Carbene-catalyzed atroposelective synthesis of axially chiral styrenes

Axially chiral styrenes bearing a chiral axis between a sterically non-congested acyclic alkene and an aryl ring are difficult to prepare due to low rotational barrier of the axis. Disclosed here is an N-heterocyclic carbene (NHC) catalytic asymmetric solution to this problem. Our reaction involves ynals, sulfinic acids, and phenols as the substrates with an NHC as the catalyst. Key steps involve selective 1,4-addition of sulfinic anion to acetylenic acylazolium intermediate and sequential E-selective protonation to set up the chiral axis. Our reaction affords axially chiral styrenes bearing a chiral axis as the product with up to > 99:1 e.r., > 20:1 E/Z selectivity, and excellent yields. The sulfone and carboxylic ester moieties in our styrene products are common moieties in bioactive molecules and asymmetric catalysis.

Carbene-Catalyzed Atroposelective Synthesis of Axially Chiral Styrenes Bearing Acyclic Alkenes

Axially chiral styrenes bearing a chiral axis between a sterically non-congested acyclic alkene and an aryl ring are difficult to prepare due to low rotational barrier of the axis. Disclosed here is an N-heterocyclic carbene (NHC) catalytic asymmetric solution to this problem. Our reaction involves ynals, sulfinic acids, and phenols as the substrates with an NHC as the catalyst. Key steps involve selective 1,4-addition of sulfinic anion to acetylenic acylazolium intermediate and sequential E-selective protonation to set up the chiral axis. Our reaction affords axially chiral styrenes bearing a chiral axis as the product with up to >99:1 e.r., >20:1 E/Z selectivity, and excellent yields. The sulfone and carboxylic ester moieties in our styrene products are common moieties in bioactive molecules and asymmetric catalysis.

Construction of isoquinolinone framework from carboxylic ester directed umpolung ring opening of methylenecyclopropanes

An unprecedented reaction pattern of functionalized methylenecyclopropanes (MCPs) has been disclosed in this paper, in which the nucleophilic attack of anionic species onto partially polarity-reversed MCP unit can be realized...

Efficient Synthesis of New Fluorinated β-Amino Acid Enantiomers through Lipase-Catalyzed Hydrolysis

An efficient and novel enzymatic method has been developed for the synthesis of β-fluorophenyl-substituted β-amino acid enantiomers through lipase PSIM (Burkholderia cepasia) catalyzed hydrolysis of racemic β-amino carboxylic ester hydrochloride salts 3a–e in iPr2O at 45 °C in the presence of Et3N and H2O. Adequate analytical methods were developed for the enantio-separation of racemic β-amino carboxylic ester hydrochlorides 3a–e and β-amino acids 2a–e. Preparative-scale resolutions furnished unreacted amino esters (R)-4a–e and product amino acids (S)-5a–e with excellent ee values (≥99%) and good chemical yields (>48%).

Divergent Synthesis of Monosubstituted and Unsymmetrical 3,6- Disubstituted Tetrazines from Carboxylic Ester Precursors

As tetrazines are important tools to the field of bioorthogonal chemistry, there is a need for new approaches to synthesize unsymmetrical and 3-monosubstituted tetrazines. Described here is a general, one-pot method for converting (3methyloxetan-3-yl)methyl carboxylic esters into 3thiomethyltetrazines. These versatile intermediates were applied as a platform for the synthesis of unsymmetrical tetrazines via Pdcatalyzed cross-coupling and in the first example of catalytic thioether reduction to access monosubstituted tetrazines. The method enables the development of new tetrazines possessing a favorable combination of kinetics, small size and hydrophilicity. The chemistry was applied to a broad range of aliphatic and aromatic ester precursors and to the synthesis of heterocycles including BODIPY fluorophores and biotin. In addition, a series of tetrazine probes for monoacylglycerol lipase (MAGL) were synthesized and the most reactive one was applied in labeling of endogenous MAGL in live cells<br>

Divergent Synthesis of Monosubstituted and Unsymmetrical 3,6- Disubstituted Tetrazines from Carboxylic Ester Precursors

As tetrazines are important tools to the field of bioorthogonal chemistry, there is a need for new approaches to synthesize unsymmetrical and 3-monosubstituted tetrazines. Described here is a general, one-pot method for converting (3methyloxetan-3-yl)methyl carboxylic esters into 3thiomethyltetrazines. These versatile intermediates were applied as a platform for the synthesis of unsymmetrical tetrazines via Pdcatalyzed cross-coupling and in the first example of catalytic thioether reduction to access monosubstituted tetrazines. The method enables the development of new tetrazines possessing a favorable combination of kinetics, small size and hydrophilicity. The chemistry was applied to a broad range of aliphatic and aromatic ester precursors and to the synthesis of heterocycles including BODIPY fluorophores and biotin. In addition, a series of tetrazine probes for monoacylglycerol lipase (MAGL) were synthesized and the most reactive one was applied in labeling of endogenous MAGL in live cells<br>

Organic-Solvent-Tolerant Carboxylic Ester Hydrolases for Organic Synthesis

ABSTRACT Biocatalysis has emerged as an important tool in synthetic organic chemistry enabling the chemical industry to execute reactions with high regio- or enantioselectivity and under usually mild reaction conditions while avoiding toxic waste. Target substrates and products of reactions catalyzed by carboxylic ester hydrolases are often poorly water soluble and require organic solvents, whereas enzymes are evolved by nature to be active in cells, i.e., in aqueous rather than organic solvents. Therefore, biocatalysts that withstand organic solvents are urgently needed. Current strategies to identify such enzymes rely on laborious tests carried out by incubation in different organic solvents and determination of residual activity. Here, we describe a simple assay useful for screening large libraries of carboxylic ester hydrolases for resistance and activity in water-miscible organic solvents. We have screened a set of 26 enzymes, most of them identified in this study, with four different water-miscible organic solvents. The triglyceride tributyrin was used as a substrate, and fatty acids released by enzymatic hydrolysis were detected by a pH shift indicated by the indicator dye nitrazine yellow. With this strategy, we succeeded in identifying a novel highly organic-solvent-tolerant esterase from Pseudomonas aestusnigri. In addition, the newly identified enzymes were tested with sterically demanding substrates, which are common in pharmaceutical intermediates, and two enzymes from Alcanivorax borkumensis were identified which outcompeted the gold standard ester hydrolase CalB from Candida antarctica. IMPORTANCE Major challenges hampering biotechnological applications of esterases include the requirement to accept nonnatural and chemically demanding substrates and the tolerance of the enzymes toward organic solvents which are often required to solubilize such substrates. We describe here a high-throughput screening strategy to identify novel organic-solvent-tolerant carboxylic ester hydrolases (CEs). Among these enzymes, CEs active against water-insoluble bulky substrates were identified. Our results thus contribute to fostering the identification and biotechnological application of CEs.