[Show abstract][Hide abstract] ABSTRACT: Dynamic reductive kinetic resolutions of racemic 3-arylalkanones have been performed by the proper combination of an alcohol dehydrogenase and a basic anionic resin. The best results were found for the bioreduction with the alcohol dehydrogenase type A from Rhodococcus ruber DSM 44541 overexpressed in Escherichia coli (E. coli/ADH-A) and the commercially available evo-1.1.200, while the Amberlite IRA-440 C and the DOWEX-MWA-1 resins allowed efficient in situ racemizations. Reaction conditions were optimized in terms of enzyme source and loading, type and amount of resin, pH, temperature and reaction times, obtaining a series of (R,R)-substituted propan-2-ols with good conversions and both diastereoselectivity and stereoselectivity. As a proof of concept, the subsequent intramolecular cyclization of a selected propan-2-ol substrate afforded a valuable isochroman heterocycle without any loss of the optical purity.
[Show abstract][Hide abstract] ABSTRACT: A series of γ-butyrolactone derivatives, including some spiranic ones, was obtained through desymmetrization of the corresponding prochiral 3-substituted cyclobutanones via Baeyer-Villiger monooxygenase (BVMO)-catalyzed oxidation. After reaction optimization using several commercial enzymes, both antipodes of various lactones were synthesized in most cases with >90% conversion and >80% enantiomeric excess under mild reaction conditions. In some cases alcohol formation was also observed (up to 40% conversion) as an undesired side reaction due to the presence of alcohol dehydrogenases in these preparations. Selected transformations were achieved on a 100 mg scale showing the possibilities of these oxidative biocatalysts as a new source of highly interesting compounds.
[Show abstract][Hide abstract] ABSTRACT: The preparation of enantiomerically pure pyrrolidine-2-phosphonic acid (phosphoproline, ProP) has been addressed through the synthesis of suitable racemates and subsequent resolution by independent enzyme-catalyzed and chiral HPLC methods. First, racemic phosphoproline derivatives bearing the necessary protecting groups have been synthesized in excellent global yields starting from inexpensive materials. Preparative HPLC resolution of the N-Cbz-protected aminophosphonate on a cellulose-based column allowed the isolation of enantiomerically pure enantiomers on a gram scale. Enzyme-catalyzed alkoxycarbonylation of the aminophosphonate was studied using different lipases, solvents, and carbonates. Candida antarctica lipase type A (CAL-A) provided the highest enantioselectivity when combined with benzyl 3-methoxyphenyl carbonate.
No preview · Article · Dec 2015 · Tetrahedron Asymmetry
[Show abstract][Hide abstract] ABSTRACT: A series of racemic trans-1,2,3,4-tetrahydronaphthalen-2-ols bearing an azole nucleus at the C-1 or C-3 position has been synthesized by ring opening reactions of the corresponding epoxides using imidazole or 1,2,4-triazole. The kinetic resolutions of these racemates were undertaken through transesterification processes, finding good levels of activities and high to excellent enantiodiscrimination values for the Pseudomonas cepacia lipase immobilized on a ceramic carrier. Investigations into the optimum reaction conditions were carried out by consideration of different organic solvents, temperatures, enzyme loadings, and reaction times. With the best conditions in hand, the experiments were later carried out toward the resolution of the related racemic cis-alcohols, which were previously obtained through a Mitsunobu and deprotection chemical sequence from the trans-stereoisomers.
No preview · Article · Jun 2015 · Tetrahedron Asymmetry
[Show abstract][Hide abstract] ABSTRACT: Laccase from Trametes versicolor together with TEMPO has been found as a very efficient system to deprotect N-benzylated primary amines, differing from previously described methods since it uses mild conditions in aqueous medium. Chemoselective removal of the benzyl group was achieved with excellent yields when secondary amine and alcohol moieties were also present
[Show abstract][Hide abstract] ABSTRACT: A versatile and general route has been developed for the asymmetric synthesis of a wide family of 3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazines bearing different pattern substitutions in the aromatic ring. While hydrolases were not suitable for the resolution of these racemic cyclic nitrogenated amines, alternative chemoenzymatic strategies were designed through independent pathways leading to both amine antipodes. On one hand, the bioreduction of 1-(2-nitrophenoxy)propan-2-ones allowed the recovery in high yields of the enantiopure (S)-alcohols using the alcohol dehydrogenase from Rhodococcus ruber (ADH-A), while the evo-1.1.200 ADH led to their counterpart (R)-enantiomers with also complete selectivity and quantitative conversions. Alternatively, lipase-catalyzed acetylation of these racemic alcohols and the complementary hydrolysis of the acetate analogues gave access to the corresponding optically enriched products with high stereodiscrimination. Particularly attractive was the design of a chemoenzymatic strategy in 6 steps for the production of (S)-(-)-7,8-difluoro-3-methyl-3,4-dihydro-2H-benzo-[b][1,4]oxazine, which is a key precursor of the antimicrobial agent Levofloxacin.
