Studies on the biosynthesis of paraherquamide A and the total synthesis of (±) VM55599
Date
2001
Authors
Stocking, Emily M., author
Williams, Robert M., advisor
Journal Title
Journal ISSN
Volume Title
Abstract
Studies that partially elucidate the biosynthetic pathway of the heptacyclic fungal metabolite, Paraherquamide A are presented. Through biosynthetic feeding experiments with stable isotope labeled compounds, it was determined that the carbon skeleton of paraherquamide A consists of three amino acids and two equivalents of dimethylallyl pyrophosphate. L-methionine was determined to be the precursor to C-29, L-tryptophan was determined to be the precursor to the oxindole moiety and L-isoleucine was determined to be the precursor to the β-hydroxy- β-methylproline ring of paraherquamide A. A subsequent feeding experiment with [5-13C3H2]-L-isoleucine indicated that L-isoleucine is converted to β-methyl-proline via a 4-electron oxidation and that the pro-S hydrogen of C-5 is retained in the oxidative cyclization. The incorporation of [1-13C]-3(S)-methyl-L-proline also indicated that L-isoleucine undergoes oxidative cyclization prior to coupling to L-tryptophan. The two dimethylallyl pyrophosphate-derived portions of paraherquamide A were found to arise via the well-known mevalonic acid pathway. In addition, it was determined that P. fellutanum, a paraherquamide A producing fungus, installs theses two dimethylallyl groups in two stereo-facially distinct manners. The C5 unit (C-19~C-23) leading to the bicyclo[2.2.2]diazaoctan ring is formed in an entirely non-stereospecific manner, while the C-5 unit (C-24~C-28) leading to the dioxepin ring is installed in a completely stereospecific manner. Only the latter observation is consistent with the mechanism of known prenylase enzymes. The first total synthesis of VM55599, a proposed precursor of paraherquamide A, was completed. Feeding experiments with doubly 13C-labeled racemic VM55599, its diastereomer and the oxidized forms of these compounds were performed on P. fellutanum. Only the diasteromer of VM55599 (244a) was incorporated. The incorporation of the bicyclic intermediate signifies that the dimethylallyl group leading to C-19~C-23 of paraherquamide A is installed prior to the dimethylallyl group leading to C-24~C-28. In addition, the incorporation 244a indicates that the oxidations of the indole ring leading to the spirooxindole and the dioxepin ring occur after the formation of the bicyclic ring system.
Description
Rights Access
Subject
Antibiotics -- Synthesis