Diastereoselective Formation of Glycoluril Dimers:  Isomerization Mechanism and Implications for Cucurbit[n]uril Synthesis

Abstract

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.

Cucurbit[n]uril Analogues.

“…7,8 The improved solubility of CB [7] and the spacious cavity of CB [8] heterodimers as a mixture of S-shaped and C-shaped diastereomers. 191,192 To rationalize the selective formation of C-shaped heterodimers, we studied the mechanism of the interconversion of II-1 and II-2. We discovered that the S-shaped to C-shaped isomerization was an intramolecular process that occurs with retention of configuration (Scheme 1).…”

“…We hypothesize that the anhydrous acidic conditions employed -to avoid potential saponification of the CO 2 Et groups -slows down the S-to C-shaped isomerization of trimeric and higher oligomers which results in oligomer formation rather than macrocyclization. 8,191 2…”

Complex Self‐Sorting Systems

“…The first report came from our group in 2002 where we used methylene bridged glycoluril dimer substructure -the fundamental building block of the cucurbit[n]uril family of macrocycles [17][18][19] -to create a self-sorted system. We designed and synthesize (±)-I-11 with the hope that it would form a square-shaped aggregate by metal-ligand interactions and the hydrophobic effect (Scheme I-5).…”

Cucurbiturilas

“…A basicidade destes compostos é bastante baixa sendo verificados pKa's do ácido conjugado do CB [6] da ordem de 3, sendo desconhecida para os outros cucurbitandos. Uma das estratégias para contornar o problema de solubilidade é a utilização de meios salinos ou ácidos para aumentar a solubilidade destes compostos pela formação de complexos com ácidos duros ou, ainda, pela protonação das carbonilas dos opérculos destas estruturas 12 4,7,[16][17][18][19][20][21][22][23][24][25][26][27] . A reação de CB [6], por exemplo com K 2 S 2 O 8 , dá origem a 12 grupos OH radiais nos carbonos terciários em meio aquoso 22,28 , enquanto que a utilização de dimetil glicolurila como monômero precursor dá origem à decametil-CB [5] …”