Synthesis Of Chiral Amino Alcohols Research Articles

Co-immobilization of amine dehydrogenase and glucose dehydrogenase for the biosynthesis of (S)-2-aminobutan-1-ol in continuous flow

Reductive amination by amine dehydrogenases is a green and sustainable process that produces only water as the by-product. In this study, a continuous flow process was designed utilizing a packed bed reactor filled with co-immobilized amine dehydrogenase wh84 and glucose dehydrogenase for the highly efficient biocatalytic synthesis of chiral amino alcohols. The immobilized amine dehydrogenase wh84 exhibited better thermo-, pH and solvent stability with high activity recovery. (S)-2-aminobutan-1-ol was produced in up to 99% conversion and 99% ee in the continuous flow processes, and the space-time yields were up to 124.5 g L-1 d-1. The continuous reactions were also extended to 48 h affording up to 91.8% average conversions. This study showcased the important potential to sustainable production of chiral amino alcohols in continuous flow processes.

Biosynthesis of Chiral Amino Alcohols via an Engineered Amine Dehydrogenase in E. coli.

Chiral amino alcohols are prevalent synthons in pharmaceuticals and synthetic bioactive compounds. The efficient synthesis of chiral amino alcohols using ammonia as the sole amino donor under mild conditions is highly desired and challenging in organic chemistry and biotechnology. Our previous work explored a panel of engineered amine dehydrogenases (AmDHs) derived from amino acid dehydrogenase (AADH), enabling the one-step synthesis of chiral amino alcohols via the asymmetric reductive amination of α-hydroxy ketones. Although the AmDH-directed asymmetric reduction is in a high stereoselective manner, the activity is yet fully excavated. Herein, an engineered AmDH derived from a leucine dehydrogenase from Sporosarcina psychrophila (SpAmDH) was recruited as the starting enzyme, and the combinatorial active-site saturation test/iterative saturation mutagenesis (CAST/ISM) strategy was applied to improve the activity. After three rounds of mutagenesis in an iterative fashion, the best variant wh84 was obtained and proved to be effective in the asymmetric reductive amination of 1-hydroxy-2-butanone with 4-fold improvements in k cat /K m and total turnover number (TTN) values compared to those of the starting enzyme, while maintaining high enantioselectivity (ee >99%) and thermostability (T 50 15 >53°C). In preparative-scale reaction, the conversion of 100 and 200 mM 1-hydroxy-2-butanone catalyzed by wh84 was up to 91–99%. Insights into the source of an enhanced activity were gained by the computational analysis. Our work expands the catalytic repertoire and toolbox of AmDHs.

Enantioselective radical C-H amination for the synthesis of β-amino alcohols.

Asymmetric, radical C–H functionalizations are rare, yet powerful tools for solving modern synthetic challenges. Specifically, the enantio- and regio-selective C–H amination of alcohols to access medicinally valuable, chiral β-amino alcohols remains elusive. To solve this challenge, a radical relay chaperone strategy was designed, wherein an alcohol is transiently converted to an imidate radical that undergoes intramolecular H-atom transfer (HAT). This regioselective HAT was also rendered enantioselective by harnessing energy transfer catalysis to mediate selective radical generation and interception by a chiral copper catalyst. The successful development of this multi-catalytic, asymmetric, radical C–H amination enables broad access to chiral β-amino alcohols from a variety of alcohols containing alkyl, allyl, benzyl, and propargyl C–H bonds. Mechanistic experiments reveal triplet energy sensitization of a Cu-bound radical precursor facilitates catalyst-mediated HAT stereoselectivity – enabling the synthesis of several important classes of chiral β-amines by enantioselective, radical C–H amination.

