = 7.1 Hz), 1.21–1.53 (12H, br m), 1.72–1.88 (3H, m), 1.89–1.94 (1H, m), 1.96–2.07 (3H, m), 2.30–2.41 (1H, m), 2.93–3.00 (1H, m), 3.02–3.16 (1H, m), 3.62 (1H, br), 5.32–5.47 (2H, m).

To a stirred solution of the above olefin (20 mg, 0.08 mmol) in EtOAc (3 mL) was added 10% Pd/C (10 mg), and the resulting suspension was stirred under a hydrogen atmosphere at 1 atm for 40 h. The catalyst was removed by filtration and the filtrate was evaporated to give 7 (R = n-Pr, R’ = n-C₇H₁₅, 20 mg, quant) as a pale yellow oil.

IR (neat) 2926, 2869, 1457 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.88 (3H, t, J = 7.1 Hz), 0.94 (3H, t, J = 7.1 Hz), 1.27–1.43 (17H, br m), 1.54 (1H, br), 1.77 (3H, m), 1.97 (3H, m), 2.90 (1H, br), 3.05 (1H, br), 3.57 (1H, br); ¹³C NMR (75 MHz, CDCl₃) δ 14.2 (q), 14.6 (q), 21.6 (t), 22.8 (t), 27.2 (t), 29.4 (t), 29.9 (t), 30.2 (t), 30.9 (t), 31.7 (t), 31.9 (t), 32.1 (t), 33.8 (t), 38.6 (t), 57.7 (d), 63.8 (d), 65.8 (d); MS 251 (M⁺), 208 (100); HRMS Calcd for C₁₇H₃₃N 251.2613, Found 251.2601; [α]_D ²⁶ +36.81 (c0.44, CHCl₃).

(3R,5S,8S)-(+)-3-Allyl-5-heptylhexahydropyrrolizine

To a stirred solution of 6 (R = n-C₆H₁₃, 91 mg, 0.31 mmol) in CH₂Cl₂ (7 mL) was added a solution of DIBAL (0.98 M in hexane, 0.35 mL, 0.34 mmol) at −50 °C, and the reaction mixture was stirred at −50 °C for 30 min. The reaction was quenched with MeOH, and then satd. Rochelle (aq) solution, and the organic layer was separated. The aqueous layer was extracted with CH₂Cl₂ (5 mL×3), and the organic layer and extracts were combined, dried over K₂CO₃, and evaporated to give a pale yellow oil, that was used directly in the next step.

To a stirred suspension of MeP⁺Ph₃I⁻ (501 mg, 1.24 mmol) in THF (10 mL) was added a solution of n-BuLi (1.6 M in hexane, 0.68 mL, 1.09 mmol) at 0 °C, and the resulting orange suspension was stirred at 0 °C for 10 min. To the suspension was added a solution of the above aldehyde in THF (3 mL) at 0 °C, and the resulting suspension was stirred at room temperature for 27 h. The reaction was quenched with H₂O, and the aqueous mixture was extracted with Et₂O (15 mL × 4). The organic extracts were combined, dried over K₂CO₃, and evaporated to give a residue, that was chromatographed on silica gel (20 g, hexane/acetone=20:1−10:1) to give the corresponding olefin (38 mg, 49%) as a pale yellow oil.

IR (neat) 3074, 2953, 2927, 2857, 1465, 909 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.87 (3H, t, J = 7.2 Hz), 1.20–1.41 (14H, br m), 1.50 (1H, m), 1.73–1.83 (3H, m), 1.91 (1H, m), 1.97–2.04 (2H, m), 2.36 (1H, m), 2.95–3.03 (2H, m), 3.57 (1H, m), 4.98 (1H, d, J = 10.2 Hz), 5.02 (1H, d, J = 15.0 Hz), 5.98 (1H, m); ¹³C NMR (75 MHz, CDCl₃) δ 14.2 (q), 22.8 (t), 28.4 (t), 29.3 (t), 30.0 (t), 30.2 (t), 31.0 (t), 31.4 (t), 31.5 (t), 31.6 (t), 31.9 (t), 43.0 (t), 57.1 (d), 64.0 (d), 66.0 (d), 115.8 (t), 136.6 (d); MS 249 (M⁺), 208 (100); HRMS Calcd for C₁₇H₃₁N 249.2455, Found 249.2473; [α]_D ²⁶ +36.81 (c 0.44, CHCl₃).

