Total Synthesis and Stereochemical Assignment of the Antimicrobial Lipopeptide Cerexin A₁

Abstract

The isolation and total synthesis of the antimicrobial lipopeptide cerexin A1 is reported. This synthesis includes the preparation of orthogonally protected γ-hydroxylysine, utilizing a nitrile Reformatsky-type reaction as a key step to yield both diastereomers more efficiently than previously reported methods. The configuration of the β-hydroxyl in the lipid tail was determined by the use of a modified Ohrui-Akasaka approach. Furthermore, new cerexin analogues from Bacillus mycoides ATCC 21929 were isolated and characterized, revealing an ε-amino succinylation of a hydroxylysine residue that is unusual in a nonribosomal peptide synthetase product.

Bidirectional Synthesis of Di-tert-butyl (2S,6S,8S)- and (2R,6R,8R)-1,7-Diazaspiro[5.5]undecane-2,8-dicarboxylate and Related Spirodiamines

“…In view of these failures, we examined the double Horner-Wadsworth-Emmons reaction of diphosphonate 36 with aldehyde 37, which is based on the work of Chen, 18 and our initial target was spirodiamine diester 39. Thus condensation of (S)aldehyde 37 19 with diphosphonate 36 in the presence of potassium carbonate gave dienone 38 (83%). It is noteworthy that the stereochemistry of the resultant spirane center is controlled by the absolute stereochemistry of the ring substituents together with the double anomeric effect as observed with derivatives of 1,7-dioxaspiro[5.5]undecane (1).…”

“…11 In our work, spirodiamine 39 was only observed as a single diastereoisomer and showed no spirane center epimerization on even on storage in chloroform solution over 48 hours or over 6 months as a solid sample (Figure 3). The double Horner-Wadsworth-Emmons homologation process was also applied for the conversion of the enantiomeric (R)aldehyde 37 19 into the enantiomeric (R,R,R)-spirodiamine 39 (48%) {[]D = -5.5} (Scheme 6).…”

Recent developments in the asymmetric Reformatsky-type reaction

“…In 2015, a nitrile Reformatsky-type reagent in situ generated from bromoacetonitrile ( 4 ) and zinc in the presence of TMSCl was added to chiral aldehyde 5 derived from L-aspartic acid [ 18 ]. The reaction, performed in THF at reflux followed by protection of the formed alcohols as silyl ethers by treatment with TPSCl (triphenylsilyl chloride), provided the corresponding chiral protected Reformatsky products 6 in 92% yield as a 77:23 mixture of ( S , R )- and ( S , S )-diastereomers ( Scheme 3 ).…”

“… Synthesis of a γ-hydroxylysine derivative through a Zn-mediated nitrile Reformatsky-type reaction [ 18 ]. …”

A vitamin K-dependent carboxylase orthologue is involved in antibiotic biosynthesis

“…10-14). Succinylation of peptide natural products has been reported, and may modify the biological activity as part of a host self-defence mechanism [32][33][34][35] . However, as no detectable quantity of succinylated 1, and only trace quantities (1 mg l -1 ) of 12 are evident in the wild-type strain, we suggest that premalonomycin 5 accumulates in ∆ mloH, and is adventitiously succinylated by the abundant cellular pool of succinyl-CoA to give the side product 12.…”