Prelog's Rule Research Articles

Enantioselective reduction of 4-chromanone and its derivatives by selected filamentous fungi

a b s t r a c t Biotransformation of 4-chromanone and its derivatives in the cultures of three biocatalysts: Didymo- sphaeria igniaria, Coryneum betulinum and Chaetomium sp. is presented. The biocatalysts were chosen due to their capability of enantiospecific reduction of low-molecular-weight ketones (acetophenone and its derivatives and - and -tetralone). The substrates were reduced to the respective S-alcohols with high enantiomeric excesses, according to the Prelog's rule. In the culture of Chaetomium sp. after longer biotransformation time an inversion of configuration of the formed alcohols was also observed. The highest yield of transformation was observed for 6-methyl-4-chromanone. In all the tested cultures, the higher was the molecular weight of a chromanone, the lower conversion percent was observed.

Asymmetric Ketone Reduction Using Targeted Yeast Collections Isolated from Chinese Liquor Pits

Plenty of bacteria, yeasts, molds have been found in Chinese liquor pits. In order to investigate the applications of specifi c yeasts on ketone reduction, we screened some yeast strains in the Yeast Library of Chinese Liquor Pits in Chengdu Institute of Biology, Chinese Academy of Sciences, using f ive carbonyl compounds as potential substrates. The results indicated that the majority of the strains were capable of ketone reduction, and most of them obeyed the Prelog's rule. Some of the strains showed excellent stereo-selectivity, indicating high application potential in chiral drug intermediates production. For example, Williopsis sp. 2.045 transfered 3,5-bis(trif luoromethyl)-acetophenone into(S)-3,5-bis(trif luoromethyl)-1-phenethanol with over 99% yield and ee; Rhodotorula sp. 2.154 changed N-methyl-3-oxo-3-(thiophen-2-yl)propanamide into(S)-3-hydroxy-N-methyl-3-(thiophen-2-yl)propanamide with a yields of 95% and 99% ee. The results suggested that Chinese liquor pits contains lots of bioresources with high ketone reducing activity. It could be used as a targeted library in the screening of microbes with ketone reductase activity, which can highly improve the eff iciency of strain screening. Fig 6, Tab 6, Ref 24

Bioconversion of Iodoacetophenones by Marine Fungi

Nine marine fungi (Aspergillus sclerotiorum CBMAI 849, Aspergillus sydowii Ce19, Beauveria felina CBMAI 738, Mucor racemosus CBMAI 847, Penicillium citrinum CBMAI 1186, Penicillium miczynskii Ce16, P. miczynskii Gc5, Penicillium oxalicum CBMAI 1185, and Trichoderma sp. Gc1) catalyzed the asymmetric bioconversion of iodoacetophenones 1-3 to corresponding iodophenylethanols 6-8. All the marine fungi produced exclusively (S)-ortho-iodophenylethanol 6 and (S)-meta-iodophenylethanol 7 in accordance to the Prelog rule. B. felina CBMAI 738, P. miczynskii Gc5, P. oxalicum CBMAI 1185, and Trichoderma sp. Gc1 produced (R)-para-iodophenylethanol 8 as product anti-Prelog. The bioconversion of para-iodoacetophenone 3 with whole cells of P. oxalicum CBMAI 1185 showed competitive reduction-oxidation reactions.

Stereoselective Bioreduction of 1-(4-Methoxyphenyl)ethanone by Whole Cells of Marine-Derived Fungi

Nine strains of marine-derived fungi (Aspergillus sydowii Ce15, A. sydowii Ce19, Aspergillus sclerotiorum CBMAI 849, Bionectria sp. Ce5, Beauveria felina CBMAI 738, Cladosporium cladosporioides CBMAI 857, Mucor racemosus CBMAI 847, Penicillium citrinum CBMAI 1186, and Penicillium miczynskii Gc5) were screened, catalyzing the asymmetric bioreduction of 1-(4-methoxyphenyl)ethanone 1 to its corresponding 1-(4-methoxyphenyl)ethanol 2. A. sydowii Ce15 and Bionectria sp. Ce5 produced the enantiopure (R)-alcohol 2 (>99% ee) in accordance with the anti-Prelog rule and, the fungi B. felina CBMAI 738 (>99% ee) and P. citrinum CBMAI 1186 (69% ee) in accordance with the Prelog rule. Stereoselective bioreduction by whole cells of marine-derived fungi described by us is important for the production of new reductases from marine-derived fungi.

