Two types of intramolecular bicyclization reactions observed between peptide aldehyde and N-terminus of the same peptide have been explored in the literature. We first tested whether grafted aldehyde can undergo intramolecular reaction with N-terminal amine followed by NaCNBH3 trapping in conditions based on reports from Malins and co-workers (NaOAC, pH = 5.5) (Figure ). After buffer scouting (Figure -12) and optimization, we found that mild acidic condition (0.1 M NH4OAc buffer, pH 4.6) gave highest reaction rate (0.16 M -1 s -1 ). In this buffer, 1 mM solution of peptide gave rise to bicyclic product with 62 % isolated yield after 2 hours (Figure , 2d, S4). NMR confirmed the structure of the bicycle formed via reductive amination (Figure ) and we refer to it as Malins bicycle. The second type of intramolecular reaction of N-terminus and aldehyde engaged 5-endo-trig reaction trapping of the imine intermediate with endogenous amide nucleophile as reported by Raj and coworkers. We observed the evidence of Raj-style cyclization in neutral-basic conditions (pH 8.5), NMR of peptide aldehyde derived from SAKGGRCYEDC uncovered a dynamic equilibrium between 4 species, the peptide-aldehyde, the imine intermediate, and a progressive appearance of two new compounds (Figure ). NMR analysis of the isolated major product proved that it was analogous to compounds reported by Raj and coworkers (Figure ). N-terminal Serine favored formation of R-isomer in 7:1 ratio (Figure , Figure ), whereas a similar peptide with N-terminal Alanine AAKGGRCYEDC in the same reaction yielded R: S = 2 :1 (Figure ), which aligns with the report that the stereoselectivity of this reaction depends on Nterminal composition. 'Raj-bicycles' were stable at neutral-basic condition (pH > 6.5) at under -20 °C (Figure ), but under mildly acidic condition (pH <5) they slowly reverted to the peptide-aldehyde (Figure ). At room temperature and neutral basic condition, isolated isomers of Raj bicycles formed a dynamic equilibrium between the isomers and peptide aldehyde. Both purified isomer solutions reached R:S ratio of 0.9:1 after 4 days (Figure , 22). This observation was consistent with the DFT calculations from Raj and coworkers that the R-isomer is more kinetically favored as the Sisomer is more thermodynamically favored. Malins bicycles were stable for several weeks in aqueous buffer (Figure ).