Kinetic Resolution of Amino Acids by Phosphine Oxide Catalyzed Enantioselective Esterification

The first highly efficient kinetic resolution (KR) of racemic amino acids with L -pyroglutaminol as an esterification reagent was reported through a novel phosphine oxide organocatalyst catalyzed under mild conditions, which provides a wide range of chiral esters and recovered amino acids with excellent stereoselectivities (s > 1057). The catalyst demonstrated excellent stereocontrol and catalytic activity, which presumably benefited from an intimate double H-bonding interaction between the pyroglutaminol core and the catalyst. Chiral amino acids find applications as versatile building blocks in the synthesis of functional molecules, as a source of chiral information in asymmetric synthesis and as tools to expand and explore the function of native biological machinery. ^1–8 Therefore, chiral amino acids represent a class of valuable and indispensable compounds whose stereoselective synthesis is a major objective within synthetic chemists and synthetic biologists. ^9–10 To the best of our knowledge, an array of effective synthetic strategies for the construction of chiral amino acids have been developed, such as asymmetric hydrogenation and nucleophilic addition of imines ^11–18 , enantioselective carbene insertion into N-H bonds of amines or amides ^19–23 , stereoselective photobiocatalytic cross-coupling ^24–27 , and stereocontrolled 1,3-nitrogen migration of carboxylic acids ²⁸ . However, identifying a highly enantioselective chiral catalyst for a specific reaction is not always an easy task. An alternative well-established strategy relies on the catalytic KR of a racemic mixture (Fig. 1a). ^29–31 The KR stands out as one of the most practical and straightforward strategies for obtaining enantioenriched molecules and recovering the starting materials, effectively allowing for access to both enantiomers from a single enantiomer of catalyst. Numerous highly efficient catalytic KR processes have been developed that reliably deliver enantiopure compounds, including chiral alcohols ^32–36 , monohydrosilanes ³⁷ , organoperoxides ³⁸ , alkynes ^39–40 , sulfonyl ketones ⁴¹ , amines ⁴² , imines ⁴³ , sulfoximines ^44–45 , aldehydes ⁴⁶ , phosphindane oxides ^47–48 , and heterocyclic compounds ^49–52 . Despite this significant progress in the field, the catalytic KR of amino acids remains a challenging task and has been rarely explored. ^53–57