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

Abstract

Several natural products containing a 1,4-oxazepane-2,5-dione-core are known. One example is serratin, isolated from Serratia marcescens. Because of the presence of a carboxylic amide, which has a preference for a trans-conformation, and the presence of a labile lactone in this core, many synthetic methodologies commonly used for the cyclization toward medium-sized heterocycles cannot be applied. As N-acyl amino acids lacking a third substituent at nitrogen failed to undergo ring-closure, several N-protecting groups were evaluated. With the use of the removable PMB-group, an N-unsubstituted 1,4-oxazepane-2,5-dione was synthesized. Via the application of pseudoprolines (i.e. serine-derived oxazolidines as another type of protecting group), a compound with the presumed structure of the natural product serratin was obtained. As a result of the differences in spectral data, the incorrect structural assignment of the natural product serratin was identified. Instead of the predicted seven-membered heterocycle, a symmetrical serratamolide analogue is proposed to be the correct structure of serratin.

One-Step Assembly of Functionalized Morpholinones and 1,4-Oxazepane-3-ones via [3 + 3]- and [3 + 4]-Annulation of Aza-Oxyallyl Cation and Amphoteric Compounds

“…Among the saturated N-heterocycles, morpholine and 1,4-oxazepane are some of the most abundant motifs featured in many pharmaceuticals and basic skeleton of natural products . We envisaged that the −C­(CO)­N– molecular skeleton of a putative azaoxyallyl cation could be a potential synthon to forge the aforementioned classes of heterocycles upon successfully engaging complementary annulation partners in the reaction.…”

Pocket-to-Lead: Structure-Based De Novo Design of Novel Non-peptidic HIV-1 Protease Inhibitors Using the Ligand Binding Pocket as a Template

“…The syntheses of compounds 8 and 9 are outlined in Scheme . First, amine 15 was condensed with 2-(4-(methylsulfonyl)­phenyl)­acetic acid by using WSCD/HCl and HOBt, followed by cyclization with t -BuOK to give 3-keto lactam 17 as a racemate. Next, 17 was alkylated with p -fluorobennzyl bromide to afford 18 as a racemate.…”

“…The residue was purified by amino silica gel column chromatography to afford 27 (9.70 g, 98%) as a brown oil. 1 2-(Benzyloxy)-1-iodo-4-(methylsulfonyl)benzene (28). To a solution of 28 (6.57 g, 23.7 mmol) in MeCN (59.1 mL) and H 2 O (6.57 mL) were added KI (19.7 g, 118 mmol) and t-BuONO (14.2 mL, 118 mmol).…”