Tricyclic ring systems, alkylative cyclization

Of the carbocyclic sesquiterpenes found in Eremophila, the most elaborate are the tetracyclic enr-zizaenes (89,90,92,93). One possible sequence for the assembly of such a nucleus is given in Scheme 24. Cyclization of 2E,6Z-farnesyl pyrophosphate between the 1 and 6 position would generate the bisabolonium cation equivalent which, after a hydride shift, could further cyclize to a spiro carbocation. The tricyclic ring system can then be assembled by invoking alkylation of the cyclohexene double bond. The tertiary carbocation generated incorporates a bicyclo[3.2.1]octane system which can rearrange in two ways leading to the tricyclic sesquiterpenes metabolites found in Eremophila. 

The cedrene isoprenologues can also be generated from the carbocation (213).which, in this case, alkylates the Si-face of CIO in a lOZ-ene. The spiro-ring system produced displays the 1,4-cis- disubstituted cyclopentane ring. Further cyclization of this intermediate generates the tricyclic ring system of the 2-ep/-cedrene metabolites as shown in Scheme 52. 

A nitroalkane has also served as nucleophile in the cyclization as shown in Scheme 8E.32 to give the eigoline ring system in high diastereo- and enantioselectivity. The initially obtained modest enanitoselectivity (66% ee) by using a catalyst derived from Pd2(dba)3 CHCl3 and (S,S)-chiraphos (2) was optimized to 95% ee by using a complex of (S)-BINAP (enr-4) and Fd(OAc)2 [169,170]. The obtained tricyclic alkylation product provided an expeditious access to (-)-chanoclavine I. 

A variety of intramolecular alkylations at ring nitrogens leading to tricyclic systems have been reported. For example compound (139) cyclized on treatment with ethanolic hydrochloric acid to give the product (140). Cyclization of compound (139) using methyl sulfonic acid gives the derivative (141) (Scheme 6) <87LAl2li>. 

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