Stereoselective Synthesis of Hexahydroisobenzofuran‐4(1H)‐ones from Chiral Substituted Cyclohex‐2‐enyl Carbamates via Asymmetric Homoaldol Reaction and THF Cyclocondensation

Abstract

AbstractThe diastereofacial selectivity of the homoaldol reaction of metalated substituted cyclohex‐2‐enyl carbamates with aldehydes is controlled by the nature of the metal complex. Allyllithiums yield syn‐configured products whereas transmetallation to Ti(NEt2)3 gives access to anti‐configured 3‐(1‐hydroxyalkyl)cyclohexenes. The syn‐configured homoaldol products were transformed into annulated all‐cis‐tetrahydrofurans by Lewis acid‐mediated cyclocondensation with aldehydes. Analogous cis,trans,cis‐substituted hexahydroisobenzofuran‐4(1H)‐ones, the core structure of many biologically active natural products, were synthesized starting from anti‐configured homoaldol products. The configurations of the products were determined by 1H NMR coupling constants, nOe‐studies, and X‐ray crystal structure analysis. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)