Ring Closing Metathesis for the Asymmetric Synthesis of (S)-Homopipecolic Acid, (S)-Homoproline and (S)-Coniine

Abstract

Diastereoselective conjugate addition of lithium (S)-N-allyl-N-α-methylbenzylamide to α,β-unsaturated esters or Weinreb amides, followed by ring closing metathesis is used to afford the cyclic β-amino acids (S)-homopipecolic acid and (S)-homoproline and the amine (S)-coniine in high ee.

Key words

lithium amide - conjugate addition - ring closing metathesis - asymmetric synthesis - cyclic β-amino acids

References

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10

As shown by ¹H NMR spectroscopic analysis of the crude reaction mixture.

12

By ¹H NMR spectroscopic analysis in the presence of (R)-2,2,2-trifluoro-1-(9-anthryl)-ethanol and comparison with an authentic racemic standard.

15

Ring closing metathesis procedure for the synthesis of 9: RuCl₂(=CHPh)(PCy₃)₂ (0.2 g, 0.25 mmol) was added to a stirred solution of 8 (2.1 g, 6.3 mmol) in DCM (200 mL) under Ar and refluxed for 18 hours. After concentration in vacuo, the residue was purified by column chromatography on silica gel (40-60 petrol-Et₂O, 18:1) to furnish 9 as a clear yellow oil (1.4 g, 77%); [α]_D ²⁴ -132.0 (c 0.99, CHCl₃); IR(film)/ cm^-1: 1728 (C=O); δ_H (500 MHz, CDCl₃), 1.46 [3 H, d, J = 6.7 Hz, C(α)Me], 1.49 [9 H, s, OC(Me)₃], 2.37 (1 H, dd, J = 14.5 Hz, J = 8.9 Hz, CHCO₂ ^t Bu), 2.63 (1 H, dd, J = 14.5 Hz, J = 4.0 Hz, CHCO₂ ^t Bu), 3.38-3.43 and 3.60-3.64 (2 × 1 H, m, NCH ₂ ), 3.88 [1 H, q, J = 6.7 Hz, C(α)H], 4.16-4.21 (1 H, m, NCHCH₂), 5.70-5.78 (2 H, m, CH=CH), 7.22-7.36 (5 H, m, Ph); δ_c (125 MHz, CDCl₃) 22.8, 28.0, 43.0, 58.3, 62.0, 64.7, 80.0, 126.6, 126.8, 127.3, 128.2, 130.6, 144.7, 171.3; m/z (APCI⁺) 288 (MH⁺, 80%), 219 (MH⁺-C₄H₈); HRMS (CI⁺) C₁₈H₂₆NO₂ requires 288.1964; found 288.1967.

16

As shown by LiAlH₄ reduction to the N-α-methyl benzyl protected amino alcohol and subsequent ¹H NMR chiral shift studies in the presence of (R)- and (±)-O-acetyl mandelic acid.