Total Synthesis of the Proposed Structure of (-)-Novofumigatamide, Isomers Thereof, and Analogues. Part I

The total synthesis of the suggested structure of (-)-novofumigatamide, a natural product containing a C3-reverse prenylated N-acetyl-exo-hexahydropyrrolo [2,3-b]indole motif fused to a 10-membered ring lactam, was achieved using the macrolactam formation in advance of a diastereoselective bromocydization and reverse prenylation steps. Since the NMR data of the synthetic sample did not match those of the natural product, the endo-bromo precursor of a N-Boc analogue and additional diastereomers derived from L-Trp were also synthesized. Five alternative synthetic routes, which differed in the order of final key steps used for the construction of the 10-membered ring lactam and the hexahydropyrrolo[2,3-b]indole framework within the polycydic skeleton and also in the amide bond selected for the ring-dosing of the macrolactam, were thoroughly explored. Much to our dismay, the lack of spectroscopic correlations between the proposed structure of natural (-)-novofumigatamide and the synthetic products suggested a different connectivity between the atoms. Additional synthetic efforts to assemble alternative structures of the natural product and isomers thereof (see accompanying paper; DOI: 10.1021/acs.joc.2c01228) further highlighted the frustrating endeavors toward the identification of a natural product.

Automated summary

The total synthesis of the suggested structure of (-)-novofumigatamide was achieved, but the NMR data did not match that of the natural product. Further synthetic efforts were made to assemble alternative structures, but none of them matched the natural product. This highlights the challenges in identifying the structure of natural products.