A Practical Aryl Unit for Azlactone Dynamic Kinetic Resolution: Orthogonally Protected Products and A Ligation‐Inspired Coupling Process

Abstract

The first strategy for bringing about enantioselective azlactone dynamic kinetic resolution to generate orthogonally protected amino acids has been developed. In the presence of a C2-symmetric squaramide-based catalyst, benzyl alcohol reacts with novel yet readily prepared tetrachloroisopropoxycarbonyl-substituted azlactones to generate trapped phthalimide products of significant synthetic interest with excellent enantiocontrol. These materials are masked amino acids which are demonstrably orthogonally protected: cleavage of the phthalimide can be achieved in the presence of the ester and vice versa. This process could be utilized to bring about a highly stereoselective ligation-type coupling of protected serines (at stoichiometric loadings) with racemic azlactones derived from both natural and abiotic amino acids. After deprotection, a subsequent base-mediated O→N acyl transfer occurs to form a dipeptide.

Stereodivergent entry to β-branched β-trifluoromethyl α-amino acid derivatives by sequential catalytic asymmetric reactions

“…However, a preliminary screening of many of these methods suggested the squaramide Cinchona catalyzed alcoholytic ring opening 20 as most promising option, despite its resemblance with the biased achiral amine promoted reaction. State-of-the-art Cinchona squaramide dimeric catalysts derived from quinidine ( QD-1 ) and quinine ( QN-1 ) ( Scheme 2 ) were initially employed with enantioenriched azlactone 3d under standard conditions (dichloromethane, allyl alcohol, 0 °C).…”

“…The last three entries 14–16 of Table 2 display the results obtained by applying alcohols other than allyl in the alcoholytic process with substrate 1d . The peculiarity of the present reaction system makes the tolerance to different primary alcohols, known for the DKR of simple azlactones, 20 less than obvious, especially in the case of the syn -selective protocol. However, it was pleasing to observe that results in line with the allyl derivatives 4d were obtained for the products of methyl, benzyl and isobutyl alcohols 4q–s , although lower yields were observed in the latter case.…”

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

“…Among these reactions, the dynamic kinetic resolution (DKR) through ring-opening reactions in the presence of nucleophiles (alcohols, amines, or thiols) is widely employed in the attainment of enantioenriched α-amino-acid derivatives . Thus over the past decade, several catalytic protocols for the DKR of azlactones have been developed, including the use of Lewis acids, Lewis bases, , peptides, and bifunctional catalysis. − On the contrary, the use of chiral Brønsted acids as catalysts for this transformation is still considerably underdeveloped, with only two described protocols (Scheme ), , which, in some cases, present limitations concerning the control of the stereochemical outcome of the products. In this context, a better comprehension of the reaction mechanism and the key interactions responsible for the enantioselectivity is highly desirable and would greatly contribute toward the development of novel protocols for the Brønsted-acid-catalyzed DKR of azlactones, as is currently occurring for other DKR reactions. − Moreover, especially for azlactones, this type of approach has been previously described only for methodologies involving the formation of intermediates between azlactone and the catalyst through covalent bonds, such as benzotetramisole catalysis …”

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

“…The dynamic kinetic resolution (DKR) of azlactones by alcoholysis is an attractive method of generating enantioenriched protected α-amino acid derivatives. , In addition to hydrolytic enzymes and transition metal complexes, a variety of organocatalysts have been developed for this transformation, including chiral DMAP, ,, diketopiperazine, (thio)­urea-based bifunctional catalysts, cinchona alkaloid, benzotetramisole, phosphoric acid, tetrapeptide, and 1,3-ketoenol . Among these organocatalysts, chiral acyl transfer catalysts are of particular interest because the first organocatalyst used in DKR of azlactones was a chiral DMAP (Figure ).…”