31087-44-2Relevant academic research and scientific papers
Discovery and Redesign of a Family VIII Carboxylesterase with High (S)-Selectivity toward Chiral sec-Alcohols
Park, Areum,Park, Seongsoon
, p. 2397 - 2402 (2022/02/17)
Highly enantioselective lipase has been widely utilized in the preparation of versatile enantiopure chiral sec-alcohols through kinetic or dynamic kinetic resolution. Lipase is intrinsically (R)-selective, and it is difficult to obtain (S)-selective lipase. Recent crystal structures of a family VIII carboxylesterase have revealed that the spatial array of its catalytic triad is the mirror image of that of lipase but with a catalytic triad that is distinct from lipase. We, therefore, hypothesized that the family VIII carboxylesterase may exhibit (S)-enantioselectivity toward sec-alcohols similar to (S)-selective serine protease, whose catalytic triad is also spatially arrayed as its mirror image. In this study, a homologous enzyme (carboxylesterase from Proteobacteria bacterium SG_bin9, PBE) of a known family VIII carboxylesterase (pdb code: 4IVK) was prepared, which showed not only moderate (S)-selectivity toward sec-alcohols such as 3-butyn-2-ol and 1-phenylethyl alcohol but also (R)-selectivity toward particular sec-alcohols among the substrates explored. Furthermore, the (S)-selectivity of PBE has been significantly improved by rational redesign based on molecular modeling. Molecular modeling identified a binding pocket composed of Ser381, Ala383, and Arg408 for the methyl substituent of (R)-1-phenylethyl acetate and suggested that larger residues may increase the enantioselectivity by interfering with the binding of the slow-reacting enantiomer. As predicted, substituting Ser381with larger residues (Phe, Tyr, and Trp) significantly improved the (S)-selectivity of PBE toward all sec-alcohols explored, even the substrates toward which the wild-type PBE exhibits (R)-selectivity. For instance, the enantioselectivity toward 3-butyn-2-ol and 1-phenylethyl alcohol was improved from E = 5.5 and 36.1 to E = 2001 and 882, respectively, by single mutagenesis (S381F).
Half-sandwich rhodium complex with ortho-position carborane benzoxazole structure as well as preparation method and application of half-sandwich rhodium complex
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Paragraph 0057-0062, (2021/03/24)
The invention relates to a half-sandwich rhodium complex with an ortho-position carborane benzoxazole structure as well as a preparation method and application of the half-sandwich rhodium complex. The structural formula of the rhodium complex is shown in the specification. The preparation method comprises the following steps: firstly, adding an n-BuLi solution into an ortho-position carborane solution, and then reacting for 30-60 minutes at room temperature; adding bromo-benzoxazole, and carrying out a reaction for 6-8 h at a room temperature; and adding [Cp * RhCl2] 2, reacting at room temperature for 3-5 hours, and carrying out post-treatment to obtain the rhodium complex. The rhodium complex can be used as a catalyst to catalyze the asymmetric reduction reaction of aliphatic chiral alcohol compounds synthesized from aliphatic ketones. Compared with the prior art, the rhodium complex disclosed by the invention has the advantages of simple preparation method, stable physicochemical properties, high catalytic activity for asymmetric reduction reaction of aliphatic ketone, mild reaction conditions and the like.
London Dispersion Interactions Rather than Steric Hindrance Determine the Enantioselectivity of the Corey–Bakshi–Shibata Reduction
Eschmann, Christian,Song, Lijuan,Schreiner, Peter R.
supporting information, p. 4823 - 4832 (2021/02/01)
The well-known Corey–Bakshi–Shibata (CBS) reduction is a powerful method for the asymmetric synthesis of alcohols from prochiral ketones, often featuring high yields and excellent selectivities. While steric repulsion has been regarded as the key director of the observed high enantioselectivity for many years, we show that London dispersion (LD) interactions are at least as important for enantiodiscrimination. We exemplify this through a combination of detailed computational and experimental studies for a series of modified CBS catalysts equipped with dispersion energy donors (DEDs) in the catalysts and the substrates. Our results demonstrate that attractive LD interactions between the catalyst and the substrate, rather than steric repulsion, determine the selectivity. As a key outcome of our study, we were able to improve the catalyst design for some challenging CBS reductions.
Facile Stereoselective Reduction of Prochiral Ketones by using an F420-dependent Alcohol Dehydrogenase
Martin, Caterina,Tjallinks, Gwen,Trajkovic, Milos,Fraaije, Marco W.
, p. 156 - 159 (2020/10/26)
Effective procedures for the synthesis of optically pure alcohols are highly valuable. A commonly employed method involves the biocatalytic reduction of prochiral ketones. This is typically achieved by using nicotinamide cofactor-dependent reductases. In this work, we demonstrate that a rather unexplored class of enzymes can also be used for this. We used an F420-dependent alcohol dehydrogenase (ADF) from Methanoculleus thermophilicus that was found to reduce various ketones to enantiopure alcohols. The respective (S) alcohols were obtained in excellent enantiopurity (>99 % ee). Furthermore, we discovered that the deazaflavoenzyme can be used as a self-sufficient system by merely using a sacrificial cosubstrate (isopropanol) and a catalytic amount of cofactor F420 or the unnatural cofactor FOP to achieve full conversion. This study reveals that deazaflavoenzymes complement the biocatalytic toolbox for enantioselective ketone reductions.
