Carbon atom insertion bicycloannulation: total syntheses of ishwarane and ishwarone

Abstract

Insertion of a carbon atom into a methyl cyclohexene, leading in a single synthetic step to a bicyclo[3.2.1.02.7]octane by carbene addition to the double bond and carbene insertion into a methyl C—H bond, has been accomplished by treating the cyclohexene with carbon tetrabromide and methyllithium at low temperatures. This new bicycloannulation method has been employed in a total synthesis of ishwarane (1), the naturally occurring parent hydrocarbon of the ishwarane class of tetracyclic sesquiterpenes. Although this reaction was not successful with various possible precursors of ishwarone (2), this natural product was prepared in low yield by a two-step version of the carbon atom insertion bicycloannulation (CAIB) procedure involving addition of bromoform-derived dibromocarbene to the octalone (5) followed by treatment of the resulting dibromocyclopropane (56) with methyllithium. The same two-step sequence was also successful in the first synthesis of norishwarane (20), the hydrocarbon comprising the bare ring system of the ishwarane sesquiterpenoids. The Diels–Alder synthesis used in the preparation of the octalin precursor (18) of norishwarane could not be used for the terpenes themselves because of the lack of dienophilic reactivity of the required cyclohexenone (7). A regioselective Diels–Alder equivalent sequence was therefore developed, consisting of conjugate addition of lithium di(3-methyl-3-butenyl)cuprate (42) to 2,3,4-trimethylcyclohex-2-en-1-one (7), epoxidation, base-catalyzed cyclization of the resulting epoxide (47) to a mixture of primary and tertiary alcohols (50 and 49, respectively), and dehydration of 49 to give 5. In the case of ishwarane, the octalin precursor (62) was synthesized by conjugate addition of lithium dimethylcuprate to octalone 59, addition of methyl magnesium bromide to the resulting decalone (60) to give octalol 61, and dehydration.