Chemoenzymatic Preparation of Optically Active Long-Chain 3-Hydroxyalkanoates

Abstract

The synthesis of optically active 3-hydroxyalkanoates of varying chain length (C,,, C,, and C18) was investigated using chemoenzymatic methods. While bakers' yeast mediated reduction of 3oxoalkanoates gave (R)-3-hydroxyalkanoates (e.e. >80%, yield -lo%), both enantiomers were obtained by enzymatic resolution of racemic methyl 3-butanoyloxyalkanoates using Geotrichum candidum lipase with moderate to good optical purity (e.e. 32-92%, yield 4040% for both enantiomers). Lipase-catalysed interesterification, however, was found to proceed with similar enantioselectivity but with slow rate of conversion. the other hand, asymmetric reduction of 3-oxoalkanoates using a chirally modified hydrogenation catalyst led to 3-hydroxy derivatives with better than 80% e.e. (Nakahata et al., 1982). Furthermore, optically pure 3-hydroxyalkanoates were obtained in a six step sequence starting from (R)or (S)-malic acid (Larchevsque and Henrot, 1987).In this study we compare the applicability of different chemoenzymatic methods-i.e. yeast reduction, enzymatic hydrolysis and enzymatic transesterification-for the synthesis of enantiomerically enriched long-chain 3-hydroxyalkanoates with a total chain length of Cl0, C14 and C18 (for a preliminary communication see Feichter, Faber and Griengl, 1989). In addition, a branched derivative was investigated since fatty acids of such type have been found to be constitutents of microbial lipopolysaccharides (Wollenweber et al., 1985). MATERIALS AND METHODS GeneralMelting points were determined on a Tottoli apparatus and are uncorrected. Preparative column chromatography was performed on silica gel 60 (230-400 mesh, Merck) and for TLC Merck silica gel 60 FZ4 plates were used. Compounds were visualized either with UV-light or by spraying with vanilline/conc. H2S04 and heat treatment, GLC-analyses were performed on a Hewlett-Packard 7620A chromatograph (2.2 m X l/8" glass column, 3% OV 225 on Supelcoport 100/120) equipped with an FID. Elemental analyses (C, H) of all novel compounds were within 0.5% of calculated values. Optical rotations ([a13 were measured on a Jasco DIP 370 polarimeter in CHC13 solution. 'H and 19FNMR spectra were recorded on a Bruker MSL 300 (300 and 282MHz, respectively) or a Hitachi-Perkin-Elmer R-24-B (60 MHz) spectrometer in CDC13 solution unless otherwise stated. Chemical shifts are reported from TMS or CFC13 as internal standard in ppm (6-scale) and coupling constants (J) in Hz (s = singlet, d = doublet, t = triplet, m = multiplet). All commercially obtained compounds were used as received except acid chlorides which were distilled prior to use. Crude enzyme preparations were employed without further purification. Lipases A, A-6, AY-30,

Redox Enzymes Used in Chiral Syntheses Coupled to Coenzyme Regeneration

“…The D-dehydrogenase was inhibited by haloacetates [264], allyl bromide [265], and fatty acids [266]. Other classes of compounds used in asymmetric syntheses involving baker's yeast were: α-monosubstituted β-ketoesters [267], β-ketoacids [268], cyclic β−diketones [269], α-diketones [270], compounds having nitro-groups [271], heterocyclic functional groups [272], organometallic compounds [273], compounds containing sulfur [274], and fluorinated compounds [275].…”

Triterpenoids from Acokanthera schimperi in Ethiopia

“…The IR absorptions indicated the presence of hydroxyl group (3455 cm -1 ) and carbonyl group (1714 cm -1 ). Analysis of the 1 H and 13 C NMR spectra of 1 (Table 1) showed a set of triterpenoid [17,18]. Compared with 3,20-dihydroxylupane, the downfield of H-3 (+1.34), C-3 (+2.4) and upfield of C-2 (-3.9) of 1 indicated that the fatty acid was esterified with 3-OH [19,20], which was confirmed by the correlation of H 4.54 (H-3) and C 172.7 (C-1') in the HMBC spectrum (Figure 3).…”

A Process in Need Is a Process Indeed: Scalable Enantioselective Synthesis of Chiral Compounds for the Pharmaceutical Industry

“…Synthesis of a single enantiomer of 3 seems less demanding than that of viracept 1 and its central four‐carbon intermediates such as 10 (Schemes and ), 32 c (Scheme ), and 34 (Scheme ), because 3 possesses only one stereogenic center (Figure 1). However, it is ironic that scalable processes to access either ( R )‐ or ( S )‐ 3 are few notwithstanding various synthetic methodologies explored so far, which actually cover the following alternatives: 1) resolution of (±)‐ 3 14–17 via diastereomeric salt formation with basic resolving agents;14b, 15, 18 2) kinetic resolution of (±)‐ 3 and its methyl ester via lipase‐catalyzed enantioselective O‐acetylation;14a, 19, 20 3) asymmetric bioreduction of β ‐keto acid;16, 20a 4) asymmetric reduction of β ‐keto ester over chiral metal/complex catalysts;14c, 21–23 5) stereoselective functionalization through Sharpless' asymmetric epoxidation24 and dihydroxylation;25 6) stereoselective construction of homoallyl alcohol through Brown's asymmetric allyboration;26 7) chiral pool synthesis starting from ( S )‐ β ‐hydroxy‐ γ ‐butyrolactone27 or ( S )‐epichlorohydrin 4. Thus, the scope and limitation intrinsic to each methodology will be discussed from the pragmatic viewpoint in the sections that follow.…”

“…Asymmetric reduction of β ‐keto ester : Asymmetric reduction of prochiral β ‐keto ester 42 (Scheme ) and its parent acid would represent a logical method to access a single enantiomer of 3 . When β ‐keto tertradecanoic acid and its potassium salt were treated with fermenting bakers' yeast16 and Saccharomyces cerevisiae Hansen,20a respectively, asymmetric reduction proceeded with high enantioselectivity to give ( R )‐ 3 in > 97 % ee. Treatment with diazomethane gave methyl ester ( R )‐ 43 , which was then purified by silica gel chromatography; however, the isolation yield was too low for either bioreduction to be run in industry: 22 % yield for the bakers' yeast reduction;16 and 10 % yield for the S. cerevisiae Hansen reduction 20a…”