39532-38-2Relevant academic research and scientific papers
Chemoenzymatic Route to Oxyfunctionalized Cembranoids Facilitated by Substrate and Protein Engineering
Le-Huu, Priska,Rekow, Dominik,Krüger, Claudia,Bokel, Ansgar,Heidt, Tanja,Schaubach, Sebastian,Claasen, Birgit,H?lzel, Sebastian,Frey, Wolfgang,Laschat, Sabine,Urlacher, Vlada B.
, p. 12010 - 12021 (2018)
Cembranoids constitute a large family of 14-membered oxygenated macrocyclic diterpenoids with potential as therapeutic agents. Selective late-stage oxidations of cembranoid scaffolds remain a challenge for chemical catalysts but can be accomplished by enzymes. Here, a new chemoenzymatic route to oxyfunctionalized 14-membered macrocycles including cembranoids is described. This route combines a metal-catalyzed ring-closing metathesis with a subsequent P450 BM3-catalyzed hydroxylation and delivers cembranoid-like analogues. Systematic substrate probing with a set of synthetic 14-membered macrocycles revealed that the regioselectivity of a P450 BM3-based biocatalyst increased with increasing ring rigidity as well as size and polarity of the exocyclic substituents. Enzyme regioselectivity could further be improved by first-sphere active site mutagenesis. The V78A/F87A variant catalyzed hydroxylation of cembranoid-ol (9S/R)-3 d with 90 % regioselectivity for C5 position. Extensive NMR analysis of Mosher esters and single crystal X-ray structure determination revealed a remarkable diastereoselectivity of this P450 BM3 mutant depending on substrate stereochemistry, which led exclusively to the syn-cembranoid-diols (5S,9S)-4 and (5R,9R)-4.
High-Field FT NMR Application of Mosher's Method. the Absolute Configurations of Marine Terpenoids
Ohtani, Ikuko,Kusumi, Takenori,Kashman, Yoel,Kakisawa, Hiroshi
, p. 4092 - 4096 (2007/10/02)
Mosher's (1H) method to elucidate the absolute configuration of secondary alcohols was reexamined by use of high-Held FT NMR spectroscopy, which enables assignment of most of the protons of complex molecules. There is a systematic arrangement of Δδ (δs - δR) values obtained for the (R)- and (S)-MTPA esters of (-)-menthol, (-)-borneol, cholesterol, and ergosterol, the absolute configurations of which are known. Analysis of the Δδ values of these compounds led to a rule that could predict the absolute configurations of natural products. When this rule was applied to some marine terpenoids including cembranolides and xenicanes, their absolute configurations were assigned and a part of the results were confirmed by X-ray structural analyses. In the case of sipholenol A, which has a sterically hindered OH group, this rule is inapplicable. But the problem is overcome by inverting the OH group to a less sterically hindered position; the resulting epimer gives systematically arranged Δδ values, which enabled the elucidation of the absolute configuration. Comparison of the present method with Mosher's 19F method indicates that the latter one using 19F NMR lacks in reliability.
