Total Synthesis and Biological Evaluation of the Glycosylated Macrocyclic Antibiotic Mangrolide A

Abstract

The macrocyclic antibiotic mangrolide A has been described to exhibit potent activity against a number of clinically important Gram-negative pathogens. Reported is the first enantioselective total synthesis of mangrolide A and derivatives. Salient features of this synthesis include a highly convergent macrocycle preparation, stereoselective synthesis of the disaccharide moiety, and two β-selective glycosylations. The synthesis of mangrolide A and its analogues enabled the re-examination of its activity against bacterial pathogens, and only minimal activity was observed.

Total Synthesis of Tiacumicin B: Implementing Hydrogen Bond Directed Acceptor Delivery for Highly Selective β‐Glycosylations

“…b) The rhamnosylation was carried out on the macrolide, using an imidate donor (a/b: 1/4, b: 62 %). Following similar strategies, Gademann also synthesized three congeners of Tcn-B: tiacumicin A [12] and mangrolides A [14] and D. [15] In 2019, de Brabander also reported a total synthesis of mangrolide D. [16] As to our contribution, we reported two related synthetic pathways leading to the aglycone. [17] We designed an original strategy for the synthesis of the C12-C15 diene region of this aglycone and this resulted in the discovery that Pd-nanoparticles catalyze the Kumada-Corriu reaction of vinylsulfides, [18] and also led us to study Griggs allene/alkyne cross-coupling and to propose a mechanism based on DFT calculations.…”

Total Synthesis of Tiacumicin B: Implementing Hydrogen Bond Directed Acceptor Delivery for Highly Selective β‐Glycosylations

“…b) The rhamnosylation was carried out on the macrolide, using an imidate donor ( α / β : 1/4, β : 62 %). Following similar strategies, Gademann also synthesized three congeners of Tcn‐B: tiacumicin A and mangrolides A and D . In 2019, de Brabander also reported a total synthesis of mangrolide D .…”

Applications of Yamaguchi Method to Esterification and Macrolactonization in Total Synthesis of Bioactive Natural Products

“…The improvement of lead structures with novel molecular scaffolds and mechanisms of action comprises a significant goal. The macrocyclic antibiotic mangrolide A ( 17) was isolated from the SNA18 strain of Actinoalloteichus sp.. [57] From a preliminary biological study it was evident that this secondary metabolite ( 17) is active against Gram-negative bacteria such as Pseudomonas aeruginosa (minimum inhibitory concentration MIC = 1.0 μg mL À 1 ) and Acinetobacter baumannii (MIC = 0.25 μg mL À 1 ). [57][58][59][60] In 2018, a convergent and modular strategy for the first total synthesis of mangrolide A (17) was conducted by Gademann and co-workers using Yamaguchi method as a key step.…”

“…The macrocyclic antibiotic mangrolide A ( 17) was isolated from the SNA18 strain of Actinoalloteichus sp.. [57] From a preliminary biological study it was evident that this secondary metabolite ( 17) is active against Gram-negative bacteria such as Pseudomonas aeruginosa (minimum inhibitory concentration MIC = 1.0 μg mL À 1 ) and Acinetobacter baumannii (MIC = 0.25 μg mL À 1 ). [57][58][59][60] In 2018, a convergent and modular strategy for the first total synthesis of mangrolide A (17) was conducted by Gademann and co-workers using Yamaguchi method as a key step. [57] The desired iodide ( 13) was synthesized from oxazolidin-2-one ( 12) and then the authors desired to prepare linear polyene (16) through Yamaguchi method.…”

“…[57][58][59][60] In 2018, a convergent and modular strategy for the first total synthesis of mangrolide A (17) was conducted by Gademann and co-workers using Yamaguchi method as a key step. [57] The desired iodide ( 13) was synthesized from oxazolidin-2-one ( 12) and then the authors desired to prepare linear polyene (16) through Yamaguchi method. At first, iodide (13) underwent Suzuki coupling [61] to Scheme 11.…”