(3S,5S,8R)-(+)-3-Heptyl-5-propylhexahydropyrrolizine (7, R = n-C₇H₁₅, R’ = _n-Pr)

To a stirred solution of the above olefin (25 mg, 0.10 mmol) in EtOAc (3 mL) was added 10% Pd/C (13 mg), and the resulting suspension was stirred under a hydrogen atmosphere at 1 atm for 44 h. The catalyst was removed by filtration and the filtrate was evaporated to give 7 (R = n-C₇H₁₅, R’ = n-Pr, 24 mg, 95%) as a pale yellow oil.

IR (neat) 2966, 2927, 2851, 1458 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.87 (3H, t, J = 7.1 Hz), 0.90 (3H, t, J = 6.9 Hz), 1.40–1.50 (19H, br m), 1.56 (1H, m), 1.79 (2H, m), 1.98 (2H, m), 2.92 (1H, m), 3.08 (1H, br), 3.64 (1H, br); ¹³C NMR (75 MHz, CDCl₃) δ 14.2 (q), 14.4 (q), 20.4 (t), 22.7 (t), 28.3 (t), 29.3 (t), 30.0 (t), 30.1 (t), 30.7 (t), 31.3 (t), 31.7 (t), 31.9 (t), 32.1 (t), 40.4 (t), 57.8 (d), 64.0 (d), 66.0 (d); MS 251 (M⁺), 208 (100); HRMS Calcd for C₁₇H₃₃N 251.2613, Found 251.2620; [α]_D ²⁶ +25.48 (c 0.47, CHCl₃).

(5S)-(−)-5-Propyl-2-oxopyrrolidine (8, R = n-Pr)

To a stirred suspension of CuI (3.8 g, 20 mmol) in THF (30 mL) was added a solution of EtMgBr (0.96 M in THF, 42 mL, 40 mmol) at −35 °C, and the resulting suspension was stirred at the same temperature for 30 min. To the suspension was added a solution of 1 (1.8 g, 8 mmol) in THF (15 mL) at −35 °C, and then the reaction mixture was stirred at −35 °C for 18 h. The reaction was quenched with satd. NH₄Cl (aq) solution, and the insoluble material was filtered off and washed with CHCl₃. The organic layer was separated, and the aqueous layer was extracted with CHCl₃ (30 mL × 2). The organic layer and extracts were combined, dried over MgSO₄, and evaporated to give a residue, that was chromatographed on silica gel (50 g, hexane/acetone=20:1−2:1) to give 8 (R = n-Pr, 525 mg, 52%) as a pale yellow oil.

IR (neat) 3193, 1699, 1286 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.93 (3H, t, J = 7.2 Hz), 1.36 (2H, m), 1.44 (1H, m), 1.51 (1H, m), 1.69 (1H, m), 2.25 (1H, m), 2.32 (2H, m), 3.63 (1H, quint, J = 6.8 Hz), 6.42 (1H, br); ¹³C NMR (75 MHz, CDCl₃) δ 13.6 (q), 18.7 (t), 26.8 (t), 30.2 (t), 38.6 (t), 54.3 (d), 178.3 (s); MS 127 (M⁺), 84 (100); HRMS Calcd for C₇H₁₃ON 127.0997, Found 127.1001; [α]_D ²⁶ −9.20 (c 1.19, CHCl₃).

