Syn−Anti Isomerization of Aldols by Enolization

Ward, Dale E.; Sales, Marcelo Magalhães; Sasmal, Pradip K.

doi:10.1021/jo049626o

Cited by 29 publications

(21 citation statements)

References 53 publications

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“…In this system, each amino donor (1phenylethylamine (1), 1-aminotetralin (2), or 2-aminotetralin (3)) is added as pure (S)-or (R)-enantiomer in separate reactions. Pyruvate (4) acts as amino acceptor to form the corresponding ketones (6,7,8) in HEPES buffer (50 mm, pH 7.0 or 8.2) at 37 8C. mology structure and variants.…”

Section: Reversal Of Enantiomeric Preferencementioning

confidence: 99%

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Key Amino Acid Residues for Reversed or Improved Enantiospecificity of an ω‐Transaminase

et al. 2012

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Transaminases inherently possess high enantiospecificity and are valuable tools for stereoselective synthesis of chiral amines in high yield from a ketone and a simple amino donor such as 2‐propylamine. Most known ω‐transaminases are (S)‐selective and there is, therefore, a need of (R)‐selective enzymes. We report the successful rational design of an (S)‐selective ω‐transaminase for reversed and improved enantioselectivity. Previously, engineering performed on this enzyme group was mainly based on directed evolution, with few exceptions. One reason for this is the current lack of 3D structures. We have explored the ω‐transaminase from Chromobacterium violaceum and have used a homology modeling/rational design approach to create enzyme variants for which the activity was increased and the enantioselectivity reversed. This work led to the identification of key amino acid residues that control the activity and enantiomeric preference. To increase the enantiospecificity of the C. violaceum ω‐transaminase, a possible single point mutation (W60C) in the active site was identified by homology modeling. By site‐directed mutagenesis this enzyme variant was created and it displayed an E value improved up to 15‐fold. In addition, to reverse the enantiomeric preference of the enzyme, two other point mutations (F88A/A231F) were identified. This double mutation created an enzyme variant, which displayed substrate dependent reversed enantiomeric preference with an E value shifted from 3.9 (S) to 63 (R) for 2‐aminotetralin.

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Section: Reversal Of Enantiomeric Preferencementioning

confidence: 99%

“…This makes them useful for synthesis of chiral amines, which are of high importance as building blocks for production of pharmaceuticals. [1][2][3][4][5][6][7][8][9][10][11][12] For this, either enantiomer may be desired. By using protein engineering approaches, both the enantiomeric preference and the level of enantiospecificity of an enzyme can be altered.…”

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confidence: 99%

Key Amino Acid Residues for Reversed or Improved Enantiospecificity of an ω‐Transaminase

et al. 2012

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“…To determine the absolute configuration of the anti Mannich products, a modified syn-anti epimerization protocol was established by utilizing 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) instead of the more conventional imidazole; [10,21] due to the enhanced basicity of DBU, the isomerization process could be significantly improved in terms of reaction time (20 min instead of 17 h). [10] Thus, when the syn-11 product was epimerized at C3, all 4 possible diastereomers were obtained (B!A), whereas the reaction of (2S,3S)-11 (C!D) gave an equal amount of the two diastereomers (1:1) including (2S,3R)-11.…”

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confidence: 99%

(S)‐Indoline‐3‐Carboxylic Acid: A New Organocatalyst for the Anti Mannich‐Type Reaction

