Synthesis of D-pseudoprolines to Facilitate the Chemical Synthesis of Difficult D-

Task description for ENSTBB-traineeship at Pepscan Therapeutics

The chemical synthesis of large peptides is still hampered by problems associated with secondary structure formation (e.g. β-sheet (beta-sheet), which significantly reduces coupling rates and/or Fmoc-deprotection rates.[1][2][3] Pseudoproline residues (see figure)[5][6][7] have been reported to modify the intrinsic properties of peptides responsible for aggregation and secondary structure and are nowadays frequently used to improve synthesis for difficult peptides. Pseudoprolines consist of - (Oxa) or -derived oxazolidines [Oxa(5- Me)], and -derived thiazolidines (THz) with -like ring structure (see top right). Pseudoprolines fulfill two functions simultaneously: they serve (1) as temporary side-chain protection for Ser, Thr, and Cys and (2) as solubilizing building blocks to increase solvation and coupling rates during and in subsequent chain assembly.

Pseudoproline a powerful tool for improving the quality of synthetic peptides.[12] Pseudoproline have greatly increased the success rate for synthesizing both long and difficult peptides. Pseudoproline dipeptides can be introduced in the same manner as other amino acid derivatives. The routine use of pseudoproline (oxazolidine) dipeptides in the FMOC solid phase pepdide sysnthesis (SPPS) of serine- and threonine-containing peptides leads to remarkable improvements in quality and yield of crude products and helps avoid unnecessary repeat synthesis of failed sequences. Pseudoproline dipeptides have proven particularly effective in the synthesis of intractable peptides, long peptides/small , and cyclic peptides, enabling in many cases the production of peptides that otherwise could not be made. These dipeptides are extremely easy to use: simply substitute a serine or threonine residue together with the preceding amino acid residue in the peptide sequence with the appropriate pseudoproline (see the figure on your right). The native sequence is regenerated on cleavage and deprotection.

Structure of the L-pseudoproline “Ser-Ala”

Despite the frequence use of L-pseudoprolines, which are commercially available, the use of D- pseudoprolines is hardly described, most likely because of their non-availability. The first aim of this project is the successful synthesis of a D-pseudoproline, the mirror image counterpart of the readily available L-pseudoprolines. Once the procedure has been worked out and fully optimized, we aim for making a second or third D-pseudoproline. The project should last 4- 5months in total, in which we hope to make 2-3 D-pseudoprolines on multigram-scale quantities.

Literature References: 1. Mutter, M., Vuilleumier, S., Angew. Chem., (1989) 101, p.551; Angew. Chem. Int. Ed. Engl., (1989) 28, p.535 2. Toniolo. C, Bonora. G. M., Multer. M., Pillai. V.N.R., Makromol. Chem. (1981) 182. p.1997 3. Mutter. M., Pillai. V. N. R., Anzinger. H., Bayer, E., Toniolo, C, In Peptides (1980) Brunfeldt. K. Ed., Scriptor: Copenhagen. (1981) pp.660