In Pursuit of a Competitive Target: Total Synthesis of the Antibiotic Kendomycin

Abstract

Kendomycin is a novel polyketide having a unique quinone methide ansa structure and an impressive biological profile. Herein we provide a chronological overview of the synthetic work towards the title compound. Thus far, over a period of about eight years, eight groups worldwide have published on their synthetic efforts resulting in five total syntheses, one formal synthesis, and a number of fragment syntheses. Most approaches roughly mimic the biogenetic pathway, starting with an aromatic polyphenol subunit to which a polyketide chain is attached. Subsequent key steps include macrocyclization and the formation of the densely substituted tetrahydropyran ring, and then a late-stage oxidation and lactol formation.

Investigations to the Antibacterial Mechanism of Action of Kendomycin

“…Under aerobic growth conditions and in the presence of sufficient amounts of glucose, S . aureus cells preferentially catabolize glucose via glycolysis, whereas the TCA cycle is repressed [ 45 ]. The utilization of glucose via glycolysis generates pyruvate, which under aerobic growth conditions is catabolized to acetyl-CoA and subsequently to acetyl-phosphate.…”

The Emergence of Quinone Methides in Asymmetric Organocatalysis

“…para -Quinone methides ( p -QMs) are structural isomers of o -QMs, displaying a cyclohexadiene core with a carbonyl group and an exocyclic alkylidene residue placed at the para position. Also, p -QMs exist in a variety of natural products, pharmaceuticals [51,52], and can be found as reactive intermediates in many chemical and biological processes [53]. The synthesis and the reactivity of p -QMs depend on the nature of the electron-donating substituents installed on the cyclohexadiene core.…”

Isothiourea-Catalyzed Enantioselective α-Alkylation of Esters via 1,6-Conjugate Addition to para-Quinone Methides

“…Quinone methides (QMs) are electrophilic compounds composed of a cyclohexadiene core bearing a carbonyl either ortho or para to an exocyclic alkylidene unit [1,2]. Due to their electrophilicity [3][4][5][6], QMs have been used in a variety of biological and medicinal processes [1, 2,7], are present within natural products and pharmaceuticals [1,2,[8][9][10][11], and have been applied as electrophiles in a variety of synthetic reactions [1,2,[12][13][14][15][16][17][18]. While ortho-QMs have been used extensively in enantioselective catalysis [19], particularly as components in formal [4+2] cycloaddition reactions, the use of para-QMs has only recently received increased attention [19][20][21][22][23].…”