Synthesis of New Seven-Membered Ring Cyclic Dipeptides From Functionalized β-Amino Acids

Abstract

A short synthesis of new, functionalized seven‐membered ring cyclic dipeptides is described. After the coupling of N‐protected β‐amino acids to N‐substituted α‐amino tert‐butyl esters, the protective groups of the terminal functions were removed and the cyclization took place diastereoselectively in the presence of the coupling agent BOP. Amide substitution was found to be effective in promoting the cyclization of linear dipeptides.

Synthesis of 1,4-Oxazepane-2,5-diones via Cyclization of Rotationally Restricted Amino Acid Precursors and Structural Reassignment of Serratin

“…This compound was synthesized by ring closing acid 12c (1 equiv, 0.14 g, 0.50 mmol) according to general procedure D. After purification via flash chromatography (ethyl acetate/petroleum ether 2:1), 84 mg (0.31 mmol, 62% yield) of cyclic compound 4c was obtained. This resulted in a colorless powder: mp 81−83 °C; Yield: 62%; R f = 0.23 (ethyl acetate/petroleum ether 2:1); 1 H NMR (400 MHz, CDCl 3 ): δ = 0.88 (3H, t, J = 6.8 H), 1.20−1.80 (16H, m), 2.85 (1H, dd, J = 17.5 Hz, 9.5 Hz), 2.91 (1H, dd, J = 17.5 Hz, 3.7 Hz), 3.08 (3H, s), 3 Methyl N-(3-Hydroxydodecanoyl)glycinate 11d. This compound was synthesized by reacting glycine methyl ester hydrochloride 10d (1 equiv, 1.89 g, 15 mmol) with β-hydroxydodecanoic acid 9b (1 equiv, 3.24 g, 15 mmol), following general procedure A.…”

“…This resulted in a colorless powder: mp 92−94 °C; Yield: 94%; 1 H NMR (400 MHz, CD 3 OD): δ = 0.80 (3H, t, J = 6.9 Hz), 1.14−1.43 (16H, m), 2.25 (1H, dd, J = 14.3 Hz, 7.6 Hz), 2.30 (1H, dd, J = 14. 3 Methyl N-Benzyl-N-(3-hydroxynonanoyl)glycinate 15a. This compound was synthesized by reacting the methyl ester of N-benzyl glycine 14a (1 equiv, 0.59 g, 3.0 mmol) with β-hydroxynonanoic acid 9a (1 equiv, 0.52 g, 3.0 mmol), following general procedure B to yield 0.55 g (1.6 mmol, 55% yield) of ester 15a.…”

The synthesis of cyclic peptides

“…A number of reports have described cyclooligomerisation reactions where, when presented with appropriate reaction conditions, simple peptides undergo spontaneous assembly to form cyclic products. One such example uses various metal ions to dimerise linear dipeptide methyl esters and thereby assist Scheme 3 formation of C 2 -symmetric cyclic tetrapeptides (9). Acidolytic metal ion removal them provided macrocyclic peptides with varying ring sizes (Scheme 6).…”

Solid-Phase Synthesis of Conformationally Constrained Peptidomimetics Based on a 3,6-Disubstituted-1,4-diazepan-2,5-dione Core

“…Although this heterocycle offers an attractive structure for the development of new biologically active compounds, all the syntheses reported until now describe the preparation of 1,4-diazepan-2,5-diones. The syntheses proceeded through the lactonization of the terminal NH 2 and the β-COOH of a dipeptide containing aspartic acid 6 or the head-to-tail cyclization of a dipeptide containing phenylalanine …”