Pestalotin

Two new compounds, pestalotin 4'-O-methyl-β-mannopyranoside (1) and 3S,4R-(+)-4-hydroxymellein (2), were isolated from an organic extract of a Xylaria feejeensis, which was isolated as an endophytic fungus from Hintonia latiflora. In addition, the known compounds 3S,4S-(+)-4-hydroxymellein (3), 3S-(+)-8-methoxymellein (4), and the quinone derivatives 2-hydroxy-5-methoxy-3-methylcyclohexa-2,5-diene-1,4-dione (5), 4S,5S,6S-4-hydroxy-3-methoxy-5-methyl-5,6-epoxycyclohex-2-en-1-one (6), and 4R,5R-dihydroxy-3-methoxy-5-methylcyclohexen-2-en-1-one (7) were obtained. The structures of 1 and 2 were elucidated using a set of spectroscopic and spectrometric techniques. The absolute configuration of the stereogenic centers of 1 and 2 was determined using ECD spectroscopy combined with time-dependent density functional theory calculations. In the case of 1, comparison of the experimental and theoretical (3)J6-7 coupling constants provided further evidence for the stereochemical assignments. Compounds 2 and 3 inhibited Saccharomyces cerevisiae α-glucosidase (αGHY), with IC50 values of 441 ± 23 and 549 ± 2.5 μM, respectively. Their activity was comparable to that of acarbose (IC50 = 545 ± 19 μM), used as positive control. Molecular docking predicted that both compounds bind to αGHY in a site different from the catalytic domain, which could imply an allosteric type of inhibition.

All four chiral pestalotin diastereomers were synthesized in a straightforward and divergent manner from common (R)-glycidol. Catalytic asymmetric Mukaiyama aldol reactions of readily-available bis(TMSO)diene (Chan's diene) with (S)-2-benzyloxyhexanal derived from (R)-glycidol produced asyn-aldol adduct with high diastereoselectivity and enantioselectivity using a Ti(iOPr)4/(S)-BINOL/LiCl catalyst. Diastereoselective Mukaiyama aldol reactions mediated by catalytic achiral Lewis acids directly produced not only a (1'S,6S)-pyrone precursor via thesyn-aldol adduct using TiCl4, but also (1'S,6R)-pyrone precursor via the antialdol adduct using ZrCl4, in a stereocomplementary manner. A Hetero-Diels-Alder reaction of similarly available mono(TMSO)diene (Brassard's diene) with (S)-2-benzyloxyhexanal produced the (1'S,6S)-pyrone precursor promoted by Eu(fod)3and the (1'S,6R)-pyrone precursor Et2AlCl. Debenzylation of the (1'S,6S)-precursor and the (1'S,6R)-precursor furnished natural (-)-pestalotin (99% ee, 7 steps) and unnatural (+)-epipestalotin (99% ee, 7 steps), respectively. Mitsunobu inversions of the obtained (-)-pestalotin and (+)-epipestalotin successfully produced the unnatural (+)-pestalotin (99% ee, 9 steps) and (-)-epipestalotin (99% ee, 9 steps), respectively, in a divergent manner. All four of the obtained chiral pestalotin diastereomers possessed high chemical and optical purities (optical rotations,1H-NMR,13C-NMR, and HPLC measurements).

Two new depsipeptides (1 and 2), together with three known related compounds, pestalotin (3), pestalotiopyrone L (4), and PC-2 (5), were discovered in the extract of a mangrove derived fungus Sarocladium kiliense HDN11-112. The structures of saroclides A and B were established by interpretation of extensive NMR spectroscopic data and X-ray crystallographic analysis. Compound 1 was also produced by Simplicillium lamellicola HDN13-430. Compounds 1 and 2 were inactive against five cancer cell lines and four pathogenic microorganisms, while compound 1 showed a lipid-lowering effect.