Ester Reductions Research Articles

A Bifunctional Copper Catalyst Enables Ester Reduction with H2: Expanding the Reactivity Space of Nucleophilic Copper Hydrides.

Employing a bifunctional catalyst based on a copper(I)/NHC complex and a guanidine organocatalyst, catalytic ester reductions to alcohols with H2 as terminal reducing agent are facilitated. The approach taken here enables the simultaneous activation of esters through hydrogen bonding and formation of nucleophilic copper(I) hydrides from H2, resulting in a catalytic hydride transfer to esters. The reduction step is further facilitated by a proton shuttle mediated by the guanidinium subunit. This bifunctional approach to ester reductions for the first time shifts the reactivity of generally considered "soft" copper(I) hydrides to previously unreactive "hard" ester electrophiles and paves the way for a replacement of stoichiometric reducing agents by a catalyst and H2.

Ruthenium-Catalyzed Ester Reductions Applied to Pharmaceutical Intermediates

Ruthenium pincer complexes were synthesized and used for catalytic ester reductions under mild conditions (∼5 bar of hydrogen). An experimental design approach was used to optimize the conditions f...

Chiral Brønsted Acids Catalyze Asymmetric Additions to Substrates that Are Already Protonated: Highly Enantioselective Disulfonimide-Catalyzed Hantzsch Ester Reductions of NH–Imine Hydrochloride Salts

While imines are frequently used substrates in asymmetric Brønsted acid catalysis, their corresponding salts are generally considered unsuitable reaction partners. Such processes are challenging because they require the successful competition of a catalytic amount of a chiral anion with a stoichiometric amount of an achiral one. We now show that enantiopure disulfonimides enable the asymmetric reduction of N–H imine hydrochloride salts using Hantzsch esters as hydrogen source. Our scalable reaction delivers crystalline primary amine salts in great efficiency and enantioselectivity and the discovery suggests potential of this approach in other Brønsted acid catalyzed transformations of achiral iminium salts. Kinetic studies and acidity data suggest a bifunctional catalytic activation mode.

Continuous-Flow Amide and Ester Reductions Using Neat Borane Dimethylsulfide Complex.

Reductions of amides and esters are of critical importance in synthetic chemistry, and there are numerous protocols for executing these transformations employing traditional batch conditions. Notably, strategies based on flow chemistry, especially for amide reductions, are much less explored. Herein, a simple process was developed in which neat borane dimethylsulfide complex (BH3⋅DMS) was used to reduce various esters and amides under continuous‐flow conditions. Taking advantage of the solvent‐free nature of the commercially available borane reagent, high substrate concentrations were realized, allowing outstanding productivity and a significant reduction in E‐factors. In addition, with carefully optimized short residence times, the corresponding alcohols and amines were obtained in high selectivity and high yields. The synthetic utility of the inexpensive and easily implemented flow protocol was further corroborated by multigram‐scale syntheses of pharmaceutically relevant products. Owing to its beneficial features, including low solvent and reducing agent consumption, high selectivity, simplicity, and inherent scalability, the present process demonstrates fewer environmental concerns than most typical batch reductions using metal hydrides as reducing agents.

La[N(SiMe3)2]3-Catalyzed Ester Reductions with Pinacolborane: Scope and Mechanism of Ester Cleavage

Tris[N,N-bis(trimethylsilyl)amido]lanthanum (LaNTMS) is an efficient, highly active, and selective homogeneous catalyst for ester reduction with pinacolborane (HBpin). Alkyl and aryl esters are cle...

Stabilization of NaBH4 in Methanol Using a Catalytic Amount of NaOMe. Reduction of Esters and Lactones at Room Temperature without Solvent-Induced Loss of Hydride.

Rapid reaction of NaBH4 with MeOH precludes its use as a solvent for large-scale ester reductions. We have now learned that a catalytic amount of NaOMe (5 mol %) stabilizes NaBH4 solutions in methanol at 25 °C and permits the use of these solutions for the reduction of esters to alcohols. The generality of this reduction method was demonstrated using 22 esters including esters of naturally occurring chiral γ-butyrolactone containing dicarboxylic acids. This method permits the chemoselective reductions of esters in the presence of cyano and nitro groups and the reductive cyclization of a pyrrolidinedione ester to a fused five-membered furo[2,3-b]pyrrole and a (-)-crispine A analogue in high optical and chemical yields. Lactones, aliphatic esters, aromatic esters containing electron-withdrawing groups, and heteroaryl esters are reduced more rapidly than aryl esters containing electron-donating groups. The 11B NMR spectrum of the NaOMe-stabilized NaBH4 solutions showed a minor quartet due to monomethoxyborohydride (NaBH3OMe) that persisted up to 18 h at 25 °C. We postulate that NaBH3OMe is probably the active reducing agent. In support of this hypothesis, the activation barrier for hydride transfer from BH3(OMe)- onto benzoic acid methyl ester was calculated as 18.3 kcal/mol.

Highly efficient and chemoselective zinc-catalyzed hydrosilylation of esters under mild conditions.

A mild and highly efficient catalytic hydrosilylation protocol for room-temperature ester reductions has been developed using diethylzinc as the catalyst. The methodology is operationally simple, displays high functional group tolerance and provides for a facile access to a broad range of different alcohols in excellent yields.

Systematic investigation of Saccharomyces cerevisiae enzymes catalyzing carbonyl reductions.

