An efficient and step-economic new approach to alkyl citrate natural products from a cyclobutene diester is presented. The key sequence involves a formal [2 + 2]-cycloaddition of a silylketene acetal with dimethylacetylene dicarboxylate to provide the cyclobutene diester 14 with 4.5:1 stereoselectivity. Exposure of diester 14 in acidic methanol effected a hydrolysis, intramolecular oxy-Michael reaction, and cyclobutanone methanolysis cascade to give the triester 15. Iodination and elimination then afforded a key alkyl citrate alkene intermediate, which was converted into the natural products (-)-CJ-13,982 (1), (-)-CJ-13,981 (2), and (-)-L-731,120 (3) via a cross-metathesis and subsequent reduction.

The nargenicin family of antibiotics are macrolides containing ar are ether-bridged cis-decalin motif.S everal of these compounds are highly active against multi-drug resistant organisms.D espite the identification of the first members of this family almost 40 years ago,t he genetic basis for the production of these molecules and the enzyme responsible for formation of the oxabridge,remain unknown. Here,the 85 kb nargenicin biosynthetic gene cluster was identified from ah uman pathogenic Nocardia arthritidis isolate and this locus is solely responsible for nargenicin production. Further investigation of this locus revealed ap utative iron-a-ketoglutarate-dependent dioxygenase,w hichw as found to be responsible for the formation of the ether bridge from the newly identified deoxygenated precursor,8 ,13-deoxynargenicin. Uncovering the nargenicin biosynthetic locus provides amolecular basis for the rational bioengineering of these interesting antibiotic macrolides. Figure 1. A) Comparison of HPLC traces of N. arthritidis AUSMDU00012717 extract with authenticn argenicin A1 standard at 265 nm. B) Structure of nargenicin A1.[*] Dr.

The nargenicin family of antibiotics are macrolides containing a rare ether-bridged cis-decalin motif. Several of these compounds are highly active against multi-drug resistant organisms. Despite the identification of the first members of this family almost 40 years ago, the genetic basis for the production of these molecules and the enzyme responsible for formation of the oxa-bridge, remain unknown. Here, we identified the 85 kb nargenicin biosynthetic gene cluster from a human pathogenic Nocardia arthritidis isolate and show that this locus is solely responsible for nargenicin production. Further investigation of this locus revealed a putative iron-α-ketoglutarate dependent dioxygenase, which was found to be responsible for formation of the ether bridge from the newly identified deoxygenated precursor, 8,13-deoxynargenicin. Uncovering the nargenicin biosynthetic locus provides a molecular basis for the rational bioengineering of these interesting antibiotic macrolides.

The total synthesis of viridiofungins A (1) and B (2) via β-lactone 3 in 13 steps is reported. Key steps included an HF-mediated rearrangement of cyclobutene diester 9 to form a bicyclic lactone 6, an olefin cross metathesis between disubstituted alkene 3 and alkene 4 in which isomerization was suppressed, and a novel β-lactone ring opening to form the amide. Deprotection then gave either viridiofungin A (1) or B (2) in high yield.