Palladium(II)-catalyzed enyne cyclization strategies toward the podophyllotoxin ring system

A functionally enriched ABCD ring system of podophyllotoxin was generated through Pd(II)-templated cyclization of an alkynoic alkene, prepared in five steps from commercially available 6-bromopiperonal. This research expands upon the recent carboesterification methodology of Dong et al. (Angew. Chem., Int. Ed. 2009, 48, 9690-9692) by the application of PdCl2(MeCN)2, LiCl, and CuCl2 conditions, which yielded the desired podophyllotoxin scaffold with an embedded vinyl chloride moiety. Likewise, these conditions were successfully applied to a propargylic alkene prepared in three steps from 6-bromopiperonal. The resulting product contains the ABCD ring system of podophyllotoxin, but substitutes a D-ring furan for the D-ring lactone. Application of the recent methodology of Lu et al. (J. Org. Chem. 1995, 60, 1160-1169) on a related 1,6-enyne substrate led to functionalized α-methylene γ-butyrolactones instead (Pd2(dba)3·CHCl3, LiBr, and CuBr2). The latter conditions applied to an alkynoic alkene afforded the ABCD ring system of podophyllotoxin with a vinyl bromide group. These vinyl halides allow for derivatization at a critical juncture in order to access novel podophyllotoxin analogs.

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