The Synthesis of Caryophyllene

The synthesis of caryophyllene was another major challenge for the synthetic chemist and again it was E. J. Corey who rose to meet it.7 18,7 19 

Treatment of hydroxytosylate (7.155) with base leads, as discussed, to the bicyclic ketone (7.159) which contains the nine-membered ring and trans-double bond required for caryophyllene. Epimerisation back to the trans-ring fusion and subsequent Wittig reaction of the resultant ketone 

The rearrangements of isocaryophyllene (7.138) are more straightforward than those of caryophyllene (7.163). It does produce neoclovene 

2-carbon shift allows ring expansion to relieve the strain of the four-membered ring. The positive charge of the product (7.183) is then trapped by the electrons of the endo-cyclic double bond to give the tricyclic carbocation (7.184). Elimination of a proton from this gives the observed olefin (7.185). In this sequence, we see the more usual order of olefin reactivity towards a Bronsted acid, i.e. the 1,1-disubstituted double bond reacts before the 1,1,2-trisubstituted one. This is a clear indication 

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To give you an idea of the kind of thinking required for the synthesis of a complicated molecule, we will look at the S5mlhesis of lysergic acid, which was done by R. B. Wo ward, and the synthesis of caryophyllene, which was done by E. J. Corey. Woodward (in 1965) and Corey (in 1990) both received the Nobel Prize for their contributions to synthetic organic chemistry. 

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