Abstract
Flavan-4-ols are a subclass of flavonoids that are present in complex molecules with application in the industrial sector as pigments, antioxidants, or antimitotics, among many others. The most traditional way to achieve their synthesis is from naturally abundant flavanones, asymmetric transfer hydrogenation reactions or bioreduction being well known strategies, while their preparation from racemic flavan-4-ols has been less explored. In this article, we have focused on the synthesis of a series of trans-flavan-4-ols bearing different substitution patterns in the aromatic ring to explore later the potential of lipases as biocatalysts for stereoselective acylation reactions. Therefore, a series of flavanones have been chemically prepared, starting from the corresponding benzaldehydes by aldol condensation with 2′-hydroxyacetophenone in a strongly basic medium, and later transformed into the corresponding racemic trans-flavan-4-ols following a carbonyl reduction, Mitsunobu reaction, and ester deprotection sequence. A screening of lipases and optimization of the reaction conditions for the stereoselective acylation of racemic 2-phenylchroman-4-ol were performed before expanding the best reaction conditions to the kinetic resolution of other 2-arylchroman-4-ols. Interestingly, the combination of AK lipase from Pseudomonas fluorescens as enzyme and vinyl acetate as both acyl donor and solvent allowed the performance of highly asymmetric transformations (E > 200, 50–99% eeS and >99% eeP) under mild reaction conditions (30 °C and 250 rpm).
Highlights
Flavan-4-ols, known as 2-arylchroman-4-ols or 3-deoxyflavoids, are privileged structures in flavonoid chemistry [1], since their structural cores are present in many biologically active compounds with interesting properties as anticarcinogenic, antidiabetic, antioxidant, antimitotic, and biocidal agents [2,3]
Flavanone 1a was selected as aselected commercial starting material for the for synthesis of of tran the depicted strategy depicted in 2, Scheme which involves the r trans-flavan-4-olflavan-4-ol followingfollowing the strategy in Scheme which2,involves the duction in the carbonyl group of ketone
Regarding the enzymes employed in this contribution, Pseudomonas cepacia (PSL, 23,000 U/g), lyophilized lipase AK from Pseudomonas fluorescens (AK, 23,700 U/g), and Acylase from Aspergillus melleus (>0.5 U/g) were purchased from Sigma-Aldrich (Steinheim, Germany), Candida antarctica type A lipase (CAL-A) was obtained from ChiralVision (3000 U/g, Den Hoorn, Netherlands), while Candida antartica type B lipase (CAL-B, Novozym-435, 7300 PLU/g) and Rhizomucor miehei lipase (RML, 150 IUN/g) were kindly donated by Novozymes company (Bagsværd, Denmark)
Summary
Flavan-4-ols, known as 2-arylchroman-4-ols or 3-deoxyflavoids, are privileged structures in flavonoid chemistry [1], since their structural cores are present in many biologically active compounds with interesting properties as anticarcinogenic, antidiabetic, antioxidant, antimitotic, and biocidal agents [2,3]. The most straightforward approaches to produce racemic flavan-4-ols consist of reductions in flavanones and flavones, selectively leading to the corresponding cis-isomers as major products. Janeczko and co-workers described the synthesis of racemic trans-flavan-4-ol from its cis-isomer through a bimolecular nucleophilic substitution by alcohol activation with
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