Total Synthesis of the Tetracyclic Pyridinium Alkaloid epi‐Tetradehydrohalicyclamine B

Abstract

The first total synthesis of a tetracyclic marine pyridinium alkaloid hinged on recent advances in chemoselectivity management: While many classical methods failed to afford the perceptively simple pyridine-containing core of the target, nickel/iridium photoredox dual catalysis allowed the critical CÀ C bond to be formed in good yield. Likewise, ring closing alkyne metathesis (RCAM) worked well in the presence of the unhindered pyridine despite the innately Lewis acidic Mo(+ 6) center of the alkylidyne catalyst. Finally, an iridium catalyzed hydrosilylation was uniquely effective in reducing a tertiary amide without compromising an adjacent pyridine and the lateral double bonds; this transformation is largely without precedent. The second strained macrocycle enveloping the core was closed by intramolecular N-alkylation with formation of the pyridinium unit; the reaction proceeded site-and chemoselectively in the presence of an a priori more basic tertiary amine.

Revisiting the manzamine biosynthetic hypothesis

“…Over the past 20 years, several other family members of this group have succumbed to total synthesis, including nakadomarin A, [17][18][19][20][21][22][23][24] Sarain A, 25,26 haliclonacyclamine C, 27 madangamines A-E, 28,29 and epi-tetradehydrohalicyclamine B. 30 In general, though, these compounds do not display bioactivities as potent or as diverse as manzamine A.…”