Eighteen key reductases from baker's yeast (Saccharomyces cerevisiae) have been overproduced in Escherichia coli as glutathione S-transferase fusion proteins. A representative set of alpha- and beta-keto esters was tested as substrates (11 total) for each purified fusion protein. The stereoselectivities of beta-keto ester reductions depended both on the identity of the enzyme and the substrate structure, and some reductases yielded both L- and D-alcohols with high stereoselectivities. While alpha-keto esters were generally reduced with lower enantioselectivities, it was possible in all but one case to identify pairs of yeast reductases that delivered both alcohol antipodes in optically pure form. Taken together, the results demonstrate not only that individual yeast reductases can be used to supply important chiral building blocks, but that GST-fusion proteins allow rapid identification of synthetically useful biocatalysts (along with their corresponding genes).

Purification and Identification of an Escherichiacoli β‐Keto Ester Reductase as 2,5‐Diketo‐d‐gluconate Reductase YqhE

An NADPH-dependent enzyme that reduces ethyl 2-methylacetoacetate stereoselectively to ethyl (2R)-methyl-(3S)-hydroxybutanoate was purified 730-fold from Escherichia coli. The N-terminal amino acid sequence data obtained from the purified reductase were used to search the E. coli genome, and a single match was found at the start of the yqhE open reading frame. The YqhE protein had been identified previously by Yum et al. as a 2,5-diketo-D-gluconate reductase on the basis of sequence similarity to other bacterial homologues [Yum, D.-Y.; Lee, B.-Y.; Pan, J.-G. Appl.Environ. Microbiol. 1999, 65, 3341-3346]; however, it had not been examined for beta-keto ester reductions. Our results thus link a key enzyme in the microbial production of ascorbate with stereoselective beta-keto ester reductions, two important fields in biocatalysis. The purified YqhE reductase accepts ethyl acetoacetate and a variety of 2-substituted derivatives, and its sequence is similar to other aldose reductase superfamily members that also reduce alpha-substituted beta-keto esters to syn-(2R,3S) alcohols.

Highly stereoselective reagents for beta-keto ester reductions by genetic engineering of baker's yeast.

While whole cells of baker's yeast (Saccharomyces cerevisiae) are a convenient biocatalytic reducing agent for a wide variety of carbonyl compounds, mixtures of stereoisomeric alcohols are often observed since the organism contains a large number of reductase enzymes with overlapping substrate specificities but differing stereoselectivities. We sought to improve the performance of baker's yeast for beta-keto ester reductions by using recombinant DNA techniques to alter the levels of three enzymes known to play important roles in these reactions (fatty acid synthase, Fasp; aldo-keto reductase, Ypr1p; alpha-acetoxy ketone reductase, Gre2p). A complete set of "first-generation" yeast strains that either lack or overexpress each of these three enzymes was created and tested for improvements in stereoselective reductions of a series of beta-keto esters. On the basis of these results, multiply modified ("second-generation") strains were created that combined gene knockout and overexpression in single strains. In some cases, these additional modifications further improved the stereoselectivities of beta-keto ester reductions, thereby making several beta-hydroxy ester building blocks readily available by reactions that can be performed by nonspecialists. This work also revealed that additional yeast proteins participate in reducing beta-keto esters, and further progress using this strategy will require either additional genetic manipulations or the expression of yeast reductases in hosts that lack enzymes with overlapping substrate specificity.

ChemInform Abstract: Preparative β‐Keto Ester Reductions and Ester Hydrolyses by Yeast, Using Free Cells in Organic Media.

ChemInformVolume 21, Issue 17 Other Subjects ChemInform Abstract: Preparative β-Keto Ester Reductions and Ester Hydrolyses by Yeast, Using Free Cells in Organic Media. T. HAAG, T. HAAG Lab. Org. Chem., ETH-Zentrum, 8092 Zuerich, SwitzerlandSearch for more papers by this authorT. ARSLAN, T. ARSLAN Lab. Org. Chem., ETH-Zentrum, 8092 Zuerich, SwitzerlandSearch for more papers by this authorD. SEEBACH, D. SEEBACH Lab. Org. Chem., ETH-Zentrum, 8092 Zuerich, SwitzerlandSearch for more papers by this author T. HAAG, T. HAAG Lab. Org. Chem., ETH-Zentrum, 8092 Zuerich, SwitzerlandSearch for more papers by this authorT. ARSLAN, T. ARSLAN Lab. Org. Chem., ETH-Zentrum, 8092 Zuerich, SwitzerlandSearch for more papers by this authorD. SEEBACH, D. SEEBACH Lab. Org. Chem., ETH-Zentrum, 8092 Zuerich, SwitzerlandSearch for more papers by this author First published: April 24, 1990 https://doi.org/10.1002/chin.199017300AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume21, Issue17April 24, 1990 RelatedInformation

Chemistry of amino acids. 3. Reduction of phenylalanine ethyl ester and its derivatives with sodium borohydride.

Eleven kinds of ethyl 2-substituted-3-phenylpropionates (Ia∼k) were reduced with sodium borohydride under a similar reaction condition and the effects of the α-substituents on the reduction were examined. Some esters (Ia∼c, e, f, j, k) were hydrolyzed with alkali. The obtained data of hydrolysis rate constants were roughly parallel to those of ester reductions. These results may be explained by considering both inductive and steric effects of the α-substituents.