Francesco G. Gatti

Biocatalytic methods for the synthesis of enantioenriched odor active compounds.

2.1.3. Ionones and Derivatives 4044 2.1.4. Damascones 4045 2.1.5. Lavandulol 4046 2.1.6. Miscellaneous 4047 2.2. Artificial Odorants 4048 2.2.1. Floral Fragrances 4048 2.2.2. Wood and Balmy Fragrances 4059 2.2.3. Miscellaneous 4060 3. Chiral Fragrances and Flavors by Biocatalyzed Stereoselective Reactions 4062 3.1. Stereoselective Oxidations 4062 3.1.1. Terpene Oxidations 4062 3.1.2. Miscellaneous 4063 3.2. Stereoselective Reductions 4065 4. Conclusions 4067 Appendix 4067 Author Information 4068 Biographies 4068 Acknowledgment 4069 References 4069

Cascade Coupling of Ene Reductases with Alcohol Dehydrogenases: Enantioselective Reduction of Prochiral Unsaturated Aldehydes

The baker’s yeast (BY)‐mediated reduction of a set of α‐substituted derivatives of cinnamaldehyde to give the corresponding saturated alcohols was investigated. Our study demonstrates that the ene reductases of BY (OYEu20092 or OYEu20093) preferentially reduce the Cuf8feC double bond of stereoisomers with the phenyl group trans to the carbonyl group. Moreover, the alcohol dehydrogenases (ADHs) chemoselectively reduce (oxidise) the carbonyl group (hydroxyl group) of saturated aldehydes (alcohols) if the side chain does not contain a heteroatom such as oxygen or sulphur and is longer than an ethyl group. Using isolated OYEs instead of BY, the saturated aldehydes partially lost their optical purity during the biotransformation, even with the inu2005situ substrate feeding product removal (SFPR) technology. This limitation can be overcome by the combination of an isolated ene reductase (OYEu20092 or OYEu20093) together with an ADH (horse liver alcohol dehydrogenase) in a cascade system which allowed both yields and enantioselectivities to improve.

Synthesis of Robalzotan, Ebalzotan, and Rotigotine Precursors via the Stereoselective Multienzymatic Cascade Reduction of α,β-Unsaturated Aldehydes

A stereoselective synthesis of bicyclic primary or secondary amines, based on tetralin or chroman structural moieties, is reported. These amines are precursors of important active pharmaceutical ingredients such as rotigotine (Neupro), robalzotan, and ebalzotan. The key step is based on a multienzymatic reduction of an α,β-unsaturated aldehyde or ketone to give the saturated primary or secondary alcohol, in a high yield and with a high ee. The catalytic system consists of the combination of an ene-reductase (ER; i.e., OYE2 or OYE3 belonging to the Old Yellow Enzyme family) with an alcohol dehydrogenase (ADH), applying the in situ substrate feeding product removal technology. By this system the formation of the allylic alcohol side product and the racemization of the chirally unstable α-substituted aldehyde intermediate are minimized. The primary alcohols were elaborated via a Curtius rearrangement. The combination of OYE2 with a Prelog or an anti-Prelog ADH allowed the preparation of the secondary alcohols with ee > 99% and de > 87%. The absolute configuration of the primary amines was unambiguously assigned by comparison with authentic samples. The stereochemistry of secondary alcohols was assigned by X-ray crystal structure and NMR analysis of Mosher esters.

Old Yellow Enzyme-mediated reduction of β-cyano-α,β-unsaturated esters for the synthesis of chiral building blocks: stereochemical analysis of the reaction

Bakers yeast and Old Yellow Enzyme-mediated reduction of the carbon–carbon double bonds of β-cyano-α,β-unsaturated esters was investigated, in order to broaden the applicability of this kind of reaction in the field of preparative organic chemistry. The synthetic significance of the enantioselective reduction of these difunctionalised substrates was shown by considering the conversion of saturated chiral cyanoesters into γ2-amino acid derivatives for foldamer chemistry applications. The stereochemical outcome of the biotransformations was carefully analysed by means of deuterium labeling experiments. The results of this analysis were employed to rationalise the effects of substrate-control on the stereoselectivity of a certain class of ene-reductase-mediated reduction reactions. A simple model was developed to describe the structural prerequisites for the optimal arrangement of the substrates within the binding site of OYE1-3 enzymes.

Enantioselective synthesis of benzylic stereocentres via Claisen rearrangement of enantiomerically pure allylic alcohols: preparation of (R)- and (S)-3-methyl-2-phenylbutylamine

Abstract The Johnson–Claisen rearrangement of enantiopure allylic alcohols in triethylorthopropionate is the key step for the preparation of chiral molecules with benzylic stereogenic carbon atoms bearing an isopropyl moiety. The synthetic procedure is applied to the preparation of ( R )- and ( S )-3-methyl-2-phenylbutylamine.

