Highly efficient asymmetric bioreduction of 1-aryl-2-(azaaryl)ethanones. Chemoenzymatic synthesis of lanicemine.

Different ketoreductases (KREDs) have been used to promote a highly selective reduction of several 1-aryl-2-(azaaryl)ethanones (azaaryl = pyridinyl, quinolin-2-yl), the corresponding secondary alcohols being obtained with very high yields and enantiomeric excesses (ee > 99%). The absolute configuration of each optically active alcohol has been assigned by means of modified Mosher and Kelly methods, two shielding effects being evaluated: (1) the Mosher phenyl ring effect on the azaaryl protons and (2) the one of the azaaryl ring on the Mosher methoxy group. In addition, the biologically active amine lanicemine has been synthesized from (R)-1-phenyl-2-(pyridin-2-yl)ethanol, thus proving the utility of the secondary alcohols here prepared.

Chemoenzymatic synthesis of optically active phenolic 3,4-dihydropyridin-2-ones: a way to access enantioenriched 1,4-dihydropyridine and benzodiazepine derivatives.

A chemoenzymatic approach for the synthesis of optically active 4-(3-acetoxyphenyl)-5-(alkoxycarbonyl)-6-methyl-3,4-dihydropyridin-2-ones (3,4-DHP-2-ones) and their hydroxyphenyl derivatives has been developed, the key step being a Candida rugosa lipase (CRL)-catalyzed hydrolysis reaction. As a result, different optically active 3,4-DHP-2-ones have been prepared with very high enantiomeric excesses (ee = 94-99%) and good yields. The enantioenriched 3,4-DHP-2-ones have easily been converted into highly functionalized (R)- and (S)-1,4-dihydropyridines (1,4-DHPs) by means of a Vilsmeier-Haack reaction. Finally, the coupling of the 1,4-DHPs with benzene-1,2-diamine using TFA as an acid promoter provided us the corresponding optically active hybrid 1,5-benzodiazepine-1,4-dihydropyridine (BZD-DHP) derivatives. No racemization took place in these processes and all optically active compounds were obtained in excellent yields.

Enantioselective bacterial hydrolysis of amido esters and diamides derived from (±)-trans-cyclopropane-1,2-dicarboxylic acid.

Different optically active amido esters, mixed acid esters, amido acids, and diamides derived from trans-cyclopropane-1,2-dicarboxylic acid were prepared from the commercially available diethyl (±)-trans-cyclopropane-1,2-dicarboxylate. The key step was the Rhodococcus rhodochrous IFO 15564 catalyzed hydrolysis of the corresponding racemic amide. The amidase present in this microorganism showed moderate to high enantioselectivity towards these substrates. In addition a simple and efficient Curtius rearrangement of some of the enzymatically prepared cyclopropanecarboxylic acids allowed us to obtain optically active ß-aminocyclopropanecarboxylic acid derivatives with high yields and enantiomeric excesses.

Regioselective enzymatic acylation of complex natural products: expanding molecular diversity.

Enzymatic catalysis has become a common tool in both academia and industrial chemistry. The efforts of chemists over recent decades have led to the rationalization of the mechanism of action of biocatalysts, which have been routinely incorporated into many synthetic sequences. Nowadays, a further step consists in expanding the application of enzymes to the modification of complex molecular scaffolds common to many pharmaceutical leads isolated from nature. Regioselective enzymatic acylation is a process which has been profitably applied for this purpose in recent times, leading to new drugs with improved activity, stability and pharmacokinetic properties. This tutorial review provides an overview of this subject employing two classes of enzymes, hydrolases and acyltransferases, in the recently concluded decade although some representative older studies are commented upon, if required. We shall place special emphasis on those examples in which the novel acylated derivatives have improved the activity or properties of the parental molecules.

Straightforward preparation of biologically active 1-aryl- and 1-heteroarylpropan-2-amines in enantioenriched form.

Because of the importance of developing stereoselective syntheses for single enantiomers, a selected panel of racemic biologically active 1-aryl- and 1-heteroarylpropan-2-amines has been prepared, followed by a study of their behavior in enzymatic kinetic resolution (KR) processes. For this purpose, lipase B from Candida antarctica (CAL-B) proved to be an ideal biocatalyst allowing the preparation of the corresponding enantioenriched (R)-amides and (S)-amines by aminolysis reactions. Likewise, dynamic kinetic resolutions (DKR) have been successfully achieved combining the use of CAL-B and Shvo's catalyst. This research constitutes the first example of a lipase-catalyzed DKR process of ß-substituted isopropylamines.

Developing a Biocascade Process: Concurrent Ketone Reduction-Nitrile Hydrolysis of 2-Oxocycloalkanecarbonitriles.

