Diastereoselective formation of glycoluril dimers: isomerization mechanism and implications for cucurbit[n]uril synthesis.
Cucurbit[6]uril (CB[6]) is a macrocyclic compound, prepared in one pot from glycoluril and formaldehyde, whose molecular recognition properties have made it the object of intense study. Studies of the mechanism of CB[n] formation, which might provide insights that allow the tailor-made synthesis of CB[n] homologues and derivatives, have been hampered by the complex structure of CB[n]. By reducing the complexity of the reaction to the formation of S-shaped (12S-18S) and C-shaped (12C-18C) methylene bridged glycoluril dimers, we have been able to probe the fundamental steps of the mechanism of CB[n] synthesis to a level that has not been possible previously. For example, we present strong evidence that the mechanism of CB[n] synthesis proceeds via the intermediacy of both S-shaped and C-shaped dimers. The first experimental determination of the relative free energies of the S-shaped and C-shaped dimers indicates a thermodynamic preference (1.55-3.25 kcal mol(-)(1)) for the C-shaped diastereomer. This thermodynamic preference is not because of self-association, solvation, or template effects. Furthermore, labeling experiments have allowed us to elucidate the mechanism of this acid-catalyzed equilibrium between the S-shaped and C-shaped diastereomers. The equilibration is an intramolecular process that proceeds with high diastereoselectivity and retention of configuration. On the basis of the broad implications of these results for CB[n] synthesis, we suggest new synthetic strategies that may allow for the improved preparation of CB[n] (n > 8) and CB[n] derivatives from functionalized glycolurils.
Chakraborty
Arindam
A
Department of Chemistry and Biochemistry, University of Maryland, College Park, College Park, Maryland 20742, USA.
Wu
Anxin
A
Witt
Dariusz
D
Lagona
Jason
J
Fettinger
James C
JC
Isaacs
Lyle
L
D000480:Alkynes; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D018360:Crystallography, X-Ray; D019281:Dimerization; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry*; D007700:Kinetics; D008968:Molecular Conformation; D012997:Solvents; D013237:Stereoisomerism; D013816:Thermodynamics; D047028:Macrocyclic Compounds; D000099246:Cucurbit(n)urils; D006574:Heterocyclic Compounds, 2-Ring; D048289:Imidazolidines
D000480:Alkynes; D001952:Bridged-Ring Compounds; D007093:Imidazoles; D012997:Solvents; C454805:cucurbit(6)uril; D047028:Macrocyclic Compounds; D000099246:Cucurbit(n)urils; C092018:glycoluril; D006574:Heterocyclic Compounds, 2-Ring; D048289:Imidazolidines