Asymmetric Defluoroallylation of 4-Trifluoromethylpyridines Enabled by Umpolung C-F Bond Activation

Carbon-fluorine bond activation reaction of the trifluoromethyl group represent an important approach to fluorine-containing molecules. While selective defluorofunctionalization reactions of CF3-containing substrates have been achieved by invoking difluorocarbocation, difluorocarboradical, or difluoroorganometallic species as the key intermedi-ate, the transformations via fluorocarbanion mechanism remained a limited success. Furthermore, the enantioselective defluorotransformation of CF3 group has not yet been realized. Herein, we report a defluorofunctionalization reaction of 4-trifluoromethylpyridines involving pyridyldifluoromethyl anion as the key intermediate, which was developed based upon our previous studies on the N-boryl pyridyl anion chemistry. When combined with Ir-catalysis, asymmetric defluoroallylation of 4-trifluoromethylpyridines could be achieved to forge a difluoroalkyl-substituted chiral center. The present work opens up a new opportunity for the defluorofunctionalization of CF3 group, and provides new insights into the N-boryl pyridyl anion chemistry.

Deuterium Labelling to Extract Local Stereochemical Information by VCD Spectroscopy in C-D Stretching Region: A Case Study of Sugars

Stereochemical elucidation of molecules with multiple chiral centers is difficult. Even with VCD spectroscopy, excluding all but one diastereomeric structural candidates is challenging because stereochemical inversion of one chiral center...

Timeless Classics: on the Applicability of Bochvar's Three-Valued Logic B3 to the Description of an Absolute Configuration in Stereochemistry§ (Author's View)

t is shown that the absolute configuration of a chiral center can be successfully described in terms of Bochvar's three-valued logic.

Synthesis of α-deuterioalcohols by single-electron umpolung reductive deuteration of carbonyl using D2O as deuterium source

Deuterium incorporation can effectively stabilize the chiral centers of drug and agrochemical candidates that hampered by rapid in vivo racemization. In this work, the synthetically challenging chiral center deuteration of alcohols has been achieved via a single-electron umpolung reductive deuteration protocol using benign D2O as deuterium source and mild SmI2 as electron donor. The broad scope and excellent functional group tolerance of this method has been showcased by the synthesis of 43 respective α-deuterioalcohols in high yields and ≥98% deuterium incorporations. The potential application of this versatile method has been exemplified in the synthesis of 6 deuterated drug derivatives, 1 deuterated human hormone and 3 deuterated natural products. This method using D2O is greener and more efficient compared to traditional pyrophoric metal deuteride mediated reductive deuterations.

Studies in simultaneous generation of central and axial chirality via the Buchwald-Hartwig reaction.

The Buchwald-Hartwig reaction has been investigated previously by the Viirre group to show that intramolecular cyclization using palladium and (R)-(+)-2-(diphenylphosphino)-2′-methoxy-1,1′-binaphthyl, can instill enantioselectivity. This system was continued to show that steric bulk on the 2’ position on the phenyl ring attached to the nitrogen malonamide can lock the rotation ending in a chiral axis. The diastereomers resulting from this chiral axis can be selectively formed when the substrate is 2-(2-bromobenzyl)-N1,N3-bis(2-(tert-butyl)phenyl)-2-methylmalonamide and using a similar ligand (R)-dicyclohexyl(2'-methoxy-[1,1'-binaphthalen]-2-yl)phosphane with enantio- and diastereoselectivities of 88% and 99% respectively. The work presented in this thesis continues on this class of substrates to include N,1-Di([1,1'-biphenyl]-2-yl)-3-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamide, as well as a newer class of monoamide substrates. The monoamide substrates allowed the interpretation of events occurring in the Buchwald-Hartwig reaction, ultimately showing that the chiral center on the substrate has some control as to the outcome of the chiral axis. Lastly, a timed sampling kinetics experiment was done to investigate if the enantiomers of the starting material were being consumed at different rates or if one diastereomeric product was being produced favourably. The kinetics experiment shows that the system does not have a preference as to the starting material or product being produced.

Studies in simultaneous generation of central and axial chirality via the Buchwald-Hartwig reaction.

The Buchwald-Hartwig reaction has been investigated previously by the Viirre group to show that intramolecular cyclization using palladium and (R)-(+)-2-(diphenylphosphino)-2′-methoxy-1,1′-binaphthyl, can instill enantioselectivity. This system was continued to show that steric bulk on the 2’ position on the phenyl ring attached to the nitrogen malonamide can lock the rotation ending in a chiral axis. The diastereomers resulting from this chiral axis can be selectively formed when the substrate is 2-(2-bromobenzyl)-N1,N3-bis(2-(tert-butyl)phenyl)-2-methylmalonamide and using a similar ligand (R)-dicyclohexyl(2'-methoxy-[1,1'-binaphthalen]-2-yl)phosphane with enantio- and diastereoselectivities of 88% and 99% respectively. The work presented in this thesis continues on this class of substrates to include N,1-Di([1,1'-biphenyl]-2-yl)-3-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamide, as well as a newer class of monoamide substrates. The monoamide substrates allowed the interpretation of events occurring in the Buchwald-Hartwig reaction, ultimately showing that the chiral center on the substrate has some control as to the outcome of the chiral axis. Lastly, a timed sampling kinetics experiment was done to investigate if the enantiomers of the starting material were being consumed at different rates or if one diastereomeric product was being produced favourably. The kinetics experiment shows that the system does not have a preference as to the starting material or product being produced.

Synergistic Catalysis of Tandem Michael Addition/Enantioselective Protonation Reactions by an Artificial Enzyme

Enantioselective protonation is conceptually one of the most attractive methods to generate an α-chiral center. However, enantioselective protonation presents major challenges, especially in water as a solvent. Herein, we report an artificial enzyme catalyzed tandem Michael addition and enantioselective protonation reaction of α-substituted acroleins with 2-acyl imidazole derivatives in water. The artificial enzyme uses a synergistic combination of two abiological catalytic sites: a genetically encoded non-canonical p-aminophenylalanine residue and a Lewis acid Cu(II) complex. The exquisite stereochemical control achieved in the protonation of the transient enamine intermediate generated by conjugate addition of the Michael donor is illustrated by the >20:1 dr and up to >99% ee obtained for the products. These results illustrate the potential of exploiting synergistic catalysis in artificial enzymes for challenging reactions.<br>

Synergistic Catalysis of Tandem Michael Addition/Enantioselective Protonation Reactions by an Artificial Enzyme

Enantioselective protonation is conceptually one of the most attractive methods to generate an α-chiral center. However, enantioselective protonation presents major challenges, especially in water as a solvent. Herein, we report an artificial enzyme catalyzed tandem Michael addition and enantioselective protonation reaction of α-substituted acroleins with 2-acyl imidazole derivatives in water. The artificial enzyme uses a synergistic combination of two abiological catalytic sites: a genetically encoded non-canonical p-aminophenylalanine residue and a Lewis acid Cu(II) complex. The exquisite stereochemical control achieved in the protonation of the transient enamine intermediate generated by conjugate addition of the Michael donor is illustrated by the >20:1 dr and up to >99% ee obtained for the products. These results illustrate the potential of exploiting synergistic catalysis in artificial enzymes for challenging reactions.<br>