BIRT 377, cell adhesion inhibitor

The same authors have shown that the direct a-amination reaction could also be used to construct the quaternary stereocenter in the enantioselective total synthesis of the cell-adhesion inhibitor BIRT-377 [7b]. The i-proline-derived tetrazole 3c catalyzed the direct a-amination of 3-(4-bromophenyl)-2-methylpropanal 8 with dibenzyl azodicarboxylate 2b to give the amino aldehyde 9 in 95% yield and with... 

Scheme 2.29 The application of organocatalytic enantioselective a-amination reaction of 3-(4-bromophenyl)-2-methylpropanal 8 for the total synthesis of the optically active cell-adhesion inhibitor BIRT-377 [7b].

Chowdari and Barbas [22] reported the enantioselective total synthesis of potent cell adhesion inhibitor BIRT-377 (56) in 2005, which has potential for the treatment of a number of inflammatory and immune disorders. Asymmetric synthesis of quaternary amino acids is a challenging task for synthetic chemists [23]. Barbas described the efficient L-proUne-derived, tetrazole-catalyzed direct asymmetric a-amination to construct an aldehyde 55 with the amino-substituted quaternary stereocenter and elaborate this aldehyde into BIRT-377 (56) (Scheme 17.7). 

The quaternization method is also highlighted by the short asymmetric synthesis of cell adhesion molecule BIRT-377 (Scheme 5.24), which is a potent inhibitor of the interaction between intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1) [16]. Thus, asymmetricp-bromobenzylation of the alanine derivative 42 (R1 = Me) with (S)-18 under similar phase-transfer conditions as described above gave rise to p-bromobenzylalanine ester 10 in 97% ee (83% yield). A similar asymmetric p-bromobenzylation of alanine ethyl ester 42 (R1 = Me, R= Et) gave the amino ester 47 (R= Et) in 90% ee (86% yield). The amino ester 47 (R = t-Bu or Et) was treated with 3,5-dichlorophenyl isocyanate in the presence of sodium carbonate in dimethylsulfoxide (DMSO) to furnish the hydantoin 48 in 86%... 

BIRT-377 (1), a small molecule inhibitor of lymphocyte function-associated antigen 1 (LFA-1), was first discovered by Kelly and coworkers in 1999. It was shown to have potential therapeutic utility in the treatment of a variety of inflammatory and immune disorders. In binding to intercellular adhesion molecules, the cell-surface receptor LFA-1 allows many cell-cell adhesion events that control immunological functions. A lack of these synaptic functions leads to potentially life-threatening immunodeficiency diseases. In case of overactive immune responses, an LFA-1 inhibitor can be used to attenuate the inflammatory responses. These immunosuppressive activities have been tested in vitro, and early clinical trials on transplantation have already been undertaken. ... 

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