12 research outputs found
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
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
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%)
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%)
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
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
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
Dynamic Kinetic Resolution of 1,3-Dihydro-2<i>H</i>-isoindole-1-carboxylic Acid Methyl Ester: Asymmetric Transformations toward Isoindoline Carbamates
Asymmetric syntheses of isoindoline carbamates have been successfully achieved through enzyme-mediated dynamic kinetic resolution processes and without requirement of metal or acid–base catalyst for the substrate racemization. Optically active carbamates were obtained in good yields and an excellent degree of stereoselectivity when <i>Pseudomonas cepacia</i> lipase (PSL) was used as biocatalyst, with diallyl or dibenzyl carbonates being both adequate reagents in alkoxycarbonylation reactions
Dynamic Kinetic Resolution of 1,3-Dihydro-2<i>H</i>-isoindole-1-carboxylic Acid Methyl Ester: Asymmetric Transformations toward Isoindoline Carbamates
Asymmetric syntheses of isoindoline carbamates have been successfully achieved through enzyme-mediated dynamic kinetic resolution processes and without requirement of metal or acid–base catalyst for the substrate racemization. Optically active carbamates were obtained in good yields and an excellent degree of stereoselectivity when <i>Pseudomonas cepacia</i> lipase (PSL) was used as biocatalyst, with diallyl or dibenzyl carbonates being both adequate reagents in alkoxycarbonylation reactions
Stereoselective Chemoenzymatic Synthesis of Enantiopure 2‑(1<i>H</i>‑imidazol-yl)cycloalkanols under Continuous Flow Conditions
The development of continuous flow processes for the
synthesis
of chiral enantiopure 1-(2-hydroxycycloalkyl)imidazoles is reported.
For the ring-opening reaction microwave batch processes and continuous
flow reactions have led to similar results in terms of conversion,
although the productivity is clearly improved under flow. The use
of continuous flow systems for the lipase-catalyzed kinetic resolution
of the racemic 2-(1<i>H</i>-imidazol-yl)cycloalkanols with
either immobilized CAL-B or PSL-C has been demonstrated to be significantly
more efficient than the corresponding batch processes. The continuous
flow biotransformations have allowed us to easily increase the production
of these chiral imidazoles, adequate building blocks in the synthesis
of chiral ionic liquids