Journal of Peptide Research 2004-08-01

Synthesis and modification of dibenzylglycine derivatives via the Suzuki-Miyaura cross-coupling reaction.

S Kotha, M Behera

Index: J. Pept. Res. 64(2) , 72-85, (2004)

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Abstract

The objective of this paper is to describe in details of various available methods to prepare C(alpha,alpha)-dibenzylglycine (Dbzg) and then include our work involving the synthesis of side chain Dbzg derivatives. alpha,alpha-Disubstituted amino acids (alpha,alphaAAs) are important members in the family of modified amino acids. Replacement of the alpha-hydrogens of glycine 1 by alkyl groups leads to alpha,alphaAAs. The steric hindrance of the quaternary centre of Aib 2 combined with the helix-forming capacity has attracted the attention of structural biologists and protein crystallographers. Dbzg 3 is a special structural variant of Aib. The presence of two benzyl groups at C(alpha)-position not only impart rigidity to the peptide backbone in which it is incorporated, but also acts as a useful vehicle for studying pi-pi interactions. Although several C(alpha,alpha)-disubstituted glycines such as C(alpha,alpha)-diethyl glycine (Deg), C(alpha,alpha)-dipropyl glycine (Dpg) etc. have been studied in detail, not much has been known about Dbzg because of limited availability of synthetic procedures. Various Dbzg derivatives 19a-f have been prepared using ethyl isocyanoacetate 14 as a glycine equivalent (eq.). A useful and simple methodology has been developed using the Suzuki-Miyaura cross-coupling reaction for the modification of Dbzg derivatives 17d, 19d, 22. Using this 'Building Block Approach' (Accounts of Chemical Research 36, 2003, 342) one can generate a variety of Dbzg derivatives 20a-f and 23a-e, which may find useful applications in combinatorial synthesis and QSAR studies.