Enzymatic Cascade Reactions for the Synthesis of Chiral Amino Alcohols from L-lysine

Amino alcohols are versatile compounds with a wide range of applications. For instance, they have been used as chiral scaffolds in organic synthesis. Their synthesis by conventional organic chemistry often requires tedious multi-step synthesis processes, with difficult control of the stereochemical outcome. We present a protocol to enzymatically synthetize amino alcohols starting from the readily available L-lysine in 48 h. This protocol combines two chemical reactions that are very difficult to conduct by conventional organic synthesis. In the first step, the regio- and diastereoselective oxidation of an unactivated C-H bond of the lysine side-chain is catalyzed by a dioxygenase; a second regio- and diastereoselective oxidation catalyzed by a regiodivergent dioxygenase can lead to the formation of the 1,2-diols. In the last step, the carboxylic group of the alpha amino acid is cleaved by a pyridoxal-phosphate (PLP) decarboxylase (DC). This decarboxylative step only affects the alpha carbon of the amino acid, retaining the hydroxy-substituted stereogenic center in a beta/gamma position. The resulting amino alcohols are therefore optically enriched. The protocol was successfully applied to the semipreparative-scale synthesis of four amino alcohols. Monitoring of the reactions was conducted by high performance liquid chromatography (HPLC) after derivatization by 1-fluoro-2,4-dinitrobenzene. Straightforward purification by solid-phase extraction (SPE) afforded the amino alcohols with excellent yields (93% to >95%).

Enzymatic Cascade Reactions for the Synthesis of Chiral Amino Alcohols from L-lysine.

Amino alcohols are versatile compounds with a wide range of applications. For instance, they have been used as chiral scaffolds in organic synthesis. Their synthesis by conventional organic chemistry often requires tedious multi-step synthesis processes, with difficult control of the stereochemical outcome. We present a protocol to enzymatically synthetize amino alcohols starting from the readily available L-lysine in 48 h. This protocol combines two chemical reactions that are very difficult to conduct by conventional organic synthesis. In the first step, the regio- and diastereoselective oxidation of an unactivated C-H bond of the lysine side-chain is catalyzed by a dioxygenase; a second regio- and diastereoselective oxidation catalyzed by a regiodivergent dioxygenase can lead to the formation of the 1,2-diols. In the last step, the carboxylic group of the alpha amino acid is cleaved by a pyridoxal-phosphate (PLP) decarboxylase (DC). This decarboxylative step only affects the alpha carbon of the amino acid, retaining the hydroxy-substituted stereogenic center in a beta/gamma position. The resulting amino alcohols are therefore optically enriched. The protocol was successfully applied to the semipreparative-scale synthesis of four amino alcohols. Monitoring of the reactions was conducted by high performance liquid chromatography (HPLC) after derivatization by 1-fluoro-2,4-dinitrobenzene. Straightforward purification by solid-phase extraction (SPE) afforded the amino alcohols with excellent yields (93% to >95%).

Heterogeneous Catalytic Hydrogenation of Chiral Amino Acid Methyl Esters to Amino Alcohols with Retention of Configuration Over Mg-Modified Cu/ZnO/Al2O3 Catalyst

Selective hydrogenation of amino acid methyl esters to chiral amino alcohols is an important and fascinating process. The CuZn0.3Mg0.1AlOx catalyst for the synthesis of chiral amino alcohols was prepared by the fractional co-precipitation method in the 50–100 g scale. The effect of the reduction gas on the catalytic activity, and the effects of the reaction conditions (R-p-m/Cat, temperature, reaction time, H2 pressure and solvent) on the catalytic hydrogenation of R-phenylglycine methyl ester (marked as R-p-m) were investigated. When R-p-m in the ethanol solvent was hydrogenated at 5 MPa of H2 and 80 °C for 10 h over this catalyst reduced by H2, 87.7% yield of R-phenylglycinol with ~ 100% ee value was obtained, and its reaction activation energy (Ea) was 36.7 kJ/mol. After repeated usage 16 times, its catalytic activity was hardly varied. Using this catalyst to catalyze the preparation of other amino alcohols, the high yield of product with ~100% ee value was obtained also.

Biocatalytic Approaches towards the Synthesis of Chiral Amino Alcohols from Lysine: Cascade Reactions Combining alpha‐Keto Acid Oxygenase Hydroxylation with Pyridoxal Phosphate‐ Dependent Decarboxylation

AbstractAmino alcohols are a very common structural motif in natural and synthetic molecules. Starting from l‐lysine and hydroxy‐l‐lysine, a straightforward biocatalytic synthesis of beta‐ and gamma‐amino alcohols is presented. Diastereoselective C–H oxidation catalyzed by an alpha‐keto acid‐dependent oxygenase followed by cleavage of the carboxylic acid moiety of the corresponding chiral hydroxy amino acid by a pyridoxal phosphate‐dependent decarboxylase enabled the formation of the target amino alcohols with moderate to complete conversions. Four beta‐ and gamma‐amino alcohols were obtained on a small scale in excellent yields and stereoselectivities.magnified image

Stereodivergent Synthesis of Chiral Amino Alcohols by Copper(I) Catalyst

Stereodivergent Synthesis of Chiral Amino Alcohols by Copper(I) Catalyst

Identification of novel thermostable taurine-pyruvate transaminase from Geobacillus thermodenitrificans for chiral amine synthesis.

