Verucopeptin

A synthesis program for structurally complex macrocycles is very challenging. Herein, we propose a biosynthesis pathway of the pyranylated cyclodepsipeptide verucopeptin to make enough supply and to diversify verucopeptin by genetic manipulation and one-step semisynthesis. The synthesis relies on the intrinsic reactivity of the interchangeable hemiketal pyrane and opened keto along with adjacent alkene. Biological evaluation of verucopeptin-oriented analogs delivers a potent AMP-activated protein kinase (AMPK) agonist, antibacterial agent, and selective NFκB modulator.

For the prediction of the relative stereochemistry of 1,3-dimethyl substitution in alkyl chains, a simple approach based on (1)H NMR data was recently proposed; Δδ values of methylene protons located between methyl-substituted methine carbons can be diagnostic for predicting it. Here we applied this empirical "geminal proton rule" to verucopeptin, a lipopeptide from Streptomyces sp. To determine the absolute stereochemistry of the 1,3,5-trimethyl-substituted alkyl chain in verucopeptin, we converted the corresponding alkyl chain to a carboxylic acid by oxidative cleavage. The geminal proton rule clearly predicted the relative stereochemistry as 31S*,33S*,35R*. This prediction was definitely confirmed by synthesizing four possible diastereomers and comparing their NMR spectra. Furthermore, we reinvestigated the geminal proton rule using reported compounds and our synthesized compounds. Our result strongly suggests that the rule was solid, at least for predicting the stereochemistry of 2,4-dimethylated and 2,4,6-trimethylated fatty acids.

[reaction: see text]. An efficient [2 + 2 + 2]-fragment condensation strategy is described for obtaining the cyclodepsipeptide core of verucopeptin. The 19-membered macrocycle was established through a Carpino HATU mediated macrolactamization, which proceeded in good yield under high-dilution conditions.