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Lipase-Catalyzed Kinetic Resolution of Dimethyl and Dibutyl 1-Butyryloxy-1-Carboxymethylphosphonates

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Lipase-Catalyzed Kinetic Resolution of Dimethyl and Dibutyl 1-Butyryloxy-1-Carboxymethylphosphonates catalysts Article Lipase-Catalyzed Kinetic Resolution of Dimethyl and Dibutyl 1-Butyryloxy-1-carboxymethylphosphonates Paulina Majewska Laboratory of Biotechnology, Department of Biochemistry, Molecular Biology and Biotechnology, Faculty of Chemistry, Wrocław University of Science and Technology, Wybrzeze˙ Wyspia´nskiego27, 50-370 Wrocław, Poland; [email protected]; Tel.: +48-71-320-4614 Abstract: The main objective of this study is the enantioselective synthesis of carboxyhydroxyphos- phonates by lipase-catalyzed reactions. For this purpose, racemic dimethyl and dibutyl 1-butyryloxy- 1-carboxymethylphosphonates were synthesized and hydrolyzed, using a wide spectrum of commer- cially available lipases from different sources (e.g., fungi and bacteria). The best hydrolysis results of dimethyl 1-butyryloxy-1-carboxymethylphosphonate were obtained with the use of lipases from Candida rugosa, Candida antarctica, and Aspergillus niger, leading to optically active dimethyl 1-carboxy- 1-hydroxymethylphosphonate (58%–98% enantiomeric excess) with high enantiomeric ratio (reaching up to 126). However, in the case of hydrolysis of dibutyl 1-butyryloxy-1-carboxymethylphosphonate, the best results were obtained by lipases from Burkholderia cepacia and Termomyces lanuginosus, leading to optically active dibutyl 1-carboxy-1-hydroxymethylphosphonate (66%–68% enantiomeric excess) with moderate enantiomeric ratio (reaching up to 8.6). The absolute configuration of the products after biotransformation was also determined. In most cases, lipases hydrolyzed (R) enantiomers of both compounds. Keywords: biocatalysis; hydroxyphosphonates; lipolytic activity; determination of absolute configu- Citation: Majewska, P. Lipase- ration; enantiomers Catalyzed Kinetic Resolution of Dimethyl and Dibutyl 1-Butyryloxy-1- carboxymethylphosphonates. Catalysts 2021, 11, 956. https:// 1. Introduction doi.org/10.3390/catal11080956 Enantioselective biocatalysis has long been used as an alternative to traditional meth- ods for obtaining pure chemical isomers [1]. It has been used in many industrial fields; Academic Editor: Takeshi Sugai in particular, the use of whole-cell biocatalysts and enzymes has become common in pro- ducing enantiomeric active drugs [2–5]. This is due to the associated highly regioselective Received: 15 July 2021 and enantioselective reactions, carried out mainly in water under mild conditions [6]. Accepted: 9 August 2021 Published: 10 August 2021 Biotransformations are applied to obtain enantiopure compounds by enantioselective reactions, such as deracemization, desymmetrization, or asymmetric synthesis [7,8]. Hy- Publisher’s Note: MDPI stays neutral droxyphosphonates are among the countless different classes of compounds obtained by with regard to jurisdictional claims in enantioselective biocatalysis [9,10]. These compounds have a wide range of biological published maps and institutional affil- properties, serving as antibacterial, antiviral, and anticancer agents, as well as enzyme iations. inhibitors or pesticides; they can also be used as precursors of other biologically active compounds [11–14]. Their bioavailability depends on their three-dimensional structure; therefore, obtaining them as enantiopure isomers with a specific absolute configuration is crucial for therapeutic effectiveness and drug safety [15]. Similar compounds, diethyl 1-carboxy-1-hydroxymethylphosphonate and its ester Copyright: © 2021 by the author. Licensee MDPI, Basel, Switzerland. were previously synthesized, and enantioselective kinetic resolution of diethyl 1-carboxy-1- This article is an open access article hydroxyphosphonate was investigated [16]. Dimethyl, dibutyl and diisopropyl 1-carboxy- distributed under the terms and 1-hydroxymethylphosphonates were also previously synthesized as intermediates of the conditions of the Creative Commons synthesis to obtain dioxolanone-substituted dialkyl phosphonates, and their spectroscopic Attribution (CC BY) license (https:// data were not determined [17]. creativecommons.org/licenses/by/ The aim of this study was to synthesize two—as yet unexploited—1-carboxy-1- 4.0/). hydroxymethylphosphonates, obtaining them with good enantiomeric excesses. For this Catalysts 2021, 11, 956. https://doi.org/10.3390/catal11080956 https://www.mdpi.com/journal/catalysts Catalysts 2021, 11, x FOR PEER REVIEW 2 of 11 The aim of this study was to synthesize two—as yet unexploited—1-carboxy-1-hy- Catalysts 2021, 11, 956 droxymethylphosphonates, obtaining them with good enantiomeric excesses. For2 ofthis 10 purpose, biocatalytic hydrolysis by lipases was carried out. Despite the fact that the bio- logical