Synthetic approaches to haplophytine. 1. Synthesis of 1-methoxy- and 1-hydroxy-6-phenyl-6-(2-pivaloylamidophenyl)non-8-ene-4,5-dione and 1-methyl-3-phenyl-3-(2-pivaloylamidophenyl)-2-pyrrolidinone
An analysis of the structures of the alkaloid haplophytine and its dihydrobromide which is formed with rearrangement, shows that they are both derived from a 7-(2-amino-3-hydroxyphenyl)-7-aryl-9-(methylamino)-5,6-dioxononanoic acid moiety (3). Approaches to the synthesis of compounds related to 3 are described. The dianion 13 of phenyl(2-pivaloylamidophenyl)methane, that of methyl 2-phenyl-2-(2-pivaloylamidophenyl)acetate, and the trianion 37 of 2-phenyl-2-(2-pivaloylamidophenyl)acetic acid undergo C-alkylation and C-acylation with nucleophiles. Acylation of 13 with methyl 2,2,5-trimethoxypentanoate followed by hydrolysis gives 6-methoxy-1-phenyl-1-(2-pivaloylamidophenyl)-2,3-hexanedione. This with allyl bromide and sodium carbonate gives the O-allyl derivative, which on thermolysis is converted to its C-allyl isomer, 1-methoxy-6-phenyl-6-(2-pivaloylamidophenyl)non-8-ene-4,5-dione. The corresponding 1-hydroxy compound was prepared analogously via acylation of 13 with methyl tetrahydro-2-methoxyfuran-2-carboxylate. C-allylation of the trianion 37 gives 2-phenyl-2-(2-pivaloylamidophenyl)pent-4-enoic acid, whose methyl ester on ozonolysis followed by treatment with methylamine hydrochloride and sodium cyanoborohydride gives 1-methyl-3-phenyl-3-(2-pivaloylamidophenyl)-2-pyrrolidinone, a potential advanced intermediate for the synthesis of compounds related to 3.