(±)-6-Benzyl-3,3-dimethylmorpholine-2,5-dione and its 5-monothio and 2,5-dithio derivatives

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The treatment of diluted solutions of the hydroxy diamides 6a and 6b in toluene with HCl gas at 100°gave the dimeric, 14-membered cyclodepsipeptide 10 in up to 72% yield (Scheme 3). The same product was formed from the linear dimer of 6b, the depsipeptide 11, under the same conditions (cf. Scheme 4). All attempts to prepare the cyclic seven-membered monomer 9, starting with different precursors and using different lactonization methods failed, and 10 was the only product which was isolated (cf. Scheme 6). For example, the reaction of the ester 20 with NaH in toluene at 80°led exclusively to the cyclodimer 10. On the other hand, the base-catalyzed cyclization of the hydroxy diester 22, which is the 'O-analogue' of 20, yielded neither the seven-membered dilactone, nor the 14-membered tetralactone, but only the known trimer 23 and tetramer 24 of 2,2-dimethylpropano-3-lactone (cf. Scheme 7). 2The treatment of diluted solutions of the hydroxydiamides 6a and 6b in toluene with HCl gas at 100 o gave the dimeric, 14-membered cyclodepsipeptide 10 in up to 72% yield (Scheme 3).The same product was formed from the linear dimer of 6b, the depsipeptide 11, under the same conditions (Scheme 4). All attempts to prepare the cyclic 7-membered monomer 9, starting with different precursors and using different lactonization methods failed, and 10 was the only product which was formed (Scheme 6). For example, the reaction of the ester 20 with NaH in toluene at 80 o led exclusively to the cyclodimer 10. On the other hand, the base catalyzed cyclization of the hydroxydiester 22, which is the 'O-analogue' of 20, yielded neither the 7-membered dilactone, nor the 14-membered tetralactone, but only the known trimer 23 and tetramer 24 of 2,2-dimethylpropiolactone (Scheme 7).3

Section: Methodsmentioning

confidence: 99%

An Unexpected Formation of a 14‐Membered Cyclodepsipeptide

Iliev

Linden

Heimgartner

2003

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“…2, c), 11b [21]). The six-membered rings of 4aa and 10a (polymorph 1) have a conformation midway between that of a highly flattened boat and a twist-boat, where C(6) shows the most significant deviation from the ring plane.…”

mentioning

confidence: 96%

“…The N(4)ÀH group forms an intermolecular H-bond with the amide O(5)-atom and the S(5)-atom, respectively, of a neighboring molecule. This interaction forms closed loops, thereby linking pairs of molecules into centrosymmetric dimers, which have a graph set motif [20] of R 2 2 (8) (for a similar structure, see [21]). In another crystallization of 10a, a second polymorph was obtained, in which two symmetry-independent molecules are in the asymmetric unit.…”

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confidence: 99%

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Synthesis and Crystal Structure of 3,3,6,6‐Tetramethylmorpholine‐2,5‐dione, and Its 5‐Monothioxo and 2,5‐Dithioxo Derivatives

Mawad¹,

Pour²,

Linden³

et al. 2010

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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].

Transformation of 5‐Hydroxy‐ to (5‐Chloropentanoyl)amino Derivatives under ‘Direct Amide Cyclization’ Conditions

Iliev

Verma

Linden

et al. 2006

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The application of the 'direct amide cyclization' conditions to the linear delta-hydroxy diamide 11 is described (Scheme 3). Instead of the cyclization to the expected nine-membered cyclodepsipeptide, only the chloro acid 12 was obtained. Its formation could be explained by consecutive formation of the 1,3-oxazol-5(4H)-one 16 and the six-membered imino lactone 17 as intermediates (Scheme 4). The spontaneous isomerization of the latter gave 12 in a good yield.