Insight into the Stereospecificity of Short-Chain Thermus thermophilus Alcohol Dehydrogenase Showing pro-S Hydride Transfer and Prelog Enantioselectivity

The stereochemistry of the hydride transfer in reactions catalyzed by NAD(H)-dependent alcohol dehydrogenase from Thermus thermophilus HB27 was determined by means of (1)H-NMR spectroscopy. The enzyme transfers the pro-S hydrogen of [4R-(2)H]NADH and exhibits Prelog specificity. Enzyme-substrate docking calculations provided structural details about the enantioselectivity of this thermophilic enzyme. These results give additional insights into the diverse active site architectures of the largely versatile short-chain dehydrogenase superfamily enzymes. A feasible protocol for the synthesis of [4R-(2)H]NADH with high yield was also set up by enzymatic oxidation of 2-propanol-d(8) catalyzed by Bacillus stearothermophilus alcohol dehydrogenase.

How carbonyl reductase controls stereoselectivity: Approaching the goal of rational design

Although Prelog's rule and two hydrophobic binding pockets model have been used to predict and explain the stereoselectivity of enzymatic ketone reduction, the molecu- lar basis of stereorecognition by carbonyl reductases has not been well understood. The stereo selectivity is not only determined by the structures of enzymes and substrates, but also affected by the reaction conditions such as temperature and reaction medium. Structural analysis coupled with site-directed mutagenesis of stereocomplementary carbonyl reductases readily reveals the key elements of controlling stereoselectivity in these enzymes. In our stud- ies, enzyme-substrate docking and molecular modeling have been engaged to understand the enantioselectivity diversity of the carbonyl reductase from Sporobolomyces salmonicolor (SSCR), and to guide site-saturation mutagenesis for altering the enantioselectivity of this en- zyme. These studies provide valuable information for our understanding of how the residues involved in substrate binding affect the orientation of bound substrate, and thus control the reaction stereoselectivity. The in silico docking-guided semi-rational approach should be a useful methodology for discovery of new carbonyl reductases.

Enzymatic synthesis of chiral heteroaryl alcohols using plant fragments as the only biocatalyst and reducing agent

The enzymatic reduction of prochiral heterocyclic ketones by carrot (Daucus carota) root in water afforded the corresponding S-alcohols in accordance with the Prelog's rule. The reaction was performed under various conditions in order to optimize the procedure of bioreduction regarding reaction time, yield, and optimal mass of carrot. The optimized procedure was used to test the ability of other plants to carry out the reaction. In the latter experiment, it was observed that, with regard to stereospecificity, most vegetables tested were poorer reducing agents compared to D. carota.

Asymmetric Reduction and Oxidation of Aromatic Ketones and Alcohols Using W110A Secondary Alcohol Dehydrogenase from Thermoanaerobacter ethanolicus

An enantioselective asymmetric reduction of phenyl ring-containing prochiral ketones to yield the corresponding optically active secondary alcohols was achieved with W110A secondary alcohol dehydrogenase from Thermoanaerobacter ethanolicus (W110A TESADH) in Tris buffer using 2-propanol (30%, v/v) as cosolvent and cosubstrate. This concentration of 2-propanol was crucial not only to enhance the solubility of hydrophobic phenyl ring-containing substrates in the aqueous reaction medium, but also to shift the equilibrium in the reduction direction. The resulting alcohols have S-configuration, in agreement with Prelog's rule, in which the nicotinamide-adenine dinucleotide phosphate (NADPH) cofactor transfers its pro-R hydride to the re face of the ketone. A series of phenyl ring-containing ketones, such as 4-phenyl-2-butanone (1a) and 1-phenyl-1,3-butadione (2a), were reduced with good to excellent yields and high enantioselectivities. On the other hand, 1-phenyl-2-propanone (7a) was reduced with lower ee than 2-butanone derivatives. (R)-Alcohols, the anti-Prelog products, were obtained by enantiospecific oxidation of (S)-alcohols through oxidative kinetic resolution of the rac-alcohols using W110A TESADH in Tris buffer/acetone (90:10, v/v).