ω-Transaminases (ω-TAs) are one of the most popular candidate enzymes in the biosynthesis of chiral amines. Determination of yet unidentified ω-TAs is important to broaden their potential for synthetic application. Taurine-pyruvate TA (TPTA, EC 2.6.1.77) is an ω-TA belonging to class III of TAs. In this study, we cloned a novel thermostable TPTA from Geobacillus thermodenitrificans (TPTAgth) and overexpressed it in Escherichia coli. The enzyme showed the highest activity at pH 9.0 and 65 °C, with remarkable thermostability and tolerance toward organic solvents. Its K M and v max values for taurine were 5.3 mM and 0.28 μmol s(-1) mg(-1), respectively. Determination of substrate tolerance indicated its broad donor and acceptor ranges for unnatural substrates. Notably, the enzyme showed relatively good activity toward ketoses, suggesting its potential for catalyzing the asymmetric synthesis of chiral amino alcohols. The active site of TPTAgth was identified by performing protein sequence alignment, three-dimensional structure simulation, and coenzyme pyridoxamine phosphate docking. The protein sequence and structure of TPTAgth were similar to those of TAs belonging to the 3N5M subfamily. Its active site was found to be its special large pocket and substrate tunnel. In addition, TPTAgth showed a unique mechanism of sulfonate/α-carboxylate recognition contributed by Arg163 and Gln160. We also determined the protein sequence fingerprint of TPTAs in the 3N5M subfamily, which involved Arg163 and Gln160 and seven additional residues from 413 to 419 and lacked Phe/Tyr22, Phe85, and Arg409.

A Selective Transformation of Enals into Chiral γ-Amino Alcohols

A one-pot synthesis of chiral amino alcohols from α,β-unsaturated aldehydes is reported which circumvents competitive 1,2- versus 1,4-boryl addition, by means of using a sterically hindered amine-derived imine. In addition to the complete chemoselectivity, modification of the Cu(I) catalyst with readily available chiral diphosphines, such as (R)-DM-BINAP, gave the 1,4-boryl addition products with high levels of asymmetric induction.

Convenient Methods for the Synthesis of Chiral Amino Alcohols and Amines

Simple, convenient methods have been developed using readily available, easy-to-handle reagents to access a variety of chiral amino alcohols and amines, which have considerable potential for applications in asymmetric organic transformations. Scholars from this laboratory in India have made significant contributions to this field, which is the subject of the current review.

ChemInform Abstract: An Enantiopure Galactose Oxidase Model: Synthesis of Chiral Amino Alcohols Through Oxidative Kinetic Resolution Catalyzed by a Chiral Copper Complex.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Highly Enantioselective and Diastereoselective Synthesis of Chiral Amino Alcohols by Ruthenium‐Catalyzed Asymmetric Hydrogenation of α‐Amino Aliphatic Ketones.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Highly Efficient Small Organic Molecules for Enantioselective Direct Aldol Reaction in Organic and Aqueous Media

A series of highly efficient organocatalysts have been derived from naturally available amino acids for carrying out enantioselective direct aldol reaction in both organic and aqueous medium. The aldol products were obtained in high diastereoselectivities (up to 99:1) and enantioselectivities (up to >99% ee) for a broader range of substrates using 1 mol % of a catalyst. The results demonstrate that the structural features of organocatalysts play a crucial role in obtaining high optical purity of aldol adducts in an aqueous medium. Further, the role of water in increasing the rate and enantioselectivity of the reaction has been illustrated. Moreover, the aldol products have been employed in the synthesis of chiral amino alcohols which act as useful intermediates for building up complex natural products.

