Cephalotaxine is the major constituent of the alkaloidal fraction obtained from several Cephalotaxus species (Japanese plum yew). Various (alpha)-hydroxysuccinate esters of cephalotaxine known as the harringtonines are also isolated and have been shown to have pronounced antileukemic activity. The compounds are characterized by spiro-fused five membered rings annular to a benzazepine ring system. The ultimate goal of this research is the total synthesis of cephalotaxine and the various members of the harringtonine family. The immediate goal was the synthesis of cephalotaxinone via the appropriately functionalized tetracyclic keto-enamine, 2-desoxy-11,12-(DELTA)-cephalotaxinone. The same keto-enamine should serve as a precursor to 11-hydroxycephalotaxine, which could be used to synthesize the harringtonines via a synthetic scheme involving intramolecular transesterification. The synthetic strategy to be employed for the construction of the cephalotaxine ring system is via intramolecular cyclization of suitably functionalized (alpha)-aryl,(beta)-alkyl cyclopentenones. Development of flexible methodology for a general synthesis of enones has been achieved by a triply-convergent synthesis utilizing (beta)-epoxy sulfones as doubly-charge inverted ynone synthons previously unreported. The one or two pot synthesis involves: (1) Conjugate addition of hard organometallic reagents (pk(,a) > 25) to (gamma)-oxygenated (alpha),(beta)-unsaturated sulfones in a stereospecific fashion; (2) Alkylation in situ of the resultant (alpha)-sulphonyl carbanion; and (3) Oxidation-elimination to the desired enone. The overall sequence is quite general and provides enones in an average overall yield of 62%. Conjugate-addition to (gamma)-oxido vinylsulfones affords predominantly cis adducts whereas (gamma)-silyloxy vinylsulfones afford trans products. Use of the t-butylsulfone rather than the corresponding phenylsulfone gave addition products in higher yields. Application of the above methodology to more highly functionalized systems provided the desired enones for cyclization to the key tetracyclic keto-enamine, 2-desoxy-11,12-(DELTA)-cephalotaxinone. Intramolecular cyclization to date has been unsuccessful. The synthesis and chemistry of the Cephalotaxus family of alkaloids is also reviewed.



Subject Area

Organic chemistry

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