No preview · Article · Mar 2015 · The Journal of Organic Chemistry
[Show abstract][Hide abstract] ABSTRACT: A mild one-pot methodology has been developed to deracemise rac-2-phenyl-1-propanol by combining the use of non-selective laccase/TEMPO-mediated oxidation with enantioselective bioreduction of the racemic aldehyde intermediate under dynamic conditions. The process was easily scalable and stereocontrollable by selecting the suitable biocatalyst.
No preview · Article · Feb 2015 · Catalysis Science & Technology
[Show abstract][Hide abstract] ABSTRACT: Horse liver alcohol dehydrogenase (HLADH) has been found to be a versatile biocatalyst for the desymmetrization of prochiral 3-arylpentane-1,5-diols, based on a two-step one-pot oxidation. This procedure has allowed the formation of valuable (S)-lactones in good to excellent conversions and enantiomeric excess. The catalytic performance of HLADH has been studied using several cofactor regeneration systems and cosolvents, finding great improvements in terms of activity with L-lactate dehydrogenase, while the stereoselectivity of the process was significantly improved when using tetrahydrofuran. Docking studies has revealed the pattern substitution importance in the selectivity and activity of this oxidative process.
[Show abstract][Hide abstract] ABSTRACT: A one-pot chemoenzymatic method has been described for the synthesis of γ-butyrolactones starting from the corresponding ketones through a Baeyer-Villiger reaction. The approach is based on a lipase-catalyzed perhydrolysis for the formation of peracetic acid, which is the responsible for the ketone oxidation. Optimization studies have been performed in the oxidation of cyclobutanone, finding Candida antarctica lipase type B, ethyl acetate and urea-hydrogen peroxide complex as the best system. The relative ratio of these reagents has also been analyzed in depth. This synthetic approach has been successfully extended to a family of 3-substituted cyclobutanones in high substrate concentration, yielding the corresponding lactones with excellent isolated yields and purities, under mild reaction conditions and after a simple extraction protocol.
No preview · Article · Sep 2014 · Journal of Molecular Catalysis B Enzymatic
[Show abstract][Hide abstract] ABSTRACT: The synthesis and enzyme-catalyzed desymmetrization of meso-1,2-diaryl-1,2- diaminoethanes have been investigated. A family of aromatic meso-1,2-diamines, containing different substitution patterns in the aromatic ring, was first prepared and then desymmetrized enantioselectively using lipases as biocatalysts. Selective alkoxycarbonylation of one of the amino groups was achieved using allyl carbonates, isolating the corresponding allyl monocarbamates with moderate to high enantiomeric excess at 45 C. Candida antarctica lipase types A (CAL-A) and B (CAL-B) displayed the best activities and stereopreferences, with a dramatic influence being observed depending on the diamine structure. Non substituted and para-substituted aryldiamines led to the formation of allyl carbamates with good enantiomeric excess, using CAL-A for the less hindered substrates and CAL-B for the more hindered ones. On the other hand meta- and ortho-derivatives afforded low or negligible conversions and selectivities, respectively.
No preview · Article · Aug 2014 · Tetrahedron Asymmetry
[Show abstract][Hide abstract] ABSTRACT: The Cover Picture: Straight through the tunnel. Instead of taking the long railway track over the mountains the transaminase-train allows to speed up the asymmetric synthesis of a precursor for the pharmaceutical Ramatroban. Thereby a multi-step synthesis route was reduced to a single step which takes 4 hours instead of previously reported 50 hours giving the amine precursor with >99% ee and 96% isolated yield. The front cover picture was designed by Marba Jos dlvarez and Eduardo Busto. More details can be found in the communication on pages 1937–1942 (E. Busto, R. C. Simon, B. Grischek, V. Gotor-Fernández, W. Kroutil, Adv. Synth. Catal. 2014, 356, 1937–1942; DOI: 10.1002/adsc.201300993).
