Enoate Reductase-Mediated Preparation of Methyl (S)-2-Bromobutanoate, a Useful Key Intermediate for the Synthesis of Chiral Active Pharmaceutical Ingredients

Abstract

Enoate reductases belonging to the Old Yellow Enzyme (OYE) family were employed to develop a biocatalysed approach to methyl (S)-2-bromobutanoate, a key intermediate for the introduction of a particular stereogenic unit into the molecular skeleton of a certain class of chiral drugs. Methyl (Z)-2-bromocrotonate afforded, respectively, (S)-2-bromobutanoic acid (ee = 97%) and methyl (S)-2-bromobutanoate (ee = 97%) by baker's yeast fermentation and by OYE1À3 biotransformations. The bioreductions of other methyl 2-haloalkenoates were also considered. It was observed that the (Z)-and (E)-diastereoisomers of Rbromo unsaturated esters afforded the same enantiomer of the corresponding reduced product.

Ene‐reductases and their Applications

“…However, whole cell biotransformations often result in the formation of significant amounts of saturated alcohols due to the presence of prim-alcohol dehydrogenases (ADHs) in the cells [20,21]. Moreover, α-substituted aldehydes show relatively low chemical stability, resulting in spontaneous chemical racemization and therefore low optical purity [22]. A convenient strategy for the production of α-methyldihydrocinnamaldehyde derivatives, the fragrances in the perfumes Lilial™ (1b) and Helional™ (2b), was developed via enzymatic bioreduction of the corresponding cinnamaldehyde precursors (1a, 2a).…”

“…This allowed for the production of both enantiomers of methyl 2-chloro-iodopropionate, 2-bromoiodopropionate, and 2-iodopropionate in good to excellent enantiopurity via enzyme-based stereocontrol using OYEs ( Figure 18.3a) [45]. Enantiopure α-haloesters are, in particular, valuable synthons for the synthesis of chiral active pharmaceutical ingredients used for the treatment of noninsulindependent type-2 diabetes mellitus (T2DM) [22]. Additionally, the use of a carboxylic function in the starting material can offer advantages, in contrast to aldehydes, such as increased stability of the stereogenic center toward spontaneous chemical racemization or the inertness of the acid group toward bioreduction.…”

“…Additionally, the use of a carboxylic function in the starting material can offer advantages, in contrast to aldehydes, such as increased stability of the stereogenic center toward spontaneous chemical racemization or the inertness of the acid group toward bioreduction. A practical synthesis of an enantioenriched stereogenic unit, needed for the inclusion in the structural skeleton of relevant pharmaceutical ingredients for the treatment of T2DM, was developed in Brenna's group [22]. Excellent stereoselectivities were obtained with (S)-configured α-halo-β-substituted acids and methyl esters.…”

Asymmetric bioreduction of activated alkenes to industrially relevant optically active compounds

“…Enantiopure α-haloesters in particular are valuable chiral synthons for the synthesis of several therapeutic agents used for the treatment of non-insulin dependent type 2 diabetes mellitus (T2DM) (Brenna et al, 2011c). Brenna and co-workers investigated the bioreduction of various methyl α-halo-β-substituted acrylates using isolated OYE1-3 and baker's yeast (Fig.…”

On the stereochemistry of the Baker's Yeast-mediated reduction of regioisomeric unsaturated aldehydes: Examples of enantioselectivity switch promoted by substrate-engineering

“…Since the early seventies the growing interest for small chiral molecules, to be used as building blocks for the synthesis of more complex enantiopure compounds, [1] has promoted the study of microbial transformations of non conventional substrates [2][3][4]. However, the major drawback of this approach is that biocatalysed reactions usually afford only one enantiomer of the final molecule with high enantioselectivity.…”