| The first synthesis of (+/-)-eusynstyelamide A has been accomplished in 6 steps. Yb(OTf)3-catalyzed coupling of 6-bromoindole and methyl glycidate gave the methyl ester of 6-bromoindole-alpha-hydoxypropanoic acid. Hydrolysis of the ester and coupling of the resulting acid with Boc-protected agmatine gave the hydroxy amide. IBX promoted oxidation provided the corresponding keto amide, which underwent the key NaOH-catalyzed dimerization under oxygen-free conditions to provide tetra-Boc protected eusynstyelamide A. Deprotection of the Boc groups completed the synthesis providing (+/-)-eusynstyelamide A in 13% overall yield.;nor-Platencin, the first synthetic analogue of platencin, was prepared and its antibacterial activity was determined. The synthesis began with an asymmetric Diels-Alder reaction between acrolein and 1-benzyloxymethyl-1,3-cyclohexadiene to provide a bicyclic aldehyde, which was homologated by a Horner-Wittig reaction followed by hydrolysis of the resulting enol ether. The homologated product reacted with MeMgBr. Hydrogenation, Swern oxidation of the resulting diol, and intramolecular aldol condensation gave (8aS)-1,2,3,4,8,8a-Hexahydro- 7H-2,4a-ethanonaphthalen-7-one. Elaboration of this tricyclic ketone to nor-platencinic acid was carried out using procedures previously developed for the synthesis of platencin and platencimysin: methylation at the alpha-position, followed by reaction with methyl acrylate and hydrolysis to introduce the propanoic acid motif. Finally, nor-platencinic acid was coupled with the 2-(trimethylsilyl)ethyl ester of 3-amino-2,4-dihydroxybenzoic acid in the presence of HATU and Et3N to furnish nor-platencin after removal of the TMSE group. The biological activity of nor-platencin four to sixteen times less than platencin in several resistant cell lines. Approaches to the synthesis of platencin were unsuccessfully investigated.;Several synthetic approaches to cinachyramine, a novel antitumor alkaloid with a hydrazone and two aminals, were explored. The most interesting one produced a bicyclic amidine dimethylhydrazone in four steps starting from 2-amino-3-hydroxy pyridine. This route should be useful for the efficient synthesis of bicyclic amidines. |
