RATIONALE: The [3+3]-cyclocondensation reactions of chiral (1R,2R)-1,2-diaminocyclohexane with aromatic or aliphatic bis-aldehydes to form trianglimine macrocycles were reported a decade ago and were believed to proceed through a stepwise mechanistic pathway; however, no intermediates were ever isolated or detected and characterized. METHODS: We investigated the mechanism of the [3+3]-cyclocondensation reaction using a selection of dialdehyde starting materials using real-time electrospray ionization time-of-flight mass spectrometry. RESULTS: We observed up to a maximum of 16 reaction intermediates along the reaction pathway, more than for any other multistep reaction reported. We also probed the dynamic reversibility of trianglimines using selected small dynamic combinatorial libraries and showed that trianglimine formation is indeed fully reversible. CONCLUSIONS: This study represents a significant contribution towards understanding the mechanism of trianglimine formation and its potential applicability can be extended to include other cascade reactions.
RATIONALE: The [3+3]-cyclocondensation reactions of chiral (1R,2R)-1,2-diaminocyclohexane with aromatic or aliphatic bis-aldehydes to form trianglimine macrocycles were reported a decade ago and were believed to proceed through a stepwise mechanistic pathway; however, no intermediates were ever isolated or detected and characterized. METHODS: We investigated the mechanism of the [3+3]-cyclocondensation reaction using a selection of dialdehyde starting materials using real-time electrospray ionization time-of-flight mass spectrometry. RESULTS: We observed up to a maximum of 16 reaction intermediates along the reaction pathway, more than for any other multistep reaction reported. We also probed the dynamic reversibility of trianglimines using selected small dynamic combinatorial libraries and showed that trianglimine formation is indeed fully reversible. CONCLUSIONS: This study represents a significant contribution towards understanding the mechanism of trianglimine formation and its potential applicability can be extended to include other cascade reactions.