Asymmetric synthesis of the marine alkaloid (−)-(S)-nakinadine C

The first asymmetric synthesis of the marine alkaloid (−)-(S)-nakinadine C is described. This synthesis employs the conjugate addition of lithium dibenzylamide to an N-α-phenylacryloyl SuperQuat derivative followed by diastereoselective protonation of the intermediate enolate using 2-pyridone as the key step to introduce the stereochemistry. (−)-(S)-Nakinadine C was isolated in 13% yield over 9 steps from commercially available atropic acid, 98:2 dr [(Z):(E) ratio] and >99% ee.     

New synthesis of harzialactone A via kinetic resolution using recombinant Fusarium proliferatum lactonase

A new synthesis of harzialactone A together with its stereoisomers was achieved starting from phenyl acetone. The key step of this new route is the kinetic bioresolution of racemic cis- and trans-isomers by recombinant Escherichia coli JM109 cells expressing Fusarium proliferatum lactonase gene (reFPL). Harzialactone A was isolated in excellent ee (>99%), while moderate to good enantioselectivities (80% to >99% ee) were obtained for its isomers.     

Diastereomeric P1-chiral diamidophosphites with terpene fragments in asymmetric catalysis

Diamidophosphite P¹-monodentate, ligands based on terpene alcohols and (S)- or (R)-(2-anilinomethyl)pyrrolidine, induce high enantioselectivities (ee’s up to 99%) in Pd-catalyzed allylic substitution reactions. In the Pd-catalyzed deracemization of ethyl (E)-1,3-diphenylallyl carbonate up to 92% enantioselectivity has been achieved. The Rh-catalyzed asymmetric hydrogenation of α-dehydrocarboxylic acid esters leads to a maximum of 56% ee with quantitative conversion. Diastereomeric diamidophosphites prepared from [(1S)-endo]-(−)-borneol were found to be the most efficient stereoselectors.     

Synthesis of enantiopure β-amino alcohols via AKR/ARO of epoxides using recyclable macrocyclic Cr(III) salen complexes

A series of chiral macrocyclic Cr(III) salen complexes 1-8 were synthesized and characterized. These complexes were found to be highly active, regio-, diastereo-, and enantioselective catalysts in aminolytic kinetic resolution (AKR) of racemic trans-epoxides as well as asymmetric ring opening (ARO) of prochiral meso-epoxides with various anilines as nucleophiles at room temperature in 18-24 h. Excellent yields (>99% with respect to the nucleophile) with high enantioselectivity (ee, >99%) of chiral anti-β-amino alcohols was achieved with concomitant recovery of corresponding epoxides in high ee (up to >99%). The complex 1 also catalyzed the ARO of meso-epoxides to provide corresponding syn-β-amino alcohols in high yield (99%) and ee (up to 91%). Due to built-in basic sites in the catalyst, no external base (as an additive) was required to promote AKR and ARO reactions. The catalyst 1 was conveniently recycled several times with retention of its performance. The AKR of trans-stilbene oxide with aniline was successfully demonstrated at relatively higher scale (10 mmol) using the catalyst 1.     

Asymmetric epoxidation of (Z)-enol esters catalyzed by titanium(salalen) complex with aqueous hydrogen peroxide

Titanium(salalen) complex 1 was an effective catalyst for asymmetric epoxidation of enol esters. Although (E)-enol esters were reluctant to proceed, (Z)-enol esters underwent asymmetric epoxidation to give the epoxides in high yields with high enantioselectivity ranging from 86 to >99% ee in the presence of aqueous hydrogen peroxide as the stoichiometric oxidant. Complete enantioselectivity was observed in the reaction of (Z)-3,3-dimethylbut-1-en-1-yl 4-methoxybenzoate. The obtained epoxide was readily transformed into the corresponding 1,2-diol by reduction with lithium borohydride without erosion of the high enantiomeric excess.     

