α‐Cyano‐β‐styrenyl esters for amide bond formation

Abstract

Abetractp-X-a-cyano-p-styrenyl esters ( X = H, C1, CF NO ) of N-benzyloxycarbonyl valine were prepared. The rate constant foZ'ami8e formation with methyl valinate was assayed: it increases with increasing electron attracting power of the para substituent. The p-hydroxysuccinimidoyl ester and the p-H-acyano-p-styrenyl ester of valine have comparable reactivities. Ukroduct i wThere is a vivid interest in synthetic methods for peptides, required as servants for research and medicine.A concept which has hitherto resisted reduction to practice is that of the transformation of an unreactive ester of an amino acid ( o r of an oligopeptide) to a reactive one. In this connection, some years ago Treiber (1) published a short note describing the one-pot conversion shown below in Scheme 1. SCHEME.The relatively inert phenacyl esters of the N-protected amino acid react with HCN/KCN in dimethylformamide (DMF) solvent to yield a-cyano-p-styrenyl esters Prot-Xaa-OCs, which reportedly (1) couple with methyl glycinate (12 h) to the dipeptide in an overall yield of m 50% (quantitative thin layer chromatography). As this unsatisfactory yield could be due either to incomplete conversion of the amino acid phenacyl ester to Prot-Xaa-OCs o r to a low reactivity of the latter, we now report (i) on the preparation and isolation of the compounds Prot-Xaa-OCs by other routes and (ii) on a study of their reactivity towards amino acid esters.-267 -

The Active Ester α‐Cyano‐4‐Nitrostyrene‐β‐yl Acetate is also the Captodative Olefin 2‐Acetoxy‐1‐Cyano‐1‐(4‐Nitrophenyl)Ethene. Synthesis of 2,4‐bis(4‐Nitrophenyl)Pent‐2‐Enedinitrile

“…The solid residue is pure 2, ca 35% E and 65% Z . Note : if the acylation of 1 is carried out with neat acetic anhydride and at higher temperatures, an unidentified additional product is formed ( The basis of the Z/E assignment is 6w Z > > 6Hp E. This criterium was incontrovertibly verified for 1, on the basis of a 13C, l H shift correlation study (2). Note : the present data show that a previously isolated stereomer of 2, erroneously assigned as E (l), is actually the Z-isomer.…”

“…To styrenol 1 (760 mg, 4 mmol) (2), dissolved in 5 mL THF, is added under stirring acetic anhydride (0.5 mL, 5.3 mmol). After an additional 2 h the mixture is concentrated on a rotatory evaporator.…”

“…For instance, by acylating valine methyl ester (Val-OMe) with N-benzyloxycarbonylvaline a-cyano-4-nitrostyrene-p-yl ester (Z-Val-OCs(p-NO,)) an excellent yield of shining white recrystallized dipeptide Z-Val-Val-OMe was obtained (2). Yet the reaction mixture had a greenish tinge, and a thin layer chromatogram showed two coloured spots, a yellow one due to the triethylammonium salt of the cyanonitrostyrenol 1, and a bright blue one, which gradually disappeared (days) on exposure to air.…”