A Practical Synthesis of Enantiopure 4,5-Dihydroisoxazole-5-carboxylic Acids

Abstract

The 1,3-dipolar cycloaddition of a variety of aromatic and aliphatic nitrile oxides to 2,5-trans-2,5-diphenylpyrrolidine ­derived acrylamide and cinnamamide efficiently affords the corresponding 4,5-dihydroisoxazole-5-carboxamides in a highly regio- and stereoselective manner. The cycloaddition of aliphatic nitrile oxides to the analogue methacrylamide proceeds also smoothly to afford the expected cycloadducts in moderate yields and very high regio- and stereoselectivity. In sharp contrast, aromatic nitrile ­oxides react with the same amide to afford 5-methyl-4,5-dihydroisoxazole-5-carboxamides in higher yields but as near 1:1 mixtures of diastereoisomers. Acid hydrolysis of these products afforded enantiopure 4,5-dihydroisoxazole-5-carboxylic acids.

Key words

asymmetric synthesis - cycloadditions - heterocycles - ­nitrile oxides - isoxazolines

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12

Crystal data for (R,R)-10: C₃₂H₂₈N₂O₂, M = 472.56, monoclinic, space group P2 ₁ , a = 13.4615 (9) Å, b = 10.5455 (7) Å, c = 17.8450 (12) Å, β = 101.0960 (10)°, V = 2485.9 (3) ų, T = 100 K, Z = 4, λ (Mo K_{α 1}) = 0.71073 Å, 30258 reflections measured, 6046 unique (R _int = 0.0296) which were used in all calculations. The final wR(F ^² ) = 0.0848 (all data). Full crystallographic data for this structure have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication CCDC 265218. These data can obtained free of charge on application to CCDC, 12, Union Road, Cambridge CB2 1EZ, UK;
fax: [phone]; or e-mail: [e-mail].

15

Crystal data for (S)-23: C₂₇H₂₄Cl₂N₂O₂, M _r = 479.38, orthorhombic, space group P2 ₁ 2 ₁ 2 ₁ (no. 19), a = 6.2026 (4) Å, b = 15.5003 (10) Å, c = 24.4725 (16) Å, V = 2352.8 (3) ų, T = 173 (2) K, Z = 4, λ (Mo K_{α 1}) = 0.71073 Å, 14856 reflections measured, 5519 unique (R _int = 0. 0311) which were used in all calculations. The final wR(F ^² ) = 0. 0617 (all data). Full crystallographic data for this structure have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication CCDC 265219. These data can obtained free of charge on application to CCDC, 12, Union Road, Cambridge CB2 1EZ, UK; fax: [phone]; or e-mail: [e-mail].