Dedicated to Prof. Andre  S. Dreiding on the occasion of his 80th birthday
The use of amino thioacids in the azirine/oxazolone method led to completely epimerized Aib-containing endothiodipeptides (Aib 2-aminoisobutyric acid). It could be established that the epimerization occurred during the acidic hydrolysis of the primarily formed dipeptide thioanilides in which the thiocarbonyl group was shifted from the last to the penultimate amino-acid residue. Several conditions for the hydrolysis were tested, and, in some of them, the degree of epimerization could be reduced. By treatment of the Aib-containing dipeptide thioanilides 21 with ZnCl 2 in AcOH followed by HCl in AcOH, the isomeric endothiodipeptide anilides 25 were formed, i.e., the thiocarbonyl group was again shifted from the last to the penultimate amino acid residue. Under optimized reaction conditions, this novel isomerization proceeded in high yields and without any epimerization. Two conceivable mechanisms are proposed in Scheme 12. X-Ray diffraction analyses were performed for ZÀGlyÀAib-Y(CS )ÀN( Me)Ph (21f) and the isomeric ZÀGly-Y(CS )ÀAibÀN( Me)Ph (25f).
The reaction of 2H-azirin-3-amines with amino thiocarboxylic acids could offer a possibility to prepare peptides with a combination of these two backbone modifications. First attempts in this field were made by the treatment of thiobenzoic acid with N,N,2,2-tetramethyl-2H-azirin-3-amine (1a) [27]. Further experiments were carried out with O-(tert-butyl) dl-thiomandelic acid (3), prepared from O-(tert-butyl)-dlmandelic acid (2) by activation with 1,1'-carbonyldiimidazole ( 1,1'-carbonylbis[1Himidazole]; CDI ) and subsequent treatment with H 2 S (Scheme 1) [28]. Reaction of crude 3 with 1a in MeCN at 08 3 room temperature led to the thioamide 4 in 74% yield with respect to 2. Sequential treatment of a solution of 4 in toluene with HCl (gas) and Me 2 NH gave the isomeric thioamide 5 in 53% yield. Several control experiments have shown that the isomerization of 4 to 5 occurred via initial formation of 1,3-oxazole-5(4H )-thione A which rearranged to the 1,3-thiazol-5(4H )-one B [27] [28]. The latter could be isolated in 60% yield; ring opening with Me 2 NH then yielded 5.
In addition, ZÀGlyÀAib-Y(CS)ÀN(Me)Ph ( 6), which was obtained by the reaction of Z-thioglycine with N,2,2-trimethyl-N-phenyl-2H-azirin-3-amine (1b), was hydrolyzed under the standard conditions of the azirine/oxazolone method (3m HCl, THF/H 2 O 1 : 1, 358) [29] (Scheme 2; Z (benzyloxy)carbonyl). After 34 h, a mixture of endothiodipeptide 7, dipeptide 8, and Z-glycine (9) was isolated in a ratio of ca. 10 : 3 : 1. Treatment of the crude mixture with N,N'-dicyclohexylcarbodiimide ( DCC ) followed by the addition of benzocaine ( 10) and (AE)-camphor-10-sulfonic acid (CSA ) led to the endothiotripeptide 11 in 33% yield and to 12 in 20% yield. Scheme 1