Enantioselective Synthesis of Substituted Dihydropyrans by Organocatalyst-Mediated Domino Michael/Enolization/Acetalization Reactions

This letter is dedicated to Prof. Brindaban C. Ranu on the occasion of his 75^th birthday.

Abstract

A highly enantioselective synthetic method for 3,4-trans-dihydropyrans was developed by the reaction of α-acyl-β-aryl-substituted acrylonitrile and aldehyde catalyzed by diphenylprolinol silyl ether. This is an asymmetric domino reaction via a catalytic Michael reaction/enolization/acetalization.

Key words

dihydropyrans - asymmetric synthesis - organocatalysis - diphenylprolinol silyl ether - domino reaction - α-acyl-β-aryl-substituted acrylonitrile

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• 19 The enantiomeric excess of 8a and 8b would be the same as that of 4aa (97% ee), because there is no racemization step.
• 20 trans-3aa was prepared by the reduction of lactone trans-6, which was separated from lactone cis-6. See the Supporting Information for details.
• 21 Enantiomers could not be separated by HPLC by the reported chiral column (ref. 13). We did not know the reason.
• 22 General Procedure of Acetates 4A–C First Step To a solution of aldehyde 1 (0.60 mmol) and cyanide 2 (0.20 mmol) in MeCN (0.40 mL), 3,5-dinitrobenzoic acid (8.5 mg, 0.040 mmol), water (10.8 μL, 0.60 mmol), and organocatalyst (13.0 mg, 0.040 mmol) were added at room temperature. After stirring the reaction mixture at this temperature for the indicated time, the reaction mixture was directly purified by column (n-hexane only to n-hexane/EtOAc = 5:1) to give 3,4-dihydro-2H-pyran derivatives as an inseparable diastereomeric mixture. Second Step To a solution of 3,4-dihydro-2H-pyran derivatives 3 in CH₂Cl₂ (0.20 M), acetic anhydride (1.5 equiv.) and DMAP (0.20 equiv.) were added at room temperature. After stirring the reaction mixture at this temperature for 20 min, the reaction mixture was directly purified by column chromatography on silica gel (n-hexane only to n-hexane/EtOAc = 10:1) to give the acetates 4 as an inseparable diastereomeric mixture. (2S,3R,4S)-5-Cyano-3,6-dimethyl-4-phenyl-3,4-dihydro-2H-pyran-2-yl Acetate (4aaA), (2R,3R,4S)-5-Cyano-3,6-dimethyl-4-phenyl-3,4-dihydro-2H-pyran-2-yl Acetate (4aaB), and (2S,3R,4R)-5-Cyano-3,6-dimethyl-4-phenyl-3,4-dihydro-2H-pyran-2-yl Acetate (4aaC) Following the general procedure, 4aaA, 4aaB, and 4aaC were isolated as colorless oil in 92% overall yield (total 49.9 mg, A:B:C = 65:24:11, trans/cis = 8.1:1 at C3/C4). ¹H NMR (400 MHz, C₆D₆): δ = 7.12 (d, J = 8.0 Hz, 1 H), 7.08–7.04 (m, 1 H), 6.96 (d, J = 7.2 Hz, 2 H), 6.18 (d, J = 2.4 Hz, 0.24 H, B), 6.06 (d, J = 5.6 Hz, 0.11 H, C), 5.84 (d, J = 8.0 Hz, 0.65 H, A), 3.51 (d, J = 5.6 Hz, 0.11 H, C), 3.16 (d, J = 10.8 Hz, 0.24 H, B), 2.73 (d, J = 8.8 Hz, 0.65 H, A), 1.90 (d, J = 1.6 Hz, 0.33 H, C), 1.89 (d, J = 1.6 Hz, 0.72 H, B), 1.86 (d, J = 2.0 Hz, 1.95 H, A), 1.84–1.68 (m, 1 H), 1.58 (d, J = 2.0 Hz, 0.72 H, B), 1.57 (d, J = 2.0 Hz, 0.33 H, C), 1.47 (d, J = 1.6 Hz, 1.95 H, A), 0.52 (d, J = 6.8 Hz, 1.95 H, A), 0.46 (d, J = 6.8 Hz, 0.72 H, B), 0.35 (d, J = 7.2 Hz, 0.33 H, C) ¹³C NMR (100 MHz, CDCl₃): δ = 169.3, 169.1, 169.0, 164.1, 164.0, 162.9, 139.4, 139.3, 137.0, 129.0, 128.9, 128.7, 128.5, 128.5, 128.3, 128.0, 127.8, 127.6, 118.5, 118.3, 118.1, 94.9, 93.1, 91.6, 89.7, 88.4, 87.0, 45.5, 42.1, 40.5, 37.5, 36.5, 34.0, 20.9, 20.8, 20.6, 19.6, 19.6, 19.5, 14.5, 13.6, 12.0. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₆H₁₇NNaO₃ ⁺: 294.1101; found: 294.1104. IR (neat): ν = 2974, 2210, 1762, 1641, 1389, 1217, 1186, 1028, 753, 702 cm^–1. The enantiomeric excess of 4aaA (97% ee) was determined by HPLC using CHIRALPAK^® OZ-H (n-hexane/i-PrOH = 99:1; flow rate 1.0 mL/min; major isomer t _R = 40.6 min, minor isomer t _R = 58.1 min). The enantiomeric excess of 4aaB (97% ee) was determined by HPLC using CHIRALPAK^® OZ-H (n-hexane/i-PrOH = 333:1; flow rate 1.0 mL/min; major isomer t _R = 21.2 min, minor isomer t _R = 43.2 min). The enantiomeric excess of 4aaC (43% ee) was determined by HPLC using CHIRALPAK^® OZ-H (n-hexane/i-PrOH = 333:1; flow rate 1.0 mL/min; major isomer t _R = 28.9 min, minor isomer t _R = 37.4 min).