Eduardo García‐Urdiales

Asymmetric Organic Synthesis with Enzymes

METHODOLOGY Medium Engineering: Directed evolution: The search for new enzymes: SYNTHETIC APPLICATIONS Dynamic Kinetic Resolutions: Deracemization and Enantioconvergent Processes: Transesterification and hydrolysis of carboxylic acid derivatives, alcohols and epoxides Aminolysis and ammonolysis of carboxylic acid derivatives: Reduction Reactions: Oxidation Reactions: Making and breaking C-C bonds:

Update 1 of: Enantioselective Enzymatic Desymmetrizations in Organic Synthesis

Update 1 of: Enantioselective Enzymatic Desymmetrizations in Organic Synthesis Eduardo García-Urdiales, Ignacio Alfonso, and Vicente Gotor* Departamento de Química Org anica e Inorg anica, Facultad de Química, Universidad de Oviedo, Juli an Clavería, 8, 33006 Oviedo, Spain, and Departamento de Química Biol ogica y Modelizaci on Molecular, Instituto de Química Avanzada de Catalu~na (IQAC, CSIC), Jordi Girona, 18-26, 08034, Barcelona, Spain This is a Chemical Reviews Perennial Review. The root paper of this title was published in Chem. Rev. 2005, 105 (1), 313 354, DOI: 10.1021/cr040640a; Published (Web) December 17, 2004. Updates to this text appear in red type.

Ketone–Alcohol Hydrogen‐Transfer Equilibria: Is the Biooxidation of Halohydrins Blocked?

To ensure the quasi-irreversibility of the oxidation of alcohols coupled with the reduction of ketones in a hydrogen-transfer (HT) fashion, stoichiometric amounts of α-halo carbonyl compounds have been employed as hydrogen acceptors. The reason that these substrates lead to quasi-quantitative conversions has been tacitly attributed to both thermodynamic and kinetic effects. To provide a clear rationale for this behavior, we investigate herein the redox equilibrium of a selected series of ketones and 2-propanol by undertaking a study that combines experimental and theoretical approaches. First, the activity of the (R)-specific alcohol dehydrogenase from Lactobacillus brevis (LBADH) with these substrates was studied. The docking of acetophenone/(R)-1-phenyethanol and α-chloroacetophenone/(S)-2-chloro-1-phenylethanol in the active site of the enzyme confirms that there seems to be no structural reason for the lack of reactivity of halohydrins. This assumption is confirmed by the fact that the corresponding aluminum-catalyzed Meerwein-Ponndorf-Verley-Oppenauer (MPVO) reactions afford similar conversions to those obtained with LBADH, showing that the observed reactivity is independent of the catalyst employed. While the initial rates of the enzymatic reductions and the IR ν(C=O) values contradict the general belief that electron-withdrawing groups increase the electrophilicity of the carbonyl group, the calculated ΔG values of the isodesmic redox transformations of these series of ketones/alcohols with 2-propanol/acetone support the thermodynamic control of the reaction. As a result, a general method to predict the degree of conversion obtained in the HT-reduction process of a given ketone based on the IR absorption band of the carbonyl group is proposed, and a strategy to achieve the HT oxidation of halohydrins is also shown.

Enzymatic ammonolysis of ethyl (±)-4-chloro-3-hydroxybutanoate. Chemoenzymatic syntheses of both enantiomers of pyrrolidin-3-ol and 5-(chloromethyl)-1,3-oxazolidin-2-one

Abstract Lipase B from Candida antarctica efficiently catalysed the kinetic resolution of ethyl (±)-4-chloro-3-hydroxybutanoate through an ammonolysis reaction. Using this methodology, both enantiomers of 4-chloro-3-hydroxybutanamide were prepared and converted into pyrrolidin-3-ol and 5-(chloromethyl)-1,3-oxazolidin-2-one by simple processes consisting of a reduction reaction and a Hofmann rearrangement, respectively.

Enzymatic Desymmetrization of Prochiral 2-Substituted-1,3-Diamines : Preparation of Valuable Nitrogenated Compounds

A wide range of prochiral 1,3-diamines were first efficiently synthesized and subsequently desymmetrized by using lipase from Pseudomonas cepacia as catalyst and diallyl carbonate as alkoxycarbonylating agent. In all cases, the amino carbamates of R-configuration were recovered. Final selective cleavage of the N-allyloxycarbonyl moiety was carried out under mild reaction conditions, which demonstrates the high versatility and potential of this chemoenzymatic route as a source of intermediates in the synthesis of related optically active nitrogenated derivatives.

Enzymatic one-pot resolution of two nucleophiles: alcohol and amine

Abstract Enzymatic aminolysis of racemic secondary alcohol ester derivatives with racemic amines leads to the resolution, in one reaction, of the alcohol and the amine with very high enantioselectivity.

