Total Synthesis of the Potent and Broad-Spectrum Antibiotics Amycolamicin and Kibdelomycin

Abstract

The complex and intriguing structures of the antibiotics amycolamicin and kibdelomycin are herein confirmed through total synthesis. Careful titration of the synthetic products reveals that kibdelomycin is the salt form of amycolamicin. This synthesis employs a highly convergent strategy, which provides a modular approach for further SAR studies of this class of antibiotics.

Studies towards the Total Synthesis of Amycolamicin: A Chiral Auxiliary‐Based Diels‐Alder Approach towards the Decalin Core

“…As alluded to in the Introduction, while our own work was in progress, Li and co-workers reported the first total synthesis of amycolamicin (1), employing acyl cyanide 11 as one of three building blocks to assemble the natural product. [11] Acyl cyanide 11 had not been foreseen as an intermediate in our own strategy towards amycolamicin (1). However, in light of Li's work, we felt compelled to explore the possible conversion of acid 2 into 11.…”

“…In contrast to Kuwahara's and Baran's approaches, Li′s total synthesis of 1 [11] relied on the late stage C‐acylation of the preformed N‐glycosylated tetramic acid unit of 1 with acyl cyanide 10 (Figure 2). The latter was obtained through the glycosylation of acyl cyanide 11 with an (unprotected) N‐acyl amycolose building block.…”

“…[5,7,10] The unprecedented and challenging molecular structure of amycolamicin (1) in combination with its biological activity make it an attractive target for total synthesis and subsequent structure-activity relationship (SAR) investigations. However, in spite of its intriguing attributes, the first total syntheses of 1 have been described in the literature only very recently by the groups of Li [11] and Kuwahara, [12] respectively. While this manuscript was in preparation, Baran and co-workers published a third synthesis of 1, [13] which is very similar to the one by Kuwahara.…”

Total Synthesis of the Broad-Spectrum Antibiotic Amycolamicin

“…2c,4a Quite recently, Li and co-workers achieved the first total synthesis of amycolamicin and revealed kibdelomycin isolated by Singh's group to be a salt form of amycolamicin, clearly explaining the difference in their NMR spectra. 5 Amycolamicin (1) selectively inhibits bacterial DNA synthesis by binding to bacterial type II DNA topoisomerases in a novel binding mode without affecting human topoisomerase IIα and with no apparent toxicity in mice (LD 50 > 250 mg/kg). 2,4 Prompted by the promising pharmacological properties and the challenging chemical structure of 1, we also embarked on its total synthesis and previously disclosed a diastereoselective synthesis of three cytotoxic degradation products derived from 1 (corresponding to the DE unit of 1).…”

“…MA7385 and named it kibdelomycin . Its structure was initially assigned spectroscopically as a diastereomer of 1 but later revised to 1 based on the cocrystal structures of kibdelomycin with its target enzymes, even though amycolamicin ( 1 ) and kibdelomycin displayed distinct NMR spectra. , Quite recently, Li and co-workers achieved the first total synthesis of amycolamicin and revealed kibdelomycin isolated by Singh’s group to be a salt form of amycolamicin, clearly explaining the difference in their NMR spectra . Amycolamicin ( 1 ) selectively inhibits bacterial DNA synthesis by binding to bacterial type II DNA topoisomerases in a novel binding mode without affecting human topoisomerase IIα and with no apparent toxicity in mice (LD 50 > 250 mg/kg). , Prompted by the promising pharmacological properties and the challenging chemical structure of 1 , we also embarked on its total synthesis and previously disclosed a diastereoselective synthesis of three cytotoxic degradation products derived from 1 (corresponding to the DE unit of 1 ). , In this Communication, we describe the total synthesis of amycolamicin ( 1 ) along with some improvements for the preparation of a protected form of the DE unit.…”