The use of amino thio S-acids in the azirine/oxazolone method and a novel isomerization led to Aibcontaining endothiopeptides. With the aim of generalizing this method, a variety of Aib-containing dipeptide thioanilides have been prepared. By their treatment with ZnCl 2 in AcOH, followed by HCl-saturated AcOH, the CS group was shifted from the last to the penultimate amino acid in high yield and without epimerization. As this methodology is very useful for the specific introduction of a thioamide group, it was extended to Aibcontaining tripeptides. In addition, it could be shown that a mechanism via spirocyclic intermediates (cf. Scheme 4) is most likely for this isomerization. To establish the proposed neighboring-group participation of the N-acyl group, model dipeptide thioanilides containing no N-terminal CO group were synthesized. These derivatives did not undergo rearrangement.Introduction. ± Peptides with backbone modifications are of considerable interest. Among them are endothiopeptides with one or more peptide bonds replaced by thioamide groups within the peptide chain 2 ). These thioamides offer an almost isologous substitution of an amide linkage [5] that often leaves biological effects unaltered. However, computational studies show that this may not be generally the case, namely not in N-terminal thioamide replacements [6]. Endothio analogues of biologically active peptides can show an increased proteolytic stability [7], thus allowing higher bioavailability [8]. Moreover, enhanced biological activity and receptor selectivity can be expected but not predicted [9]. In addition, the thioamide-replacement strategy has also been applied to inhibition studies of proteases and peptidases [10]. A selection of recently published synthetic approaches to endothiopeptides provides further insights into the current synthetic developments of these modified peptides [1 ± 4] [11 ± 15].Another interesting group of backbone-modified peptides contain a-alkylated aamino acids. The introduction of a second alkyl group at the C(a)-atom of a-amino acids results in a restriction of the conformational flexibility (cf. [16], and refs. cit. therein), and stabilizes or induces helices. Two of these amino acids, Aib ( aaminoisobutyric acid) and Iva (isovaline) characterize the peptaibols, a family of natural antibiotics, which show bactericidal and hemolytic activity [17] [18]. Due to the severe steric hindrance, the synthesis of related peptides is difficult [19 ± 21], but with the azirine/oxazolone method, we developed a convenient synthetic access to such peptides, of which 3-amino-2H-azirines proved to be useful synthons for the introduction of a-alkylated a-amino acids [22 ± 26].

The morpholine ring of the title dione, C(13)H(15)NO(3), shows a boat conformation that is distorted towards a twist-boat, with the boat ends being the two Csp(3) atoms of the ring. The benzyl substituent is in the favoured 'exo' position. In the monothione derivative, (+/-)-6-benzyl-3,3-dimethyl-5-thioxomorpholin-2-one, C(13)H(15)NO(2)S, this ring has a much flatter conformation that is midway between a boat and an envelope, with the dimethyl end being almost planar. The orientation of the benzyl group is 'endo'. The dithione derivative, (+/-)-6-benzyl-3,3-dimethylmorpholine-2,5-dithione, C(13)H(15)NOS(2), has two symmetry-independent molecules, which show different puckering of the morpholine ring. One molecule has a flattened envelope conformation distorted towards a screw-boat, while the conformation in the other molecule is similar to that in the monothione derivative. Intermolecular hydrogen bonds link the molecules in the three compounds, respectively, into centrosymmetric dimers, infinite chains, and dimers made up of one of each of the symmetry-independent molecules.

When tripeptides of type Axx t -Aib-Axx-OH were coupled with amino acid methyl esters by means of commonly used coupling reagents, the formation of 1,3-thiazol-5(4H)-imines and 1,3-oxazol-5(4H)-imines was observed. With the aim of understanding which structure elements are required for this reaction, several model peptides have been prepared according to our recently described methodology, a modification of the −azirine/ oxazolone method×, followed by selective isomerization of the peptide thioamides. In addition, attempts to prepare peptides that contain more than one CS group by the same methodology also led to the formation of 1,3-thiazol-5(4H)-imine-containing derivatives. An additional CS group can be introduced into the peptide, when the 1,3-thiazol-5(4H)-imines were treated with H 2 S, although mixtures of epimers were obtained. The structures of an endothiohexapeptide, two 1,3-thiazol-5(4H)-ones, and two peptides containing a 1,3-thiazol-5(4H)-imine moiety have been established by X-ray crystal-structure analysis.Introduction. ± Recently, it has been shown that the reaction of 2H-azirin-3-amines with a-amino thioic S-acids followed by selective isomerization of the thioamide function offers a convenient synthetic access to peptides containing a combination of two backbone modifications, i.e., thioamide groups and a,a-disubstituted a-amino acids [1 ± 5]. A mechanism via spirocyclic intermediates is conceivable for the isomerization in which the CS group is shifted from the last to the penultimate amino acid [5]. With the aim of demonstrating the efficiency of our method, we started a program for the synthesis of Aib-containing endothiopeptides 2 ).The coupling of the peptide acid Boc-Trp-Ile-Ala-Y(CS)-Aib-Ile-OH (1) with HVal-Aib-Leu-Aib-Pro-OMe (2) with the coupling reagent [(1H)-benzotriazol-1-yl)oxy]tris[pyrrolidin-1-yl]phosphonium hexafluorophosphate (PyBOP) in the presence of EtN(i-Pr) 2 led unexpectedly to a mixture (ratio 62 : 38) of the epimeric 1,3-thiazol-5(4H)-imine-containing endothiodecapeptide 3 [4] (Scheme 1).Similar to the known epimerization of 1,3-thiazol-5(4H)-ones [6], the epimerization of Ala(3) is assumed to be catalyzed by acid during the workup, which includes washing the organic solution of 3 with a 5% KHSO 4 solution. The proposed mechanism for the formation of the 1,3-thiazol-5(4H)-imines is depicted in Scheme 2. Nucleophilic attack of the S-atom of the thioamide group in A at the C-atom of the neighboring amide group leads to the zwitterionic heterocycle B, which yields the 1,3-thiazol-5(4H)-imine D after elimination of H 2 O.In the present work, we describe further investigation of the formation of the 1,3-thiazol-5(4H)-imines with the intention of clarifying which conditions and structural

No abstract

The synthesis of the new 2H-azirin-3-amines (−3-amino-2H-azirines×) 11, 20, 28, and 33 as dipeptide synthons is described. The reactions of the starting amides with Lawesson reagent gave the corresponding thioamides, and consecutive treatment with COCl 2 , 1,4-diazabicyclo[2.2.2]octane (DABCO), and NaN 3 led to the desired products. It is shown that these 2H-azirin-3-amines can conveniently be used as building blocks of the dipeptides Aib-(Me)Axx (Axx alanine, valine), Aib-Homoproline, and Iva-Pro in the synthesis of several model peptides. However, some limitations apply for the synthesis of such 2H-azirin-3-amines. The starting material for the azirine synthesis, the corresponding thioamides, cannot generally be synthesized, and the 2H-azirin-3-amines could not be obtained in all cases from the thioamides prepared.