(2S)-(+)-2-Heptyl-5-oxopyrrolidine (8, R = n-C₇H₁₅)

To a stirred suspension of CuI (4.52 g, 23.8 mmol) in THF (30 mL) was added a solution of n-C₇H₁₅MgBr, prepared from n-C₇H₁₅Br (7.34 mL, 52.31 mmol) and Mg (1.26 g, 52.31 mmol) in THF (50 mL) at reflux, at −35 °C, and the resulting suspension was stirred at same temperature for 30 min. To the suspension was added a solution of 1 (2.14 g, 9.51 mmol) in THF (15 mL) at −35 °C, and then the reaction mixture was stirred at −35 °C for 18 h. The reaction was quenched with satd. NH₄Cl (aq) solution, and the insoluble material was filtered off and washed with CHCl₃. The organic layer was separated, and the aqueous layer was extracted with CHCl₃ (30 mL × 2). The organic layer and extracts were combined, dried over MgSO₄, and evaporated to give the residue, that was chromatographed on silica gel (50 g, hexane/acetone=20:1−5:1) to give 8 (R = n-C₇H₁₅, 870 mg, 50%) as a pale yellow oil.

IR (neat) 3209, 1698, 1284 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.88 (3H, t, J = 7.2 Hz), 1.30 (9H, m), 1.43–1.54 (2H, m), 1.68–1.76 (2H, m), 2.23 (1H, m), 2.33 (2H, m), 3.62 (1H, quint, J = 6.9 Hz), 5.77 (1H, br); ¹³C NMR (75 MHz, CDCl₃) δ 13.84 (q), 22.4 (t), 25.5 (t), 26.9 (t), 28.9 (t), 29.2 (t), 30.3 (t), 31.5 (t), 36.5 (t), 54.6 (d), 178.3 (s); MS 183 (M⁺), 84 (100); HRMS Calcd for C₁₁H₂₁ON 183.1623, Found 183.1608; [α]_D ²⁶ +8.30 (c 0.89, CH₂Cl₂), Lit. [α]_D ²⁶ +9.0 (c 2.0, CH₂Cl₂).

(2R)-(−)-5-Propyl-2-oxopyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred solution of 8 (R = n-Pr, 247 mg, 1.94 mmol) in MeCN (10 mL) was added DMAP (261 mg, 2.14 mmol) at 0 °C, and the reaction mixture was stirred at 0° C for 30 min. To the reaction mixture was added Boc₂O (508 mg, 2.33 mmol) at 0 (C, and then the resulting mixture was stirred at room temperature for 43 h. The solvent was removed under reduced pressure, and the residue was chromatographed on silica gel (20 g, hexane/acetone=30:1−15:1) to give the title Boc-imide (414 mg, 94%) as a pale yellow oil.

IR (neat) 1786, 1749, 1714, 1306, 1153 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.95 (3H, t, J = 7.2 Hz), 1.34 (1H, m), 1.39 (1H, m), 1.52 (9H, s), 1.69–1.78 (2H, m), 2.42 (1H, m), 2.57 (1H, m), 4.10 (1H, m); ¹³C NMR (75 MHz, CDCl₃) δ 13.6 (q), 18.5 (t), 22.1 (t), 27.6 (q), 31.0 (t), 31.5 (t), 35.4 (t), 57.4 (d), 82.0 (s), 149.3 (s), 173.8 (s); MS 227 (M⁺), 84 (100); HRMS Calcd for C₁₂H₂₁O₃N 227.1522, Found 227.1527; [α]_D ²⁶ −62.86 (c 0.87, CHCl₃).

(2R)-(−)-2-Heptyl-5-oxopyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred solution of 8 (R = n-C₇H₁₅, 602 mg, 3.29 mmol) in MeCN (20 mL) was added DMAP (442 mg, 3.62 mmol) at 0 °C, and the reaction mixture was stirred at 0 °C for 30 min. To the reaction mixture was added Boc₂O (862 mg, 3.95 mmol) at 0 °C, and then the resulting mixture was stirred at room temperature for 48 h. The solvent was removed under reduced pressure, and the residue was chromatographed on silica gel (40 g, hexane/acetone=30:1−15:1) to give the desired Boc-imide (866 mg, 93%) as a pale yellow oil.