Enantioselective oxidation of secondary alcohols by the flavoprotein alcohol oxidase from Phanerochaete chrysosporium
Tjallinks, Gwen,Martin, Caterina,Fraaije, Marco W.
, (2021/05/03)
The enantioselective oxidation of secondary alcohols represents a valuable approach for the synthesis of optically pure compounds. Flavoprotein oxidases can catalyse such selective transformations by merely using oxygen as electron acceptor. While many flavoprotein oxidases preferably act on primary alcohols, the FAD-containing alcohol oxidase from Phanerochaete chrysosporium was found to be able to perform kinetic resolutions of several secondary alcohols. By selective oxidation of the (S)-alcohols, the (R)-alcohols were obtained in high enantiopurity. In silico docking studies were carried out in order to substantiate the observed (S)-selectivity. Several hydrophobic and aromatic residues in the substrate binding site create a cavity in which the substrates can comfortably undergo van der Waals and pi-stacking interactions. Consequently, oxidation of the secondary alcohols is restricted to one of the two enantiomers. This study has uncovered the ability of an FAD-containing alcohol oxidase, that is known for oxidizing small primary alcohols, to perform enantioselective oxidations of various secondary alcohols.
Biaryl diphosphine ligands and their ruthenium complexes: Preparation and use for catalytic hydrogenation of ketones
Abdur-Rashid, Kamaluddin,Abdur-Rashid, Kareem,Dasgupta, Tara,Jia, Wenli,Lorraine, Shannen,Maragh, Paul
, (2020/07/10)
Procedures for the preparation of the nucleophilic diphosphine ligands (R)-(4,4′,6,6′-tetramethoxybiphenyl-2,2′-diyl)bis(diphenylphosphine) ((R)-Ph-Garphos, 2a) and (S)-(4,4′,6,6′-tetramethoxybiphenyl-2,2′-diyl)bis(diphenylphosphine) ((S)-Ph-Garphos, 2b) were described. The ligands were used to prepare the ruthenium(II) Ph-Garphos complexes, chloro(p-cymene)(R)-(4,4′,6,6′-tetraamethoxybiphenyl-2,2′-diyl)bis(diphenylphosphine)ruthenium(II) chloride ([RuCl(p-cymene)(R)-Ph-Garphos]Cl (3)) and chloro(p-cymene)(S)-(4,4′,6,6′-tetraamethoxybiphenyl-2,2′-diyl)bis(diphenylphosphine)ruthenium(II) chloride ([RuCl(p-cymene)(S)-Ph-Garphos]Cl (4)). In the presence of the chiral diamine co-ligands (1R,2R)-1,2-diphenylethane-1,2-diamine (R,R-DPEN) and (1S,2S)-1,2-diphenylethane-1,2-diamine (S,S-DPEN), complexes 3 and 4 were found to be catalyst precursors for the enantioselective reduction of aryl ketones under mild conditions (room temperature and 3–4 atm of H2). The chiral alcohols were isolated in moderate to good yields and with enantioselectivities of up to 93percent. The ruthenium complexes chloro(p-cymene)(R)-(4,4′,6,6′-tetramethoxybiphenyl-2,2′-diyl)bis(bis(3,5-dimethylphenyl)-phosphine)ruthenium(II) chloride ([RuCl(p-cymene)(R)-Xyl-Garphos]Cl (5)) and chloro(p-cymene)(S)-(4,4′,6,6′-tetramethoxybiphenyl-2,2′-diyl)bis(bis(3,5-dimethylphenyl)-phosphine)ruthenium(II) chloride ([RuCl(p-cymene)(S)-Xyl-Garphos]Cl (6)) were also prepared and used as catalyst precursors for the hydrogenation of aryl ketones in the presence of (R,R)-DPEN and (S,S)-DPEN. Significant improvements in the enantioselectivities of the alcohols (up to 98percent ee.) were afforded. A combination of 6 and (S,S)-DPEN afforded (R)-1-(3-methoxyphenyl)ethanol in 89percent yield and with 95percent ee which was shown to be a suitable precursor for the preparation of (S)-rivastigmine.
Synthesis and electrochemical characterization of iminophosphine-based ruthenium(II) complexes and application in asymmetric transfer hydrogenation reaction as catalysts
Kele?, Mustafa,Kele?, Hülya,Y?lmaz, Mustafa Kemal
, p. 945 - 951 (2019/04/10)
A range of Ru(II) complexes have been prepared with chiral iminophosphine ligands ([(2-PPh2)C6H4CH=NCH(CH3)C6H5(4-R)]; R = –H, p-CH3, p-NO2) and characterized by 1H, 13C, 31P{1H} NMR and FTIR spectroscopy. The electrochemical properties of the [Ru(PN)2Cl2] complexes were investigated in ACN/TBAP solution with cyclic voltammetry and square wave voltammetry techniques. The use of chiral [Ru(PN)2Cl2] complexes as catalysts for the asymmetric transfer hydrogenation of aromatic and aliphatic ketones was studied in 2-propanol in an attempt to demonstrate the effect of substituents, which attached to the phenyl ring bonded to the nitrogen donor, on the catalytic activity and enantioselectivity. It was seen that the electronic effects of these substituents did not contribute to the catalytic efficiency of the ruthenium(II) catalysts.
