Asymmetric Chemoenzymatic Synthesis of Ramatroban Using Lipases and Oxidoreductases

A chemoenzymatic asymmetric route for the preparation of enantiopure (<i>R</i>)-ramatroban has been developed for the first time. The action of lipases and oxidoreductases has been independently studied, and both were found as excellent biocatalysts for the production of adequate chiral intermediates under very mild reaction conditions. CAL-B efficiently catalyzed the resolution of (±)-2,3,4,9-tetrahydro-1<i>H</i>-carbazol-3-ol that was acylated with high stereocontrol. On the other hand, ADH-A mediated bioreduction of 4,9-dihydro-1<i>H</i>-carbazol-3­(2<i>H</i>)-one provided an alternative access to the same enantiopure alcohol previously obtained through lipase-catalyzed resolution, a useful synthetic building block in the synthesis of ramatroban. Inversion of the absolute configuration of (<i>S</i>)-2,3,4,9-tetrahydro-1<i>H</i>-carbazol-3-ol has been identified as a key point in the synthetic route, optimizing this process to avoid racemization of the azide intermediate, finally yielding (<i>R</i>)-ramatroban in enantiopure form by the formation of the corresponding amine and the convenient functionalization of both exocyclic and indole nitrogen atoms

One-Pot, Two-Module Three-Step Cascade To Transform Phenol Derivatives to Enantiomerically Pure (<i>R</i>)- or (<i>S</i>)‑<i>p</i>‑Hydroxyphenyl Lactic Acids

Readily available phenol derivatives were substituted in <i>para</i>-position via a C–C bond formation to give enantiomerically pure (<i>R</i>)- or (<i>S</i>)-3-(<i>para</i>-hydroxyphenyl) lactic acids. The transformation was achieved by designing a biocatalytic cascade consisting of three linear steps, namely, (i) the C–C coupling of the phenol and pyruvate in the presence of ammonia to afford the corresponding l-tyrosine derivative, followed by (ii) oxidative deamination and (iii) enantioselective reduction. Compatibility analysis showed that the reaction rate of the first step is slowed in the presence of the product of the third step; consequently, the three-step cascade was subdivided in two modules (module 1 = step 1; module 2 = steps 2 and 3), which were run in one pot sequentially. Because of the exquisite selectivity achieved in the C–C coupling step, <i>para</i>-isomers were obtained exclusively. By choosing the appropriate alcohol dehydrogenase, the (<i>R</i>)- as well as the (<i>S</i>)-isomer were isolated in enantiopure form. Preparative transformations of 2-, 3-, and 2,3-disubstituted phenols (23–96 mM) afforded the corresponding (<i>R</i>)- and (<i>S</i>)-<i>para</i>-hydroxyphenyl lactic acids in high yield (58%–85%) and enantiopure form (<i>ee</i> > 97%)

Highly Stereoselective Chemoenzymatic Synthesis of the 3<i>H</i>-Isobenzofuran Skeleton. Access to Enantiopure 3-Methylphthalides

A straightforward synthesis of (<i>S</i>)-3-methylphthalides has been developed, with the key asymmetric step being the bioreduction of 2-acetylbenzonitriles. Enzymatic processes have been found to be highly dependent on the pH value, with acidic conditions being required to avoid undesired side reactions. Baker’s yeast was found to be the best biocatalyst acting in a highly stereoselective fashion. The simple treatment of the reaction crudes with aqueous HCl has provided access to enantiopure (<i>S</i>)-3-methylphthalides in moderate to excellent yields

Chemoenzymatic Asymmetric Synthesis of 1,4-Benzoxazine Derivatives: Application in the Synthesis of a Levofloxacin Precursor

A versatile and general route has been developed for the asymmetric synthesis of a wide family of 3-methyl-3,4-dihydro-2<i>H</i>-benzo­[<i>b</i>]­[1,4]­oxazines bearing different pattern substitutions in the aromatic ring. Whereas hydrolases were not suitable for resolution of these racemic cyclic nitrogenated amines, alternative chemoenzymatic strategies were designed through independent pathways leading to both amine antipodes. On one hand, bioreduction of 1-(2-nitrophenoxy)­propan-2-ones allowed the recovery of the enantiopure (<i>S</i>)-alcohols in high yields using the alcohol dehydrogenase from <i>Rhodococcus ruber</i> (ADH-A), whereas evo-1.1.200 ADH led to their counterpart (<i>R</i>)-enantiomers also with complete selectivity and quantitative conversion. 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 six steps for the production of (<i>S</i>)-(−)-7,8-difluoro-3-methyl-3,4-dihydro-2<i>H</i>-benzo-[<i>b</i>]­[1,4]­oxazine, which is a key precursor of the antimicrobial agent Levofloxacin

