Clovene synthesis

Intramolecular C—insertion is, essentially, a method for specific remote functionalization of hydrocarbons. An important implication of this for synthetic strategy is that the C—H insertion process can dissolve symmetry, thus leading from a simple precursor to a much more complex product. Both the clovene synthesis, by Dreiding, and the pentalenolactone E synthesis, by Cane, take advantage of this idea. It is further illustrated by the pentalenolactone E synthesis reported by Taber (Scheme 1). In the key step, P-keto ester (139), which has a single stereogenic center, is transformed into the tricyclic ketone (140), which has four stereogenic centers. 

Revision Problem 5 This molecule (TM 400) was used by Raphael in his synthesis of the natural product clovene. How could you make it. 

The formation of an enamine from an a,a-disubstituted cyclopentanone and its reaction with methyl acrylate was used in a synthesis of clovene (JOS). In a synthetic route to aspidospermine, a cyclic enamine reacted with methyl acrylate to form an imonium salt, which regenerated a new cyclic enamine and allowed a subsequent internal enamine acylation reaction (309,310). The required cyclic enamine could not be obtained in this instance by base isomerization of the allylic amine precursor, but was obtained by mercuric acetate oxidation of its reduction product. Condensation of a dihydronaphthalene carboxylic ester with an enamine has also been reported (311). 

This alkynone thermolysis has served as the key step in several natural product syntheses. The considerations that lead to regio- and stereochemical control are illustrated by an elegant synthesis of clovene 725. Thermolysis of the symmetrical alkynone 4 could lead to three different enones, two of which (5 and 6) arc illustrated. In fact, only 8-methyltricyclo[8.3.1.01 5]dodec-3-en-2-one (5) is isolated, in 80% yield. The structure of 5 was confirmed by straightforward conversion to the tricyclic hydrocarbon clovene. The outcome of the thermolysis was anticipated, as it had previously been observed that C-H insertion is most facile when the intermediate alkylidene can achieve coplanarity with the target C-H bond. In this system, such coplanarity is achievable only via the boat conformation of one of the two symmetrical rings. 

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