Baker's Yeast Mediated Reduction Research Articles

Chemo‐ and Stereoselective Reduction of β‐Keto‐α‐oximino Nitriles by Using Baker's Yeast

AbstractThe baker's yeast mediated reduction of β‐keto‐α‐oximino nitriles 3 at 20 °C gave β‐hydroxy‐α‐oximino nitriles 4 in high yields with high enantiomeric purity [enantiomeric excess (ee) values >99 %]. At room temperature, the same reaction afforded the product in a slightly lower yield. The β‐hydroxy‐α‐oximino nitriles 4 were obtained as single stereoisomers according to chiral GC–MS analyses and the 1H and 19F NMR spectra of the corresponding Mosher esters. The absolute stereochemistry of alcohol 4a was determined by hydrolysis of its oximino nitrile group followed by conversion into its corresponding α‐hydroxy ester. The β‐hydroxy‐α‐oximino nitrile products were further submitted to oxime‐ and nitrile‐selective transformations. This chemo‐ and stereoselective reduction can be used to generate important chiral building blocks.

ChemInform Abstract: Baker′s‐Yeast‐Mediated Reduction of Sulfur‐Containing Compounds

AbstractReview: 149 refs.

Enantioselective Synthesis of Natural Trinorsesquiterpene Tetralones by Chemo-enzymatic Approaches

The enantioselective syntheses of both the enantiomeric forms of the four natural tetralones 1a-d are here described. The aforementioned trinorsesquiterpenes were prepared starting either from substituted (S)-3-arylbutanols 5a-c or from substituted (S)-2-arylpropanols 7a-c. The latter chiral building blocks were in turn obtained through two different kinds of enzymatic transformations consisting of the baker's yeast mediated reduction of substituted (E)-3-aryl-but-2-enals 4a-c and the lipase-mediated resolution of racemic 2-arylpropanols 7a-c, respectively. Further key steps of the presented syntheses were C1 and C2 homologation procedures as well as the ring closure of the substituted 4-aryl-pentanoic acids 3a-c. By these means the target compounds were obtained in good yields and with very high stereoisomeric purity. In addition, the trinorsesquiterpene schiffnerone-B was synthesized for the first time and its absolute configuration was unambiguously assigned.

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

Abstract The Baker's Yeast (BY) reduction of ( Z )-2-chloromethyl-3-arylacrylaldehydes was found to afford ( R )-2-methyl-3-aryl-propanols showing high enantiomeric excess values. Deuterium incorporation experiments were performed, in order to investigate the mechanism of the bioreduction: the formation of the corresponding substituted 2-benzylacrylaldehydes, as intermediates to be effectively reduced by Baker's Yeast, was suggested. These intermediates were synthesized and submitted to BY reduction to afford the corresponding saturated ( R )-alcohols, thus confirming the conclusions drawn from labelling experiments. The enantioselectivity of their bioreduction was found to be opposite with respect to that observed for the corresponding regioisomeric 2-methylcinnamaldehydes. The preparation of the two enantiomers of 2-methyl-3-aryl-propanols by fermentation of two regioisomers represents an interesting example of substrate-controlled enantioselective reaction.

Stereoselective bioreduction of 1-(5-phenylfuran-2-yl)-ethanones mediated by baker's yeast

Baker's yeast mediated reduction of various phenylfuran-2-yl-ethanones has been studied. The influence of the reaction conditions, the type and position of the substituents, as well the presence of various additives on the enantiomeric composition of the products and the reaction yield are discussed. The absolute configuration of the reaction products was established using a retrosynthetic procedure.

Biocatalytic enantioselective approach to 3-aryl-2-nitropropanols: Synthesis of enantioenriched (R)-5-methoxy-3-aminochroman, a key precursor to the antidepressant drug Robalzotan

The results of our studies on the biocatalytic enantioselective synthesis of different 3-aryl-2-nitropropanols are presented. These compounds could be obtained in moderate to good ee both by baker's yeast mediated reduction of (E)-2-nitro-3-arylprop-2-en-1-ol precursors and by lipase kinetic resolution of racemic 3-aryl-2-nitropropanols. The synthesis of enantioenriched (R)-5-methoxy-3-aminochroman is also achieved. This important moiety is present in different molecules active toward the central nervous system and is also the precursor for the synthesis of Robalzotan (NAD299), a potent 5-HT1A antagonist.

