THE FIRST EXAMPLES OF NONENZYMIC, BIOMIMETIC POLYENE PENTACYCLIZATIONS - TOTAL SYNTHESIS OF THE PENTACYCLIC TRITERPENOID SOPHORADIOL

The first examples of nonenzymic, biomimetic, polyene pentacyclizations are reported. A series of closely related (E,E,Z,Z)-polyenes 10-13 with the same tetraene carbon backbone but with differing initiator groups were synthesized and cyclized. The polyenes 10-12 were all synthesized from the known bromo triene 14 using established protocol, Polyene 13 was prepared from aldehyde 16 by reaction of 16 with (l-methyl-l-cyclopropyl)magnesium bromide to give cyclopropylcarbinol 21. Rearrangement of 21 with MgBr2 to bromide 22 and then alkylation of the lithium enolate of ethyl 3,3-dimethylacrylate with 22 furnished 23. Isomerization of the double bond into conjugation with the ester and dimethylation of enoate 24 gave 13. Polyene acetal 10 was cyclized with SnCl4 to pentacycles 26 (4 beta:4 alpha, 5.5:1) in 51% isolated yield accompanied by regiospecific in situ dehydrofluorination. Polyene 11, with the aldehyde initiator, was cyclized with SnCl4 to yield alcohols 27 (4 beta:4 alpha, 5.4:1) in 49% yield, again with loss of HF. Cyclization of the epoxide 12 using the preferred conditions of (i-PrO)TiCl3 as the Lewis acid gave pentacycle 28 as a major product (GC yield, 21%; 10% isolated) along with the bicyclic ether 29 (13%) and backbone-rearranged bicyclic triene 30 (24%). The protic acid-catalyzed cyclization of tetramethylallyl alcohol 13 furnished fluoropentacycle 33 as the major product in 31% yield. In contrast, the Lewis acid-catalyzed cyclization of 13 gave the dehydrofluorinated pentacycle 32 in 50% yield. Fluoropentacycle 33 was converted to sophoradiol (3), a biologically active pentacyclic triterpenoid of the oleanane series, by oxidative cleavage of the C3 isopropylidene and C22 vinylidene groups, regiospecific dehydrofluorination to introduce the C12-13 alkene, and finally stereoselective reduction of diketone 35. The conversion of 13 --> 33 --> 3 has demonstrated that the tetramethylallylic alchol group is an effective substitute for the epoxide (cf. 12 --> 28) as an initiator of biomimetic polyene cyclizations.