Synthesis of Longifolene

The total synthesis of longifolene represents a very serious challenge for the natural products chemist. The first synthesis was achieved by one of the greatest masters of the art, E.J. Corey of Harvard University.7 16,7 17 

Deprotonation of (7.111) gives the ring expanded ketone (7.102). Such are the forces driving selectivity of this reaction that only 5% of the starting material followed other reaction paths. 

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A discussion of the synthesis of longifolene appears in Section 6.1 of Part One. 

Corey and co-workers developed an alternate approach to homologation of 6-merabered enones in their synthesis of longifolene. Selective ketaliza-tion of l,6-dioxo-8a-methyl-l,2,3,4,6,7,8,8a-octahydronaphthalene (25) " with... 

The synthesis of longifolene in Scheme 13.30 commenced with a Birch reduction and tandem alkylation of methyl 2-methoxybenzoate (see Section 5.6.1.2). Step C is an intramolecular cycloaddition of a diazoalkane that is generated from an aziridinoimine intermediate. 

An enantiospecific synthesis of longifolene was done starting with camphor, a natural product available in enantiomerically pure form (Scheme 13.31) The tricyclic ring was formed in Step C by an intramolecular Mukaiyama reaction. The dimethyl Multistep Syntheses substituents were formed in Step E-l by hydrogenolysis of the cyclopropane ring. 

Another enantiospecific synthesis of longifolene shown in Scheme 13.32 used an intramolecular Diels-Alder reaction as a key step. An alcohol intermediate was resolved in sequence B by formation and separation of a menthyl carbonate. After oxidation, the dihydropyrone ring was introduced by 7-addition of the ester enolate of methyl 3-methylbutenoate, followed by cyclization. 

Fallis, in the synthesis of longifolene (53), a bridged sesquiterpene, performed the intramolecular cycloaddition of compound 51 as a key reaction in the construction of the bridged system (Scheme 9.13) [55]. 

The first successful synthesis of longifolene was described in detail by E. J. Corey and co-workers in 1964. Scheme 13.19 presents a retrosynthetic analysis corresponding to this route. A key disconnection is made on going from I => II. This transformation simplifies the tricyclic skeleton to a bicyclic one. For this disconnection to correspond to a reasonable synthetic step, the functionality in the intermediate to be cyclized must engender mutual reactivity between C-7 and C-10. This is achieved in diketone II, because an enolate generated by deprotonation at C-10 can undergo an intramolecular Michael addition to C-... 

Lei, B. and Fallis, A.G., Direct total synthesis of (+)-longifolene via an intramolecular Diels-Alder strategy,... 

In the synthesis of occidentalol (ref. 13), a eudesmane-type compound consisting of a cis-fused decalin containing a homoannular 1,3-diene system, dihydrocarvone was converted by a typical Robinson annellation reaction to the basic reguired bicyclic structural unit. (It is of interest that a related bicyclic methyldecalenone structure, the Wieland-Miescher ketone, has been employed for the synthesis of longifolene (ref.14), copaene (ref.15) and sativene (ref.16) by three totally different strategies outside the present concept of the semi-synthetic approach). 

Another synthesis of longifolene is summarized later in this chapter. 

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