The small 12-membered ring size of macrocyclic tetrapeptides can make their synthesis difficult, resulting in low yields and dimers as the major product. Macrocyclic tetrapeptides are potential candidates for drug development because of their low molecular weight and expected metabolic stability in vivo. The all L-amino acid macrocyclic tetrapeptide cyclo[Pro-Val-Pro-Tyr], Figure 1, a potent inhibitor of tyrosinase, was isolated from the lactic bacterium Lactobacillus helveticus (Kawagishi et al. Tetrahedron Lett. 1993,  34, 3439-3440), but to date no successful synthesis of this natural product has been reported (White and Yudin. Nature, 2011,  3, 509-524). Only the tyrosine epimer, cyclo[Pro-Val-Pro-D-Tyr], was obtained in the reported attempted synthesis (Schmidt and Langner. J. Pept. Res., 1997,  49, 67-73). We are synthesizing CJ-15,208 (cyclo[Phe-D-Pro-Phe-Trp]) and its analogs using a modified synthetic protocol (Senadheera et al. In Peptides, Building Bridges, American Peptide Soc., M. Lebl, Ed., 2011,  pp 346-347) to prepare larger quantities of these macrocyclic tetrapeptides for detailed pharmacological evaluation in vivo. To prove the strengths of our improved and optimized cyclization methodology we attempted the synthesis of cyclo[Pro-Val-Pro-Tyr] and successfully generated this all L-amino acid macrocyclic tetrapeptide in moderate yield (21%). The product that would result from C-terminal epimerization was also synthesized to verify the chiral integrity of the tyrosinase inhibitor. This research was supported by NIDA grants R01 DA018832 and R01 DA023924.

First successful synthesis of the all L-amino acid natural product macrocyclic tetrapeptide <i>cyclo</i>[Pro-Val-Pro-Tyr]

246th National Meeting (2013)

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First successful synthesis of the all L-amino acid natural product macrocyclic tetrapeptide cyclo[Pro-Val-Pro-Tyr]