Full solid-phase total synthesis of macrocyclic natural peptides using four-dimensionally orthogonal protective...

Area of Science:

• Organic Chemistry
• Peptide Chemistry
• Synthetic Chemistry

Background:

• Fmoc-based solid-phase synthesis is a key method for creating linear and macrocyclic peptides.
• Synthesizing complex macrocyclic polyamides requires multiple protective groups with orthogonal reactivities.
• Selective exposure of amine and carboxylic acid groups is crucial for amide bond formation in peptide synthesis.

Purpose of the Study:

• To review four-dimensionally orthogonal protective group strategies for solid-phase synthesis.
• To demonstrate the application of these strategies in synthesizing complex macrocyclic peptides.
• To highlight the synthesis of branched-chain peptides (polymyxin E2, daptomycin) and a tricyclic peptide (lacticin 481).

Main Methods:

• Focus on Fmoc (9-fluorenylmethoxycarbonyl) based solid-phase synthesis.
• Utilizing orthogonal protective group strategies with distinct reactivities.
• Application in the synthesis of complex peptide architectures.

Main Results:

• Demonstration of efficient synthesis of macrocyclic peptides with branched chains.
• Successful synthesis of a tricyclic natural peptide.
• Validation of four-dimensionally orthogonal protective group strategies for complex peptide synthesis.

Conclusions:

• Fmoc-based solid-phase synthesis, combined with orthogonal protection, enables efficient construction of complex macrocyclic peptides.
• These strategies are vital for accessing challenging peptide structures, including those with branched chains and multiple rings.
• The reviewed methods provide a robust platform for the synthesis of diverse and complex peptide natural products.