Stereochemical Course of Baker's Yeast Mediated Reduction of the Tri‐ and Tetrasubstituted Double Bonds of Substituted Cinnamaldehydes

AbstractA comprehensive study of the stereochemical course of baker's yeast mediated reduction of substituted cinnamaldehydes is reported. Hydride addition to the β position of β‐methylcinnamaldehydes preferentially afforded isomers of (3S)‐3‐phenylbutan‐1‐ol. The reduction of (E)‐2,3‐dimethylcinnamaldehyde (15) produced a mixture of (2S,3S)‐ and (2R,3S)‐2‐methyl‐3‐phenylbutan‐1‐ol (13and14), respectively, with 93 %ee. Conversely (Z)‐2,3‐dimethylcinnamaldehyde (16) afforded a mixture of13and14with 33 %ee. Accordingly, the reduction of trisubstituted β‐methylcinnamaldehydes34and35proceeded with the same stereochemical preference and with higher enantioselectivity to give (S)‐3‐phenylbutan‐1‐ol (37). In addition, deuterium incorporation and2H NMR studies demonstrated that the addition of the second hydrogen atom to the α position proceeded with very low stereochemical control and the overall process is formally a mixture ofcis/transhydrogen addition to the double bond. Alternatively, α‐methylcinnamaldehyde is reduced to (S)‐2‐methyl‐3‐phenylpropan‐1‐ol (24) with preferential addition of the hydride to the opposite β face with good stereochemical control of thetransaddition of hydrogen to the double bond. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

A Chemoenzymatic, Preparative Synthesis of the Isomeric Forms of p‐Menth‐1‐en‐9‐ol: Application to the Synthesis of the Isomeric Forms of the Cooling Agent 1‐Hydroxy‐2,9‐cineole

AbstractA preparative‐scale synthesis of the four p‐menth‐1‐en‐9‐ol isomers 2a–5a has been achieved by means of two chemoenzymatic processes. Both synthetic pathways start from the enantiomeric forms of limonene that are converted into p‐mentha‐1,8‐dien‐9‐al isomers 12 and 15. The baker's yeast mediated reduction of the latter aldehydes afforded compounds 3a and 5a, respectively, with very high enantioselectivity. Moreover, chemical reduction of 12 and 15 gives the mixtures of enantiopure diastereoisomers 2a/3a and 4a/5a, respectively. PPL (Porcine pancreas lipase) mediated resolution of the latter mixtures followed by fractionating crystallization of derivatives 2b–5b allowed the enantio‐ and diastereoisomerically pure alcohols 2a–5a to be obtained. Compounds 2a–5a have then been used as starting materials for the preparation of four isomers of the cooling agent 1‐hydroxy‐2,9‐cineole (6–9). (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Baker's yeast mediated reduction of substituted acenaphthenequinones: Regio- and enantioselective preparation of mono-hydroxyacenaphthenones

Baker's yeast mediated reduction of acenaphthenequinone within 4–10 h afforded mono-hydroxyacenaphthenone mainly with low enantioselectivity, the substrate and mono-hydroxyacenaphthenone product almost converted to dihydroxyacenaphthene after 48 h. By control of the reaction time and in the presence of DMF as co-solvent, the reduction of 6-substituted acenaphthenequinones under vigorous agitation afforded the corresponding 2-hydroxyacenaphthenones in 24–84% yields with 10–93% ee.

Baker's Yeast Mediated Reduction of Optically Active Diketone

AbstractBaker's yeast mediated reduction of optically active diketone is described. The two keto pups are efficiently differentiated and the ee value of the recovered material is considerably raised. It affords highly optically active key intermediates efficiently for the synthesis of natural polyhydroxylated agarofuran products.

Baker's yeast mediated biohydrogenation of sulphur-functionalised methacrolein derivatives. Stereochemical aspects of the reaction and preparation of the two enantiomers of useful C 4 bifunctional chiral synthons

The baker's yeast mediated reduction of sulphur-functionalised methacroleins 11, 15 and 18 leads to the preparation of the bifunctional methyl branched C 4 chiral synthons 6 and 7. The stereochemical aspects of the biohydrogenation have been investigated. Both the oxidation state of sulphur and the isomeric position of the double bond affected the enantioselectivity of the reduction strongly, thus, offering access to the two enantiomeric forms of 6 and 7.

Baker's yeast mediated reduction of β-keto esters and β-keto amides in an organic solvent system

The baker's yeast mediated reduction of four β-keto esters in petroleum ether indicated that the size of the group attached to the keto carbon affected their reactivity. Ethyl 3-phenyl-3-oxopropanoate (1), which has a phenyl group directly attached to the keto carbon, is incompletely reduced using 20 g yeast/mmol substrate, ethyl 4-phenyl-3-oxobutanoate (2), which has one methylene group between the phenyl and keto carbon, was also incompletely reduced using 20 g yeast/mmol, although the extent of reduction was about double that of (1), ethyl 5-phenyl-3-oxopentanoate (3), which has two methylene groups between the phenyl and keto carbon, is completely reduced using 10 g yeast/mmol and ethyl 3-oxobutanoate (4), which has a methyl group attached to the keto carbon shows complete reduction using only 1 g yeast/mmol. The corresponding β-keto amides are considerably less reactive than the corresponding β-keto esters with only the amides derived from ethyl 3-oxobutanoate indicating any significant reduction using 20 g yeast/mmol.

Practical Production of (S)-1,2-Propanediol and Its Derivative through Baker's Yeast-Mediated Reduction.

The enantiomeric excess (ee) of (S)-1,2-propanediol produced by baker's yeast-mediated reduction of 1-acetoxy-2-propanone was improved to 96% ee by a fed-batch operation of the substrate. A similar reduction of 1-benzoyloxy-2-propanone stopped because of the inhibition toward the enzymes for NADPH regeneration by the reduction product. The inhibition was prevented using resin that adsorbs the product from the reaction mixture, and 70 g/l substrate was reduced yielding (S)-1-benzoyloxy-2-propanol at > 99% ee.

