A Flexible Carbanionic Approach to Protected trans-(2R,3S)-2-Substituted 3-Aminopyrrolidines: Application to the Asymmetric Synthesis of (+)-Absouline

Abstract

Based on the use of phenyl thioether (3S)-7 as a synthetic equivalent to the N- and α-dianions (3S)-2a, a new carbanionic approach to trans-(2R,3S)-2-substituted 3-aminopyrrolidines (10) is described. Application of the method to the asymmetric synthesis of 1-aminopyrrolizidine alkaloid (+)-absouline is also reported.

Key words

asymmetric synthesis - additions - pyrrolidine - carbanions - reductive lithiation

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All new compounds gave satisfactory analytical and spectral data.

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General Procedure for the One-Pot Synthesis of Compounds 10a-h:
To a solution of phenyl thioether 7 (0.48 mmol) in anhyd THF (1.6 mL) at -78 °C was added successively n-BuLi (2.0 M solution in n-hexane, 0.69 mmol) and freshly prepared lithium naphthalenide (1.5 M solution in THF, 1.36 mmol). After being stirred for 30 min, an electrophile (0.70 mmol) was added. The stirring was maintained at -78 °C for 1 h, then allowed to warm to 0 °C. A sat. aq solution of NH₄Cl was added and the mixture was extracted with CH₂Cl₂ (3 × 5 mL). The combined organic layers were dried over Na₂SO₄, filtered and concentrated in vacuo. Flash chromatography (EtOAc-petroleum ether = 1:3) of the crude afforded the desired product 10b-i and a small amount of reduced product 10a.
Data for 10b: Electrophile used: acetone. Yield 86%; colorless oil; [α]_D ²⁰ -4.95 (c 1.0, CHCl₃). IR (film): ν_max = 3421, 3319, 2975, 1697, 1669, 1535, 1399, 1246, 1170, 1122 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ(rotamers) = 1.15 (br s, 3 H), 1.34 (br s, 3 H), 1.48 (s, 9 H), 1.68-1.78 (m, 1 H), 2.20-2.32 (m, 1 H), 3.28-3.36 (m, 1 H), 3.60-3.80 (m, 2 H), 4.10-4.20 (m, 1 H), 4.80-5.00 (m, 2 H), 5.10 (m, 2 H), 7.28-7.40 (m, 5 H). ¹³C NMR (125 MHz, DMSO-d ₆): δ(rotamers) = 28.26 (1 C), 28.38 (1 C), 29.58 (3 C), 30.19, 30.66, 31.10 (1 C), 43.88, 44.15 (1 C), 49.89 (1 C), 50.38, 50.68 (1 C), 65.57, 65.70 (1 C), 72.22 (1 C), 78.51, 78.83 (1 C), 128.00, 128.06, 128.48, 128.57, 137.23, 137.38 (6 C), 153.72 (1 C), 155.68, 155.97 (1 C). MS (ESI): m/z (%) = 379 (100) [M + H⁺], 401 (60) [M + Na⁺]. HRMS: m/z calcd for [C₂₀H₃₀N₂O₅ + H]⁺: 379.2234; found: 379.2233.

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In the reported ¹H NMR and ¹³C NMR spectral data of 1-aminopyrrolizidine and its derivatives (13, [10a] 14, [10a] [12] 4, [11] [12] and 5 [11] [12] ), some differences exist from one to the other. This may be due to conformational isomerism and/or H-bond formation in the 1-aminopyrrolizidine ring system. In addition, these molecules were shown to be labile.

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We thank Dr. C. Poupat (Institut de Chimie des Substances Naturelles, CNRS, France) for sending us a sample of natural absouline.