Total Synthesis of Aquayamycin

Abstract

An efficient and practical total synthesis of aquayamycin has been accomplished. The highly oxidized and stereochemically complex tetracyclic ring system was constructed using three key reactions: 1) highly diastereoselective 1,2-addition of C-glycosyl naphthyllithium to a cyclic ketone, 2) indium-mediated site-selective allylation-rearrangement sequence of naphthoquinone, and 3) diastereoselective intramolecular pinacol coupling. This synthetic strategy offers a novel and efficient pathway to prepare aquayamycin-type angucycline antibiotics.

Total Synthesis and Structure–Activity Relationship Study of Vineomycin A1

“…Saquayamycin G (6). To a stirred solution of silyl ether 13 (1.70 mg, 2.03 μmol) in DMF (6.9 μL) was added TASF (3.35 mg, 12.2 μmol) in DMF (24.3 μL) under an Ar atmosphere at 0 °C.…”

“…Due to its important biological activity and novel molecular architecture, 1 is a prime target for chemical synthesis. Indeed, total syntheses of the aglycon, aquayamycin ( 2 ), have been reported by two groups including ours. , Synthetic studies of the deoxyoligosaccharide portion of the vineomycin family and related antibiotics have also been reported. , However, the total synthesis of 1 with its two deoxydisaccharides has not been accomplished. It is difficult to introduce the acid-labile deoxydisaccharide (α- l -acurosyl-α- l -rhodinose) to the aglycon due to the low nucleophilicity of the tert -alcohol, which can lead to β-elimination of the tert -hydroxy group β to the carbonyl group during the Lewis acid-mediated glycosylation (Figure ).…”

“…Indeed, total syntheses of the aglycon, aquayamycin (2), have been reported by two groups including ours. 5,6 Synthetic studies of the deoxyoligosaccharide portion of the vineomycin family and related antibiotics have also been reported. 7,8 However, the total synthesis of 1 with its two deoxydisaccharides has not been accomplished.…”

Asymmetric Synthesis of Tertiary α -Hydroxyketones by Enantioselective Decarboxylative Chlorination and Subsequent Nucleophilic Substitution

“…Chiral tertiary alcohols are important synthetic intermediates for the preparation of medicinally relevant compounds because numerous biologically active compounds contain the tertiary hydroxy moiety in their structure [1][2][3][4][5][6]. Using oxidative α-hydroxylation of carbonyl compounds is a useful method for introducing a hydroxy group onto a chiral carbon center.…”

Himalaquinones A–G, Angucyclinone-Derived Metabolites Produced by the Himalayan Isolate Streptomyces sp. PU-MM59

“…Angucyclines are ubiquitous aromatic polyketide metabolites signified by a benz­[ a ]­anthraquinone aglycone, variation in the A and B ring oxidation state, and differential glycosylation commonly observed on the A, B, and D rings (at the 3-, 8-, 9-, and/or 12b-positions). − These fused tetracyclic aromatic metabolites contribute to a range of molecular mechanisms that primarily manifest in potent anticancer and antibacterial activities. − Thus, the discovery of novel angucycline natural products sets the stage for new bioactive probe development and provides access to unique genomic tools for biosynthetic and bioengineering efforts. − Within this context, we report the discovery of seven new microbial aromatic polyketides (himalaquinones A–G, 1 – 7 ; Chart and Supporting Information, Figure S3), produced by Streptomyces sp. PU-MM59 isolated from a Himalayan region of Pakistan.…”