Structure Determination, Biosynthetic Origin, and Total Synthesis of Akazaoxime, an Enteromycin-Class Metabolite from a Marine-Derived Actinomycete of the Genus Micromonospora

Abstract

A new enteromycin-class antibiotic, akazaoxime (1), possessing an aldoxime functionality in place of O-methyl nitronic acid, was isolated from the cultured extract of a marine-derived actinomycete of the genus Micromonospora, along with known A-76356 (2). The structure of 1, including the absolute stereochemistry of three chiral centers, was established by comprehensive analysis of nuclear magnetic resonance (NMR) and mass spectrometry data coupled with magnetic anisotropy analysis of its phenylglycine methyl ester derivatives. The stereochemistry of 2, not determined previously, was proven to be the same as that of 1 on the basis of the similarity of their NMR and specific rotation data. Precursor feeding experiments using 13C-labeled compounds elucidated that the carbon skeletons of 1 and 2 are constructed from propionate (methylmalonate), leucine, and glycine. Establishment of the concise and flexible synthetic route to 1 enabled us to implement biological evaluation of 1 and its unnatural analogues, demonstrating weak to moderate antimicrobial activities of 1 against Gram-positive Kocuria rhizophila [minimum inhibitory concentration (MIC) of 50 μg/mL] and those of synthetic analogues against a plant pathogen Glomerella cingulata (MIC of 50 μg/mL) and a human pathogen Trichophyton rubrum (MIC of 25–50 μg/mL).

Marine natural products

“…Feeding experiments using 13 C-labeled compounds determined that the carbon skeletons present in both 44 and 45 are derived from propionate, leucine, and glycine. 16 Applying the GNPS molecular networking platform to a Nocardiopsis aegyptia sample resulted in the identication of four new anthraquinone derivatives, saliniquinones G-I 46-48 and heraclemycin E 49. 17 MS/MS-based molecular networking and follow-up isolation studies yielded the new p-terphenyl derivatives nocarterphenyls D-H 50, 51-54 from the ferment of a Nocardiopsis species.…”

“…Feeding experiments using 13 C-labeled compounds determined that the carbon skeletons present in both 44 and 45 are derived from propionate, leucine, and glycine. 16…”

Micromonospora: A Prolific Source of Bioactive Secondary Metabolites with Therapeutic Potential

“…The total synthesis of 371 was performed on the basis of its biosynthetic pathway using N-Boc-L-leucinol as the starting material (Scheme 16). 357 4.7.3. Other Alkaloids.…”

Atom-economical synthesis of 1,2-bis(phosphine oxide)ethanes from calcium carbide with straightforward access to deuterium- and13C-labeled bidentate phosphorus ligands and metal complexes

“…[1][2][3] Labels, namely, deuterium and carbon-13, provide essential data for tuning the absorption, distribution, metabolism, and excretion of drugs. 4,5 The identification of products, [6][7][8][9][10][11][12] reaction mechanisms, [13][14][15][16][17][18][19][20][21] spectroscopy, 22 and many other applications [23][24][25][26][27][28][29][30][31][32][33] require the incorporation of a deuterium label at a specific position.…”