This thesis describes the development of a radical cyclization approach to the BC ring system of the C19 quassinoid, 5(S)-polyandrane. The polyandranes are a small group of terpenoids that belong to the quassinoid family of natural products. The quassinoids display a variety of biological properties and have long been of interest to the organic synthesis community.
The work described herein relies on the use of an allene radical cyclization to prepare the BC ring of the trans-perhydroindan substructure of the polyandranes. The hope was that the allene substrates would solve radical translocation problems suffered during the radical cyclization in earlier approaches to the polyandranes. Model studies were first performed on allenyl substrates 100 and 101. These substrates were obtained in moderate yields and selectivity from treatment of aldehyde 58 using organotitanium reagent 99. The aldehyde was prepared in a series of 4 steps from methyl 3,5-dimethylbenzoate. Upon successful synthesis of the allenyl alcohols, the crucial task was accomplishing the free radical cyclization. Treatment of both 100 and 101 with catalytic AIBN and tri-n-butyltin hydride provided good yields of C-7 epimers 107 and 108.
The success of this research led to the study of the same reaction sequence on substrates that contained a methoxy group at C-11 as they closely resemble the quassinoids. The free radical cyclization reaction results of substrates 109 and 110 were similar to those obtained with substrates 100 and 101. An important advance was the use of organoborane 113 in place of organotitanium 99 to construct the cyclization substrates. This provided much better diastereoselectivity at the C7 stereogenic center.
When organoborane 113 was used to prepare the cyclization substrates 100 and 101, a comparable increase in diastereoselectivity was observed from 2:1 to 16:1 of the desired 7S isomer. Independent studies showed that the bromine played a critical role in the stereoselectivity of this reaction. Treatment of the substrate 115, lacking the C9 bromine, gave only 2:1 diastereoselectivity at C7 of allenols 116 and 117 instead of the 16:1 diastereoselectivity observed with allenols 100 and 101.