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 coupling of 2,2-dimethyl-2H-azirin-3-amines 2 with 2-hydroxyalkanoic acids 1. Thionation of 4a with Lawessons 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.Introduction. -In the last 30 years, we have demonstrated that the direct amide cyclization [1] is a useful method for the synthesis of cyclodepsipeptides, which contain a,a-disubstituted a-amino acids, e.g., a-aminoisobutyric acid (Aib) [2]. The combination with the azirine/oxazolone method [3] for the preparation of the linear precursors offers a convenient and efficient access to this class of compounds. For example, the reaction sequence starting with an a-hydroxy acid 1 and azirine 2a yielding compound 3 (n ¼ 1), followed by repeated hydrolysis and azirine coupling, and finally cyclization leads to cyclodepsipeptides of type 4 with 6-, 9-, 12-, and 15-membered rings [1b] (Scheme 1). Analogously, 16-and 19-membered cyclodepsipeptides are accessible from b-hydroxy acids [4]. Furthermore, cyclodepsipeptides with an alternating sequence of a-hydroxy and a,a-disubstituted a-amino acids can be prepared by coupling segments of type 3, followed by direct amide cyclization [1c] [5].The synthesis and stability of morpholine-2,5-diones (4a), which are the smallest cyclodepsipeptides, was studied already 60 years ago [6]. But only in the last couple of years have these compounds attracted increasing interest as natural products [7], biologically active compounds [8], and particularly as monomers of biodegradable polymers [9]. There are three types of cyclization leading to 4a, i.e., lactonization, lactamization, and cyclization of N-(2-bromoacetyl)glycine sodium salts (for reviews, see [10]). In the case of a,a-disubstituted glycines, a very simple and efficient protocol is the direct amide cyclization of 3 (n ¼ 1) [1b]. Surprisingly, all attempts to prepare the analogous seven-membered 1,4-oxazepane-2,5-diones 5 by the same method failed, and only the 14-membered cyclodimers were obtained [11].