IR (neat) 1788, 1750, 1714, 1308, 1153 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.88 (3H, t, J = 7.2 Hz), 1.28 (10H, m), 1.46 (1H, br), 1.52 (9H, s), 1.76 (2H, m), 2.08 (1H, m), 2.41 (1H, m), 2.53 (1H, m), 4.09 (1H, m); ¹³C NMR (75 MHz, CDCl₃) δ 13.9 (q), 22.3 (t), 22.4 (t), 25.4 (t), 27.8 (q), 29.0 (t), 31.2 (t), 31.5 (t), 33.5 (t), 57.8 (d), 82.2 (s), 149.5 (s), 174.0 (s); MS 283 (M⁺), 57 (100); HRMS Calcd for C₁₆H₂₉O₃N 283.2148, Found 283.2128; [α]_D ²⁶ −57.34 (c 1.21, CHCl₃).

(1R)-(+)-[1-(3-Oxohept-7-enyl)butyl]carbamic acid tert-butyl ester (9, R = n-Pr)

To a stirred solution of the above Boc-imide (1.08 g, 4.75 mmol) in THF (15 mL) was added a solution of 4-butenylMgBr, prepared from 1-bromo-4-butene (1.45 mL, 14.27 mmol) and Mg (342 mg, 14.27 mmol) in THF (60 mL) at reflux, and TMEDA (2.27 mL, 14.27 mmol) at −78 °C, and the resulting mixture was stirred at the same temperature for 1.5 h. The reaction was quenched with i-PrOH (5 mL), and the reaction mixture was diluted with Et₂O. The organic layer was washed with 10% HCl (aq) solution, dried over MgSO₄, and evaporated to give a pale yellow oil, that was chromatographed on silica gel (40 g, hexane/acetone=50:1−40:1) to give 9 (R = n-Pr, 1.28 g, 95%) as a colorless solid (mp 64~66 °C).

IR (KBr) 3349, 3083, 1707, 1685, 1528, 1174 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.89 (3H, t, J = 7.2 Hz), 1.26–1.38 (5H, br m), 1.42 (9H, s), 1.50 1H, m), 1.72 (1H, m), 2.30 (2H, q, J = 7.2 Hz), 2.48 (3H, q, J = 7.2 Hz), 3.51 (1H, br), 4.23 (1H, br d, J = 9.1 Hz), 4.94 (1H, d, J = 9.5 Hz), 5.01 (1H, d, J = 15.0 Hz), 5.79 (1H, m); ¹³C NMR (75 MHz, CDCl₃) δ 13.7 (q), 18.9 (t), 27.5 (t), 28.1 (q), 29.0 (t), 37.9 (t), 39.1 (t), 41.6 (t), 49.8 (d), 78.3 (s), 114.7 (t), 136.6 (d), 155.4 (s), 209.2 (s); MS 283 (M⁺), 57 (100); HRMS Calcd for C₁₆H₂₉O₃N 283.2148, Found 283.2142; [α]_D ²⁶ +5.10 (c 1.15, CHCl₃).

(1R)-(−)-[1-(3- Oxohept-7-enyl)octyl]carbamic acid tert-butyl ester (9, R = n-C₇H₁₅)

To a stirred solution of the above Boc-imide (724 mg, 2.56 mmol) in THF (10 mL) was added a solution of 4-butenylMgBr, prepared from 1-bromo-4-butene (0.78 mL, 7.68 mmol) and Mg (185 mg, 7.68 mmol) in THF (40 mL) at reflux, and TMEDA (1.16 mL, 7.68 mmol) at −78 °C, and the resulting mixture was stirred at the same temperature for 1.5 h. The reaction was quenched with i-PrOH (5 mL), and the reaction mixture was diluted with Et₂O. The organic layer was washed with 10% HCl (aq) solution, dried over MgSO₄, and evaporated to give a pale yellow oil, that was chromatographed on silica gel (30 g, hexane/acetone=50:1−30:1) to give 9 (R = n-C₇H₁₅, 850 mg, 98%) as a colorless solid (mp 48~50 °C).

