Combinatorial Solution-Phase Synthesis of (2S,4S)-4-Acylamino-5-oxopyrrolidine-2-carboxamides

Abstract

Solution-phase combinatorial synthesis of (2S,4S)-4-acylamino-5-oxopyrrolidine-2-carboxamides was studied. First, di-tert-butyl (2S,4S)-4-amino-5-oxopyrrolidine-1,2-dicarboxylate hydrochloride was prepared as the key intermediate in five steps from (S)-pyroglutamic acid. Acylation of the amino group followed by acidolytic deprotection gave (2S,4S)-4-acylamino-5-oxopyrrolidine-2-carboxylic acids, which were then coupled with amines to furnish a library of (2S,4S)-4-acylamino-5-oxopyrrolidine-2-carboxamides. Four coupling reagents, BPC, EEDQ, TBTU, and PFTU, were tested for the amidation reactions in the final step. Amidations with EEDQ and TBTU led to the desired carboxamides. On the other hand, BPC and PFTU were not suited, since diketopiperazines were sometimes obtained instead of the desired carboxamides.

Synthesis and Biological Evaluation of tert-Butyl Ester and Ethyl Ester Prodrugs of L-γ-Methyleneglutamic Acid Amides for Cancer

“…The syntheses of tert-butyl ester prodrugs of the Lγ-methyleneglutamic acid amides (11 and 13-20, Figure 4A), starting from the commercially available L-pyroglutamic acid 41 (Scheme 1), were performed by following our previously published report. 11 An esterification of 41 with tert-butyl acetate in the presence of perchloric acid 13 produced 42 in 70% yield. A Boc-protecting reaction of the amide 11,14 of 42 gave 43 in 87% yield.…”

“…Scheme 1. Syntheses of tert-butyl ester prodrugs of the L-γ-methyleneglutamic acid amides (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Reagents and conditions: a) AcO t Bu, HClO4, 23 °C, 18h, 70%; b) (Boc)2O, DMAP, Et3N, CH2Cl2, 23 °C, 18 h, 87%; c) i. LiHMDS, CF3CO2CH2CF3, THF, -78 °C, 4 h, ii.…”

“…The capacity for the tert-butyl ester and ethyl ester prodrugs of the L-γ-methyleneglutamic acid amides (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) and the cyclic metabolite and its tert-butyl ester and ethyl ester prodrugs (31 -35) to inhibit the growth of the three breast cancer cell lines MCF-7, SK-BR-3, and MDA-MB-231 and the non-malignant MCF-10A breast cell line was assessed after 72 h of treatment (Figure 8). The potencies of all compounds on MCF-7 or SK-BR-3 cell lines were markedly reduced compared to those of previously identified leads (5, 6, or 9; Figure 2), and none exhibited a significant increase in potency compared to positive controls or were equipotent to compounds 5, 6, or 9.…”

“…Cell death for the tert-butyl ester and ethyl ester prodrugs of the L-γ-methyleneglutamic acid amides (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) and the cyclic metabolite and its tert-butyl ester and ethyl ester prodrugs (31 -35) on the three breast cancer cell lines MCF-7, SK-BR-3, and MDA-MB-231 and the non-malignant MCF-10A breast cell line was also assessed after 72 h of treatment (Figure 9). No compound exhibited significantly greater or equipotent effects to promote cancer cell death compared to 5, 6, or 9 on any breast cancer cell line.…”

“…All solvents were distilled and stored under an argon or nitrogen atmosphere before use. 1 H NMR and 13 C NMR spectra were recorded on a Bruker-400 or a Bruker-500 spectrometer using CDCl3 or DMSO-d6 as the solvent. Chemical shifts (δ) were recorded in parts per million (ppm) and referenced to CDCl3 (7.26 ppm for 1 H NMR and 77.16 ppm for 13 C NMR) or DMSO-d6 (2.50 ppm for 1 H NMR and 39.52 ppm for 13 C NMR).…”