Pietruszka¹,

Simon²

2010

ChemCatChem

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The Mannich reaction [1] is a powerful method for generating ß-amino carbonyls or g-carbonyl-a-amino acid derivatives through CÀC bond formation, a structural motif common in natural-and pharmaceutical products. Furthermore, the asymmetric version of this reaction allows the creation of two adjacent stereogenic centers in one reaction step. Diastereoand enantioselective approaches were not just successfully investigated with organometallic species, [2] but also utilizing organocatalysts. [3] Due to the advantages of organocatalytic processes [4] over their metal-mediated counterparts (price, toxicity, availability, sensitivity to moisture), they have become a very powerful tool for the synthesis of chiral building blocks. [5] The most investigated catalyst in this area is the natural amino acid proline which catalyzes a broad range of various reactions, for example, inter-and intramolecular aldol-, Michael-, Henry-and cascade-reactions. [6] It has also been studied in the direct [7] and indirect [8] asymmetric Mannich-type reaction of unmodified carbonyl compounds yielding highly enantiomerically enriched syn products. Based on this concept, several other prolinebased derivatives were designed, most of them affording the syn isomers. [7a, 9] In 2002, Córdova and Barbas found that (S)-methoxymethylpyrrolidine (SMP; 1) was the first organocatalyst providing anti isomers in high enantiomeric excess (up to 92 %) and in good yield (up to 78 %). [10] Since then, considerable efforts have been devoted to finding other catalysts yielding anti-Mannich products in a highly diastereo-and enantioselective manner, but the reports are still limited; [11] highly effective catalysts are for example 3,4-bis(trifluoromethanesulfonamido)pyrrolidine [12] 2, 5-methyl-3-pyrrolidinecarboxylic acid [13] 3, and 3-pyrrolidine-carboxylic acid [14] 4, all affording the products in almost perfect diastereoand enantioselectivity. The stereochemical outcome of the reaction was explained by a boat-like transition state leading to a reversal of the facial selectivity (E-cis attack instead E-trans onto the electrophile). [12,13] Although some theoretical DFT studies were performed concerning the position of the acidic function [15a] (a versus b) and the stereoselectivity, [15b] the seminal work on the mechanism of proline catalysis by Seebach and co-workers [16] indicate that there might be an additional equilibrium between the enamine and the oxazolidine intermediate.Nevertheless, during the course of our studies on the application of biocatalysts in organic chemistry, [17] we recently

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“…To determine the absolute configuration of the anti isomers we used a method recently disclosed by our group; a syn – anti epimerisation of aldehydes with 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) as base 18. In contrast to previously described methods, which used imidazole as base for the epimerisation of various carbonyl compounds,24 a significant enhancement on the reaction rate was obtained (20 min versus 17 h) by changing the base, without effect on the outcome of the reaction. Although there is a major difference in the carbonyl activity of aldehydes and ketones, our method ought to be transferable to ketones.…”

Section: Resultsmentioning

confidence: 99%

Indoline‐3‐Carboxylic Acid Derived Organocatalysts for the anti‐Mannich Reaction

Pietruszka

Simon

2010

Chemistry A European J

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Mannich type reactions of a preformed aldimine with various carbonyl compounds were investigated with a series of functionalised indoline derivatives as catalysts: indoline-3-carboxylic acid, the diphenylcarbinol analogue and O-protected silyl ether analogues. All compounds were readily prepared in enantiopure form by using an enzymatic kinetic resolution as a key step (E≫100). The alcohol and ether catalysts failed to induce complete chirality transfer but did afford the Mannich bases in good yields and high diastereomeric ratios, whereas the acid catalyst gave the products in a highly diastereo- and enantioselective manner. The absolute configuration of the products was determined by a syn-anti isomerisation protocol, initiated by the sterically demanding base 1,8-diazabicyclo[5.4.0]undec-7-ene.

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Syn−Anti Isomerization of Aldols by Enolization

Cited by 29 publications

References 53 publications

Key Amino Acid Residues for Reversed or Improved Enantiospecificity of an ω‐Transaminase

Key Amino Acid Residues for Reversed or Improved Enantiospecificity of an ω‐Transaminase

(S)‐Indoline‐3‐Carboxylic Acid: A New Organocatalyst for the Anti Mannich‐Type Reaction

Indoline‐3‐Carboxylic Acid Derived Organocatalysts for the anti‐Mannich Reaction

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