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Enantioselective Synthesis of Non‐Natural Aromatic α‐Amino Acids
Author(s) -
Krebs Andreas,
Ludwig Verena,
Pfizer José,
Dürner Gerd,
Göbel Michael W.
Publication year - 2004
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200305421
Subject(s) - enantiopure drug , racemization , chemistry , amino acid , alkylation , suzuki reaction , enantioselective synthesis , peptide synthesis , tripeptide , aryl , protecting group , stereochemistry , stereoselectivity , substituent , combinatorial chemistry , organic chemistry , alkyl , catalysis , biochemistry
We present two complementary methods for the stereoselective synthesis of non‐natural α‐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 α‐amino acids should be compatible with solid‐phase peptide synthesis. This was confirmed by the successful synthesis of a series of tripeptides.