Enantioselective synthesis of non-natural aromatic alpha-amino acids.
We present two complementary methods for the stereoselective synthesis of non-natural alpha-amino acids with aromatic or heteroaromatic side chains. One approach is based on the chemical transformation of methionine, whereas the other applies the stereoselective Myers alkylation of glycine. The resulting product types differ in the linker length between glycine and the aromatic substituent. Since methionine and pseudoephedrine are available in both absolute configurations, R- or S-configured enantiopure amino acids with either C(2) or C(3) linkers can be obtained on gram scales. In each case the key step of the synthesis is hydroboration of the unsaturated building blocks 9 and 17, followed by palladium-catalyzed Suzuki cross-coupling with aryl halides. Attention must in certain cases be paid to the stereochemical integrity when basic Suzuki conditions are applied. Our initial difficulties are reported as well as the final "racemization-proof" procedures. The protecting groups chosen for the alpha-amino acids should be compatible with solid-phase peptide synthesis. This was confirmed by the successful synthesis of a series of tripeptides.
Krebs
Andreas
A
Institute of Organic Chemistry and Chemical Biology, Marie-Curie Strasse 11, 60439 Frankfurt/Main, Germany.
Ludwig
Verena
V
Pfizer
José
J
Dürner
Gerd
G
Göbel
Michael W
MW
D000478:Alkylation; D000596:Amino Acids / Q000138:chemical synthesis*; D005998:Glycine / Q000138:chemical synthesis; D006841:Hydrocarbons, Aromatic / Q000737:chemistry; D008715:Methionine / Q000138:chemical synthesis; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis; D013237:Stereoisomerism
D000596:Amino Acids; D006841:Hydrocarbons, Aromatic; D010455:Peptides; D008715:Methionine; D005998:Glycine