Synthesis of Aib-Pro Oligopeptides by repeated Azirine coupling with the Aib-Pro synthon

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

Highly Constrained Linear Oligopeptides Containing Heterocyclic alpha-Amino Carboxylic Acids

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 beta-bend ribbon spiral conformation

(S)-N-[(4-{(S)-1-[2-(4-Methoxybenzamido)-2-methylpropanoyl]pyrrolidine-2-carboxamido}-3,4,5,6-tetrahydro-2H-pyran-4-yl)carbonyl]proline dimethyl sulfoxide monosolvate (4-MeBz-Aib-Pro-Thp-Pro-OH)

The asymmetric unit of the title compound, C28H38N4O8·C2H6OS, contains one tetrapeptide and one disordered dimethyl sulfoxide (DMSO) molecule. The central five-membered ring (Pro2) of the peptide molecule has a disordered envelope conformation [occupancy ratio 0.879 (2):0.121 (2)] with the envelope flap atom, the central C atom of the three ring methylene groups, lying on alternate sides of the mean ring plane. The terminal five-membered ring (Pro4) also adopts an envelope conformation with the C atom of the methylene group closest to the carboxylic acid function as the envelope flap, and the six-membered tetrahydropyrane ring shows a chair conformation. The tetrapeptide exists in a helical conformation, stabilized by an intramolecular hydrogen bond between the amide N-H group of the heterocyclic [alpha]-amino acid Thp and the amide O atom of the 4-methoxybenzoyl group. This interaction has a graph set motif of S(10) and serves to maintain a fairly rigid [beta]-turn structure. In the crystal, the terminal hydroxy group forms a hydrogen bond with the amide O atom of Thp of a neighbouring molecule, and the amide N-H group at the opposite end of the molecule forms a hydrogen bond with the amide O atom of Thp of another neighbouring molecule. The combination of both intermolecular interactions links the molecules into an extended three-dimensional framework

Heterospirocyclic N-(2H-Azirin-3-yl)-L-prolinates: New Dipeptide Synthons

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 COCl2, 1,4- diazabicyclo[2.2.2]octane (DABCO), and NaN3 (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)

New 2H-Azirin-3-amines as Synthons for Sulfur-Heterocyclic α-Amino Acids

Three new spiroheterocyclic 2H-azirin-3-amines, which contain a sulfur atom, were prepared and successfully used for the synthesis of oligopeptides containing sulfur-heterocyclic α-amino acids via the ‘azirine/oxazolone method’

A novel 2H-azirin-3-amine as a synthon for a sulfur containing dipeptide segment

Starting with tetrahydro-2H-thiopyran-4-carboxylic acid and methyl prolinate, the novel 2H-azirin-3-amine (S)-N-(1-aza-6-thiaspiro[2.5]oct-1-en-2-yl)proline methyl ester was synthesized. In reactions with benzoic acid, thiobenzoic acid and Boc-valine, respectively, its usefulness as a synthon for the dipeptide (S)-N-[(4-aminotetrahydro-2H-thiopyran-4-yl)carbonyl]proline in peptide synthesis was demonstrated