Cascade Coupling of Ene‐Reductases and ω‐Transaminases for the Stereoselective Synthesis of Diastereomerically Enriched Amines

One‐pot sequential and cascade processes performed by employing ene‐reductases (ERs) together with ω‐transaminases (ω‐TAs) for the obtainment of diastereomerically enriched (R)‐ and (S)‐amine derivatives containing an additional stereocenter were investigated. By using either α‐ or β‐substituted unsaturated ketones as substrates and by coupling purified ERs belonging to the Old Yellow Enzyme (OYE) family with a panel of commercially available ω‐TAs, the desired products were obtained in up to >99u2009% conversion and >99u2009%u2009de. The sequential reactions were performed in a one‐pot fashion with no need to adapt the reaction conditions to the reductive amination step or to purify the reaction intermediate. Moreover, high chemoselectivity of the tested ω‐TAs for the saturated ketones was shown in the cascade reactions.

Enantioselective Synthesis of (R)-2-Arylpropanenitriles Catalysed by Ene-Reductases in Aqueous Media and in Biphasic Ionic Liquid–Water Systems

The enantioselective reduction of α‐methylene nitrile derivatives catalysed by ene‐reductases affords the corresponding (R)‐2‐arylpropanenitriles with high conversion values. The reaction is investigated either in aqueous medium (with an organic cosolvent or by loading the substrate onto hydrophobic resins) or in a biphasic ionic liquid–water system. The use of ionic liquids, herein with isolated ene‐reductases, is found to improve the work‐up and the substrate recovery method. The synthetic manipulation of the final chiral nitrile derivatives indicates how this biocatalysed method can be exploited for the preparation of a wide range of chiral compounds.

Exploitation of a Multienzymatic Stereoselective Cascade Process in the Synthesis of 2-Methyl-3-Substituted Tetrahydrofuran Precursors

Enantiopure 2-methyl-3-substituted tetrahydrofurans are key precursors of several biologically active products (drugs, flavors, and agrochemicals). Thus, a stereocontrolled and efficient methodology for the obtainment of these synthons is highly desirable. We exploited a two-step multienzymatic stereoselective cascade reduction of α-bromo-α,β-unsaturated ketones to give the corresponding bromohydrins in good yields, with high ee and de values. The cascade process is catalyzed by an ene-reductase and an alcohol dehydrogenase. Further manipulations of these bromohydrins, by two diastereodivergent routes, allowed the preparation of the tetrahydrofuran synthons. One route is based on a lipase catalyzed cleavage of the protecting group. The second route is characterized by a camphor sulfonic acid mediated isomerization of a β-hydroxyepoxide to give the tetrahydrofuran-2-ol. Finally, the synthesis of the most odorous and pleasant stereoisomer of the roasted meat aroma, i.e., (2S,3R)-2-methyl-3-thioacetate tetrahydrofuran, is reported as well.

Asymmetric Bioreduction of β-Acylaminonitroalkenes: Easy Access to Chiral Building Blocks with Two Vicinal Nitrogen-Containing Functional Groups

The reduction of (Z)‐β‐acylaminonitroalkenes catalyzed by ene‐reductases is described for the first time. The reaction occurs with a high conversion and excellent enantioselectivity and shows a wide substrate scope. The reduced products are valuable chiral synthons characterized by two vicinal nitrogen‐containing functional groups that can be further modified by functional group inter‐conversion thanks to the synthetic versatility of the nitro moiety. The chemo‐enzymatic synthesis of (R)‐N,N′‐(1‐phenylethane‐1,2‐diyl)diacetamide from easily accessible (Z)‐N‐(2‐nitro‐1‐phenylvinyl)acetamide is herein reported as a representative application of this synthetic procedure.

Substrate Scope Evaluation of the Enantioselective Reduction of β‐Alkyl‐β‐arylnitroalkenes by Old Yellow Enzymes 1–3 for Organic Synthesis Applications

The substrate scope of the old yellow enzyme catalyzed reduction of β‐alkyl‐β‐arylnitroalkenes is investigated. Compounds bearing either alkyl chains of increasing length at the carbon atom in position β to the nitro group or different substituents on the aromatic ring are prepared and submitted to bioreduction, to define the synthetic potential of this enantioselective reaction in the preparation of chiral fine chemicals. The versatility of the resulting nitroalkanes as chiral building blocks is shown by reducing the nitro group into a primary amine and by converting it into a carboxylic acid moiety by Meyer reaction.