Synthesis based on cyclohexadienes. Part 25. Total synthesis of (±)-allo-cedrol (khusiol)

Abstract

The first stereoselective total synthesis of (±)-allo-cedrol 20, an enantiomer of khusiol and a complex sesquiterpene having a novel tricyclo[5.2.2.0^1,5]undecane framework, is reported from 8-methoxytricyclo[6.2.2.01,6]dodec-6-en-9-one 6c. The methodology involves preparation of 9-methoxytricyclo[7.2.1.0^1,6]dodec-6-en-8-one 12 from 6c and its conversion through the compounds 8-benzyloxy-7,7-dimethyl-9-methoxytricyclo[7.2.1.0^1,6]dodec-5-ene 38, 7-benzyloxy-8-methoxy-2,6,6-trimethyltricyclo[6.2.1.0^1,5]undecane 48 into 8-methoxy-2,6,6-trimethyltricyclo[6.2.1.0^1,5]undecan-7-one 49. Wittig reaction of 49 affords the olefin 50 which has been smoothly rearranged into khusione 51. Metal-ammonia reduction of khusione under specific conditions affords (±)-allo-cedrol. Thus, bridgehead substitution of a methoxy group by a methyl group is the key reaction in this synthesis. In an alternative strategy, attempted conversion of 8-methoxy-2-methyltricyclo[6.2.1.0^1,5]undec-5-en-7-one 16 into khusione 37 results in an inseparable mixture of the isomers. A notable observation in this synthesis is the unusual formation of a γ-alkylated product 27 during Woodward methylation of 16.