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Updated: Nov 4, 2025

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Published on: June 10, 2021
Total Synthesis of Homo- and Heterodimeric Bispyrrolidinoindoline Dioxopiperazine Natural Products
Andrea Areal1, Marta Domínguez1, Pim Vendrig1
1Departamento de Química Orgánica, CINBIO, and Instituto de Investigacións Biomédicas de Vigo (IBIV), Universidade de Vigo, As Lagoas-Marcosende, 36310 Vigo, Spain.
Abstract:
Total synthesis and structural confirmation of homo- and heterodimeric bispyrrolidinoindoline dioxopiperazine alkaloids isolated from fungi and bacteria, namely, ditryptoleucine A, ditryptoleucine B (11), the N,N'-bis-demethylated analogue (+)-12, (-)-dibrevianamide F (13), (-)-SF-5280-451 (14), tetratryptomycin A (15), (-)-tryprophenaline (17), and (-)-SF-5280-415 (18), has been carried out starting from the corresponding bispyrrolidinoindolines derived from tryptophan. Our efforts to synthesize all possible diastereomers of the natural ditryptoleucine isolates uncovered structural factors that determine the rate and efficiency of dioxopiperazine ring formation, leading in some cases to mixtures of diastereomers by concomitant epimerization, to the formation of their putative monomeric dioxopiperazine dipeptide biogenetic precursors, and to the alternative formation of a dimer with a fused 1,3,5-triazepan-6-one heterocycle.
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