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

摘要

The 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(NEt_2)_3 gives access to anti-configured 3-(1-hydroxyalkyl)cyclohexenes. The syn-configured homoaldol products were transformed into annulated all-cis-tetra-hydrofurans by Lewis acid-mediated cyclocondensation with aldehydes. Analogous cis,trans,cis-substituted hexahydroiso-benzofuran-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.