Lugdunomycin,an Angucycline‐Derived Molecule with Unprecedented Chemical Architecture

The angucyclines form the largest family of polycyclic aromatic polyketides, and have been studied extensively. Herein, we report the discovery of lugdunomycin, an angucycline‐derived polyketide, produced by Streptomyces species QL37. Lugdunomycin has unique structural characteristics, including a heptacyclic ring system, a spiroatom, two all‐carbon stereocenters, and a benzaza‐[4,3,3]propellane motif. Considering the structural novelty, we propose that lugdunomycin represents a novel subclass of aromatic polyketides. Metabolomics, combined with MS‐based molecular networking analysis of Streptomyces sp. QL37, elucidated 24 other rearranged and non‐rearranged angucyclines, 11 of which were previously undescribed. A biosynthetic route for the lugdunomycin and limamycins is also proposed. This work demonstrates that revisiting well‐known compound families and their producer strains still is a promising approach for drug discovery.     

Total synthesis of BE-23254, a chlorinated angucycline antibiotic

The first synthesis of BE-23254, an unusual angucycline antibiotic, is reported. It involves regioselective condensation of naphthalenone 4 and chlorine-containing isobenzofuranone 16 as the key step.     

Total Synthesis of Angucyclines. XVII. First Synthesis of Antibiotic 100‐1, a Deoxydisaccharide Angucycline Antibiotic of the Urdamycinone B‐Type

Two routes to the deoxydisaccharide angucycline antibiotic 100‐1 (3) are described. Key steps comprise the regioselective oxidation/bromination of the 1,5‐diacetoxyolivose C‐saccharide 7 to the bromoquinone 8. Diels–Alder reaction of the bromoquinone with the diene 9 followed by HBr elimination afforded the urdamycinone B precursor 11 as a diastereomeric mixture. Selective protection as the TBDMS ether 13, acetylation and deprotection of the silyl ether afforded the alcohol 15 which was selectively glycosylated to the α‐rhamnal glycoside 17 in 72% yield (at 70% conversion) using benzoyl rhamnal (16) as the glycoside donor and scandium triflate as the promotor. The silyl group at C‐3 of the aglycone was then transformed into a hydroxyl group. Zemplén deacylation and photooxidation of the benzylic position at C‐1 then converted the two diastereoisomers into the natural product 3 and the C‐3 diastereoisomer 20. At this stage the diastereomers 3 and 20 were separated. Alternatively and more easily, the diastereomers were separated at the stage of the urdamycinone B analogues 21a and 21b, followed by a similar reaction sequence to the natural disaccharide 3.     

A hetero Diels-Alder approach to the synthesis of the first angucyclinone and angucycline 5-aza-analogues

The synthesis of two new heterodienes and their regioselective [4+2]cycloaddition reactions with several bromo-naphthoquinones allowed us to prepare the first angucyclinone and angucycline 5-aza-analogues.     

Synthesis of 5-aza-analogues of angucyclines: manipulation of the 2-deoxy-C-glycoside subunit

Based on a heterocyclic Diels-Alder strategy, a concise synthesis of 5-aza-analogues of angucyclines bearing a 2-deoxy-C-glycoside subunit is reported. Starting from a common intermediate, a peracetylated D-2-deoxyglucose could be linked to carbons C9 or C10 of the tetracyclic framework. Further manipulations of the sugar residue allowed the installation of bromo and azido substituents at carbon C6′.