Intermediates for the Synthesis of 4-Substituted Proline Derivatives

Abstract

A chemoenzymatic synthesis of a series of 2-hydroxy-5-nitro-4-substituted esters is described that uses two biotransformations in a single-pot process in which a kinetic resolution/reduction occurs. The products are valuable intermediates for the preparation of 4-substituted prolines and 5-substituted 3-hydroxypiperidinones as illustrated by the preparation of (2R,4R)-4-methylproline and (3S,5R)-3-hydroxy-5-methylpiperidinone.

Key words

biotransformations - molecular modeling - piperidin­one - proline - resolution

References and Notes

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8

Piperidinone 12: white solid; mp 149 ˚C (MeOH); [α]_D +10.6 (c 0.5, MeOH); IR (Nujol): 3336, 2929, 1755, 1290 cm^-¹; ^¹H NMR (300 MHz, D₂O): δ = 1.03 (d, J = 6.5 Hz, 3 H, 5-CH₃), 1.53 (q, J = 12.6 Hz, 1 H, 4-H_ax), 2.12-2.20 (m, 3 H, OH, 5-H and 4-H_eq), 3.22 (dd, J = 11.0, 8.5 Hz, 1 H, 6-HH), 3.31 (ddd, J = 11.0, 5.6, 2.0 Hz, 1 H, 6-HH), 4.26 (dd, J = 12.6, 5.9 Hz, 1 H, 3-H); ^¹³C NMR (75 MHz, CD₃OD): δ = 19.1, 28.8, 39.2, 50.0, 68.5 (C-3), 175.6 (C-2); MS (CI): m/z [MH]⁺ calcd for C₉H₁₂NO₂: 130.0865; found: 130.0868.
Tosylate 10: yellow oil; [α]_D -19.5 (c 1.0, CHCl₃); IR (film): 2959, 1763, 1598, 1555, 1438, 1376 cm^-¹; ^¹H NMR (300 MHz, CDCl₃): δ = 1.05 (d, J = 7.0 Hz, 3 H, 4-CH₃), 1.89-1.96 (m, 2 H, 3-H₂), 2.38 (s, 3 H, CH₃), 3.66 (s, 3 H, OCH₃), 4.26 (dd, J = 12.2, 7.3 Hz, 1 H, 4-HH), 4.33 (dd, J = 12.2, 7.3 Hz, 1 H, 4-HH), 4.96 (dd, J = 7.3, 6.0 Hz, 1 H, 2-H), 7.36 (d, J = 8.0 Hz, 2 H, ArH), 7.83 (d, J = 8.0 Hz, 2 H, ArH); ^¹³C NMR (75 MHz, CDCl₃): δ = 17.5, 21.6, 28.8, 35.5, 52.7, 74.9, 79.5, 128.0, 128.9, 129.8, 145.5, 168.5; MS (CI): m/z [MH]⁺ calcd for C₁₄H₂₀NO₇S: 346.0960; found: 346.0964.

9

The crystal structure coordinates of a ternary complex of BS-LDH containing NADH and the substrate analogue oxamate, were taken from the protein data bank (1LDN). Oxamate was replaced in the structure by the (4R)-2-keto acid (R)-5 and the conformation of the rest of the molecule was adjusted to best dock in the remaining space in the active site. This process was repeated for the S-enantiomer [(S)-5] of the substrate. Both complexes were soaked in a 5Å layer of water and energy-minimised using DISCOVER v 2.95 and the cvff force field in SGI challenge L.