IR (KBr) 3348, 3080, 1707, 1685, 1531, 1173 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.87 (3H, t, J = 7.2 Hz), 1.25 (12H, br), 1.43 (9H, s), 1.49 (1H, br), 1.77 (1H, m), 2.31 (2H, q-like, J = 7.2 Hz), 2.49 (4H, m), 3.50 (1H, br), 4.20 (1H, br d, J = 9.4 Hz), 4.95 (1H, d, J = 9.6 Hz), 5.01 (1H, d, J = 15.0 Hz), 5.79 (1H, m); ¹³C NMR (75 MHz, CDCl₃) δ 14.0 (q), 22.5 (t), 25.8 (t), 27.6 (t), 28.3 (q), 29.1 (t), 29.2 (t), 29.3 (t), 31.6 (t), 35.9 (t), 39.3 (t), 41.8 (t), 50.3 (d), 78.6 (s), 114.8 (t), 136.8 (d), 155.5 (s), 209.5 (s); MS 339 (M⁺), 57 (100); HRMS Calcd for C₁₆H₂₈O₃N 282.2068, Found 282.2091; [α]_D ²⁶ −1.04 (c 1.05, CHCl₃).

(1R)-(−)-[1-(3-Oxoheptyl)pent-4-enyl]carbamic acid tert-butyl ester (10)

To a stirred solution of the Boc-imide (239 mg, 1.00 mmol), prepared from 2 (as described in the preparation of 3), in THF (10 mL) was added a solution of n-PrMgBr, prepared from n-BuBr (0.32 mL, 3.00 mmol) and Mg (72 mg, 3.00 mmol) in THF (10 mL) at reflux, and TMEDA (0.48 mL, 3.00 mmol) at −78 °C, and the resulting mixture was stirred at the same temperature for 1.5 h. The reaction was quenched with i-PrOH (5 mL), and the reaction mixture was diluted with Et₂O. The organic layer was washed with 10% HCl (aq) solution, dried over MgSO₄, and evaporated to give a pale yellow oil, that was chromatographed on silica gel (20 g, hexane/acetone=50:1−30:1) to give 10 (292 mg, 98%) as a colorless solid (mp 42~43 °C).

IR (KBr) 3351, 3080, 1688, 1530, 1174 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.88 (3H, t, J = 7.2 Hz), 1.28 (2H, sext, J = 7.2 Hz), 1.42 (9H, s), 1.47–1.61 (5H, br m), 1.77 (1H, m), 2.08 (2H, q-like, J = 7.2 Hz), 2.38 (2H, t, J = 7.2 Hz), 2.46 (2H, t, J = 7.2 Hz), 3.50 (1H, br), 4.26 (1H, br d, J = 9.1 Hz), 4.94 (1H, d, J = 10.2 Hz), 5.00 (1H, d, J = 15.0 Hz), 5.78 (1H, m); ¹³C NMR (75 MHz, CDCl₃) δ 13.7 (q), 22.1 (t), 25.7 (t), 28.2 (q), 29.0 (t), 30.0 (t), 35.0 (t), 39.1 (t), 42.4 (t), 49.8 (d), 78.4 (s), 114.5 (t), 137.6 (d), 155.4 (s), 210.4 (s); MS 240 (M⁺-57), 57 (100); HRMS Calcd for C₁₃H₂₂O₃N 240.1600, Found 240.1616; [α]_D ²⁶ −0.47 (c 1.20, CHCl₃).

(2R,5S)-(−)-2-But-3-enyl-5-butylpyrrolidine-1-carboxylic acid tert-butyl ester (11)

To a stirred solution of 10 (279 mg, 0.94 mmol) in CH₂Cl₂ (7 mL) was added a solution of (C₆F₅)₃B (96 mg, 0.19 mmol) and Ph₃SiH (490 mg, 1.88 mmol) in CH₂Cl₂ (10 mL) at −78 °C, and the reaction mixture was stirred at −78 °C for 30 min, and then at room temperature for 24 h. The reaction was quenched with Et₃N (1.0 mL), and the resulting mixture was stirred at room temperature for 20 min. The mixture was diluted with Et₂O, and the organic layer was washed successively with 10% AcOH (aq) solution and satd. NaHCO₃ (aq) solution, dried over MgSO₄, and evaporated to give a pale yellow oil, that was chromatographed on silica gel (20 g, hexane/acetone=200:1−150:1) to give 11 (194 mg, 73%) as a colorless oil.

