On the preparation of enantiomerically pure isonitriles from amino acid esters and peptides

Abstract

An improved method for the synthesis of enantiomerically pure isonitriles from amino acid esters and dipeptides is described.

Ethyl Isocyanoacetate as a Useful Glycine Equivalent

“…19 In relation to the above substrates, Kotha and co-workers reported the synthesis of N-formyl-substituted amino acid esters 22 from glycine esters 21 using ammonium formate in acetonitrile at reflux, giving the products in good yields (Scheme 9). 20 N-Formyl derivatives are also useful building blocks for peptide chemistry.…”

Sulfur-Switch Ugi Reaction for Macrocyclic Disulfide-Bridged Peptidomimetics

“…21 Nonracemizable dehydrating conditions viz., triphosgene (0.35 equiv) and N -methyl morpholine (NMM) (2.0 equiv) at −78 °C, were employed to synthesize isocyanide 2 , and its enantiopurity was checked by chiral SFC [Supporting Information (SI)]. 22 The quantitative yield of the isocyanide was obtained as a pale yellow, odor-free solid by simple recrystallization from diethyl ether (88%). The isocyanide is bench-stable at room temperature for several months without any decomposition or racemization.…”

On the Synthesis of Conformationally Modified Peptides through Isonitrile Chemistry: Implications for Dealing with Polypeptide Aggregation

“…9 We revisited a key reaction, which we discovered, namely the coupling of a carboxylic acid ( a ) with an isonitrile ( b ) to afford an N -formylamide ( c ), presumably via the intermediacy of the formimidate carboxylate mixed anhydride (FCMA), 9a as shown. This line of conjecture led to the proposal shown in Scheme 1.…”

“…Thus, an acid ( 1 ) would combine with an amino acid–derived isonitrile 2 . 9d Following the coupling reaction described above, and subsequent discharge of the protecting group (P), there would be obtained acid 3 . Reiteration of this reaction with amino acid–derived isonitrile 4 would give rise, in principle, to 5 , containing N-formyl groups on contiguous amidic nitrogens.…”

“…Our studies commenced with coupling of the valine-related azide 9 with leucine–derived isonitrile 10 9f to afford 11 in 82% yield (Scheme 2). Cleavage of the ester generated acid 12.…”