Glycoluril† as an efficient molecular template for intramolecular Claisen-type condensations

Abstract

The readily prepared 3,4,7,8-tetramethylglycoluril 1 acts as a template to promote efficient intramolecular Claisen-like condensations between two acyl groups which are attached to the N-1 and N-6 positions. Thus, two sequential acylations of 1 give symmetric or unsymmetric diacylglycolurils 9–18 in good yield. Treatment of 9–18 with lithium tert-alkoxides furnishes N-(β-ketoacyl)glycolurils 19–27 under mild conditions and in high yields; rate-limiting deprotonation, predominantly on the least substituted of the two acyl groups, precedes a fast intramolecular Claisen-type condensation. Reduction of the keto group in 19 and 26, followed by elimination of water gives alk-2-enoylglycolurils 6 and 7; conjugate hydride addition (L-Selectride) then gives alkanoylglycoluril 5. Compounds 5–7 undergo further rounds of N-acylation then intramolecular condensation. Linear chains can thus be constructed on 1 by repetitive sequences of acylation–condensation–functional group transformation. N¹-Alk-2-enoyl-N⁶-alkanoylglycolurils 14–17 also afford condensation products with high selectivity upon treatment with L-Selectride, effecting a method for net reversal of the regioselectivity observed in the base-promoted rearrangement. The synthesized chains can be readily removed from the template, regenerating 1. The efficiency of the condensation reaction, the sequence of transformations and the ability to grow linear carbon chains in a repetitive manner mimic these aspects of the catalytic cycle of fatty acid synthases and polyketide synthases.