IR (neat) 3080, 1696, 1388 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.90 (3H, t, J = 7.2 Hz), 1.24–1.40 (6H, br m), 1.46 (9H, s), 1.61 (2H, br), 1.93 (4H, br m), 2.05 (2H, br m), 3,75 (2H, br), 4.80 (1H, d, J = 10.5 Hz), 5.03 (1H, d, J = 16.0 Hz), 5.82 (1H, m); ¹³C NMR (75 MHz, CDCl₃) δ 14.1 (q), 22.7 (t), 28.5 (q), 28.6 (t), 29.4 (t), 30.7 (t), 35.1 (t), 35.6 (t), 57.8 (d), 58.3 (d), 78.6 (s), 114.2 (t), 138.2 (d), 154.6 (s); MS 281 (M⁺), 170 (100); HRMS Calcd for C₁₇H₃₁O₂N 281.2355, Found 281.2355; [α]_D ²⁶ −2.72 (c 1.15, CHCl₃).

(2R,5S)-(−)-2-(4-Ethoxycarbonylbut-3-enyl)-5-butylpyrrolidine-1-carboxylic acid tert-butyl ester (12)

To a stirred solution of 11 (155 mg, 0.55 mmol) in CH₂Cl₂ (10 mL) were added Grubbs 2^nd catalyst (19 mg, 0.022 mmol) and ethyl acrylate (0.30 mL, 2.76 mmol), and the resulting mixture was refluxed for 5 h. After cooling, the solvent was removed under reduced pressure, and the residue was chromatographed on silica gel (20 g, hexane/acetone=100:1−60:1) to give 12 (186 mg, 96%) as a pale yellow oil.

IR (neat) 1718, 1696, 1389, 1174 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.89 (3H, t, J = 7.2 Hz), 1.20–1.37 (10H, br, including at δ 1.28, 3H, t, J = 7.2 Hz), 1.45 (9H, s), 1.60 (2H, br), 1.91 (3H, br), 2.20 (2H, br), 3.77 (2H, br), 4.17 (2H, q, J = 7.2 Hz), 5.82 (1H, d, J = 15.7 Hz), 6.96 (1H, dt, J = 15.7, 6.8 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 14.0 (q), 14.1 (q), 22.6 (t), 28.4 (q), 28.5 (t), 29.1 (t), 29.4 (t), 34.2 (t), 35.6 (t), 57.6 (d), 58.3 (d), 59.9 (t), 78.8 (s), 121.1 (d), 148.3 (d), 154.6 (s), 166.1 (s); MS 353 (M⁺), 252 (100); HRMS Calcd for C₂₀H₃₅O₄N 353.2564, Found 353.2544; [α]_D ²⁶ −2.89 (c 0.75, CHCl₃).

(3R,5S,8S)-(+)-(5-Butylhexahydropyrrolizin-3-yl)acetic acid ethyl ester (13)

To a stirred solution of 12 (100 mg, 0.28 mmol) in CH₂Cl₂ (7 mL) was added AlCl₃ (83 mg, 0.62 mmol) at 0 °C, and the resulting suspension was stirred at room temperature for 24 h. The reaction was quenched with satd. NaHCO₃ (aq) solution, and the organic layer was separated. The aqueous layer was extracted with CHCl₃ (10 mL×5), and the organic layer and extracts were combined, dried over K₂CO₃, and evaporated to give a residue. To a stirred solution of this residue in CH₂Cl₂ (7 mL) was added K₂CO₃ (78 mg, 0.57 mmol), and the resulting suspension was stirred at room temperature for 48 h. The insoluble material was filtered off, and washed with CH₂Cl₂. The filtrate was evaporated to afford a residue, that was chromatographed on silica gel (20 g, hexane/acetone=20:1−8:1) to give 13 (66 mg, 92%) as a pale yellow oil.