Chromatographic identification of (E)- and (Z)-isomers of unsaturated organic compounds using their physicochemical characteristics

The values of physicochemical properties determine completely the sequence of chromatographic elution of (Z)- and (E)-isomers of 1,2-disubstituted unsaturated compounds and can therefore be used as reference data for their GC-identification. The isomer with the minimum boiling point, relative density, and refractive index has the least retention parameters. By the ratio of the values of these properties the (Z)- and (E)-isomers form two groups: (Z) > (E) and (Z) < (E). This feature is due to the larger polarity of the (Z)-isomers of asymmetrically substituted compounds containing polar substituents at the double bond C=C. The discovered regularities may be extended to the cis- and trans-isomers of 1,2-disubstituted cycloalkanes and even to the position isomers of substituted arenes.     

Oxidation of acyclic monoterpenes by P450 BM-3 monooxygenase: influence of the substrate E/Z-isomerism on enzyme chemo- and regioselectivity

Oxidized terpenes and terpenoids are highly valuable compounds for organic chemistry. Cytochrome P450 monooxygenase P450 BM-3 from Bacillus megaterium is able to catalyze oxidation of terpenes with high efficiency. Mutations at the amino acid positions 47, 51, and 87 resulted in significantly enhanced activity and regioselectivity of the enzyme during oxidation of geranylacetone and related compounds. The activity of the mutant R47L/Y51F/F87V was in the order of ketone>alcohol>aldehyde>acid. An effect of the substrate cis/trans-isomerism on the enzyme chemo- and regioselectivity was studied. P450 monooxygenase demonstrated similar NADPH turnovers with cis/trans isomers, nerylacetone/geranylacetone (1.9×10³/2.1×10³ min⁻¹) and nerol/geraniol (5.7×10²/5.9×10² min⁻¹), however, resulted in different number of products and product distribution. The Z-isomers, nerylacetone and nerol, were oxidized resulting in several products (five and three, respectively), including allylic alcohols. In contrast, E-isomers were epoxidized exclusively. Geranylacetone was converted with high activity (2080 min⁻¹) and enantioselectivity (97% ee) to 9,10-epoxygeranylacetone, while geraniol was enantioselectively epoxidized to the 6,7-epoxide (250 min⁻¹, 90% ee) with 90% regioselectivity.     

Cyclization of N,N-diethylgeranylamine N-oxide in one-pot operation: preparation of cyclic terpenoid-aroma chemicals

Acid promoted cyclization of the geranylamine N-oxide (E)-4 followed by base-catalyzed intramolecular aldol condensation afforded 1-acetyl-4,4-dimethyl-1-cyclohexene (7) in one-pot operation. Reduction of 7, which possess strong fruity odor, followed by lipase-catalyzed kinetic resolution furnished the acetate (R)-26 (>49.9% yield, >99% ee) and the recovered alcohol (S)-25 (>49.9% yield, >99% ee, herbal odor).     

Catalytic Enantioselective Synthesis of Allylic Boronates Bearing a Trisubstituted Alkenyl Fluoride and Related Derivatives

The first catalytic method for diastereo‐ and enantioselective synthesis of allylic boronates bearing a Z‐trisubstituted alkenyl fluoride is disclosed. Boryl substitution is performed with either a Z‐ or E‐allyldifluoride and is catalyzed by bisphosphine/Cu complexes, affording products in up to 99 % yield with >98:2 Z/E selectivity and 99:1 enantiomeric ratio. A variety of subsequent modifications are feasible, and notable examples are diastereoselective additions to aldehydes/aldimines to access homoallylic alcohols/amines containing a fluorosubstituted stereogenic quaternary center.     

Asymmetric Synthesis of Monofluorinated Carbocyclic Alcohols and Vicinal Difluorinated Heterocycles and Carbocycles

A straightforward method to access novel families of enantioenriched cis-monofluorinated carbocyclic alcohols has been developed through ATH/DKR in up to 97 % yield, up to 99 : 1 dr and enantioinductions up to 97 % ee. Trans-difluorinated indans, tetrahydronaphthalenes, tetrahydroquinolines and chromans have been synthesized as well by deoxofluorination of the corresponding cis-fluoro alcohols. The reaction was performed on a series of variously substituted 3-fluorochromanols, 3-fluorotetrahydroquinolinols, 2-fluoro inden-1-ols and 2-fluoro 1,2,3,4-tetrahydronaphthalen-1-ols in up to 86 % yields, with diastereoselectivities up to 97 : 3 and enantioselectivities up to >99 % ee.     

