Asymmetric Synthesis of Bicyclic Intermediates of Natural product chemistry

Abstract

The triketone 1, a compound of reflective symmetry, could be converted by an asymmetric aldol cyclization to the optically active bicyclic 7a-methyl ketol (+)-2 in 100% chemical and 93.4% optical yield by the use of a catalytic amount (3% molar equiv) of (S)-(-)-proline. Starting with the triketone 6 the homologous 7a-ethyl bicyclic ketol (+)-7 could be obtained in optically pure form and in 71.0% chemical yield. Dehydration of (+)-2 gave the enone (+)-3 of known (7aS) absolute configuration. The homologous enone (+)-8 could be obtained by a similar dehydration of (+)-7. The CD curve of (+)-8 was very similar to that of the lower homolog (+)-3. Thus, (+)-3, (+)-8, (+)-7, and (+)-2 all have the same (7aS) absolute configuration. The CD results for (+)-2 suggested, and a single-crystal X-ray diffraction study of racemic (±)-2 confirmed, the cis conformation with an axial 7a-methyl and an equatorial 3a-hydroxyl group in the six-membered ring of the bicyclic system. On the other hand, similar measurements of (+)-7 and (±)-7 established the alternate possible cis conformation for the homologous 7a-ethyl bicyclic system. Based on the results with (S)-(-)-proline and also with other optically active reagents employed, two alternative reaction mechanisms have been proposed, both involving a three-point attachment of the bifunctional asymmetric reagent to the substrate molecule. The products [(+)-2, (+)-7, (+)- 8] of this highly efficient asymmetric synthesis are important new intermediates of natural product chemistry, e.g., steroid total syntheses. © 1974, American Chemical Society. All rights reserved.