An Enantio‐ and Diastereoselective Chemoenzymatic Synthesis of α‐Fluoro β‐Hydroxy Carboxylic Esters

Howard, J. K.; Müller, Marion; Berry, Alan; Nelson, Adam

doi:10.1002/anie.201602852

Cited by 35 publications

(51 citation statements)

References 41 publications

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“…For reactions, conversions were >99 % by 19 F NMR spectroscopy. Additionally, the anti three-bond 1 H-19 F coupling constants were smaller (14)(15)(16)(17)(18)(19)(20) than the corresponding syn coupling constants (22)(23)(24), consistent with the literature. Additionally, the anti three-bond 1 H-19 F coupling constants were smaller (14)(15)(16)(17)(18)(19)(20) than the corresponding syn coupling constants (22)(23)(24), consistent with the literature.…”

Section: Resultssupporting

confidence: 90%

“…[13] Racemic ethyl-α-fluoroacetoacetate was hydrogenated over a Cinchona-modified Pt catalyst to favor (2S,2R)-α-fluoro--hydroxy ester in 82 % enantiomeric excess and a 99:1 anti/syn ratio. [15] There are numerous reports of KRED-catalyzed enantioselective reductions of -keto esters to -hydroxy esters possessing one chiral center. [15] There are numerous reports of KRED-catalyzed enantioselective reductions of -keto esters to -hydroxy esters possessing one chiral center.…”

Section: Introductionmentioning

confidence: 99%

“…[14] The aldolase-catalyzed reaction of fluoro pyruvate with aromatic and heteroaromatic aldehydes leads to syn α-fluoro -hydroxy carboxylic acids with high diastereo-and enantioselectivity. [15] There are numerous reports of KRED-catalyzed enantioselective reductions of -keto esters to -hydroxy esters possessing one chiral center. [16][17][18][19][20][21] KREDs have also been employed in the synthesis of α-alkylatedand α-chloro--hydroxy esters possessing two chiral centers (four stereoisomers).…”

Section: Introductionmentioning

confidence: 99%

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Stereoselective Reduction of α‐Fluoro‐β‐keto Esters by NADH and NADPH‐Dependent Ketoreductases

et al. 2019

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Racemic α‐fluoro‐β‐keto esters were stereoselectively transformed to α‐fluoro‐β‐hydroxy esters through dynamic reductive kinetic resolution (DYRKR) using commercially available NAD(P)H‐dependent ketoreductases. Aromatic, alkenyl, and alkyl substrates were all reduced in high optical purities and yields. For most substrates, either anti or syn diastereomers could be produced with high enantiomeric excess, depending on the enzyme employed. The enzyme reactions with ethyl α‐fluoroacetoacetate were conveniently monitored in real time by in situ 19F NMR spectroscopy. These commercially available enzymes provide convenient access to stereoisomers of α‐fluoro‐β‐hydroxy esters from easily accessible racemic substrates.

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Section: Resultssupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Stereoselective Reduction of α‐Fluoro‐β‐keto Esters by NADH and NADPH‐Dependent Ketoreductases

et al. 2019

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“…Aldolases are an important class of biocatalysts that are finding increasing uses in the synthesis of complex compounds (33); they are particularly useful in that they can create two stereochemical centers during their reaction (34,(44)(45)(46) and the reactions can be carried out in aqueous solvent without the use of protecting groups. However, the substrate specificity of natural aldolases often has to be engineered to produce enzymes with the required substrate specificity (33,47).…”