Conformational Dynamics-Guided Loop Engineering of an Alcohol Dehydrogenase: Capture, Turnover and Enantioselective Transformation of Difficult-to-Reduce Ketones
Liu, Beibei,Qu, Ge,Li, Jun-Kuan,Fan, Wenchao,Ma, Jun-An,Xu, Yan,Nie, Yao,Sun, Zhoutong
, p. 3182 - 3190 (2019/05/15)
Directed evolution of enzymes for the asymmetric reduction of prochiral ketones to produce enantio-pure secondary alcohols is particularly attractive in organic synthesis. Loops located at the active pocket of enzymes often participate in conformational changes required to fine-tune residues for substrate binding and catalysis. It is therefore of great interest to control the substrate specificity and stereochemistry of enzymatic reactions by manipulating the conformational dynamics. Herein, a secondary alcohol dehydrogenase was chosen to enantioselectively catalyze the transformation of difficult-to-reduce bulky ketones, which are not accepted by the wildtype enzyme. Guided by previous work and particularly by structural analysis and molecular dynamics (MD) simulations, two key residues alanine 85 (A85) and isoleucine 86 (I86) situated at the binding pocket were thought to increase the fluctuation of a loop region, thereby yielding a larger volume of the binding pocket to accommodate bulky substrates. Subsequently, site-directed saturation mutagenesis was performed at the two sites. The best mutant, where residue alanine 85 was mutated to glycine and isoleucine 86 to leucine (A85G/I86L), can efficiently reduce bulky ketones to the corresponding pharmaceutically interesting alcohols with high enantioselectivities (～99% ee). Taken together, this study demonstrates that introducing appropriate mutations at key residues can induce a higher flexibility of the active site loop, resulting in the improvement of substrate specificity and enantioselectivity. (Figure presented.).
Highly Focused Library-Based Engineering of Candida antarctica Lipase B with (S)-Selectivity Towards sec-Alcohols
Cen, Yixin,Li, Danyang,Xu, Jian,Wu, Qiongsi,Wu, Qi,Lin, Xianfu
, p. 126 - 134 (2018/12/05)
Candida antarctica lipase B (CALB) is one of the most extensively used biocatalysts in both academia and industry and exhibits remarkable (R)-enantioselectivity for various chiral sec-alcohols. Considering the significance of tailor-made stereoselectivity in organic synthesis, a discovery of enantiocomplementary lipase mutants with high (R)- and (S)-selectivity is valuable and highly desired. Herein, we report a highly efficient directed evolution strategy, using only 4 representative amino acids, namely, alanine (A), leucine (L), lysine (K), tryptophan (W) at each mutated site to create an extremely small library of CALB variants requiring notably less screening. The obtained best mutant with three mutations W104V/A281L/A282K displayed highly reversed (S)-selectivity towards a series of sec-alcohol with E values up to 115 (conv. 50%, ee 94%). Compared with the previously reported (S)-selective CALB variant, W104A, a single mutation provided less selectivity, while the synergistic effects of three mutations in the best variant endow better (S)-selectivity and a broader substrate scope than the W104A variant. Structural analysis and molecular dynamics simulation unveiled the source of reversed enantioselectivity. (Figure presented.).
Homochiral Metal-Organic Cage for Gas Chromatographic Separations
Xie, Sheng-Ming,Fu, Nan,Li, Li,Yuan, Bao-Yan,Zhang, Jun-Hui,Li, Yan-Xia,Yuan, Li-Ming
, p. 9182 - 9188 (2018/07/21)
Metal-organic cages (MOCs) as a new type of porous material with well-defined cavities were extensively pursued because of their relative ease of synthesis and their potential applications in host-guest chemistry, molecular recognition, separation, catalysis, gas storage, and drug delivery. Here, we first reported that a homochiral MOC [Zn3L2] is explored to fabricate [Zn3L2] coated capillary column for high-resolution gas chromatographic separation of a wide range of analytes, including n-alkanes, polycyclic aromatic hydrocarbons, and positional isomers, especially for racemates. Various kinds of racemates such as alcohols, diols, epoxides, ethers, halohydrocarbons, and esters were separated with good enantioselectivity and reproducibility on the [Zn3L2] coated capillary column. The fabricated [Zn3L2] coated capillary column exhibited significant chiral recognition complementary to that of a commercial β-DEX 120 column and our recently reported homochiral porous organic cage CC3-R coated column. The results show that the homochiral MOCs will be very attractive as a new type of chiral selector in separation science.
