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Synthesis of a Cyclic Depsipeptide via an Amide Cyclization The synthesis of (S)‐Pms‐(R)‐Pro‐(S)‐Ala‐Aib‐N(CH3)2 (12) has been achieved according to Scheme 3. For the formation of fragment 11, the reaction of Z‐alanine (Z = benzyloxycarbonyl) and 3‐dimethylamino‐2,2‐dimethyl‐2‐azirine (1) has been used, whereby 1 serves as an aminoisobutyric‐acid dimethylamide (aib‐N(CH3)2) equivalent. Treatment of a suspension of 12 in toluene with HCl gas at 100° led to the cyclic depsipeptide 13 in 72% yield (Scheme 4). In presence of water, the acid 14 was isolated as the sole product. A mechanism for the formation of 13 and 14 via an oxazolinone intermediate, is postulated in Scheme 4.

The conformations of a protected tetrathiopeptide have been analysed by isotope labelling and two-dimensional infrared spectroscopy (2D-IR). It has been found that Boc-Ala-Gly(=S)-Ala-Aib-OMe in acetonitrile, as well as its oxopeptide analogue, can adopt a hydrogen-bonded loop conformation in coexistence with less restricted structures. The two types of conformations interconvert too quickly to be resolved on the nuclear magnetic resonance (NMR) timescale, but give rise to different cross peaks in two-dimensional infrared spectra. The hydrogen bond between the Boc terminal group and the amide proton of Aib can be broken by photoisomerisation of the thioamide bond.

The reactions of aryl (selenophen-2-yl) thioketones with CH2N2 occur with spontaneous elimination of N2, even at low temperature (-65°), to give regioselectively sterically crowded 4,4,5,5-tetrasubstituted 1,3-dithiolanes and/or a novel type of twelve-membered dithia-diselena heterocycles as dimers of the transient thiocarbonyl S-methanides. The ratio of these products depends on the type of substituent located at C(4) of the phenyl ring. Whereas the formation of the 1,3-dithiolanes corresponds to a [3 + 2] cycloaddition of an intermediate thiocarbonyl ylide with the starting thioketone, the twelvememberd ring has to be formed via dimerization of the 'thiocarbonyl ylide' with an extended biradical structure.