Synthetic endeavors toward 2-nitro-4-alkylpyrroles in the context of the total synthesis of heronapyrrole C and preparation of a carboxylate natural product analogue
The synthesis of 2-nitro-4-oligoprenyl-substituted pyrrole derivatives relevant to the heronapyrroles and related natural products was investigated. Among numerous approaches, nitration of a 3-farnesyl-substituted unprotected pyrrole using AcONO2 gave the best results, albeit still with unsatisfactory yield and regioselectivity. Therefore, the synthesis of (−)-heronapyrrole C acid, an analogue of the naturally occurring antibiotic heronapyrrole C carrying a bioisosteric carboxylate in place of the nitro group, was examined. In lieu of the unsatisfactory nitration, a regioselective acylation with Cl3CCOCl was carried out (>8:1 regioselectivity, in contrast to the 1:1.3 ratio for the nitration). The trichloromethyl ketone was converted to the desired acid in a haloform reaction at the final stage of the synthesis. Further key steps of the analogue synthesis involved a position- and stereoselective Corey–Noe–Lin dihydroxylation and an organocatalytic double Shi epoxidation. A biomimetic polyepoxide cyclization cascade established the bis-THF backbone. Thus, (−)-heronapyrrole C acid was synthesized in eight steps (14.5% overall yield) from commercially available starting materials.