Isolation and Asymmetric Total Synthesis of Fungal Secondary Metabolite Hygrophorone B¹²

Abstract

Hygrophorone B12, a new antifungal constituent from the fruiting bodies of Hygrophorus abieticola, has been isolated and subsquently synthesized in enantiomerically pure form. The total synthesis includes a Sharpless asymmetric dihydroxylation protocol as the stereodifferentiating step, followed by two diastereoselective aldol‐type reactions. The approach allows the unambiguous control of all three stereogenic centres, and, furthermore, unequivocal determination of the relative and absolute configuration of antibiotic hygrophorones B for the first time.

Total synthesis and antimicrobial evaluation of (+)-hygrophorone B12 and its analogues

“…Due to their unique structural features, hygrophorones have been drawing increasing attention and become a target for total synthesis. Numerous efforts have been devoted to the total synthesis of this class of natural products, and so far, three methods have been reported for the total synthesis of hygrophorone-B-type compounds and hygrophorone A 12 ( 2 ) 17 – 19 . Westermann et al reported the asymmetric total synthesis of hygrophorone A 12 ( 2 ) and B 12 ( 4 ) using a biomimetic strategy, in which the stereo-controlled dihydroxylation of fatty acid ester 9 is the key step ( 9 → 10 ).…”

“…Westermann et al reported the asymmetric total synthesis of hygrophorone A 12 ( 2 ) and B 12 ( 4 ) using a biomimetic strategy, in which the stereo-controlled dihydroxylation of fatty acid ester 9 is the key step ( 9 → 10 ). (+)- 2 and (−)- 4 were obtained using AD-mix-alpha, and the enantiomers (−)- 2 and (+)- 4 using AD-mix-beta (Scheme 1 a) 17 . Rao et al achieved the stereoselective synthesis of (−)-6- epi -hygrophorone B 14 ( 6 ) from D-mannose ( 11 ) using a stereoselective Grignard reaction for the insertion of the hydrocarbon chain, the Bernet–Vasella protocol ( 11 → 12 ), and a ring-closing metathesis (Scheme 1 b) 18 .…”

Synthesis and Biological Evaluation of Highly Potent Fungicidal Deoxy‐Hygrophorones

“…Among the hygrophorones studied most intensively for their biological behavior, [2] spectroscopical data, [3] synthesis, [4] and biosynthesis [5] are hygrophorone A 12 ( 1 ) and B 12 ( 2 ), which are depicted in Figure 1. They are related to pentenomycin and epi ‐pentenomycin, resp., which also show a trans ‐ and cis ‐relationship of the exocyclic hydroxyl groups [6] .…”

“…Elaborated NMR‐investigations (RDC‐based determination) on 4‐acetyl hygrophorone A 12 revealed a cis ‐configuration of the endocyclic hydroxyl group and the tertiary hydroxyl group on C‐5 [3] . With knowledge on the relative but missing information of the absolute configuration of the hygrophorones, a total synthesis of the natural product 2 was carried out to obtain this information [4] . The absolute configuration of 2 was revealed to be ( 4S,5S,6R ).…”

Stereoselective Total Synthesis of (–)–6–epi–Hygrophorone B14 and (–)–4–epi–Hygrophorone D14

“…They were named after the genus Hygrophorous which are in general edible species. Twenty new 2-(hydroxymethyl) 2-cyclopentenones were isolated from different hygrophorous species and grouped into hygrophorones A-G. For instance, 4, 6-diacetylhygrophorone [3] A 12 2 was isolated from H.persoonii and hygrophorone [4] B 12 3 was isolated from H.abieticola. Hygrophorone B 14 4 was isolated from frozen fruit bodies of H. olivaceoalbus.…”