Pd‐Catalyzed Asymmetric N‐Allylation of Amino Acid Esters with Exceptional Levels of Catalyst Control: Stereo‐Divergent Synthesis of ProM‐15 and Related Bicyclic Dipeptide Mimetics

Abstract

A general and powerful method for the stereo‐controlled Pd‐catalyzed N‐allylation of amino acid esters is reported, as a previously largely unsolved synthetic challenge. Employing a new class of tartaric acid‐derived C2‐symmetric chiral diphosphane ligands the developed asymmetric amination protocol allows the conversion of various amino acid esters to the N‐allylated products with highest levels of enantio‐ or diastereoselectivity in a fully catalyst‐controlled fashion and predictable configuration. Remarkably, the in situ generated catalysts also exhibit outstanding levels of activity (ligand acceleration). The usefulness of the method was demonstrated in the stereo‐divergent synthesis of a set of new conformationally defined dipeptide mimetics, which represent new modular building blocks for the development of peptide‐inspired bioactive compounds.

Designed nanomolar small-molecule inhibitors of Ena/VASP EVH1 interaction impair invasion and extravasation of breast cancer cells

“…The compounds employed in this study were synthesized by modular assembly of the building blocks using established coupling protocols ( 40 ). The required ProM scaffolds ProM-1 ( 41 , 43 ), ProM-2 ( 45 ), ProM-9 ( 46 ), ProM-13 ( 46 ), ProM-15 ( 47 ), and ProM-17 ( 47 ) ( Fig. 1 B ) were synthesized as separately published.…”

“…Such a modification opened the possibility to probe the underlying hydrophobic binding groove with different moieties (ProM-15 and ProM-17; Fig. 1 B ) ( 47 ). The resulting less rigid inhibitors 4a and 5a showed a greatly improved affinity toward ENAH EVH1 by –5.5 kJ/mol compared to 1a , thereby nearly restoring the binding energy of the TEDEL-containing chimera 2 N ( Table 1 ).…”

“…In the course of our research into small molecules as potential inhibitors of protein–protein interactions ( 39 ) we recently in silico designed and stereo-selectively synthesized scaffolds, coined ProMs, which mimic pairs of prolines in PPII conformation ( 40 ). The modular combination of different ProMs thereby allowed us to generate nonpeptidic secondary-structure mimetics that fulfill the steric requirements of the addressed proline-rich motif-recognizing domain ( 41 – 47 ). For the EVH1 domain, our proof-of-concept study yielded a canonically binding, nontoxic, cell-membrane-permeable, 706-Da inhibitor 1 ( Fig.…”

Improved Synthesis of MediPhos Ligands and Their Use in the Pd‐Catalyzed Enantioselective N‐Allylation of Glycine Esters

“…Unfortunately, all our attempts to obtain MediPhos‐Pd complexes as crystalline compounds remained unsuccessful so far. Therefore, it remains uncertain whether the coordination modes and geometries are similar to those of Trost‐type ligands and whether the higher activity of our ligands [8a] relates to the lack of NH units in the chiral bridge, which promote the formation of catalytically inactive tetra‐coordinate Pd(II) complexes [13]…”

“…Nevertheless, we recently reported a protocol which allows the Pd‐catalyzed asymmetric N ‐allylation of various amino acid esters with exceptional levels of catalyst control using i Pr‐MediPhos ( L3* ) as a chiral ligand (Scheme 2). [8] As an example, the N‐allylation of methyl glycinate ( 4 a ) with carbonates rac‐ 5 was achieved with high enantioselectivity and the products of type 6 were used in the synthesis of the ProM‐15 derivative 7 and related compounds [8a] …”