CIAT with simultaneous epimerization at two stereocenters. Synthesis of substituted β-methyl-α-homophenylalanines

Abstract

Diastereoselective aza-Michael additions of phenylethylamine to 3-aroylbutenoic acids are reported. During these processes, efficient control over two new stereogenic centers on the Michael acceptor has been possible via crystallization-induced asymmetric transformation (CIAT). As an application, a convenient two-step synthesis of anti-beta-methylhomophenylalanines is also described.

State of the Art in Crystallization‐Induced Diastereomer Transformations

“…( S )‐1‐Phenylethan‐1‐amine (( S )‐ 10 ) was used as a readily available chiral auxiliary and a nitrogen carrier at the same time and amino acids 123 a – g bearing ( S , S )‐configuration were isolated in all cases. We successfully expanded this chemistry to an array of related aromatic substrates 122 h – o [46a,102–105] …”

“…Since aza‐Michael reaction is associated with configurational changes at two adjacent carbons of an acceptor, it can lead to a simultaneous build‐up of two stereocenters. The reaction has reached this potential in synthesis of amino acids 123 l – o (Scheme 45A) [104,105] . In spite of initial formation of a complex diastereomeric mixture, a preferential crystallization of a single diastereomer was decisive for the ultimate reaction outcome.…”

“…The reaction has reached this potential in synthesis of amino acids 123 l-o (Scheme 45A). [104,105] In spite of initial formation of a complex diastereomeric mixture, a preferential crystallization of a single diastereomer was decisive for the ultimate reaction outcome.…”

Synthesis of (2S,3S)-3-Aroyl Pyroglutamic Acid Amides

“…This efficient methodology spread among our research group allows us to prepare aroyl alanines with high diastereoselectivity. The methodology is based on equilibration of stereoisomers in a solution, and continuous crystallization of a single isomer acts as a driving force for its gradual accumulation in the reaction suspension [6][7][8][9]. This enables isolation of products (3ag) by simple filtration.…”

The first highly stereoselective approach to the mitotic kinesin Eg5 inhibitor HR22C16 and its analogues

“…e l s e v i e r . c o m / l o c a t e / t e t a s y process via crystal-induced asymmetric transformation (CIAT) [26][27][28][29][30][31][32][33][34][35][36][37][38] in a mixed solvent of toluene and nitromethane afforded cis-4a-HCl in 93% yield and with 98% de. However, high trans-stereoselectivity rather than cis-stereoselectivity is required to satisfy the absolute configurations of the two stereogenic centers of the title compounds HR22C16 and its analogues.…”