Asymmetric Synthesis of (R)‐3‐Hydroxy‐2‐methylpropanoate (‘Roche Ester’) and Derivatives via Biocatalytic CC‐Bond Reduction

Abstract

Enoate reductases from the old yellow enzyme family were employed for the asymmetric bioreduction of methyl 2-hydroxymethylacrylate and its O-allyl, O-benzyl and O-TBDMS derivatives to furnish (R)-configurated methyl 3-hydroxy-2-methylpropionate products in up to > 99% ee Variation of the O-protective group had little influence on the stereoselectivity, but a major impact on the reaction rate.Keywords: biocatalysis; C=C-bioreduction; enoate reductase; old yellow enzyme; substrate engineeringThe asymmetric reduction of C=C bonds creates (up to) two chiral carbon centres and is thus one of the most widely employed strategies for the production of chiral materials. The biocatalytic variant, which is applicable to activated alkenes bearing an electron-withdrawing substituent is catalysed by enoate reductases [EC 1.3.1.X], [1,2] which are members of the old yellow enzyme (OYE) family.[3] Over the past few years, increasing attention has been devoted to these flavoproteins [4] in view of their substrate scope, [5] encompassing a,b-unsaturated carbonyl compounds (such as enals and enones), as well as carboxylic acids and derivatives thereof (such as esters, cyclic imides, nitriles, lactones) and nitroalkenes. As a rule of thumb, the degree of activation of the C=C-bond exerted by the electron-withdrawing effect of the activating substituent goes hand in hand with the substrate acceptance, which ensures generally fast reaction rates for enals, enones and nitroalkenes, whereas (di)carboxylic acids and esters are transformed more slowly.To illustrate the importance of this enzyme class for asymmetric synthesis, we aimed at their applicability for an industrially relevant product, that is, (R)-3-hydroxy-2-methylpropanoate, which is commonly denoted as the Roche ester. The latter is a popular chiral building block for the synthesis of vitamins (e.g., a-tocopherol [6] ), fragrance components (e.g., muscone [7] ), and antibiotics (e.g., calcimycin, [8] palinurin, [9] rapamycin, [10] 13-deoxytedanolide, [11] dictyostatin [12] ) and natural products (e.g., spiculoic acid A [13] ). Classical methods for its preparation include the diastereoselective addition of non-racemic alcohols as chiral auxiliaries, [14] the transformation of a chiral homoallylic acetate [15] or involve aldol condensation [16] and -most prominent -the transition metal-catalysed asymmetric hydrogenation of acrylate esters using Rh [17] (ee up to 99%) or Ru [18] (ee up to 94%). For the biocatalytic synthesis of the Roche ester only few examples are reported: the stereoselective oxidation of 2-methyl-1,3-propanediol by Gluconobacter and Acetobacter spp. [19] (ee up to 97%), the asymmetric reduction of ethyl 4,4-dimethoxy-3-methylcrotonate using bakers yeast [20] and the stereoseletive (formal) b-hydroxylation of isobutyric acid using Pseudomonas putida (ATCC 21244).[21] All of these biotransformations were performed using whole (fermenting) microbial cells with several enzymes being involved. Only recently, was it shown that a non-flavin NADH-dependen...

Chemoenzymatic Asymmetric Synthesis of Pregabalin Precursors via Asymmetric Bioreduction of β-Cyanoacrylate Esters Using Ene-Reductases

“…In addition, the size of the alcohol moiety of the (activating) ester group was varied in order to test its influence on the substrate-docking mode of substrates 5a – 7a within the active site. 4,6,18 All substrates were tested using a set of native ene-reductases, which have shown to possess a broad substrate spectrum on acrylic ester derivatives 5,6,15,18,19 (Scheme 1, Table 1). …”

Asymmetric bioreduction of activated alkenes to industrially relevant optically active compounds

“…( R )-3-Hydroxy-2-methylpropanoate ( 23b ), commonly denoted as ‘Roche-Ester’, is a popular chiral building block for the synthesis of vitamins (vitamin E), fragrance compounds (muscone), antibiotics (rapamycin) and natural products (Stueckler et al, 2010c). Prominent routes for its preparation include enzymatic oxidation of prochiral diols (Molinari et al, 2003) or the transition metal-catalyzed asymmetric hydrogenation of acrylate esters using Rh- (Holz et al, 2008; Qiu et al, 2009; Wassenaar et al, 2008) or Ru-catalysts (Pautigny et al, 2008).…”

“…The reaction proceeded via strict ( R )-stereoselective reduction of methyl 2-hydroxymethylacrylate derivatives (>99% ee in almost all cases; Fig. 10), with ene-reductases showing overall broad acceptance for this type of compounds (Stueckler et al, 2010c). Substrate engineering via hydroxyl-group protection (allyl-, benzyl- or TBDMS-ethers) enhanced the reaction rate significantly (up to >99% conversion) and hence allowed direct access to protected ( R )-‘Roche-Ester’ ( 23b ), a convenient intermediate for further synthesis.…”

Ene‐reductases and their Applications

“…Hydroxyl group protection (allyl, benzyl, or TBDMS ethers) did not show any influence in stereochemical outcome; however, the reaction rate was affected. Direct access to the O-protected Roche esters could be achieved, generating convenient intermediates for further synthesis, with conversions up to >99% ( Figure 18.4a) [46]. 6.…”