Highly Enantioselective and Diastereoselective Synthesis of Chiral Amino Alcohols by Ruthenium-Catalyzed Asymmetric Hydrogenation of α-Amino Aliphatic Ketones

A highly efficient asymmetric hydrogenation of racemic acyclic alpha-amino aliphatic ketones via dynamic kinetic resolution has been realized, providing chiral amino alcohols in excellent enantioselectivities and diastereoselectivities. A hydrogen-bonding transition state mode was proposed for explaining the high diastereoselectivity and enantioselectivity of the reaction.

An enantiopure galactose oxidase model: synthesis of chiral amino alcohols through oxidative kinetic resolution catalyzed by a chiral copper complex

An enantiopure galactose oxidase (GO) enzyme model has been synthesized from readily available ( R)-BINAM and Cu(OTf) 2, and the enantiopure GO model has been effectively used in situ as an efficient chiral catalyst for the synthesis of chiral amino alcohols through oxidative kinetic resolution (OKR), where molecular oxygen is used as the sole oxidant. Under the proposed catalytic conditions, both ortho- and para-substituted amino alcohols were resolved with good to excellent enantiomeric excesses through oxidative kinetic resolution.

Asymmetric Hydrogenation of α‐Primary and Secondary Amino Ketones: Efficient Asymmetric Syntheses of (−)‐Arbutamine and (−)‐Denopamine

Two beta-receptor agonists (-)-denopamine and (-)-arbutamine were prepared in good yields and enantioselectivities by asymmetric hydrogenation of unprotected amino ketones for the first time by using Rh catalysts bearing electron-donating phosphine ligands. A series of alpha-primary and secondary amino ketones were synthesized and hydrogenated to produce various 1,2-amino alcohols in good yields and with good enantioselectivies. This Rh electron-donating phosphine-catalyzed asymmetric hyderogenation represents one of the most promising and convenient approaches towards the asymmetric synthesis of chiral amino alcohols.

One‐pot synthesis of amino‐alcohols using a de‐novo transketolase and β‐alanine: Pyruvate transaminase pathway in Escherichia coli

Biocatalysis continues to emerge as a powerful technique for the efficient synthesis of optically pure pharmaceuticals that are difficult to access via conventional chemistry. The power of biocatalysis can be enhanced if two or more reactions can be achieved by a single whole cell biocatalyst containing a pathway designed de-novo to facilitate a required synthetic sequence. The enzymes transketolase (TK) and transaminase (TAm) respectively catalyze asymmetric carbon--carbon bond formation and amine group addition to suitable substrate molecules. The ability of a transaminase to accept the product of the transketolase reaction can allow the two catalysts to be employed in series to create chiral amino-alcohols from achiral substrates. As proof of principle, the beta-alanine: pyruvate aminotransferase (beta-A:P TAm) from Pseudomonas aeruginosa has been cloned, to create plasmid pQR428, for overexpression in E.coli strain BL21gold(DE3). Production of the beta-A:P TAm alongside the native transketolase (overexpressed from plasmid pQR411), in a single E.coli host, has created a novel biocatalyst capable of the synthesis of chiral amino alcohols via a synthetic two-step pathway. The feasibility of using the biocatalyst has been demonstrated by the formation of a single diastereoisomer of 2-amino-1,3,4-butanetriol (ABT) product, in up to 21% mol/mol yield, by the beta-A:P TAm, via transamination of L-erythrulose synthesized by TK, from achiral substrates glycolaldehyde (GA) and beta-hydroxypyruvate (beta-HPA). ABT synthesis was achieved in a one-pot process, using either whole cells of the dual plasmid strain or cell lysate, while the dual alcohol-amine functionality of ABT makes it an excellent synthon for many pharmaceutical syntheses.

Simple and efficient synthesis of chiral amino alcohols with an amino acid-based skeleton

Sodium bis(2-methoxyethoxy)aluminum hydride, NaAlH2(OCH2CH2OCH3)2, commercially known as Vitride® or Red-Al®, enables rapid synthesis of pure optically activeN-protected amino alcohols and peptide alcohols in very high yields. The method is very simple and attractive, as it does not require an additional step ofN-protected amino acid derivatization and proceeds without the loss of enantiomeric homogeneity.

Simple and efficient synthesis of chiral amino alcohols with an amino acid-based skeleton

Simple and efficient synthesis of chiral amino alcohols with an amino acid-based skeleton