Studies on Rhizopus arrhizus mediated enantioselective reduction of arylalkanones

The effect of substitution on the biotransformation of various arylalkanones using Rhizopus arrhizus was investigated. The organism was found to be promising for the reduction of phenylalkanones and arylethanones with good to excellent enantioselectivity. The reduction followed Prelog's rule giving the ( S)-carbinols in all the cases. The enantioselectivity of the reaction improved with increasing size of the groups flanking the carbonyl function and the electron withdrawing capacity of the substituents in the aromatic ring. However, the yield was dramatically affected with increased hydrophobicity of the substrates.

Asymmetric synthesis of ( S)-alkylamines via reductive transamination of ketones over carbon-supported palladium catalysts

Methylethylketone (MEK) and methoxyacetone (MEOAC) were transaminated with benzylamine (BzNH 2) or l-(−)-α-methylbenzylamine [ l-(−)-α-MeBzNH 2] over Pd/C catalysts in the presence of chiral modifiers ( l-alanine, l-alaninol, l-phenylalaninol, l-lysine and methyl-, t-butyl- and benzyl-esters of l-alanine) introduced either by incipient wetness impregnation or by equilibrated impregnation onto the catalyst surface. In the first step of the transamination the Schiff base was formed from the ketone and aralkylamine which was then hydrogenated to secondary amine in the second step. In the third step of the transamination the hydrogenolysis of the secondary amine resulting in primary alkylamine and a hydrocarbon was carried out. In the transamination of both MEK and MEOAC on Pd/C catalysts the highest enantiomeric excess was observed in cyclohexane (ee=−20%–21%) using l-alanine alkyl esters or l-alaninol as modifier. In different solvents the ee of the corresponding primary amine increased in the order: MeOH<Dioxan<H 2O<CH. Upon using ( l)-(−)-α-MeBzNH 2, as a chiral transaminating agent, ( S)-methoxyisopropylamine was obtained, with ee value around 70%. The conformational analysis of N-(methoxy-2-propylidene)-methylbenzylamine strongly supports the validity of Prelog's rule in the enantio- or diastereoselective hydrogenation of Schiff base over heterogeneous catalysts.

Absolute Stereochemistry of Soulattrolide and Its Analogues

The absolute stereochemistry of a group of dipyranocoumarins, some of which are potent inhibitors of HIV-1 reverse transcriptase, was examined. Soulattrolide {2H,6H,10H-benzo[1,2-b:3,4-b‘: 5,6-b‘‘]tripyran-2-one, 11,12-dihydro-12-hydroxy-6,6,10,11-tetramethyl-4-phenyl-, [10S-(10α,11β, 12β)]-; CAS Registry No. 65025-62-9} and cordatolide B, two of these dipyranocoumarins, were converted to α-methoxy-α-(trifluoromethyl)phenylacetate (MTPA) derivatives and investigated by 1H NMR spectroscopy. A correlation of 1H NMR chemical shift differences with those predicted by Mosher's concept alone was inadequate to assign confidently the absolute stereochemistries, due to the fact that in both of these molecules too few protons are present on one side of the MTPA plane. However, energetically favored conformations obtained by molecular mechanics calculations provided satisfactory rationalizations for the observed anisotropic shifts in 1H NMR data. The combined results of the two techniques allow us to assign the absolute configuration of both soulattrolide and cordatolide B as (10S,11R,12S). The absolute configurations of the other structurally related inhibitors, including inophyllums B, D, and P, costatolide, calanolides A, B, and C, and cordatolide A, are also assigned on the basis of chemical conversions and correlations of their chiroptical properties. Subtleties in the application of the Cahn−Ingold−Prelog rules to the designation of R or S configurations at some positions in these compounds make basically trivial errors particularly easy.

