CATION-STABILIZING AUXILIARIES IN POLYENE CYCLIZATIONS .7. THE FLUORINE ATOM AS A CATION-STABILIZING AUXILIARY IN BIOMIMETIC POLYENE CYCLIZATIONS .4. TOTAL SYNTHESIS OF DL-BETA-AMYRIN

A total synthesis of dl-beta-amyrin (1) is reported, utilizing as the key step a cyclization of a polyolefin having a fluorine atom as the cation-stabilizing (C-S) auxiliary. Thus polyene substrate 7, upon acid-catalyzed cyclization, gave fluoropentacycle 8, a compound having five fused rings and bearing six of the eight chiral centers found in the natural product beta-amyrin (1). The preparation of polyene 7 required the development of stereoselective methods for introducing the three alkene bonds of the cyclopentenol side chain. The trisubstituted 11-cis alkene was formed by stereoselective inversion of the corresponding trans alkene, utilizing an epoxidation/elimination sequence (84% yield, cis:trans 99:1). A new method of producing the tetrasubstituted 7-trans fluoroalkene bond was developed utilizing the Trost palladium-catalyzed alkylation of keto ester 18 with allylic acetate 17 (83% yield, trans:cis 88:12). The trisubstituted 3-trans alkene was constructed by the Brady-Julia rearrangement of cyclopropylcarbinol 22, giving bromide 23 (82% yield, trans:cis 97:3). Optimum conditions for cyclization of cyclopentenol 7 afforded 8 in 65-70% yield. The fluorine atom acting as a C-S auxiliary at pro-C-13 in 7 exerted regiocontrol over the cyclization process, creating a 6-membered ring C and enhancing the yield of pentacyclic product. Conversion of 8 to dl-beta-amyrin (1) entailed oxidative removal of the C-22 allene group, regioselective elimination of the C-13 fluorine atom to produce the C-12 alkene, enlargement and functionalization of ring A, and establishment of the trans A/B ring fusion. The identity of synthetic dl-beta-amyrin was unequivorally established by comparison of its chromatographic and spectral properties with those of the natural product. This study, together with the earlier papers in this series, enlarges the scope of practical biomimetic synthesis of polycyclic natural (and unnatural) triterpenes to include pentacyclic compounds.