Unified Approach for the Synthesis of Close Analogues of Reverse‐Prenylated Hexahydropyrrolo Indole Alkaloids

A straightforward and unified synthetic approach to reverse‐prenylated hexahydropyrrolo indole alkaloids has been established. It uses an unusual disconnection which allows for the late stage introduction of the side chain of one of the amino acids — a crucial element of structural diversity in this class of natural products. Accordingly, the obligatory tryptophan is condensed to glycine (as the minimal second amino acid), followed by a regio‐ and stereoselective introduction of the reverse prenyl group with concomitant formation of the hexahydropyrrolo indole substructure. The resulting general framework is finally alkylated at the α‐position of the glycine to formally introduce the amino acid side chain. The presented strategy is particularly suited for the synthesis of a small focused library of close natural product analogues differing in the second variable amino acid substructure. In particular, the introduction of functionalised, rare, or unnatural and d ‐amino acids is straightforward. The viability of the concept was demonstrated by a short synthesis of epi ‐Fructigenine A and dehydro‐Brevicompanine B. Notably, the two natural product analogues are accessible in only 3 and 2 steps, respectively, from the same general precursor. It is also worth mentioning that a new N ‐protecting group was developed as part of the research project presented.