Melanotan II is a synthetic cyclic heptapeptide used to prevent a sunlight-induced
skin cancer by stimulating the skin tanning process. In this paper we report the first
solution phase synthesis of the title compound. The hexapeptide sequence has been assembled by [(2+2)+1+1] scheme. After removing the orthogonal protection, a
carbodiimide mediated lactamization, involving the epsilon-amino group of
lysine and gamma-carboxy group of
aspartic acid, led to a cyclic intermediate. Appending N-acetylnorleucine concluded the assembly of
melanotan II molecule. Protection of the lateral groups in
arginine and
tryptophan was omitted for atom and step economy reasons. The total synthesis of
melanotan II was accomplished in 12 steps with 2.6% overall yield, affording >90% pure
peptide without using preparative chromatography.