Practical production of ( S)-1,2-propanediol and its derivative through baker's yeast-mediated reduction

The enantiomeric excess (ee) of ( S)-1,2-propanediol produced by baker's yeast-mediated reduction of 1-acetoxy-2-propanone was improved to 96% ee by a fed-batch operation of the substrate. A similar reduction of 1-benzoyloxy-2-propanone stopped because of the inhibition toward the enzymes for NADPH regeneration by the reduction product. The inhibition was prevented using resin that adsorbs the product from the reaction mixture, and 70 g/ l substrate was reduced yielding ( S)-1-benzoyloxy-2-propanol at > 99% ee.

The baker's yeast-mediated reduction of conjugated methylene groups in an organic solvent

The baker's yeast-mediated reduction of a series of conjugated methylene compounds was conducted in a petroleum ether reaction system. The methylene ketone, 3-phenyl-3-buten-2-one (1), was stereoselectively reduced to (R)-3-phenyl-2-butanone; no reduction of the ketone carbonyl was observed. Reduction of 2-phenyl-2-propenenitrile (7) also occurred stereoselectively to give (R)-2-phenylpropanenitrile (8) in good yield. The yeast mediated reduction of the methylene aldehyde, 2-phenyl-2-propenal (3), gave a mixture of products arising from reduction of both the methylene and carbonyl groups; stereoselective reduction of the methylene group gives (R)-2-phenylpropanal (6) which is rapidly reduced to (R)-2-phenyl-1-propanol (5), whereas reduction of the carbonyl gives 2-phenyl-2-propen-1-ol (4) which is slowly reduced to racemic (5).

Baker's yeast activity in an organic solvent system

The baker's yeast mediated reduction of ethyl 3-oxobutanoate-3-13C in hexane was conducted in an NMR tube at 20°C and a 13C NMR spectrum recorded each hour. A plot of relative peak intensity against time allowed the progress of the reaction to be monitored. A series of reactions was carried out in which the yeast was pretreated with the organic solvent system for 3, 6, 12 and 24 h prior to the addition of the substrate. From the initial rate of these reactions it was determined that in hexane the enzyme activity remained constant for about 12 h and then rapidly decreased until after 24 h very little activity remained. The reaction was also carried out at 10°C and 30°C. At the lower temperature, the reaction was slower but enzyme activity was maintained for more than 60 h, while at 30°C the enzyme activity had ceased after 8 h.

Enantioselective synthesis of cyclic dialkyl (3-hydroxy-1-alkenyl) phosphonates by baker's yeast-mediated reduction of the corresponding enones

Cyclic dialkyl (3-oxo-1-cycloalkenyl) phosphonates were subjected to baker's yeast-mediated enantioselective reductions to afford the corresponding dialkyl (3-hydroxy-1-alkenyl) phosphonates. The six- and seven-membered ring enones were reduced with moderate to good enantiomeric excesses, whereas the five-membered ring substrate always yielded the double bond reduced compound. The use of different reduction conditions did not improve the ee's markedly, but it was found, for the six-membered analogues, that the alkyl groups held by phosphorus influence dramatically the enantioselectivity of the reduction, leading to up to 95% enantiomeric excess.

Baker’s yeast‐mediated synthesis of endo‐2‐cineolylol, a starting compound for potential cosmetic odourants

Baker's yeast-mediated reduction of (+)-1,3,3-trimethyl-2-oxabicyclo[2,2,2]octan-6-one yields the corresponding 1,3,3-trimethyl-2-oxabicyclo[2,2,2]octan-6-ol as endo configuration in optically pure form. To study the reaction behaviour we have developed a RP-HPLC method. The synthesis and the olfactive character of some esters obtained from the endo-2-cineolylol are reported. A comparative odour evaluation between these esters and the corresponding compounds synthesized from the endo-exo alcohol mixture was performed.

Dynamic kinetic resolution in the baker's yeast mediated reduction of 2-Benzenesulfonylcycloalkanones

2-Benzenesulfonylcyclopentanone 1 and cyclohexanone 2 undergo efficient dynamic kinetic resolution on treatment with baker's yeast, under a range of conditions including in organic solvents, to form the corresponding cis-2-benzenesulfonylcycloalkanols 5 and 6 in excellent enantiopurity. Reduction of larger ring derivatives is much less efficient.

Baker's yeast mediated reduction of dihydroxyacetone derivatives

Several monoprotected dihydroxyacetone derivatives 4a– d and their acetates 5a– d were prepared and subjected to biotransformation with baker's yeast. The simple chemical modification of the substrates (i.e. transforming the relatively small hydrophilic hydroxymethyl group into a larger hydrophobic acetoxymethyl moiety) inverted the sense of enantiotope selectivity of these reductions yielding optically active diols 6a– d, or their enantiomeric acetates ( 7a– d) and diols ( ent- 6a– d), respectively.