Total Synthesis of (−)-Mandelalide A Exploiting Anion Relay Chemistry (ARC): Identification of a Type II ARC/CuCN Cross-Coupling Protocol

Abstract

Anion relay chemistry (ARC), an effective, multicomponent union tactic, was successfully employed for the total synthesis of the highly cytotoxic marine macrolide (−)-mandelalide A (1). The northern hemisphere was constructed via a new type II ARC/CuCN cross-coupling tactic, while the southern hemisphere was secured via a highly efficient four-component type I ARC union. Importantly, the synthesis of 1 showcases ARC as a rapid, scalable coupling strategy for the union of simple readily available building blocks to access diverse complex molecular fragments with excellent stereochemical control.

New Mandelalides Expand a Macrolide Series of Mitochondrial Inhibitors

“…This (-)-mandelalide L structure for 12 was validated via total synthesis in the Smith laboratory. 9 The same synthetic sequence (Scheme 1) developed to achieve 1 was employed, however, orthogonal protection of the 24-OH at an early stage, permitted deprotection and acylation at this position in a penultimate, otherwise TBS-protected, mandelalide A precursor.…”

“…5 Subsequently, total syntheses of the revised structure of 1 , were reported by the research groups of Fürstner, 6 Altmann, 7 Carter, 8 and Smith. 9 with several investigators noting weak or disappointing biological activity against human cancer cells. These inconsistent results reported for the cytotoxic efficacy of synthetic 1 , and recollection of the rare source tunicate in 2013, prompted our further investigation.…”

α-Silyl Amides: Effective Bifunctional Lynchpins for Type I Anion Relay Chemistry

“…This tactic was termed type II ARC and has subsequently been employed to great advantage in a number of total syntheses, including our recent synthesis of mandelalide A (Scheme 1, entry 2). 7 …”

Type II Anion Relay Chemistry: Conformational Constraints To Achieve Effective [1,5]-Vinyl Brook Rearrangements

“…6 Indeed, by employing a series of diverse dithiane ARC linchpins, a number of architecturally complex targets have been achieved, as demonstrated in synthetic ventures toward spirastrellolide E, 7 (−)-secu’amamine A, 8 rhizopodin, 9 enigmazole A, 10 and most recently mandelalide A. 11 …”