Highly enantioselective reduction of acetophenone by locally isolated Alternaria alternata using ram horn peptone

Enantiomerically pure compounds are important building blocks in the synthesis of natural products. In this study, the reduction of acetophenone to the (S)-isomer of 1-phenylalcohol with a high enantiomeric excess (ee) by locally isolated Alternaria alternata using ram horn peptone (RHP) was investigated. Ten strains of A. alternata were isolated from different plant samples. These isolates were evaluated for the reduction of acetophenone (ACP) to 1-phenylethanol (PEA). Glucose, yeast extract and RHP in a shake flask and fermenter for growth of A. alternata cultures were used. A. alternata EBK-4 isolate was found to be an effective biocatalyst for the enantiomeric bioreduction of acetophenone. Conversions of up to 100% with excellent enantiomeric excesses (>99%) were obtained. Production of PEA was achieved via a fermenter. The yield was calculated as 86%. This is the first report on the enantioselective reduction of ACP by A. alternata using ram horn peptone from waste material.     

Asymmetric reduction of a variety of ketones with a recombinant carbonyl reductase: identification of the gene encoding a versatile biocatalyst

The gene encoding a versatile biocatalyst that shows high enantioselectivity for a variety of ketones, SCR (Saccharomyces cerevisiae carbonyl reductase), has been identified, cloned, and expressed in E. coli. Recombinant E. coli co-producing SCR and GDH (glucose dehydrogenase) is an easy-to-use, synthetically useful biocatalyst, and 8 out of the 16 alcohols obtained had enantiomeric purities of >98% ee.     

Selectivity enhancement of enantio- and stereo-complementary epoxide hydrolases and chemo-enzymatic deracemization of (±)-2-methylglycidyl benzyl ether

The kinetic resolution of (±)-2-methylglycidyl benzyl ether was achieved via enantioselective biohydrolysis using microbial and plant epoxide hydrolases. Depending on the type of enzyme, opposite enantiopreference and stereo-complementary mode of action (i.e., retention vs inversion of configuration) led to hetero- and homochiral product mixtures. Optimization of the reaction conditions for Rhodococcus sp. R312 led to significantly enhanced enantioselectivity (E >200), which enabled the deracemization of (±)-2-methylglycidyl benzyl ether via biohydrolysis (proceeding with retention of configuration) followed by inverting acid-catalyzed hydrolysis to furnish (R)-1-benzyloxy-2-methylpropane-2,3-diol in >97% ee and 78% yield from the racemate.     

Triphenylphosphine as an effective catalyst for ketoximes addition to acylacetylenes: regio- and stereospecific synthesis of (E)-(O)-2-(acyl)vinylketoximes

Triphenylphosphine catalyzes the regio- and stereospecific addition of ketoximes to acylacetylenes, whereas classical conditions using acetylene (KOH/DMSO, 70 °C) are unsuitable for this purpose. The reaction proceeds under mild conditions (CH₂Cl₂, rt, 7 h) to afford (E)-(O)-2-(acyl)vinylketoximes (92-98% stereoselectivity) in a yield of up to 85%. The (E)-adducts obtained are energetically less favorable than the corresponding (Z)-isomers and are gradually enriched with (Z)-isomers, thus indicating the kinetic control of (E)-stereoselectivity of the reaction.     

Preparation of all stereoisomers of 2-allyl-2-methyl-3-hydroxycyclopentanone by desymmetric processes based on a microbial oxidation and reduction system

All stereoisomers of 2-allyl-3-hydroxy-2-methylcyclopentanones 2-5 were prepared in high conversion and in an optically pure form by microbial reduction and oxidation. The reduction of symmetric diketone 1 by Geotrichum candidum NBRC 4597 under anaerobic conditions gave 2 in 83% yield (98% conversion), >99% de, and >99% ee, whereas the reduction of 1 by G. candidum NBRC 5767 under aerobic conditions gave 3 in 75% yield (99% conversion), >99% de, and >99% ee. Oxidation of meso-diol 6 by G. candidum NBRC 5767 under aerobic conditions afforded 4 in 83% yield (99% conversion) and >99% ee, while oxidation of meso-diol 7 by Mucor heimalis IAM 6095 in the presence of cyclohexanone as a co-oxidant afforded 5 in 68% yield (75% conversion) and >99% ee.     

