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

Abstract

The 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.

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

“… a Data from refs and . b Error is in the relative free energy. The experimental value was predicted from the e.e.…”

“…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 …”

Recent Advances in Azlactone Transformations

“…[27] In this study, the first phosphoric acid (16) catalyzed DKR of azlactones (17) through aminolysis was reported (Scheme 7), complementing previous alcoholysis and thiolysis asymmetric protocols. [27] In this study, the first phosphoric acid (16) catalyzed DKR of azlactones (17) through aminolysis was reported (Scheme 7), complementing previous alcoholysis and thiolysis asymmetric protocols.…”

“…Another important contribution on DKR of azlactones was described by Shi's group in 2016 . In this study, the first phosphoric acid ( 16 ) catalyzed DKR of azlactones ( 17 ) through aminolysis was reported (Scheme ), complementing previous alcoholysis and thiolysis asymmetric protocols.…”

“…Based on NMR monitoring, we proposed that the mechanism proceed through the formation of an intermediate between the catalyst and acetonitrile, which mediate azlactone enolate formation (Scheme 8B). Moreover, both oxazolones (24) and Erlenmeyer azlactones (25) were successfully em-ployed in this protocol, affording α-amino aldehydes (27) and α-amino α, -unsaturated aldehydes (28), respectively. This protocol was successfully applied in the diastereoselective preparation of a functionalized (+/-)-streptopyrrolidine analogue.…”