Revisiting the manzamine biosynthetic hypothesis

Abstract

A re-evaluation of the biosynthetic hypothesis of the manzamine natural products is discussed. In addition to considering its unified origins with other marine alkaloids, several other plausible biosynthetic hypotheses are critically evaluated.

Relevant Developments in the Use of Three‐Component Reactions for the Total Synthesis of Natural Products. The last 15 Years

“…[53] Further reactions on 58 would afford the formyl intermediate 59 which after the final incorporation of tryptophane (55), followed by hydration and further oxidative steps would afford the full molecular architecture of manzamine. [54] After 12 years since its discovery, the first total synthesis of manzamine A was reported by Winkler et al encompassing a complex and challenging process that involved ca. 40 steps to render this marine natural product.…”

Baldwin and Whitehead’s Manzamine Alkaloids Biosynthesis Hypothesis Involves a Finely Tuned Reactivity of Acrolein: Automated Extraction of Reactivity Patterns from LC-MS2 Data

“…In that context, Baldwin and Whitehead C 3 -unit hypothesis that has been slightly modified by Marazano et al in the 1990s and 2000s (with the intervention of malondialdehyde and leading in 2008 to a mixed scenario), , may be considered as a guiding principle for genome mining of putative biosynthetic gene clusters and enzymes. Nevertheless, other worthy to note hypotheses have been put forward especially by Thomas et al, and recently, Miller, Smith et al and should also be considered.…”

“…This key C 3 unit can be traced in the structure of most manzamine-type alkaloids, mainly isolated from Haplosclerida and Dictyoceratida marine sponges. While the in vivo existence of 4 is known, its implication as a key intermediate in biosynthetic pathways, as well as the biosynthesis of manzamine alkaloids themselves, remains totally elusive even 30 years after Baldwin and Whitehead’s proposal despite the continuous discovery of new manzamine-type alkaloids . Based on this biosynthetic proposal, several bioinspired approaches were conducted, beautifully demonstrating the relevance of models starting from 3-alkyldihydropyridiniums.…”

Synthesis of a Halicyclamine-Type Macrocyclic Scaffold via Biomimetic Transannular Cyclization

“…Marine-derived manzamine alkaloids , exemplified by manzamine A, keramaphidin B ( 1 ), and halicyclamine A ( 2 ) exert intriguing biological effects such as antimalarial and antituberculosis activities and the modulation of DedA family membrane proteins (Figure ). The attractive molecular architectures of these natural products, consisting of multicyclic bisnitrogenated cores and macrocyclic alkyl loops, have untapped potential as candidates for next-generation drugs and are thus of significant interest to synthetic and medicinal chemists …”

“…The apparently flexible conformational properties of macrocyclic ring 13 compared to 12 are supported by a preliminary DFT calculation (see the Supporting Information). Most naturally occurring manzamine alkaloids such as keramaphidin B ( 1 ), halicyclamine A ( 2 ), and halicyclamine B ( 16 ) have cis -double bonds in their alkyl loops. , Thus, the installation of unsaturated alkyl loops in macrocycles was demonstrated to play key roles in facilitating the hypothetical transannular cyclizations presumably involved in the biosynthesis of bisnitrogen-containing fused scaffolds of manzamine alkaloids.…”