Asymmetric Total Synthesis of the Naturally Occurring Antibiotic Anthracimycin

Abstract

The first total synthesis of the potent antibiotic anthracimycin was achieved in 20 steps. The synthesis features an intramolecular Diels–Alder reaction to forge the trans-decalin moiety, and an unprecedented aldol reaction using a complex β-ketoester to provide the tricarbonyl motif. A Stork–Zhao olefination and Grubbs ring closing metathesis delivered the E/Z-diene and forged the macrocycle. The C2 configuration was set with a base-mediated epimerization, providing access to (−)-anthracimycin.

Marine natural products

“…The first total syntheses of six bacterial compounds were reported in the literature during 2020, included sunshinamide 261 , 87 jomthonic acid A, 88 tumescenamide C, 89 (−)-anthracimycin, 90 germicidin N, 91 and seongsanamide B. 92 The total synthesis of sunshinamide 261 enabled the configuration of the previously unassigned stereogenic centre to be determined, although large differences in the specific rotations at the same concentrations and solvent (−1.5 (MNP) vs. −37.1 (synthetic)) for the isolated and synthesised compounds could not be reconciled.…”

Exploration of Diverse Secondary Metabolites From Streptomyces sp. YINM00001, Using Genome Mining and One Strain Many Compounds Approach

“…Spores of B. anthracis have been used as bioterrorism weapons, and MRSA has become a global health challenge. Meanwhile, anthracimycin exhibits anticancer activity ( Davison et al, 2020 ). This is the first time that it has been found from endophytic Streptomyces of inland plants.…”

Ten-step asymmetric total syntheses of potent antibiotics anthracimycin and anthracimycin B

“…The key synthetic challenge of anthracimycin in the previous synthetic studies [22][23][24]27 was the inefficient construction of the trans-decalin core through the biomimetic intramolecular Diels-Alder (IMDA) reaction of the tetraene substrate. To address this Scheme 1.…”

“…In 2019, two PhD theses (J. L. Freeman 22,23 and G. Lodovici 24 ) disclosed detailed synthetic studies towards anthracimycin and presented a significant synthetic challenge of using the biomimetic intramolecular Diels–Alder (IMDA) reaction of the tetraene substrate (Scheme 1b) 25,26 to construct the decalin core. Further optimization of Freeman's thesis work enabled Brimble 27 and co-workers to achieve the first total synthesis of anthracimycin in 20 steps with 0.4 mg pure anthracimycin. It was noted that Kalesse et al 28 accomplished the total synthesis of structurally related chlorotonil A 29 in 21 steps by using the halogen-directed IMDA reaction and macrolactonization as the key steps.…”