Dynamic Kinetic Resolution Of Azlactones Research Articles

Dynamic Kinetic Resolution of Azlactones by Bifunctional Thioureas with α‑Trifluoromethyl or Methyl Groups

AbstractThe asymmetric ring opening of azlactones via dynamic kinetic resolution (DKR) is investigated by contrasting thioureas incorporating 1-arylethyl substituents against their more acidic trifluoromethylated analogs. All the catalysts under study outperform Takemoto’s thiourea because of the inclusion of an additional chiral center. However, the difference in yield and selectivity between the fluorinated and non-fluorinated catalysts is minimal. We explain this observation by analysis of calculated transition states. Our findings show that the hydrogen bond (HB) between the NH linked to the 1-arylethyl and the negatively charged oxygen in the benzyloxy ion is the longest in the HB network, whereas the HB between the ammonium group and the same oxygen atom is the shortest. Thus, the substituents and the HB donor ability of this chiral fragment attached to the thiourea are not important in the reaction.

Origin of Enantioselectivity in Chiral Phosphoric-Acid-Catalyzed Azlactone Dynamic Kinetic Resolution.

Theoretical calculations, associated with control experiments, were carried out to gain insights into the mechanism and origin of enantioselectivity in the phosphoric-acid-catalyzed dynamic kinetic resolution of azlactones. The results revealed a Münchnone intermediate as the key species involved in the isomerization of azlactone rings. The developed model was successfully employed in the comprehension and prediction of enantioselectivity under diverse of reaction conditions, including alcoholysis and aminolysis protocols.

Rational Design of 2-Substituted DMAP-N-oxides as Acyl Transfer Catalysts: Dynamic Kinetic Resolution of Azlactones.

A novel concept that conversion of chiral 2-substituted DMAP into its DMAP-N-oxide could significantly enhance the catalytic activity and still be used as an acyl transfer catalyst is presented. A new type of chiral 2-substituted DMAP-N-oxides, derived from l-prolinamides, has been rationally designed, facilely synthesized, and applied in the dynamic kinetic resolution of azlactones. Using simple MeOH as the nucleophile, various l-amino acid derivatives were produced in high yields (up to 98% yield) and enantioselectivities (up to 96% ee). Furthermore, α-deuterium labeled l-phenylalanine derivative was also obtained. Experiments and DFT calculations revealed that in 2-substituted DMAP-N-oxide, the oxygen atom acted as the nucleophilic site and the N-H bond functioned as the H-bond donor. High enantioselectivity of the reaction was governed by steric factors, and the addition of benzoic acid reduced the activation energy by participating in the construction of a H-bond bridge. The theoretical chemical study indicated that only when attack directions of the chiral catalyst were fully considered could the correct calculation results be obtained. This work paves the way for the utilization of the C2 position of the pyridine ring and the development of chiral 2-substituted DMAP-N-oxides as efficient acyl transfer catalysts.

Dynamic Kinetic Resolution of Azlactones with a Chiral DMAP Catalyst

Dynamic Kinetic Resolution of Azlactones with a Chiral DMAP Catalyst

Dynamic Kinetic Resolution of Azlactones by a Chiral N, N-Dimethyl-4-aminopyridine Derivative Containing a 1,1'-Binaphthyl Unit: Importance of Amide Groups.

A dynamic kinetic resolution (DKR) of azlactones in the presence of benzoic acid and a binaphthyl-based N, N-4-dimethylaminopyridine (DMAP) derivative 1i having two amide groups at the 3,3'-positions of a binaphthyl unit is developed. The reaction proceeded smoothly with a wide range of azlactones to provide α-amino acid derivatives with good to high enantiomeric ratios (er's). A multigram-scale reaction (2.5 g) for the DKR of azlactone 2d was also demonstrated, and the resulting product was converted to unnatural α-amino acid 6d'.

Rational Design of Amine Nucleophiles for Dynamic Kinetic Resolution of Azlactones Leading to Highly Enantioselective Synthesis of Bisamides

AbstractThe first catalytic asymmetric aminolysis of azlactones was achieved, enabling the highly enantioselective dynamic kinetic resolution of azlactones. This was demonstrated to be an efficient method for synthesizing optically pure bisamides in high yield with excellent enantioselectivity (up to 99 % yield, 99 % ee). The rational design of the amine nucleophile bearing both a sterically bulky group and an activating group was shown to be a key factor in attaining excellent enantioselectivity in the catalytic asymmetric aminolysis of azlactones. This approach not only provides easy access to biologically important enantiopure bisamides, but also enables the dynamic kinetic resolution of azlactones by using a strategy of enantioselective aminolysis, which was previously unknown in this research field.

ChemInform Abstract: Organocatalytic Dynamic Kinetic Resolution of Azlactones to Construct Chiral N‐Acyl Amino Acid Oxime Esters.

AbstractA chiral bisguanidinium salt is applied as a catalyst for the dynamic kinetic resolution of azlactones (I) and (VI) leading to N‐acyl amino acid oxime esters in high yields and excellent enantiomeric excesses (up to 97%).

