Efficient kinetic bioresolution of 2-nitrocyclohexanol

Milner, Sinéad E.; Brossat, Maude; Moody, Thomas S.; Elcoate, Curtis J.; Lawrence, Simon E.; Maguire, Anita R.

doi:10.1016/j.tetasy.2010.05.006

Cited by 16 publications

(12 citation statements)

References 14 publications

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“…The first step required the investigation of a suitable catalyst for this enzymatic transformation (Table 11). [52] The final example describes the employment of both the direct enzyme-mediated nitroaldol addition and subsequent kinetic resolution of the nitroaldol products. Moreover, in combination with an increase of the amount of enzyme catalyst and temperature to 40°C, the conversion was driven to 46 % with conservation of enantiopurity.…”

Section: Enzymatic Kinetic Resolution Of the Products Of The Henry Rementioning

confidence: 99%

Biocatalytic Approaches to the Henry (Nitroaldol) Reaction

2012

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Enantiopure β‐nitro alcohols are key chiral building blocks for the synthesis of bioactive pharmaceutical ingredients. The preparation of these target compounds in optically pure form has been the focus of much research and there has been an emergence of biocatalytic protocols in the past decade. For the first time, these biotransformations are the focus of this review. Herein, we describe two principal biocatalytic approaches to the Henry (nitroaldol) reaction. The first method is a direct enzyme‐catalysed carbon–carbon bond formation resulting in either an enantio‐enriched or enantiopure β‐nitro alcohol. The second approach describes the Henry reaction without stereocontrol followed by a biocatalytic resolution to yield the enantiopure β‐nitro alcohol.

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Section: Enzymatic Kinetic Resolution Of the Products Of The Henry Rementioning

confidence: 99%

Biocatalytic Approaches to the Henry (Nitroaldol) Reaction

2012

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“…Milner et al. carried out the kinetic resolution of 2‐nitrocyclohexanol to prepare all four of its diastereomers . This method used hydrolase‐catalysed transesterification of 2‐nitrocyclohexanol and hydrolase‐catalysed hydrolysis of 2‐nitrocyclohexyl acetate but required 24 h …”

Section: Introductionmentioning

confidence: 99%

“…This analysis clearly indicates that lipase‐catalysed kinetic resolution of racemic β‐nitro alcohols suffers either from long reaction times—that is, 12 to 24 h (or in some cases up to 7 d)—or from the need for an additional step to deprotect acyl derivative products.…”

Section: Introductionmentioning

confidence: 99%

Production of (S)‐β‐Nitro Alcohols by Enantioselective C−C Bond Cleavage with an R‐Selective Hydroxynitrile Lyase

Rao

Padhi

2019

ChemBioChem

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Hydroxynitrile lyase (HNL)‐catalysed stereoselective synthesis of β‐nitro alcohols from aldehydes and nitroalkanes is considered an efficient biocatalytic approach. However, only one S‐selective HNL—Hevea brasiliensis (HbHNL)—exists that is appropriate for the synthesis of (S)‐β‐nitro alcohols from the corresponding aldehydes. Further, synthesis catalysed by HbHNL is limited by low specific activity and moderate yields. We have prepared a number of (S)‐β‐nitro alcohols, by kinetic resolution with the aid of an R‐selective HNL from Arabidopsis thaliana (AtHNL). Optimization of the reaction conditions for AtHNL‐catalysed stereoselective C−C bond cleavage of racemic 2‐nitro‐1‐phenylethanol (NPE) produced (S)‐NPE (together with benzaldehyde and nitromethane, largely from the R enantiomer) in up to 99 % ee and with 47 % conversion. This is the fastest HNL‐catalysed route known so far for the synthesis of a series of (S)‐β‐nitro alcohols. This approach widens the application of AtHNL for the synthesis not only of (R)‐ but also of (S)‐β‐nitro alcohols from the appropriate substrates. Without the need for the discovery of a new enzyme, but rather by use of a retro‐Henry approach, it was used to generate a number of (S)‐β‐nitro alcohols by taking advantage of the substrate selectivity of AtHNL.

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“…Hydrolase enzymes have been receiving increasing attention in the context of organic synthesis in the last decade. As biocatalysts, they provide substrate specificity with high regio- and enantio-selectivity and they enable the resolution of organic substrates with great efficiency and selectivity [ 13 , 14 , 15 ]. Lipases and proteases are the most utilised forms of hydrolytic enzymes, which demonstrate diverse substrate tolerance, stability in organic solvents and at elevated temperatures [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Bioactive Indanes: Proof of Concept Study for Enantioselective Synthetic Routes to PH46A, a New Potential Anti-Inflammatory Agent

Zhang¹,

Scalabrino²,

Frankish

et al. 2018

Molecules

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PH46A is a single enantiomer and a member of the 1,2-indane dimer family. It has two contiguous stereogenic centers with S,S configurations, one of which being a quaternary center, which has been developed as a clinical candidate for the treatment of inflammatory and autoimmune conditions. The current synthetic route to PH46A involves the generation of an unwanted enantiomer (R,R)-7, thus reducing the final yield significantly. Therefore, we have investigated potential alternatives to improve the efficiency of this synthesis. The first phase of the study has demonstrated proof of principle for a chiral alkylation of ketone 3 using phase-transfer catalysis, providing a key intermediate ketone (S)-4. The parent alkaloids required for the synthesis of PH46A, quinine or cinchonidine, have also been identified. Promising enantiomeric excesses of up to 50% have been achieved to date, and the use of an alternative substrate, unsaturated ketone 9, has also opened up further avenues for optimisation in future studies. The second part of the study involved preliminary screening the effects of a panel of hydrolase enzymes on (rac)-4 in order to identify a potential chemo-enzymatic route to optimise the introduction of chirality into PH46A at early stage of the synthesis. The hydrolase module has also yielded positive results; enzyme AH-46 with MtBE providing a selectivity factor of 8.4 with enantiomeric excess of 77%. Overall, positive results were obtained in this proof of concept study described herein. It is believed that conditions of both chiral PTC alkylation and biocatalytic hydrolysis could be optimised to further enhance the selectivity and improve the overall yield. This work is currently ongoing.

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Efficient kinetic bioresolution of 2-nitrocyclohexanol

Cited by 16 publications

References 14 publications

Biocatalytic Approaches to the Henry (Nitroaldol) Reaction

Biocatalytic Approaches to the Henry (Nitroaldol) Reaction

Production of (S)‐β‐Nitro Alcohols by Enantioselective C−C Bond Cleavage with an R‐Selective Hydroxynitrile Lyase

Bioactive Indanes: Proof of Concept Study for Enantioselective Synthetic Routes to PH46A, a New Potential Anti-Inflammatory Agent

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