Best 5 On-Resin Lactam Bridge Formation Conditions (Peptide Cyclization)

Best 𝟱 𝗼𝗻-𝗿𝗲𝘀𝗶𝗻 𝗹𝗮𝗰𝘁𝗮𝗺 𝗯𝗿𝗶𝗱𝗴𝗲 𝗳𝗼𝗿𝗺𝗮𝘁𝗶𝗼𝗻 𝗰𝗼𝗻𝗱𝗶𝘁𝗶𝗼𝗻𝘀 that are robust, automation-friendly, and widely used in medicinal-chemistry peptide synthesis. These methods are ranked for efficiency, selectivity, and compatibility with automated SPPS.Key Practical Guidelines (Critical for Success)

🔹 𝗢𝗿𝘁𝗵𝗼𝗴𝗼𝗻𝗮𝗹 𝗣𝗿𝗼𝘁𝗲𝗰𝘁𝗶𝗻𝗴 𝗚𝗿𝗼𝘂𝗽𝘀 (𝗠𝘂𝘀𝘁-𝗛𝗮𝘃𝗲)

• Lys: Alloc, ivDde, or Dde

• Asp/Glu: OAllyl or ODmab

• Deprotect only the two side chains involved before cyclization

🔹 𝗥𝗲𝘀𝗶𝗻 & 𝗚𝗲𝗼𝗺𝗲𝘁𝗿𝘆 𝗖𝗼𝗻𝘀𝗶𝗱𝗲𝗿𝗮𝘁𝗶𝗼𝗻𝘀

• Use low-loading PEG or TentaGel® resin (≤0.4 mmol/g)

• Ideal ring sizes:

• i→i+3, i→i+4: highest success

• i→i+2: strained, lower yields

• i→i+5+: may need longer time or higher temp

🔹 𝗔𝘂𝘁𝗼𝗺𝗮𝘁𝗶𝗼𝗻-𝗙𝗿𝗶𝗲𝗻𝗱𝗹𝘆 𝗘𝗻𝗵𝗮𝗻𝗰𝗲𝗺𝗲𝗻𝘁𝘀

• Apply gentle heating (50–60 °C) to improve conversion

• For difficult cyclizations:

• Double coupling

• Switch from HBTU → COMU or HATU

• Wash thoroughly after cyclization to remove uronium residues

🎯 𝗤𝘂𝗶𝗰𝗸 𝗠𝗲𝘁𝗵𝗼𝗱 𝗦𝗲𝗹𝗲𝗰𝘁𝗶𝗼𝗻 𝗚𝘂𝗶𝗱𝗲

Scenario Best Method

• General on-resin lactam bridge: HATU / DIPEA

• Racemization-sensitive sites: DIC / Oxyma

• Long / hydrophobic peptides: COMU / DIPEA

• GMP / scale-up: PyBOP / DIPEA

• Cost-sensitive, simple peptides: HBTU / DIPEA

🧠 𝗘𝘅𝗽𝗲𝗿𝘁 𝗠𝗲𝗱𝗶𝗰𝗶𝗻𝗮𝗹-𝗖𝗵𝗲𝗺𝗶𝘀𝘁𝗿𝘆 𝗧𝗶𝗽𝘀

• Perform lactam cyclization before N-terminal elongation if possible.

• Confirm completion by Kaiser test + LC–MS after cleavage.

• Avoid high base concentrations that can cause Asp→isoAsp formation.

• For stubborn cases, switch to solution-phase macrolactamization after partial cleavage.

#Peptidechemistry #SPPS #Cyclicpeptide #Lactambridge #Medicinalchemistry