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C ‐Alkylation of Peptides Containing Aminomalonate and (Amino)(cyano)acetate Residues
Author(s) -
Matt Thomas,
Seebach Dieter
Publication year - 1998
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/(sici)1522-2675(19981007)81:10<1845::aid-hlca1845>3.0.co;2-l
Subject(s) - chemistry , alkylation , alkoxide , alkyl , medicinal chemistry , decarboxylation , ketone , residue (chemistry) , epimer , stereochemistry , organic chemistry , catalysis
N ‐Acetyl‐, N ‐[( tert ‐butoxy)carbonyl](Boc)‐, and N ‐[(benzyloxy)carbonyl](Z)‐protected tri‐, penta‐, and heptapeptide methyl esters, 1 – 8 , with a central aminomalonate (Ama) (allyl, methyl, benzyl, or tert ‐butyl) or (amino)(cyano)acetate (Aca) residue have been prepared by conventional techniques ( Schemes 4 – 6 ). The new peptides with acidic backbone‐bound CH groups can be C ‐alkylated with primary alkyl, allyl, and benzyl halides, under mildly basic conditions (1 equiv. MeONa or t ‐BuOK in THF); also, they can be added to Michael acceptors such as acrylates, acrylonitrile, methyl vinyl ketone, or nitrostyrene (catalytic amounts of alkoxide bases in THF) ( Schemes 7 – 16 ). In most cases, the products, 48 – 100 , are formed in excellent yields (average of 77%); one of the epimeric products prevails (2 : 1 to > 20 : 1), and the epimers have been separated, isolated in pure form, and fully characterized (without configurational assignments); addition of the co‐solvent 3,4,5,6‐tetrahydro‐1,3‐dimethylpyrimidin‐2(1 H )‐one (DMPU) or of LiBr may improve or even reverse the ratio of epimeric products formed; the heptapeptide derivative 8 had to be solubilized for alkylations in THF by the addition of 30 equiv. of LiBr. Cleavage of the Ama groups (benzyl with H 2 /Pd‐C, t ‐Bu with HCl/Et 2 O) gave carboxylate derivatives which are actually peptides containing the alkylated aminomalonic acid, the lower homolog of aspartic acid, as residue in the central position. These acids are quite resistant to decarboxylation which had to be achieved by heating at reflux in THF in the presence of 2 equiv. of LiBr and of catalytic amounts of pyridine ( Schemes 17 and 18 ). A one‐step removal of the allyl aminomalonate group is possible with Pd/PPh 3 /formate ( Scheme 19 ). The resulting peptides, 101 – 115 , were formed as separable 1 : 1 mixtures of two epimers. The CN group of the alkylated Aca residue can be removed reductively (Na/NH 3 ; Scheme 20 ). The value of the new method is compared with that of existing methods of peptide‐backbone modification.