Organocatalytic dynamic kinetic resolution of azlactones to construct chiral N-acyl amino acid oxime esters.

A direct strategy to obtain N-acyl amino acid oxime esters has been developed through the dynamic kinetic resolution of azlactones with oximes. In the presence of a chiral bisguanidinium salt catalyst, a variety of chiral N-acyl amino acid oxime esters were generated in excellent enantiomeric excesses (up to 97%) and high yields (up to 99%). The active oxime esters could be used in dipeptide synthesis.

C‐5′‐Substituted Cinchona Alkaloid Derivatives Catalyse the First Highly Enantioselective Dynamic Kinetic Resolutions of Azlactones by Thiolysis

AbstractThe highly enantioselective dynamic kinetic resolution (DKR) of azlactones by thiolysis has been achieved for the first time. Although both the parent alkaloid quinine and known C‐5′‐urea derivatives fail to promote the reaction effectively, a new class of C‐5′‐hydroxylated catalysts proved capable of catalysing the DKR of a range of azlactones derived from both unbranched‐ and, previously challenging, branched‐chain amino acids in 84–92 % ee, including an example of the synthesis of an enantioenriched N‐protected thioester derived from an extraterrestrial amino acid isolated from the Murchison meteorite.

Access to Quaternary Amino Acids via Dynamic Kinetic Resolution of Azlactones

Key words azlactones - asymmetric catalysis - peptides - quaternary amino acids

Origin of Enantioselectivity in Benzotetramisole-Catalyzed Dynamic Kinetic Resolution of Azlactones

Density functional theory (DFT) calculations were performed to investigate the origins of enantioselectivity in benzotetramisole (BTM)-catalyzed dynamic kinetic resolution of azlactones. The transition states of the fast-reacting enantiomer are stabilized by electrostatic interactions between the amide carbonyl group and the acetate anion bound to the nucleophile. The chiral BTM catalyst confines the conformation of the α-carbon and the facial selectivity of the nucleophilic attack to promote such electrostatic attractions.

The Dynamic Kinetic Resolution of Azlactones with Thiol Nucleophiles Catalyzed by Arylated, Deoxygenated Cinchona Alkaloids

A significant improvement of the available organocatalytic methods (in terms of product substrate scope and product enantiomeric excess) for the generation of enantioenriched α-amino acid thioesters via the dynamic kinetic resolution of azlactones is reported. C-9 arylated cinchona alkaloid catalysts have been found to be considerably superior to other bifunctional alkaloid catalysts as the promoters of this asymmetric process.

Organocatalytic Asymmetric Additions to meso‐Anhydrides and Azlactones

AbstractThis review charts the recent progress of two related, yet distinct organocatalytic processes: the desymmetrisation of meso‐anhydrides and the dynamic kinetic resolution of azlactones. Driven by recent advances in catalyst design, both these processes have undergone something of a renaissance in recent years and are now becoming very powerful and versatile synthetic methodologies. The material is presented in a critical fashion and the material is organised by reaction type and catalyst class.

ChemInform Abstract: Broensted Acid Catalyzed Dynamic Kinetic Resolution of Azlactones for the Synthesis of Aryl Glycine Derivatives.

AbstractThe reaction of azlactones, e.g. (I), with the β‐substituted primary alcohol (II) as the nucleophile proceeds smoothly to generate aryl glycine derivatives (III) in excellent yields and with high levels of enantioselectivity.

Brønsted Acid Catalyzed Dynamic Kinetic Resolution of Azlactones for the Synthesis of Aryl Glycine Derivatives

The dynamic kinetic resolution of C4-aryl azlactones with alcohols was investigated by employing Brønsted acid catalysis. The reaction provided an efficient complementary approach to access chiral aryl glycine derivatives with excellent yields (up to 99%) and enantioselectivities (up to 96% ee).

Dynamic Kinetic Resolution of Azlactones Catalyzed by Chiral Brønsted Acids

Dynamic Kinetic Resolution of Azlactones Catalyzed by Chiral Brønsted Acids

Phosphoric Acid Catalyzed Dynamic Kinetic Resolution of Azlactones

Phosphoric Acid Catalyzed Dynamic Kinetic Resolution of Azlactones

Dynamic Kinetic Resolution of Azlactones Catalyzed by Chiral Brønsted Acids

Chiral Brønsted acids have been shown for the first time to catalyze the dynamic kinetic resolution of azlactones. 3,3'-Bis-(9-anthryl)-BINOL phosphoric acid 3c is particularly effective in the case of 4-aryl-substituted substrates, producing 85-92% ee's.

Benzotetramisole-Catalyzed Dynamic Kinetic Resolution of Azlactones

Enantioselective acyl transfer catalyst benzotetramisole (BTM) has been found to promote dynamic kinetic resolution of azlactones providing di(1-naphthyl)methyl esters of alpha-amino acids with up to 96% ee.

The Design of Novel, Synthetically Useful (Thio)urea-Based Organocatalysts

Selected recent developments in the area of (thio)urea-mediated organocatalysis from our laboratory are summarised.