Adsorption of Chiral Alcohols on “Chiral” Metal Surfaces

Kink sites on high Miller index surfaces are either left- or right-handed and can be thought of as chiral, when the step lengths on either side of the kink site are unequal. A silver single crystal was oriented and cut to expose the Ag(643) surface on one side and the Ag(6̄4̄3̄) surface on the other side. A system is proposed for naming these surfaces as Ag(643)S and Ag(643)R, respectively , in analogy with the Cahn−Ingold−Prelog rules used in the nomenclature of organic stereoisomers. The left hand/right hand relationship of the two surfaces was manifested by the direction of the splitting of the low-energy electron diffraction (LEED) spots. The interaction of the enantiomers of a chiral alcohol ((R)-2-butanol and (S)-2-butanol) with each surface was studied using temperature-programmed desorption (TPD) measurements in order to ascertain the magnitude of the effect of surface chirality on the heats of adsorption. Desorption of the alcohols following exposure to the clean surfaces was molecular and exhibited first-order kinetics. No difference was observed between (R)- and (S)-2-butanol in either desorption temperature (225 K) or peak shape. Upon exposure to preoxidized surfaces, the alcohols deprotonated to form (R)- and (S)-2-butanoxide, both of which decomposed upon heating via β-hydride elimination. The decomposition product, 2-butanone, desorbed at 282 K. Again, no difference in the reaction kinetics of the enantiomeric alkoxides was observed on the two surfaces. From these results it can be concluded that the difference in (a) the heat of adsorption of the enantiomeric alcohols and (b) the difference in the energy barrier to β-hydride elimination for the enantiomeric alkoxides is less than 0.1 kcal/mol.

Stereoselectivity in the microbial reduction of (trifluoroacetyl)ferrocene and 2-fluoroacetophenones

Fluorine substitution on the methyl group of acetylferrocene and acetophenone strengthened anti-Prelog-type stereoselectivity in the microbial reduction with 6 strains of yeast ( e.g. , Rhodotorula rubra IFO 889) and one strain of bacterium. The cell-free extract of R. rubra was fractionated by polyacrylamide gel electrophoresis. Two fractions had prominent activity for NAD(P)H-dependent reduction of (trifluoroacetyl)ferrocene ( 1). One of the two fractions produced preferentially ( S )-2.2.2-trifluoro-1-hydroxyethylferrocene ( 2) as following Prelog's rule, while the other produced preferentially ( R )- 2 with the anti-Prelog-type stereoselectivity.

Stereoselectivity of the enzymatic reduction of aldehydic and ketonic carbonyl groups in planar chiral organomanganese complexes.

(±)-Tricarbonyl(η5-1-formyl-2-methylcyclopentadienyl)manganese (1) was optically resolved with horse liver alcohol dehydrogenase (HLADH) and two species of yeasts, Saccharomyces sp. H-1 and Rhodotorula rubra IFO 889. Usually, (1R)-1 was preferentially reduced to give (−)-alcohol 2 of ≥ 97% e.e. − 84% e.e. Ketone analogue (±)-tricarbonyl(η5-1-acetyl-2-methylcyclopentadienyl)-manganese (4) was reduced by the yeasts. The major product by S. sp. H-1 was the (1S,2R,1′S)-(+)-alcohol (5) (≥ 98% e.e.) and the minor product, the (1R,2S,1′S)-(−)-alcohol (6) (86% e.e.). R. rubra gave only the latter alcohol (≥ 99 % e.e.). The Stereodifferentiation mechanism for these bioreductions is discussed in terms of the Prelog rule. The mechanism for HLADH reduction was examined with computer graphics.

