A Versatile Chiral Pyrrolidine Aldehyde Building-Block for Synthesis and Formal Synthesis of ent-Nakadomarin A

Abstract

A stable, simple to synthesise and versatile chiral aldehyde building-block has been developed, its reactivity in Wittig, Horner-Wadsworth-Emmons and Grignard reactions investigated, and its use is demonstrated in a highly efficient synthesis of an intermediate in Dixon's synthesis of nakadomarin A.

Synthetic Studies Towards the Core Structure of Nakadomarin A by a Thioamide‐Based Strategy

“…Several total syntheses have been published, 2a as have numerous reports on the synthesis of various substructures. 3 – 9 …”

A Scalable Total Synthesis of (−)-Nakadomarin A

“…Isolated from the marine sponge Amphimedon sp. in 1997 by Kobayashi and co-workers, the manzamine alkaloid (−)-nakadomarin A ( 1 ) has demonstrated a wide range of biological properties. − These include cytotoxic activity against murine lymphoma L1210 cells (IC 50 = 1.3 μg/mL), inhibition of cyclin-dependent kinase 4 (IC 50 = 9.9 μg/mL; associated with tumorigenesis of a variety of cancers), and antimicrobial activity against the Gram-positive bacterium Corynebacterium xerosis (MIC = 11 μg/mL) and the fungus Trichophyton mentagrophytes (MIC = 23 μg/mL). , In addition to biological activity, an architecturally unique framework has garnered much attention for nakadomarin A in the synthetic community, consequently resulting in a number of total syntheses − and synthetic approaches. − A preponderant number of strategies have entailed either creating a tricyclic core encompassing rings A, B, and D or constructing a DE fragment and appending A then C. One of the two most recent efforts by Evans and co-workers features a novel strategy and is extraordinarily brief, creating ring A by combining a macrocyclic CF fragment with a chiral DE fragment. However, no synthesis to date has begun with racemic/achiral starting materials to produce the enantioenriched target, and thus, these methods require the use of chiral pool building blocks or resolution, which can limit the scalability and throughput of the synthetic route (versus, for example, chiral organocatalysis).…”

“…Under the optimized conditions, addition of acetone was required to quench any remaining hydride. Cyclization then occurred efficiently under milder conditions than for related transformations, − affording pentacyclic system 2 in a good yield (76%) due to the increased electrophilicity of the more electron-deficient vinylogous sulfimidinium ion.…”

Total Synthesis of Manzamine A and Related Alkaloids

“…To date, there have been many papers describing synthetic efforts toward the core and three published total syntheses by Winkler, Martin, and Fukuyama . The shortest route, that of Martin, was completed in 23 steps from commercial material, but the average step count still remains high at ∼28.…”