Selective Oxidation of a Keramaphidin B Model

Abstract

A crucial step in the Baldwin and Whitehead proposal for explaining the biogenesis of the marine alkaloid manzamine A is the selective oxidation of natural keramaphidin B to an iminium salt 3, which is then hydrolyzed to give the aldehyde 4. Conditions are now presented in which this selective oxidation can be performed on model compound 8, leading to the iminium salt 16. Although this salt can be considered as a model equivalent of the proposed aldehyde intermediate 4, it was found to be very resistant to hydrolysis as was the corresponding amide 20. From a synthetic point of view, the reported results illustrate the usefulness of the temporary protection of tertiary amines as aminoborane derivatives and constitute a good method for the oxidation of a sterically hindered tertiary nitrogen atom in the presence of a second nitrogen.

A Unified Approach to Polycyclic Alkaloids of the Ingenamine Estate: Total Syntheses of Keramaphidin B, Ingenamine, and Nominal Njaoamine I

“…To this end, a complete and unambiguous reassignment of the entire 12-carbon chain from C33 to C44 was mandatory; this task proved challenging because the dilute sample in [D 5 ]pyridine rendered heteronuclear long-range coupling experiments (in particular HMBC) impractical. Moreover, the limited resolution impeded assignment, especially between 1.1 and 1.7 ppm where 20 methylene protons (14 of them from the chain in question) and one methine proton resonate; likewise, there are two very similar methylene 13 C signals at 27.7 and 27.8 ppm, the correlations of which can only be separated by very high-resolution multidimensional experiments.…”

“…Studies toward keramaphidin B − as well as (nominal) xestocyclamine A , that were not intending to emulate the proposed biosynthesis have also been reported. − The different strategies notwithstanding, none of the approaches reached these targets in the end. This is also why the originally mis-assigned structure of xestocyclamine A 2 went unrecognized for over 25 years.…”

Biomimetic Synthesis of Manzamine Alkaloids

“…To test this hypothesis, the Marazano group synthesized aminonitrile 89, which was submitted to decyanation-hydrolysis using tetrafluoroboric acid in aqueous medium. Although the N 2 -iminium 90 was clearly observed by NMR, aldehyde 91 could never be obtained even under various forcing hydrolytic conditions (Scheme 6.21) [49]. This result disfavors the perception that manzamine aldehydes originate from the hydrolysis of keramaphidin-type iminium as proposed by J.E.…”

“…Scheme 6.17), consisting of studying the behavior of dihydropyridinium salt 108 in solution (generated in situ from 107), a significant amount of 109 was isolated along with awaited 110 and 111 (Scheme 6.28). Similarly, keramaphidin model 112, when submitted to regioselective photooxidative α-cyanation, was turned into halicyclamine model 113 via retroaza-Mannich fragmentation of iminium 114 and cyanide retrapping (Scheme 6.29) [49]. This result suggests that a regioselective N 1 -oxidation of keramaphidin B type alkaloids might be implicated in the biogenesis of the halicyclamines.…”

From a Biogenetic Scenario to a Synthesis of the ABC Ring of Manzamine A

“…A hypothetical biogenetic route, starting from such species, was initially proposed by Baldwin and Whitehead . This hypothesis, which focused on the chemistry of dihydropyridine intermediates, has been tested experimentally . While encouraging results were obtained in testing this model (synthesis of keramaphidin B albeit in low yield),7b the chemistry involved was limited by competitive oxido-reduction reactions of unstable dihydropyridine intermediates.…”