Synthesis and Evaluation of Cyclobutylcarbinyl Derivatives as Potential Intermediates in Diterpene Biosynthesis

Article abstract of DOI:10.1021/jo00386a031

A new mechanism for the enzyme-catalyzed bicyclization of copalyl pyrophosphate (1) to kaurene (2) and related bridged perhydrophenanthrene-type diterpenes is considered.The key steps in the mechanism are an exocyclic vinyl group ring closure of the pimar-15-en-8-yl carbocation to a D-norbeyerane-15-methyl intermediate (D) and a subsequent ring expansion (A -> D -> B) instead of the usual endocyclic pimarenyl -> beyeranyl cyclization (A -> B).Beyeran-16-one (7), prepared in six steps from isosteviol methyl ester (5b), was converted to 16-diazobeyeran-15-one (10) viathe 15,16-dione.Irradiation of the diazo ketone afforded an exo-endo mixture of D-norbeyerane-15-carboxylic acids or esters (11 and 12).The isomeric esters were separated by selective hydrolysis and reduced to the exo- and endo-cyclobutylcarbinols (13-OH and 14-OH).Acetolysis of the corresponding tosylates initiated a ring-expansion rearrangement to beyerene, kaurene, and isokaurene, as well as fragmentation to 7,15-, 8,15-, and 8(14),15-pimaradienes (Scheme III).However, the lack of incorporation of either <³H>-13-OPP or <³H>-14-OPP into kaurene upon incubation with a kaurene synthetase preparation from Marah macrocarpus ruled out the exo- and endo-cyclobutylcarbinyl pyrophosphates as free intermediates in the cyclization catalyzed by this enzyme.