Concise total synthesis and structural revision of (+)-pestalazine B

Abstract

A convergent synthesis of the proposed structure of (+)-pestalazine B has been achieved in 4 steps using the N-alkylation of an unprotected tryptophan diketopiperazine with a 3a-bromopyrrolidinoindoline as the key step. Although its structure was confirmed by X-ray analysis, the spectroscopic data did not match those of the natural product. The versatility of the methodology allowed the preparation of several diastereomers, and the database generated led to the proposal of an isomeric structure for the natural alkaloid where the d-leucine and d-phenylalanine residues exchanged positions, which was corroborated by total synthesis.

Evaluation of Biosynthetic Pathway and Engineered Biosynthesis of Alkaloids

“…There are other known natural products having similar dimerization patterns. For example, (-)-asperazine A [16] and (+)-pestalazine B [17,18] have the same C3-N1 linkage as 7, whereas (+)-asperazine [19] and (+)-pestalazine A [17,20] have a C3-C7 linkage that was not observed in our study ( Figure 6, boxed). Presumably, the biosynthesis of those dimeric diketopiperazine compounds is also catalyzed by P450 enzymes with relaxed substrate specificity, much like DtpC.…”

“…Subsequently, a series of successive oxidation steps is proposed to take place, resulting in the intramolecular cyclization of the prenyl and indole moieties to form the tricyclic chanoclavine-I (17) along with ring C of the tetracyclic core of ergot alkaloids [60]. Compound 17 is then oxidized to form chanoclavine-I-aldehyde (18) from which ergot alkaloid biosynthesis can diverge. In one pathway, 18 can undergo intramolecular cyclization to form ring D to complete the tetracyclic ergoline core structure, yielding agroclavine (19).…”

Collective Synthesis and Biological Evaluation of Tryptophan‐Based Dimeric Diketopiperazine Alkaloids

“…On the other hand, a C3(sp 3 )−C7(sp 2 ) bridge has been observed in the structure in naseseazine A ( 10 ) and naseseazine B ( 11 ) . Furthermore, in 2008, pestalazine B ( 12 ) possessing a C3(sp 3 )−N1 bridge was isolated . These alkaloids exhibit a unique architecture derived from an indole oxidation reaction of tryptophan in the biosynthesis and a wide variety of biological activities; accordingly, several biomimetic and non‐biomimetic approaches to the synthesis of these alkaloids have been reported …”

Residual Dipolar Coupling Enhanced NMR Spectroscopy and Chiroptics: A Powerful Combination for the Complete Elucidation of Symmetrical Small Molecules

“…[12] Herein, we show how the relative configuration within the monomer, as well as the relative conformation between monomer units in a homodimeric structure, can be safely and simultaneously determined by the use of one-bond protoncarbon 1 D CH RDCs. The resulting configurational/conformational information is then employed for determination of absolute configuration by ECD spectroscopy supported by DFT computations.…”