No preview · Article · Jun 2014 · Advanced Synthesis & Catalysis
[Show abstract][Hide abstract] ABSTRACT: The lipase-catalyzed synthesis of thiamphenicol derivatives has been studied through complementary acylation and hydrolytic approaches, finding Candida antarctica lipase B as the most efficient biocatalyst for the selective modification of both thiamphenicol and thiamphenicol diacetate, respectively. The best results have been obtained using acylation reactions with different vinyl esters of variable length, yielding the corresponding 3'-monoesters with excellent yields and in short reaction times. The conditions have been analyzed in terms of substrate concentration, enzyme loading and type of acyl donor. The reuse of the enzyme for five-times without significant loss of the activity has also been demonstrated. Alternatively, the hydrolytic approach has allowed the preparation of some 1'-monoesters in good yields, although the reactivity and selectivity levels were lower than the ones achieved for the complementary acetylation reaction.
Full-text · Article · Jun 2014 · Journal of the Brazilian Chemical Society
[Show abstract][Hide abstract] ABSTRACT: An efficient methodology to oxidize β,β-dihalogenated secondary alcohols employing oxygen was achieved in a biphasic medium using the laccase from Trametes versicolor/TEMPO pair, providing the corresponding ketones in a clean fashion under very mild conditions. Moreover, a chemoenzymatic protocol has been applied successfully to deracemize 2,2-dichloro-1-phenylethanol combining this oxidation with an alcohol dehydrogenase-catalyzed bioreduction.
[Show abstract][Hide abstract] ABSTRACT: Alcohol dehydrogenases (ADHs) are applied in industrial synthetic chemistry for the production of optically active secondary alcohols. However, the substrate spectrum of many ADHs is narrow, and few, for example, are suitable for the reduction of prochiral ketones in which the carbonyl group is bounded by two bulky and/or hydrophobic groups; so-called ‘bulky–bulky’ ketones. Recently two ADHs, RasADH from Ralstonia sp. DSM 6428, and SyADH from Sphingobium yanoikuyae DSM 6900, have been described, which are distinguished by their ability to accept bulky–bulky ketones as substrates. In order to examine the molecular basis of the recognition of these substrates the structures of the native and NADPH complex of RasADH, and the NADPH complex of SyADH have been determined and refined to resolutions of 1.5, 2.9 and 2.5 Å, respectively. The structures reveal hydrophobic active site tunnels near the surface of the enzymes that are well-suited to the recognition of large hydrophobic substrates, as determined by modelling of the bulky–bulky substrate n-pentyl phenyl ketone. The structures also reveal the bases for NADPH specificity and (S)-stereoselectivity in each of the biocatalysts for n-pentyl phenyl ketone and related substrates.
No preview · Article · Mar 2014 · Topics in Catalysis
[Show abstract][Hide abstract] ABSTRACT: A chemoenzymatic and selective method for the epoxidation of a series of cyclic and linear alkenes is described. Epoxides have been obtained in moderate to excellent conversions under mild reaction conditions through a two-step sequence, carried out in one-pot. This chemoenzymatic approach is based on a Rhizomucor miehei lipase-catalyzed perhydrolysis reaction to form the corresponding peracid, and subsequent epoxidation of the corresponding alkenes. Reaction parameters with influence in the biotransformation have been optimized specially focusing in the efficient enzymatic peracid formation by means of the correct choice of solvent, oxidant, and peracid precursor. This chemoenzymatic approach has been efficiently applied for the first time, in the regioselective chemical oxidation of (S)-carvone and limonene, both showing an opposite behavior for the oxidation of the internal and external C–C double bond, respectively.
[Show abstract][Hide abstract] ABSTRACT: Critical parameters affecting the stereoselective amination of (hetero)aromatic ketones using transaminases have been studied, such as temperature, pH, substrate concentration, cosolvent, and source and percentage of amino donor, to further optimize the production of enantiopure amines using both (S)- and (R)-selective biocatalysts from commercial suppliers. Interesting enantiopure amino building blocks have been obtained, overcoming some limitations of traditional chemical synthetic methods. Representative processes were scaled up, affording halogenated and heteroaromatic amines in enantiomerically pure form and good isolated yields.
No preview · Article · Dec 2013 · Organic Process Research & Development