Section: Discussionmentioning

confidence: 99%

Extending enzyme molecular recognition with an expanded amino acid alphabet

Windle

Simmons

Ault

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Natural enzymes are constructed from the 20 proteogenic amino acids, which may then require posttranslational modification or the recruitment of coenzymes or metal ions to achieve catalytic function. Here, we demonstrate that expansion of the alphabet of amino acids can also enable the properties of enzymes to be extended. A chemical mutagenesis strategy allowed a wide range of noncanonical amino acids to be systematically incorporated throughout an active site to alter enzymic substrate specificity. Specifically, 13 different noncanonical side chains were incorporated at 12 different positions within the active site of N-acetylneuraminic acid lyase (NAL), and the resulting chemically modified enzymes were screened for activity with a range of aldehyde substrates. A modified enzyme containing a 2,3-dihydroxypropyl cysteine at position 190 was identified that had significantly increased activity for the aldol reaction of erythrose with pyruvate compared with the wild-type enzyme. Kinetic investigation of a saturation library of the canonical amino acids at the same position showed that this increased activity was not achievable with any of the 20 proteogenic amino acids. Structural and modeling studies revealed that the unique shape and functionality of the noncanonical side chain enabled the active site to be remodeled to enable more efficient stabilization of the transition state of the reaction. The ability to exploit an expanded amino acid alphabet can thus heighten the ambitions of protein engineers wishing to develop enzymes with new catalytic properties.protein engineering | aldolases | chemical modification E nzymes are phenomenally powerful catalysts that increase reaction rates by up to 10 18 -fold (1, 2), and a new era of enzyme applications has been opened by the advancement of protein engineering and directed evolution to provide new, or improved, enzymes for industrial biocatalysis. Enzymes are attractive catalysts because they are highly selective, carrying out regio-, chemo-, and stereoselective reactions that are challenging for conventional chemistry. Moreover, enzymes are efficient catalysts, function under mild conditions with relatively nontoxic reagents, and enable the production of relatively pure products, minimizing waste generation. In recent years, there has been much success in engineering enzymes for desired reactions (3-5) using methods such as rational protein engineering (6-8), directed evolution (9-11), and, most recently, computational enzyme design (12-15).Enzymes found in Nature achieve catalysis using active sites generally composed of only 20 canonical amino acids, which are encoded at the genetic level, plus the rarer selenocysteine and 1-pyrrolysine. However, many enzymes also rely on one or more of 27 small organic cofactor molecules and/or 13 metal ions for their function (16). In addition, in some cases, Nature has exploited noncanonical amino acids (Ncas) in catalysis to extend its catalytic repertoire: for example, the quinones TPQ, LTQ, TTQ, and CTQ, respectively, in ...

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“…[10] We now envisioned that F-MAHTs or esterified derivatives thereof (a-fluorinated monothiomalonates, F-MTMs) would also be valuable for Mannich-type reactions and provide direct access to activated a-fluorinated b-amino acids, which could be directly incorporated into peptides (Scheme 1).…”

mentioning

confidence: 99%

Stereoselective Organocatalyzed Synthesis of α‐Fluorinated β‐Amino Thioesters and Their Application in Peptide Synthesis

et al. 2016

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a-Fluorinated b-amino thioesters were obtained in high yields and stereoselectivities by organocatalyzed addition reactions of a-fluorinated monothiomalonates (F-MTMs) to N-Cbz-and N-Boc-protected imines. The transformation requires catalyst loadings of only 1 mol % and proceeds under mild reaction conditions. The obtained addition products were readily used for coupling-reagent-free peptide synthesis in solution and on solid phase. The a-fluoro-b-(carb)amido moiety showed distinct conformational preferences, as determined by crystal structure and NMR spectroscopic analysis.

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An Enantio‐ and Diastereoselective Chemoenzymatic Synthesis of α‐Fluoro β‐Hydroxy Carboxylic Esters

Cited by 35 publications

References 41 publications

Stereoselective Reduction of α‐Fluoro‐β‐keto Esters by NADH and NADPH‐Dependent Ketoreductases

Stereoselective Reduction of α‐Fluoro‐β‐keto Esters by NADH and NADPH‐Dependent Ketoreductases

Extending enzyme molecular recognition with an expanded amino acid alphabet

Stereoselective Organocatalyzed Synthesis of α‐Fluorinated β‐Amino Thioesters and Their Application in Peptide Synthesis

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