A Synthesis of Exiguaquinol Dessulfate

Abstract

A concise and stereoselective synthesis of exiguaquinol dessulfate is described. Sequential application of a Diels–Alder cycloaddition, a desymmetrizing aldol addition, and a reductive Heck cyclization established most of the architecture of exiguaquinol, and a carefully choreographed introduction of the polar substituents afforded the title compound; unfortunately, naphthoquinol sulfation could not be achieved to deliver exiguaquinol. Our hypothesis regarding the configurational preference of the N-acyl hemiaminal, which was based upon an analysis of internal hydrogen-bonding interactions with polar functional groups, was proven correct. Unfortunately, the title compound did not demonstrate any bactericidal activity against H. pylori cultures. A desymmetrization strategy led to the synthesis of a congener of exiguaquinol, an inhibitor of the H. pylori MurI enzyme and a potential antibiotic. The pentacyclic architecture was accessed via convergent Diels–Alder and aldol additions, followed by a reductive Heck cyclization to forge the vicinal quaternary stereogenic centers.

Strategies for the Synthesis of the Halenaquinol and Xestoquinol Families of Natural Products

“…45 This work relied on an aldol reaction to append the aryl fragment and a late-stage reductive Heck reaction to forge the C-ring cyclopentanone. This latter step is inspired by the work of the Keay and Wipf groups and can be classified in the same category of C–C bond disconnections.…”

“…45 Diene 95 and maleimide ( 96 ) were converted via a Diels–Alder reaction, subsequent N- alkylation with TBS-protected 2-bromoethanol, and alkene hydrogenation to generate meso -imide 97 . BF 3 ·OEt 2 -assisted aldolization of the lithium enolate of 97 with naphthaldehyde 94 (itself made by an interesting sequence from 3,4-dibromothiophene) gave adduct 98 in high yield with complete diastereoselectivity.…”

Enantioselective Nickel-Catalyzed α-Spirocyclization of Lactones

“…2,3 Additionally, spirocyclic cores can be found in bioactive natural products such as exiguaquinol (3). 4,5 Despite the medicinal and synthetic utility of spirocycles, the enantioselective construction of these motifs remains a significant synthetic challenge, necessitating costly chiral separations and limiting their potential applications. 6 Methods for the asymmetric synthesis of spirocycles bearing a stereogenic quaternary center as the spiro atom are even less common, due to the added challenge of installing the allcarbon quaternary center enantioselectively.…”

“…Spironolactone ( 1 ), aptly named after its spirocyclic lactone core, is an FDA-approved drug for the treatment of hypertension and heart failure . Spirocycles also comprise the backbones of chiral ligands, including ( R )-SDP ( 2 ), which has been employed for enantioselective ketone hydrogenation. , Additionally, spirocyclic cores can be found in bioactive natural products such as exiguaquinol ( 3 ). , Despite the medicinal and synthetic utility of spirocycles, the enantioselective construction of these motifs remains a significant synthetic challenge, necessitating costly chiral separations and limiting their potential applications …”