Synthesis of phosphine containing amino acids: Utilization of peptide synthesis in ligand design

Abstract

Combinatorial chemistry has recently burst on the scene as a valuable tool for the discovery of new drug candidates. The ability to synthesize hundreds of compounds for screening is a useful complement to rational drug design. There are many similarities between the design of new therapeutic agents and the development of new asymmetric ligands, the most important of which is the limitation of a rational design strategy. For this reason a program was begun that would allow the use of combinatorial technology in the development of new ligands for transition metal catalyzed asymmetric reactions. Because of the large number of catalytic reactions they are involved in the system was based around phosphine ligands. This paper reports the synthesis of phosphine derivatives of alanine, proline, and the aromatic amino acids tyrosine and hydroxyphenylglycine. Examples of the use of these amino acids in the synthesis of peptides possessing helical and beta-turn secondary structures are presented. Metal complexes of these peptide-based ligands are used in hydrogenation and alkylation reactions.

Combinatorial Transition‐Metal Catalysis: Mixing Monodentate Ligands to Control Enantio‐, Diastereo‐, and Regioselectivity

“…A variety of subunits (Scheme 15) were prepared, leading to 50 combinations of heterodimers which were tested in a Pd-catalyzed allylic amination [Eq. (24); dba = trans,-trans-dibenzylideneacetone, Ar = p-tolyl]. This type of combinatorial search led to enantioselectivities of up to 97 % ee.…”

Incorporating ECE-pincer metal complexes as functional building blocks in semisynthetic metalloenzymes, supramolecular polypeptide hybrids, tamoxifen derivatives, biomarkers and sensors

“…Peptides substituted by phosphines have been used successfully as chiral backbones for transition metal catalysts in asymmetric hydrogenation, alkylation and allylic substitution reactions [83][84][85][86][87]. ECE-pincer palladium complexes, which have been broadly applied as homogeneous catalysts, e.g.…”

Bioinspired Catalyst Design and Artificial Metalloenzymes

“…[24] For this purpose several sulfur-protected phosphane-containing alanine derivatives compatible with solidphase peptide synthesis were developed (Scheme 3a). [25] In addition a phosphane-sulfide functionalised proline as alternative phosphane-peptide building blocks (Scheme 3b) and a procedure to introduce phosphane moieties into aromatic amino acids after peptide synthesis were reported (Scheme 3c).…”