Journal
JOURNAL OF ORGANIC CHEMISTRY
Volume 66, Issue 21, Pages 7118-7124Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jo015809o
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Funding
- NIA NIH HHS [AG17983] Funding Source: Medline
- NIGMS NIH HHS [GM56835] Funding Source: Medline
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The preparation of sterically hindered and polyfunctional C-alpha,C-alpha-disubstituted alpha -amino acids (alpha alpha AAs) via alkylation of ethyl nitroacetate and transformation into derivatives ready for incorporation into peptides are described. Treatment of ethyl nitroacetate with NN-diisopropylethylamine (DIEA) in the presence of a catalytic amount of tetraalkylammonium salt, followed by the addition of an activated alkyl halide or Michael acceptor, gives the doubly C-alkylated product in good to excellent yields. Selective nitro reduction with Zn in acetic acid or hydrogen over Raney Ni gives the corresponding amino ester that, upon saponification, can be protected with the fluorenylmethyl-oxycarbonyl (Fmoc) group. The first synthesis of an orthogonally protected, tetrafunctional C-alpha,C-alpha-disubstituted analogue of aspartic acid, 2,2-bis(tert-butylcarboxymethyl)glycine (Bcmg), is described. Also, the sterically demanding C-alpha,C-alpha-dibenzylglycine (Dbg) has been incorporated into a peptide using solid-phase synthesis. It was found that once sterically congested Dbg is at the peptide N-terminus, further chain extension becomes very difficult using uronium or phosphonium salts (PyAOP, PyAOP/ HOAt, HATU). However, preformed amino acid symmetrical anhydride couples to N-terminal Dbg in almost quantitative yield in nonpolar solvent (dichloroethane-DMF, 9:1).
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