IR (neat) 1733, 1181 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.90 (3H, t, J = 7.2 Hz), 1.26 (3H, t, J = 7.2 Hz), 1.28–1.43 (7H, br m), 1.52 (1H, m), 1.69 (1H, br), 1.78 (3H, m), 2.28 (1H, dd, J = 15.0, 9.8 Hz), 2.57 (1H, dd, J = 15.0, 4.3 Hz), 3.00 (1H, br), 3.40 (1H, m), 3.57 (1H, br), 4.11 (2H, q, J = 7.2 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 14.1 (q), 14.2 (q), 22.9 (t), 30.2 (t), 30.4 (t), 30.8 (t), 31.0 (t), 31.3 (t), 32.4 (t), 43.2 (t), 54.2 (d), 60.0 (t), 63.7 (d), 65.6 (d), 172.1 (s); MS 253 (M⁺), 196 (100); HRMS Calcd for C₁₅H₂₇O₂N 253.2042, Found 253.2058; [α]_D ²⁶ +21.06 (c 0.83, CHCl₃).

(3S,5S,8S)-(+)-3,5-Dibutylhexahydropyrrolizine (14)

To a stirred solution of 13 (70 mg, 0.28 mmol) in CH₂Cl₂ (7 mL) was added a solution of DIBAL (0.98 M in hexane, 0.31 mL, 0.31 mmol) at −50 °C, and the reaction mixture was stirred at −50 °C for 30 min. The reaction was quenched with MeOH, and satd. Rochelle (aq) solution, and the organic layer was separated. The aqueous layer was extracted with CH₂Cl₂ (5 mL × 3), and the organic layer and extracts were combined, dried over K₂CO₃, and evaporated to give a pale yellow oil, that was used directly in the next step.

To a stirred suspension of EtP⁺Ph₃Br⁻ (410 mg, 1.12 mmol) in THF (7 mL) was added a solution of n-BuLi (1.6 M in hexane, 0.6 mL, 0.98 mmol) at 0 °C, and the resulting orange suspension was stirred at 0 °C for 10 min. To the suspension was added a solution of the above aldehyde in THF (3 mL) at 0 °C, and the resulting suspension was stirred at room temperature for 27 h. The reaction was quenched with H₂O, and the aqueous mixture was extracted with Et₂O (15 mL × 4). The organic extracts were combined, dried over K₂CO₃, and evaporated to give a residue, that was chromatographed on silica gel (20 g, hexane/acetone=25:1−10:1) to give the corresponding olefin (31 mg, 50%) as a mixture of E- and Z-isomers.

¹H NMR (500 MHz, CDCl₃) δ 0.90 (3H, t, J = 6.8 Hz), 1.24–1.41 (8H, br m), 1.48 (1H, m), 1.62 (3H, d, J = 6.8 Hz), 1.72–1.93 (4H, br m), 1.95–2.08 (2H, m), 2.31 (1H, br), 2.96 (1H, m), 3.04 (1H, br), 3.60 (1H, br), 5.36–5.51 (2H, br m).

To a stirred solution of the above olefin (20 mg, 0.09 mmol) in EtOAc (3 mL) was added 10% Pd/C (10 mg), and the resulting suspension was stirred under a hydrogen atmosphere at 1 atm for 45 h. The catalyst was removed by filtration and the filtrate was evaporated to give 14 (20 mg, quant) as a pale yellow oil.

IR (neat) 2928, 2858, 1457, 1099 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 0.89 (3H, t, J = 7.2 Hz), 0.90 (3H, t, J = 6.8 Hz), 1.20–1.51 (15H, br m), 1.60 (1H, m), 1.81 (2H, m), 1.98 (2H, m), 2.91 (1H, m), 3.10 (1H, br), 3.68 (1H, br); ¹³C NMR (75 MHz, CDCl₃) δ 14.1 (q), 14.2 (q), 22.9 (t), 23.0 (t), 29.4 (t), 30.1 (t), 30.4 (t), 30.7 (t), 30.9 (t), 31.6 (t), 32.1 (t), 37.6 (t), 58.2 (d), 64.0 (d), 66.0 (d); MS 223 (M⁺), 55 (100); HRMS Calcd for C₁₅H₂₉N 223.2300, Found 223.2312; [α]_D ²⁶ +29.77 (c 0.40, CHCl₃).

