Enantioselective Total Synthesis of (+)-Wortmannin

Guo, Yinliang; Quan, Tianfei; Lu, Yandong; Luo, Tuoping

doi:10.1021/jacs.7b02515

Cited by 44 publications

(25 citation statements)

References 51 publications

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“…Friedel–Crafts reaction is one of the most powerful synthetic methods in organic chemistry because it directly constructs carbon–carbon bonds in an atom‐economical manner and provides advanced intermediates for total synthesis of natural products –. In particular, an enantio‐ and diastereoselective Friedel–Crafts reaction has been a fascinating and perplexing endeavour because the carbocation intermediate involved in the reaction would bring about racemic and diastereomeric mixture or it would undergo a carbocationic rearrangement giving rise to regioisomers.…”

Section: Figurementioning

confidence: 99%

Enantiospecific Total Syntheses of (+)‐Hapalindole H and (−)‐12‐epi‐Hapalindole U

Dethe

Das

Kumar

et al. 2018

Chemistry A European J

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Enantiospecific total syntheses of (+)-hapalindole H and (-)-12-epi-hapalindole U as well as the formal syntheses of (+)-hapalindole Q and (+)-12-epi-fischerindole U isothiocyanate have been described. Key steps of our approach feature expedient, highly regio- and diastereoselective Lewis acid catalyzed Friedel-Crafts reaction of indole with cyclic allylic alcohols and intramolecular reductive Heck reaction. Efficiency of the synthetic route also relies on an alkynyl aluminate complex driven regioselective nucleophilic epoxide opening from a sterically hindered site.

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Section: Figurementioning

confidence: 99%

Enantiospecific Total Syntheses of (+)‐Hapalindole H and (−)‐12‐epi‐Hapalindole U

Dethe

Das

Kumar

et al. 2018

Chemistry A European J

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“…Notably, a semisynthetic analog of wortmannin, PX-866, was tested in a phase II clinical trial for treating cancers 11 . The intriguing structures and excellent biological activities of furanosteroids have thus led to extensive efforts toward their total chemical synthesis over the past 20 years, and the stereoselective synthesis of wortmannin and (–)-viridin was finally achieved in 2017 12 , 13 . However, as compared with the progress in chemical synthesis, the biosynthesis of these important molecules in fungi is poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Biosynthetic pathway for furanosteroid demethoxyviridin and identification of an unusual pregnane side-chain cleavage

et al. 2018

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Furanosteroids, represented by wortmannin, viridin, and demethoxyviridin, are a special group of fungal-derived, highly oxygenated steroids featured by an extra furan ring. They are well-known nanomolar-potency inhibitors of phosphatidylinositol 3-kinase and widely used in biological studies. Despite their importance, the biosyntheses of these molecules are poorly understood. Here, we report the identification of the biosynthetic gene cluster for demethoxyviridin, consisting of 19 genes, and among them 15 biosynthetic genes, including six cytochrome P450 monooxygenase genes, are deleted. As a result, 14 biosynthetic intermediates are isolated, and the biosynthetic pathway for demethoxyviridin is elucidated. Notably, the pregnane side-chain cleavage requires three enzymes: flavin-dependent Baeyer-Villiger monooxygenase, esterase, and dehydrogenase, in sharp contrast to the single cytochrome P450-mediated process in mammalian cells. Structure–activity analyses of these obtained biosynthetic intermediates reveal that the 3-keto group, the C1β–OH, and the aromatic ring C are important for the inhibition of phosphatidylinositol 3-kinase.

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“…No correlations to cross-conjugated carbonyl carbon C-7 were observed, but a signal at δ C 172.7 for the corresponding carbon was present in the 13 C NMR spectrum, matching well with literature data. 12 Correlations from both H 3 -26 and H 3 -25 to a methylene carbon at δ C 27.2 and a methine carbon at δ C 40.8, together with additional correlations from H 3 -24 and H-23 to ester carbon C-22 completed the 2-methylbutyrate unit. Finally, a correlation from oxymethine H-11 to C-22 confirmed the placement of the 2-methylbutyrate unit at C-11, leading to the assignment of structure 1 .…”

Section: Resultsmentioning

confidence: 99%

Wortmannin and Wortmannine Analogues from an Undescribed Niesslia sp.

Dischler

et al. 2019

J. Nat. Prod.

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In the course of our studies of coprophilous fungi as sources of antifungal agents, a strain of an undescribed species in the genus Niesslia (TTI-0426) was isolated from horse dung collected in Texas. An extract from fermentation cultures of this strain afforded two new antifungal wortmannin derivatives, wortmannins C and D (1 and 2), as well as four additional new related compounds, wortmannines B1–B4 (3-6), containing an unusual ring system. The structures of these metabolites were established mainly by analysis of HRESIMS and 2D NMR data. Relative configurations were assigned using NOESY data, and the structure assignments were supported by NMR comparison with similar compounds. Wortmannins C and D showed activity against Cryptococcus neoformans and Candida albicans in disk assays, but low MIC potency observed for 1 was suggested to be due in part to efflux processes on the basis of assay results for a Schizosaccharomyces pombe efflux mutant in comparison to wild-type.

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Enantioselective Total Synthesis of (+)-Wortmannin

Cited by 44 publications

References 51 publications

Enantiospecific Total Syntheses of (+)‐Hapalindole H and (−)‐12‐epi‐Hapalindole U

Enantiospecific Total Syntheses of (+)‐Hapalindole H and (−)‐12‐epi‐Hapalindole U

Biosynthetic pathway for furanosteroid demethoxyviridin and identification of an unusual pregnane side-chain cleavage

Wortmannin and Wortmannine Analogues from an Undescribed Niesslia sp.

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