The poly-L-proline type II (PPII) secondary structure is a critical recognition element in mediating protein-protein interactions and therefore regulating cellular signaling. Therefore the design of PPII mimics is highly desirable, as they can potentially be used as chemotherapeutic agents. These PPII mimics can be obtained from the peptide constructed using proline templated amino acids. In our ongoing efforts towards the design and synthesis of such PPII mimics, we have synthesized the 4-substituted proline templated lysine (1) in 8 easy steps starting from commercially available materials, with an overall yield of more than 25%. The only reported synthesis of the target molecule is an 18-step scheme starting with a chiral synthon. An interesting feature observed was the wittig reaction yielding a mixture of regioisomeric double bonds (endo and exo to the pyrrolidine ring). The key feature of our strategy included a one pot stereoselective reduction of the double bond, accompanying the reduction of the nitrile group to the corresponding amine and simultaneous protection of the newly generated primary amine. All these three transformations were achieved in one pot without deprotecting the pyrrolidine nitrogen, thereby providing us the cis alkyl substituent bearing the nitrogen functionality on the 4-position of the proline ring as required in the target molecule. Proper selection of the protecting groups and the sequence of reactions were instrumental towards the synthesis.
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