Synthesis and Crystal Structure of 3,3,6,6-Tetramethylmorpholine-2,5-dione, and its 5-Monothio- and 2,5-Dithio-Derivatives

The synthesis of 3,3-dimethylmorpholine-2,5-diones 4a was achieved conveniently via the ‘direct amide cyclization’ of the linear precursors of type 3, which were prepared by the coupling of 2,2-dimethyl-2H-azirin-3-amines 2 with 2-hydroxyalkanoic acids 1. Thionation of 4a with Lawesson’s reagent yielded the corresponding 5-thioxomorpholin-2-ones 10 and morpholine-2,5-dithiones 11, respectively, depending on the reaction conditions. The structures of 3aa, 4aa, 10a and 11a were established by X-ray crystallography. All attempts to prepare S-containing morpholine-2,5-dione analogs or thiomorpholine-2,5-diones by cyclization of corresponding S-containing precursors were unsuccessful and led to various other products. The structures of some of them have also been established by X-ray crystallography

Introduzione

Chemical analysis of an Australian marine sediment-derived Aspergillus sp. (CMB-M081F) yielded the new diketomorpholine (DKM) shornephine A (1) together with two known and one new diketopiperazine (DKP), 15b-β- hydroxy-5-N-acetyladreemin (2), 5-N-acetyladreemin (3), and 15b-β-methoxy-5-N-acetyladreemin (4), respectively. Structure elucidation of 1−4 was achieved by detailed spectroscopic analysis, supported by chemical degradation and derivatization, and biosynthetic considerations. The DKM (1) underwent a facile (auto) acid-mediated methanolysis to yield seco-shornephine A methyl ester (1a). Our mechanistic explanation of this transformation prompted us to demonstrate that the acid-labile and solvolytically unstable DKM scaffold can be stabilized by N-alkylation. Furthermore, we demonstrate that at 20 μM shornephine A (1) is a noncytotoxic inhibitor of P-glycoprotein-mediated drug efflux in multidrug-resistant human colon cancer cells