activity of carboxyhydroxyphosphonates is unknown, pure enantiomers of these compounds may be used as chiral auxiliaries, useful in 31P NMR spectroscopy to deter- minepurpose, the biocatalyticenantiomeric hydrolysis purity and by lipasesabsolute was configuration carried out. of Despite different the factclasses that of the com- bio- poundslogical activity [18]. Moreover, of carboxyhydroxyphosphonates they can be used as precursors is unknown, of aminophosphonates pure enantiomers [12], of these due compounds may be used as chiral auxiliaries, useful in 31P NMR spectroscopy to determine to the fact that many of aminophosphonic acids are biologically active [19]. Dimethyl 1- the enantiomeric purity and absolute configuration of different classes of compounds [18]. carboxy-1-hydroxymethylphosphonate can be transformed to its (4-nitrophenyl)methyl Moreover, they can be used as precursors of aminophosphonates [12], due to the fact ester, which can be used in the synthesis of 2-substitued-3-carboxy carbapenem antibiotics that many of aminophosphonic acids are biologically active [19]. Dimethyl 1-carboxy-1- [20]. hydroxymethylphosphonate can be transformed to its (4-nitrophenyl)methyl ester, which can be used in the synthesis of 2-substitued-3-carboxy carbapenem antibiotics [20]. 2. Results 2.1.2. Results Synthesis of Enzymatic Hydrolysis Substrates 2.1. SynthesisRacemic ofdimethyl Enzymatic 1-carboxy- Hydrolysis1-hydroxymethylphosphonate Substrates 1a and dibutyl 1-car- boxy-1-hydroxymethylphosphonateRacemic dimethyl 1-carboxy-1-hydroxymethylphosphonate 1b were obtained by the1a and addition dibutyl 1-carboxy-of dime- thylphosphite1-hydroxymethylphosphonate or dibutylphosphite1b were to glyoxylic obtained byacid the with addition isolated of dimethylphosphiteyield reaching up orto 98.1%dibutylphosphite for compound to glyoxylic 1a and 82.3% acid with for compound isolated yield 1b reaching. Afterwards, up to dimethyl 98.1% for 1-butyryloxy- compound 1a 1-carboxymethylphosphonateand 82.3% for compound 1b. Afterwards, 2a and dibutyl dimethyl 1-butyryloxy-1-carboxymethylphosphonate 1-butyryloxy-1-carboxymethylphosphonate 2b2a andwere dibutyl obtained 1-butyryloxy-1-carboxymethylphosphonate by simple acylation of compounds 1 with2b butyrylwere obtained chloride by (see simple Scheme acy- 1)lation with of moderate compounds yield1 with reaching butyryl up chloride26.4% and (see 32.8% Scheme for1 )compounds with moderate 2a and yield 2b reaching, respec- tively.up 26.4% and 32.8% for compounds 2a and 2b, respectively. O O Cl O O O O O O O R P R P O NEt3 R P O O OH O H + OH O OH R O CH Cl R H R OH 3 O 1: a R = CH3 2: a R = CH3 b R = C H b R = C H 4 9 4 9 Scheme 1.1. SynthesisSynthesis ofof 1-carboxy-1-hydroxymethylphosphonates1-carboxy-1-hydroxymethylphosphonates 11 andand 1-butyryloxy-1-carboxy- 1-butyryloxy-1-carbox- ymethylphosphonatesmethylphosphonates 2 .2. 2.2. Enzymatic Enzymatic Hydrolysis Compounds 22 werewere hydrolyzed hydrolyzed by by different different lipases, lipases, in order in order to obtain to obtain optically optically pure hydroxyphosphonatespure hydroxyphosphonates 1 (Scheme1 (Scheme 2 and Figure2 and 1). Figure It was1). only It was possible only to possible obtain compound to obtain 1a Candida rugosa 1acompound with an ee with> 98% an when ee > 98%using when a lipase using from a lipase Candida from rugosa (Table 1).(Table Satisfying1). Satisfying results results were obtained during the hydrolysis of butyryloxyphosphonate 2a using Candida were obtained during the hydrolysis of butyryloxyphosphonate 2a using Candida antarc- antarctica and Aspergillus niger lipases (enantioselectivities of 6.3 and 5.4, respectively). tica and Aspergillus niger lipases (enantioselectivities of 6.3 and 5.4, respectively). Hydrox- Hydroxyphosphonate 1b was obtained with moderate enantioselectivity when using yphosphonate 1b was obtained with moderate enantioselectivity when using Burkholderia Burkholderia cepacia and Termomyces lanuginosus lipases (enantioselectivities of 8.6 and 6.8, cepacia and Termomyces lanuginosus lipases (enantioselectivities of 8.6 and 6.8, respectively; respectively; Table2). As can be observed, only Aspergillus niger lipase hydrolyzed fairly Table 2). As can be observed, only Aspergillus niger lipase hydrolyzed fairly well both sub- well both substrates, and only compound 2b was hydrolyzed by all tested enzymes. strates, and only compound 2b was hydrolyzed by all tested enzymes. Table 1. Lipase-catalyzed hydrolysis of dimethyl 1-butyryloxy-1-carboxymethylphosphonate 2a. Lipase Time [h] Conversion [%] ee of Product (R) ee of Substrate (S)E CRL 168 12 >98 25 126 CAL 24 24 68 20 6.3 ANL 168 28 58 36 5.4 PCL 168 <10 - - - SchemePFL 2. Biocatalytic 168 hydrolysis of <10 compounds 2. - - - BCL 168 <10 - - - MRL 168 <10 - - - RNL 168 <10 - - - MJL 168 <10 - - - RML 168 <10 - - - PPL 168 <10 - - - N435 168 <10 - - - ROL
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