A stereoselective bioreduction of 2-oxocycloalkanecarbonitriles was concurrently coupled to a whole cell-catalyzed nitrile hydrolysis in one-pot. The first step, mediated by ketoreductases, involved a dynamic reductive kinetic resolution, which led to 2-hydroxycycloalkanenitriles in very high enantio- and diastereomeric ratios. Then, the simultaneous exposure to nitrile hydratase and amidase from whole cells of Rhodococcus rhodochrous provided the corresponding 2-hydroxycycloalkanecarboxylic acids with excellent overall yield and optical purity for the all-enzymatic cascade.

Candida antarctica Lipase-Catalyzed Doubly Enantioselective Aminolysis Reactions. Chemoenzymatic Synthesis of 3-Hydroxypyrrolidines and 4-(Silyloxy)-2-oxopyrrolidines with Two Stereogenic Centers.

Aminolyses of racemic and prochiral 3-hydroxyesters with racemic amines are effectively catalyzed by Candida antarctica lipase. In these processes, the simultaneous resolution of the ester and the amine, or the corresponding asymmetrization-resolution, takes place. In all cases, the high enantioselectivity shown by the lipase toward all the reactants allows the preparation of enantiopure 3-hydroxyamides with very high diastereomeric ratios. These 3-hydroxyamides are used as starting materials in the synthesis of 3-hydroxy- and 2-oxopyrrolidines, both containing two stereogenic centers in their structures.

Enzymatic dynamic kinetic resolution of (+/-)-cis-N-(alkoxycarbonyl)cyclopentane-1,2-diamines based on spontaneous racemization.

Lipase B from Candida antarctica is an excellent catalyst for the enantioselective acetylation of different (+/-)-cis-N-(alkoxycarbonyl)cyclopentane-1,2-diamines. Depending on the alkoxycarbonyl group, a simple kinetic resolution (Boc-derivative) or an interesting dynamic kinetic resolution (DKR with Cbz-, Alloc, and ethoxycarbonyl derivatives) has been developed. Racemization for the DKR occurred due to the N,N' intramolecular migration of the alkoxycarbonyl group.

trans-cyclopentane-1,2-diamine: the second youth of the forgotten diamine.

Despite its early description, trans-cyclopentane-1,2-diamine has been underestimated historically. Its non-commercial availability, extreme instability and complexity of the classical reported syntheses have produced far less interest amongst chemists than its higher homologue trans-cyclohexane-1,2-diamine, perhaps the most widely used diamine for the synthesis of ligands and receptors. However, the recent development of novel and efficient synthetic approaches has stimulated renewed interest in this chiral motif for a broad range of applications. In the first part of this tutorial review we shall discuss the existing methods for the preparation of trans-cyclopentane-1,2-diamine and some of its derivatives, in both racemic and enantioenriched forms. In subsequent sections, recent findings employing this diamine as a scaffold for chiral ligands, receptors and biologically active compounds will be highlighted.

A biocatalytic approach to synthesizing optically active orthogonally protected trans-cyclopentane-1,2-diamine derivatives.

A straightforward chemoenzymatic synthesis of optically active trans-N,N-dialkylcyclopentane-1,2-diamines has been efficiently developed starting out from their analogous (+/-)-trans-2-(N,N-dialkylamino)cyclopentanols. The route involves the one-pot stereospecific transformation of the racemic amino alcohols into racemic diamines and a subsequent kinetic resolution by means of lipase-B from Candida antarctica-catalyzed acylation reactions. The careful selection of both the alkyl substituents present in the diamine and the derivatization strategy applied to the enzymatic reaction enabled the easy preparation of other synthetically valuable optically active trans-cyclopentane-1,2-diamines derivatives.

Optically active trans-2-aminocyclopentanols: chemoenzymatic preparation and application as chiral ligands.

Optically active trans-2-(N,N-dialkylamino)cyclopentanols and their acetates derivatives were obtained with very good chemical yields and enantiomeric excesses (95->/=99%), through a chemoenzymatic methodology based on the lipase-catalyzed acylation of the hydroxyl group. The utility of these compounds was shown by the preparation of the cyclopentylic analog of vesamicol and by their use as ligands in the enantioselective addition of diethylzinc to benzaldehyde.

Chemoenzymatic preparation of optically active trans-cyclohexane-1,2-diamine derivatives: an efficient synthesis of the analgesic U-(-)-50,488.

Stereoespecific syntheses of (+/-)-trans-N,N-cyclohexane-1,2-diamines ((+/-)-4 a-g) were carried out from the corresponding (+/-)-trans-N,N-dialkylaminocyclohexanols by successive treatment with mesyl chloride and aqueous ammonia. The stereochemical outcome indicates the formation of a meso-aziridinium ion intermediate. Kinetic resolutions of diamines (+/-)-4 were efficiently accomplished in aminolysis reactions catalyzed by lipase B from Candida antarctica with ethyl acetate as the solvent and acyl donor. Acetamides and the remaining diamines, isolated as the benzyloxycarbonyl derivatives, were obtained with very high ee values (92-99%). One of the carbamates was used as a precursor of the analgesic U-(-)-50,488.