One-Pot Synthesis of Enantiopure 3,4-Dihydroisocoumarins through Dynamic Reductive Kinetic Resolution Processes

A straightforward chemoenzymatic synthesis of enantiopure 4-alkyl-3-methyl-3,4-dihydroisocoumarins through a ketoreductase-catalyzed one-pot dynamic reductive kinetic resolution is reported. <i>E. coli</i>/ADH-A cells have shown outstanding diastereo- and enantioselectivity toward the bioreduction of a series of racemic ketones, with the use of anion exchange resins or triethylamine being compatible in the same aqueous reaction medium. The so-obtained enantiopure alcohols were subsequently cyclized in acid media affording the corresponding lactones in good to excellent conversions (72–96%) and excellent selectivities (dr ≥99:1 and ee >99%)

Stereoselective Synthesis of 2,3-Disubstituted Indoline Diastereoisomers by Chemoenzymatic Processes

Racemic indolines including a variety of structural motifs such as C-2 and C-3 substitutions (alkyl or aryl), <i>cis</i>/<i>trans</i> relative stereochemistry and functionalization of the aromatic ring (fluoro, methyl or methoxy groups) have been efficiently prepared through Fischer indolization and subsequent diastereoselective reduction of the unprotected indoles. Combination of <i>Candida antarctica</i> lipase type A and allyl 3-methoxyphenyl carbonate has been identified as the best tandem for their kinetic resolutions, observing excellent stereodiscriminations for most of the tested indolines

One-Pot Synthesis of Enantiopure 3,4-Dihydroisocoumarins through Dynamic Reductive Kinetic Resolution Processes

A straightforward chemoenzymatic synthesis of enantiopure 4-alkyl-3-methyl-3,4-dihydroisocoumarins through a ketoreductase-catalyzed one-pot dynamic reductive kinetic resolution is reported. <i>E. coli</i>/ADH-A cells have shown outstanding diastereo- and enantioselectivity toward the bioreduction of a series of racemic ketones, with the use of anion exchange resins or triethylamine being compatible in the same aqueous reaction medium. The so-obtained enantiopure alcohols were subsequently cyclized in acid media affording the corresponding lactones in good to excellent conversions (72–96%) and excellent selectivities (dr ≥99:1 and ee >99%)

Biocatalytic Transamination for the Asymmetric Synthesis of Pyridylalkylamines. Structural and Activity Features in the Reactivity of Transaminases

A set of transaminases has been investigated for the biocatalytic amination of 1-(4-chloropyridin-2-yl)­alkan-1-ones. The influence of the chain length of the <i>n</i>-1-alkanone at the C-2 position of the pyridine has been studied in the reaction with different (<i>R</i>)- and (<i>S</i>)-selective transaminases. Thus, enantiopure amines were isolated with high purity starting from a wide selection of prochiral ketones. On the one hand, excellent yields (from 97 to >99% conversion, up to 93% isolated yield) and stereoselectivity values (>99% ee for both amine enantiomers) were found for <i>n</i>-1-alkanone linear short chain substituents such as ethanone or propanone. On the other hand, more hindered substrates were accepted only when using evolved enzymes such as an evolved variant of (<i>R</i>)-<i>Arthrobacter</i> (ArRmut11-TA). An initial common structural feature was the presence of a chlorine atom on the C-4 position of the pyridine core, which was found to increase the reactivity of the starting ketone, giving extra versatility for the introduction of other chemical functionalities toward more complex and applicable organic molecules. In order to gain a deeper understanding about the substrate specificity of different transaminases, additional structural features were considered by variation of the acetyl group position on the pyridine ring and the use of related acetophenone derivatives

Versatile Synthesis of Polyfunctionalized Carbazoles from (3-Iodoindol-2-yl)butynols via a Gold-Catalyzed Intramolecular Iodine-Transfer Reaction

The controlled gold-catalyzed preparation of 3-iodo 2,4,6-trisubstituted 9<i>H</i>-carbazoles has been developed by starting from (3-iodoindol-2-yl)­butynols. These results could be explained through an initial 6-<i>endo</i>-dig alkyne carbocyclization by chemo- and regiospecific attack of the C3-indole position at the external alkyne carbon followed by a stepwise 1,3-iodine transfer and dehydration. This reaction outcome for the gold-catalyzed transformation of (3-iodoindol-2-yl)­alkynols sharply contrasts with that observed for conventional metal-catalyzed processes of iodoarenes, because iodine transfer is feasible. This selective reaction has been studied experimentally; additionally, its mechanism has been investigated by means of density functional theory calculations

Transaminases Applied to the Synthesis of High Added-Value Enantiopure Amines

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 (<i>S</i>)- and (<i>R</i>)-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