Synthetic studies with podocarpic acid

Abstract

A series of reactions of podocarpic acid has been investigated. These include the preparation and ozonolysis of some podocarpa-8,11,13-6β,19-olides, the diborane-boron trifluoride reduction of the 7-keto and the 6β,19-lactone groups of 12-methoxy-7-oxypodocarpa-8,11,13-trien-6β,19-olide (21), and the addition of bromine azide to some 12-methoxypodocarpa-6,8,11,13-tetraene derivatives which gave products of unexpected stereochemistry. Ozonolysis of podocarpic acid gave the 8α,12-lactone of 8β-hydroperoxy-(13-17)-pentanorlabdan-19-oic acid (82) which was reduced to the hydroxy-lactone (83) and the keto-diacid (84). The esters (81) and (87) of compounds (83) and (84) were prepared and used as model compounds for the attempted synthesis of the fungicide LL-21271α. An efficient method for generating an exocyclic methylene group at C-8 of the (13-17)-pentanorlabdane skeleton was found, and the preparation and some reactions of the epoxides of dimethyl (13-17)-pentanorlabd-8(17)-en-12,19-dioate (130) and dimethyl (13-17)-pentanorlabd-8(9)-en-12,19-dioate (133) have been investigated. Bromination of 8-oxo-(13-17)-pentanorlabdan-dioic acid esters gave unexpected 7α-bromo derivatives. Methyl, hydrogen 7α-bromo-8-oxo-(13-l7)-pentanorlabdan-12,l9-dioate (162) was found to undergo an unusual elimination and decarboxylation reaction to give the methylene ketone (166) which underwent dimerisation affording compound (167). Some C-19 oxygenated compounds that were expected to have ambergris-type odours were prepared and found to be odourless. An improved method of reduction of methyl-12-methoxy-7-oxopodocarpa-5,8,11,13-tetraen-19oate (199) to 12-methoxypodocarpa-5,8,11,13-tetraen-19-ol (201) was found and the mechanism was studied. A series of C-19 methyl ethers of podocarpic acid derivatives was prepared in order to elucidate the above reduction mechanism. Also investigated were the functionalisation of the C-10 axial methyl group of podocarpic acid via photolysis of the 6β-nitrite ester for the preparation of 12-methoxy-19-norpodocarpa-3,5,8,11,13-tetraen-7-one (237), and the photo-oxygenation of 12-methoxy podocarpa-6,8,11,13-tetraen-19-oic acid (57) to give a 4-hydroperoxide (240) which was subsequently reduced to 12-methoxy podocarpa-4,8,11,13-tetraen-7-one (243).