(1R)-(+)-[1-(3-Oxohept-7-enyl)pentyl]carbamic acid tert-butyl ester (15)

To a stirred solution of 2⁸(337 mg, 2.42 mmol) in MeCN (20 mL) was added DMAP (326 mg, 2.67 mmol) at 0 °C, and the reaction mixture was stirred at 0 °C for 30 min. To the reaction mixture was added Boc₂O (633 mg, 2.90 mmol) at 0 °C, and the resulting mixture was stirred at room temperature for 45 h. The volatiles were evaporated, and the residue was chromatographed on silica gel (20 g, hexane/acetone=15:1) to give the Boc-imide (550 mg, 95%) as a colorless oil.

IR (neat) 3078, 1785, 1750, 1714, 1308, 1153 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 1.52 (9H, s), 1.59 (1H, m), 1.78 (1H, m), 1.90 (1H, m), 2.03–2.19 (3H, br m), 2.43 (1H, ddd, J = 9.0, 8.5, 2.1 Hz), 2.57 (1H, dd, J = 9.0, 8.5 Hz), 4.12 (1H, m), 5.01 (1H, d, J = 10.7 Hz), 5.04 (1H, d, J = 15.0 Hz), 5.80 (1H, m); ¹³C NMR (75 MHz, CDCl₃) δ 21.9 (t), 27.7 (q), 29.6 (t), 31.0 (t), 32.4 (t), 57.1 (d), 82.2 (s), 115.0 (t), 136.7 (d), 149.3 (s), 173.7 (s); MS 182 (M⁺-57), 84 (100); HRMS Calcd for C₁₃H₂₁O₃N 239.1520, Found 239.1534; [α]_D ²⁶ −56.68 (c 2.34, CHCl₃).

To a stirred solution of the above Boc-imide (239 mg, 1 mmol) in EtOAc (10 mL) was added 10% Pd/C (50 mg), and the resulting suspension was stirred under a hydrogen atmosphere at 1 atm for 48 h. The catalyst was removed by filtration and the filtrate was evaporated to give the corresponding imide as a pale yellow oil, that was used directly in the next step.

To a stirred solution of the imide prepared above in THF (5 mL) was added a solution of 4-butenylMgBr, prepared from 4-bromo-1-butene (0.30 mL, 3.00 mmol) and Mg (72 mg, 3.00 mmol) in THF (8 mL) at reflux, and TMEDA (0.48 mL, 3.00 mmol) at −78 °C, and the resulting mixture was stirred at the same temperature for 1.5 h. The reaction was quenched with i-PrOH (5 mL), and the reaction mixture was diluted with Et₂O. The organic layer was washed with 10% HCl (aq) solution, dried over MgSO₄, and evaporated to give a pale yellow oil, that was chromatographed on silica gel (20 g, hexane/acetone=50:1−30:1) to give 15 (284 mg, 96%) as a colorless solid (mp 38~39 °C).

IR (KBr) 3355, 3070, 1709, 1685, 1530, 1174 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.88 (3H, t, J = 7.2 Hz), 1.30 (6H, br m), 1.43 (9H, s), 1.51 (1H, br), 1.78 (1H, m), 2.31 (2H, q-like, J = 6.9 Hz), 2.49 (4H, m), 3.50 (1H, br), 4.21 (1H, br d, J = 9.0 Hz), 4.96 (1H, d, J = 10.2 Hz), 5.00 (1H, d, J = 16.0 Hz), 5.82 (1H, m); ¹³C NMR (75 MHz, CDCl₃) δ 13.6 (q), 22.2 (t), 27.3 (t), 27.7 (t), 28.0 (q), 28.9 (t), 35.2 (t), 39.0 (t), 41.4 (t), 49.9 (d), 78.0 (s), 114.5 (t), 136.5 (d), 155.3 (s), 209.0 (s); MS 297 (M⁺), 57 (100); HRMS Calcd for C₁₇H₃₁O₃N 297.2304, Found 297.2315; [α]_D ²⁶ +2.76 (c 1.04, CHCl₃).