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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.
Highlights
415 [18], has been carried out starting from the corresponding bispyrrolidinoindolines derived from tryptophan
Permutations on the amino acids acting as biogenetic building blocks (Ala, Leu, Val, Phe, Trp, Pro) that condense with the bispyrrolidinoindoline core and covalent modifications at the indole and dioxopiperazine nitrogen substituents are commonly found in the structures of these dimeric natural products
Departing from the biomimetic oxidative dimerization, synthetic efforts have mainly focused on the construction of bispyrrolidinoindolines such as 9 (Figure 1) and ent-10 from bisoxindole diamines26 and of (−)-9, (+)-10 (Figure 1), and a 1′-(2-phenylethylene)ditryptophenaline derivative27,28 by the Co(I)-mediated dimerization of 3a-bromocyclotryptophans.27−32 On the basis of the bioinspired Co(I)promoted dimerization we have reported the synthesis of (+)-10 (Figure 1) starting from C3-bromopyrrolidinoindoline 21 (Scheme 2) and extended the protocol to nonsymmetrical dimeric alkaloids including (+)-16 (Figure 1)
Summary
415 [18], has been carried out starting from the corresponding bispyrrolidinoindolines derived from tryptophan. Bioactive natural products with 2,5-dioxopiperazine scaffolds are known to be produced by marine and terrestrial fungi, bacteria, plants, and even animals.. Bioactive natural products with 2,5-dioxopiperazine scaffolds are known to be produced by marine and terrestrial fungi, bacteria, plants, and even animals.1 Within this family, the dimeric tryptophan-derived bispyrrolidinoindoline dioxopiperazine alkaloids, which have been mainly isolated from Streptomyces sp. Radical recombination of dioxopiperazine units gives rise to C3/C-3′ homodimer (−)-ditryptophenaline 9.3−6 Additional natural products, including 8 (Scheme 1), are alternatively generated through connection of the monomeric pyrrolidinoindoline dioxopiperazine radical at C-3 of 6 to the N-1′ position (C-6′/C-3 or C-7′/C-3 heterodimeric positional isomers have been isolated) of the radical species generated in 6 (and stabilized by resonance with the indole ring as depicted in 7).−. Permutations on the amino acids acting as biogenetic building blocks (Ala, Leu, Val, Phe, Trp, Pro) that condense with the bispyrrolidinoindoline core and covalent modifications at the indole and dioxopiperazine nitrogen substituents are commonly found in the structures of these dimeric natural products.
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