Asymmetric synthesis of β-substituted alcanoic acids via highly stereoselective conjugate additions of organocopper compounds to chiral enoates

Conjugate additions of organocopper compounds RCu·.BF₃ to encates of sulfonamide-shielded alcohols 1x and 1n quite generally proceed with > 99% ee and > 90% yield.     

Chemoenzymatic synthesis of optically active γ-alkyl-γ-butenolides

rac-Hept-1-en-3-ol 4 was subjected to an enantioselective esterification in the presence of Novozyme 435 and vinyl crotonate as the acyl donor to give (3S)-oct-1-en-3-yl crotonate 7 in >99% ee and (3R)-alcohol 4 in 99% ee. The E-value of this enzymatic reaction was found to be >1000. The (S)-crotonic ester 7 was converted by ring-closing metathesis (RCM) using Grubbs’ catalyst to give (S)-oct-2-en-4-olide 1 in 96% yield while keeping the high enantiomeric excess.     

Synthesis of the (1S,2S)- and (1R,2S)-stereoisomers of the respective E- and Z-isomers of ethyl 4-[(2-hydroxycyclohexyl)methyl]phenoxy-3-methyl-2-butenoate using yeast whole cell bioreduction of the parent ketones

Saccharomyces cerevisiae, strain DBM 2115, was successfully employed in the reduction of the separated Z- and E-isomers of ethyl 4-[(2-oxocyclohexyl)methyl]phenoxy-3-methyl-2-butenoates 1 and 2, in order to prepare the (1S,2S)- and (1R,2S)-enantiomers of the corresponding ethyl 4-[(2-hydroxycyclohexyl)methyl]phenoxy-3-methyl-2-butenoates 3–6. The products were obtained with the required absolute configuration: (1S,2S)-3 (ee = 98%; yield 48%), (1R,2S)-4 (ee = >99%; yield 45%), (1S,2S)-5 (ee = 98.5%; yield 47%), and (1R,2S)-6 (ee = >99%; chemical yield 44%).     

Preparative access to medicinal chemistry related chiral alcohols using carbonyl reductase technology

Libraries of highly enantioenriched secondary alcohols in both enantiomeric forms were synthesised by enzymatic reduction of their parent ketones using selectAZyme? carbonyl reductase (CRED) technology. Commercially available CREDs were able to reduce a range of substrate classes efficiently and with very high enantioselectivity. Matching substrate classes to small subsets of CREDs enabled the fast development of preparative bioreductions and the rapid generation of 100–1500 mg samples of chiral alcohols in typically >95% ee and the majority in ?99.0% ee. The conditions for small scale synthesis were then scaled up to 0.5 kg to deliver one of the chiral alcohols, (S)-1-(4-bromophenyl)-2-chloroethanol, in 99.8% ee and 91% isolated yield.     

Synthesis of both enantiomers of ethyl-4-chloro-3-hydroxbutanoate from a prochiral ketone using Candida parapsilosis ATCC 7330

Candida parapsilosis ATCC 7330 when grown in a medium containing glycerol reduced ethyl-4-chloro-3-oxobutanoate to (R)-ethyl-4-chloro-3-hydroxybutanote (ee >99%, yield: 94%) while glucose and sucrose grown cells yielded (S)-ethyl-4-chloro-3-hydroxybutanote (ee >99%, yield: 96%). The activity of ethyl-4-chloro-3-oxobutanoate reductase was higher in glucose-grown cells (160 U/g protein) when compared to sucrose (158 U/g protein) and glycerol (22 U/g protein). Both the enantiomers of ethyl-4-chloro-3-hydroxybutanoate (ee >99%) can thus be obtained using Candida parapsilosis ATCC 7330 by altering the carbon source in the growth medium.