The in vitro ketone reduction of warfarin and analogues: Substrate stereoselectivity, product stereoselectivity and species differences

The in vitro metabolic ketone reduction of warfarin and its 4'-analogues acenocoumarol (4'-nitrowarfarin) and 4'-chlorowarfarin has been investigated using microsomal and cytosolic fractions of several species. Both subcellular fractions showed ketone reductase activity. The cytosolic fractions, in most species, exhibited strong substrate stereoselectivity as well as product stereoselectivity, i.e. the R(+)enantiomer was preferred as a substrate to be reduced mainly to the RS alcohol. Phenobarbital and methylcholanthrene induced cytosolic ketone reductase activity in the rat 5- to 11-fold and 3- to 7.4-fold, respectively. The microsomal fractions also showed substrate and product stereoselectivity. Contrary to the cytosolic fractions a general pattern for substrate and product stereoselectivity could not be seen. Stereoselectivity seemed species dependent (e.g. sheep vs bovine and pig). Rat liver microsomes showed practically no ketone reductase activity. Induction by phenobarbital or methylcholanthrene resulted in only a slight rise, if any, in rat microsomal ketone reductase activity. Both cytosolic and microsomal ketone reductases proved to be NADPH dependent. Substitution of the 4'-hydrogen of warfarin resulted in a change in reduction rates and in some cases, even in a change in substrate or product stereoselectivity. The data indicate that microsomal ketone reductases are different from cytosolic ketone reductases. Prelog's rule for product stereoselectivity of metabolic ketone reduction, when applied to the ketone reduction of the warfarin analogues did not agree with all data presented here.

The configurations of (−)-2,3,3-trimethyl-2-hydroxybutanoic acid, Me 3CC(Me)(OH)CO 2H, (−)-3,3,4-trimethyl-3-hydroxy-1-pentyne and (−)-3- [formula omitted]-butyl-3-methyl-1-chloroallene

The configurations of the title compounds are reassigned, based on stereoselective syntheses of the hydroxyacid and corresponding glycol and application of Cram's, Prelog's and Sharpless' rules.

The computational application of the Cahn–Ingold–Prelog rules 1 and 2

AbstractCahn–Ingold–Prelog (CIP) rules 1 and 2 (material differences) have been expressed in the formal logic of a high‐level computer language (FORTRAN IV) on a laboratory minicomputer (PDP 11/40) by the program CHIRAL. An oversight in the CIP formalism in the treatment of rings was treated on an ad hoc basis; the problem has been expressed simply in terms of elementary graph theory in a way consistent with and similar to chemical notation. An example of the operation of CHIRAL is provided and the internal procedures discussed.

Asymmetric reduction of .ALPHA.-ketoesters with sodium borohydride by chiral phase transfer catalysts.

Single and double asymmetric inductions were achieved by the sodium borohydride reduction of α-ketoesters in the presence of chirai phase transfer catalysts. The quaternary ammonium salts with hydroxyl group in the substituent moiety showed the effective catalytic activity. The reduction of (–)-(3R)-menthyl benzoylformate gave (3R)-menthyl (S)-mandelate in contrast to the prediction by the Prelog rule.

Asymmetric hydrogenation of unsaturated peptides.

Eleven unsaturated peptides, containing one or two dehydro-phenylalanyl (dehydro-Phe) residues and a C-terminal L-amino acid have been hydrogenated in the presence of palladium-on-charcoal. Hydrolysis of the saturated peptides thus obtained gave optically active phenylalanine showing the occurrence of asymmetric induction during the hydrogenation. Both mono-unsaturated dipeptides and doubly unsaturated tripeptides with L-Glu, L-Leu and L-Val as chiral end-group afforded L-Phe in 40-50% optical yield. In the case of the tripeptide N-acetyl-(dehydro-Phe)-(dehydro-Tyr)-L-Glu the asymmetric induction was higher (70%) for the unsaturated residue which is farther from the chiral end-group along the peptide chain. The results are discussed on the bases of Prelog rule and the rigid dissymmetric conformation of the dehydropeptides in solution.

Organomagnesien reactif reducteur : V. Induction asymetrique dans la reduction des esters chiraux α-β ethyleniques

Prelog's rule, predicting the stereoselectivity of nucleophilic addition to the α-ketoesters of chiral alcohols, is also applicable to the reduction of α,β-ethylenic esters by LiAlH 4, but this rule is no longer valid when organomagnesium halides are used as reducing agents. This difference between the two reactions is rationalized by the degree of complexation of the metallic ions of the two reducing agents in the transition states.