Carbon atom insertion bicycloannulation: total syntheses of ishwarane and ishwarone

Insertion of a carbon atom into a methyl cyclohexene, leading in a single synthetic step to a bicyclo[3.2.1.0 2.7 ]octane by carbene addition to the double bond and carbene insertion into a methyl CH 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.