Orthogonal protection, solution phase synthesis

Scheme 5 Combined Solid-Phase and Solution Strategy for the Synthesis of Regioselectively Addressable Functionalized Templates (RAFT) with Four Orthogonally Protected Lysine Side Chains for Sequential Attachment of Four Different Peptide Sequences 171...

The appeal of cyclic peptides as a rich source of biologically active molecules makes the synthesis of combinatorial libraries of these compounds desirable. However, few avenues for the synthesis of large arrays of cyclic peptides exist. This is primarily caused by the difficult orthogonal deprotection requirements, which require a careful choice of synthetic strategy. For example, if a solution-phase head-to-tail cyclization is undertaken (15) (Fig. 2A), the peptide must be purified at each step of the synthesis (i.e., after synthesis of the linear, cyclized protected and after deprotection) (see Note 1). 

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