A total synthesis of racemic trichodiene

Abstract

A highly stereoselective, convergent synthesis of ( )-trichodiene was developed using a Lewis acid catalyzed Nazarov cyclization to form the adjacent quaternary centers with the correct stereochemistry. The dienone intermediate, 2,5-dimethyl-1-cyclohexen-1-yl 2-methyl-1-cyclopenten-1-yl ketone (18), was synthesized by Friedel-Crafts acylation of the acid chloride of 2-methyl-1-cyclopentene-1-carboxylic acid (21) onto 1,4-dimethylcyclohexene followed by dehydrohalogenation with alkoxide. Dienone 18 underwent an electrocyclic Nazarov cyclization upon treatment with BF(,3)(.)Et(,2)O in refluxing chloroform to form the key intermediate 5,8,9-trimethyltricyclo{7,3,0,0('3,8)}dodec-4-en-2-one (20). Several ring cleavage methods were investigated, including Baeyer-Villiger reactions, Barton oxidations, Grob type ring fragmentations, (alpha) nitroso ketone rearrangement, photolytic cleavage, and Beckmann rearrangements, before it was discovered that the oxime of ketone 20 would undergo a secondary Beckmann rearrangement to produce cyano dienes 57a and 57b. These dienes were reduced to the corresponding amine dienes with LAH. The diene functionality was then reduced in a dissolving metal reduction to produce 1,4-dimethyl-1-(2-aminomethyl-1-methylcyclopentyl)-3-cyclohexene (61). Amine 61 was methylated and oxidized to the corresponding N,N-dimethylalkylamine N-oxide which underwent Cope elimination upon heating to produce trichodiene (1). As part of this dissertation project, an improved synthesis of 2-methyl-1-cyclopentene-1-carboxylic acid (21) was developed. Acid 21 was synthesized in high yield through the action of KOCl on 1-acetyl-2-methylcyclopentene (26), which was prepared by various means. The most economical preparation of 26 was by reaction of acetyl chloride and AlCl(,3) with cyclohexane.