Influence of the Nucleophile on the Candida antarctica Lipase B‐Catalysed Resolution of a Chiral Acyl Donor

The resolution of methyl (±)‐3‐hydroxypentanoate catalysed by Candida antarctica lipase B has been performed by using ammonia and benzyl amine as nucleophiles. In all cases, the lipase reacts faster with the R enantiomer of the ester, but when benzyl amine is used, the enantiomeric ratio is approximately three times as high as that measured for ammonia. The analysis of the molecular dynamics simulations carried out over the corresponding deacylation transition state analogues indicated specular binding modes between enantiomers that vary greatly upon the nucleophile used. For the case of ammonia, an intramolecular hydrogen bond between the β‐hydroxyl group and the protons of the nucleophile is established. However, the presence of the substituent in benzyl amine disrupts this interaction. Instead, the acyl chain binds to a more restrictive area of the protein where the higher number of contacts established with the side chains of Thr40, Gln157 and Ile189 have been identified as the reason for the higher enantioselectivity observed in the aminolysis reaction.

Study of the enantioselectivity of the CAL-B-catalysed transesterification of α-substituted α-propylmethanols and α-substituted benzyl alcohols

Abstract A study of the enantioselectivity exhibited by the lipase B from Candida antarctica in the transesterification of different α-substituted α-propylmethanols with vinyl acetate is shown. The best results are obtained when the large-sized (L) substituent of the alcohol is either a phenyl group or more especially a cyclohexyl group, although the reaction rates are lower than when linear or slightly branched groups are present. It is also found that ramification at the β-position of the L substituent has a deleterious effect on both lipase activity and enantioselectivity. Moreover, some α-substituted benzyl alcohols bearing medium-sized (M) substituents larger than an ethyl and smaller than a propyl group are resolved by means of this methodology with moderate-good enantioselectivities (E=46–57) and similar reaction rates.

Kinetic Resolution of (±)‐1‐Phenylbutan‐1‐ol by Means of CALB‐Catalyzed Aminolyses: A Study on the Role of the Amine in the Alcohol Resolution

The kinetic resolution of (±)-1-phenylbutan-1-ol [(±)-1] by means of CALB-catalyzed aminolysis of its acetyl derivative [(±)-2] using (±)-1-phenylethanamine [(±)-3] as nucleophile is a slower but more enantioselective process (E = 50) than the corresponding CALB-catalyzed transesterification of (±)-1 with vinyl acetate (E = 19). The use of triethylamine and acetanilide as additives in the transesterification of (±)-1 enhanced the enantiomeric ratio (E = 43 and 38, respectively), thus showing that both the basic character of the amine as well as its structural nature could be responsible for the enantioselectivity differences observed between the transesterification and aminolysis reactions. We have also carried out the aminolysis of (±)-2 using different chiral and non-chiral amines. Enantiomeric ratio values varied significantly with the amine employed, but the enzyme always remained more selective towards the R-enantiomer of the substrate. Among all the amines tested, (±)-1-phenylpropan-1-amine [(±)-5] was the nucleophile of choice. Analysis of the conversion values for each enantiomer of (±)-2 showed that the selectivity differences exhibited by the lipase in the aminolysis reactions were due to the different stabilization of the fast-reacting enantiomer of the substrate [(R)-2] during the catalytic process. The CALB behavior in these reactions could be explained on the basis of substrate imprinting effects, which were corroborated by means of enzyme recycling experiments. Finally, a solvent screening allowed the kinetic resolution of this alcohol for synthetic purposes.

Computational Study of the Lipase-Mediated Desymmetrisation of 2-Substituted-Propane-1,3-Diamines

The enantioselectivity displayed by the lipase from Pseudomonas cepacia towards a wide range of prochiral 2‐substituted‐propane‐1,3‐diamines was studied by means of molecular dynamics simulations (MDS). In all cases the enzyme allows the recovery of the corresponding amino carbamates of R configuration. However, the enantioselectivity is only synthetically useful if no ortho substituent is present and the aromatic ring is directly bonded to the 2‐carbon of the 1,3‐diamine core. Analysis of the MDS trajectories revealed that the homologation of 2‐aryl substituents by means of a methylene group lowers enantioselectivity by alleviating the conformational tension of the slow‐reacting orientations due to unfavourable intramolecular contacts between the ortho carbons of the aryl group and the nucleophilic nitrogen, as well as between the chiral carbon and the oxyanion. Additionally, the relative solvent accessible surfaces of the atoms of the aryl ring nicely correlate with the effect of the location of the substituent on enantioselectivity.