The synthesis of methyl N-(1-aza-6-oxaspiro[2.5]oct-1-en-2-yl)-l-prolinate (1e) has been performed by consecutive treatment of methyl N-[(tetrahydro-2H-pyran-4-yl)thiocarbonyl]-l-prolinate (5) with COCl 2 , 1,4diazabicyclo[2.2.2]octane (DABCO), and NaN 3 (Scheme 1). As the first example of a novel class of dipeptide synthons, 1e has been shown to undergo the expected reactions with carboxylic acids and thioacids (Scheme 2). The successful preparation of the nonapeptide 16, which is an analogue of the C-terminal nonapeptide of the antibiotic Trichovirin I 1B, proved that 1e can be used in peptide synthesis as a dipeptide building block (Scheme 3). The structure of 7 has been established by X-ray crystal-structure analysis ( Figs. 1 and 2).
A new synthesis of (Aib-Pro)n oligopeptides (n = 2, 3, and 4) via azirine coupling by using the dipeptide synthon methyl N-(2,2-dimethyl-2H-azirin-3-yl)-l-prolinate (1b; Fig. 1) is presented. The most important feature of the employed protocol is that no activation of the acid component is necessary, i.e., no additional reagents are required, and the coupling reaction is performed under mild conditions at room temperature. As an attempt to provide an answer to the question of the preferred conformation of the prepared molecules, we carried out experiments by using NMR techniques and X-ray crystallography. For example, in the case of the hexapeptide 11, it was possible to compare the conformations in the crystalline state and in solution. After the selective hydrolysis of the methyl ester p-BrBz-(Aib-Pro)4-OMe (13) under basic conditions, the corresponding octapeptide acid was obtained, which was then converted into the octapeptide amide p-BrBz-(Aib-Pro)4-NHC6H13 (15) by using standard coupling conditions and activating reagents (HOBt/TBTU/DIEA) of the peptide synthesis. The conformation of this compound, as well as those of the tetrapeptides 14 and 18, was also established by X-ray crystallography and in solution by NMR techniques. In the crystalline state, a beta-bend ribbon structure is the preferred conformation, and similar conformations are formed in solution. A new synthesis of (Aib-Pro) n oligopeptides (n ¼ 2, 3, and 4) via azirine coupling by using the dipeptide synthon methyl N-(2,2-dimethyl-2H-azirin-3-yl)-l-prolinate (1b; Fig. 1) is presented. The most important feature of the employed protocol is that no activation of the acid component is necessary, i.e., no additional reagents are required, and the coupling reaction is performed under mild conditions at room temperature. As an attempt to provide an answer to the question of the preferred conformation of the prepared molecules, we carried out experiments by using NMR techniques and X-ray crystallography. For example, in the case of the hexapeptide 11, it was possible to compare the conformations in the crystalline state and in solution. After the selective hydrolysis of the methyl ester p-BrBz-(Aib-Pro) 4 -OMe (13) under basic conditions, the corresponding octapeptide acid was obtained, which was then converted into the octapeptide amide p-BrBz-(Aib-Pro) 4 -NHC 6 H 13 (15) by using standard coupling conditions and activating reagents (HOBt/TBTU/DIEA) of the peptide synthesis. The conformation of this compound, as well as those of the tetrapeptides 14 and 18, was also established by X-ray crystallography and in solution by NMR techniques. In the crystalline state, a b-bend ribbon structure is the preferred conformation, and similar conformations are formed in solution.
Two spiroheterocyclic 2H‐azirin‐3‐amines, 1f and 1g, were shown to be useful synthons for the dipeptides N‐(4‐aminotetrahydro‐2H‐pyran‐4‐yl)prolinate (Thp‐Pro) and the corresponding thiopyran derivative, Tht‐Pro, respectively. By coupling of 4‐bromobenzoic acid with 1f or 1g and saponification, followed by repeating the coupling and saponification steps, oligopeptides of type 4‐BrBz‐(Thp‐Pro)n‐OMe and 4‐BrBz‐(Tht‐Pro)n‐OMe were prepared, and their conformations were evaluated in solution by NMR techniques and in the crystalline state by X‐ray crystallography. All of these sterically highly congested oligopeptides adopt fairly rigid helical conformations. It is interesting to note that the hexapeptide with Thp forms a 310‐helix, whereas the Tht analog has a β‐bend ribbon spiral confirmation.
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