Thorpe–Ingold effects in cyclizations to five-membered and six-membered rings containing planar segments. The rearrangement of N(1)-alkyl-substituted dihydroorotic acids? to hydantoinacetic acids in base

Organic & Biomolecular Chemistry Pub Date: 2004-03-10 DOI: 10.1039/B400248B

Abstract

While the gem-dimethyl effect (GDME) is quantitatively similar for cyclizations to cyclopentane and cyclohexane rings and their homomorphs, in systems containing planar segments the GDME is stronger for the formation of five-membered rings. Planar pentagons have smaller angles than planar hexagons and their formation is helped by the decrease in the potential internal bond angle caused by substituents, as suggested by Thorpe and Ingold for small rings. The phenomenon is illustrated with crystal structure data on five-membered hydantoins and six-membered dihydrouracils containing four-atom planar segments. Such a Thorpe-Ingold effect explains the rearrangement in base of N-alkyl substituted dihydroorotic acids 1 to hydantoinacetic acids 3. The reaction involves initial hydrolysis to N-(N-alkylcarbamoyl)aspartic acids 2 and their subsequent cyclization. The unsubstituted N-carbamoylaspartic acid 2a is stable in 1 M KOH, the N(1)-methyl and ethyl compounds 2b and 2c are in equilibrium with the hydantoinacetic acids 3, while the cyclization of the N(1)-isopropyl and cyclohexyl derivatives 2d and 2e is irreversible. Experimental data on equilibria and pKas for ionization of the carboxy and NH groups allow equilibria and rates involving the N-unsubstituted compounds to be estimated and compared with those for the N-alkyl derivatives. The strongest effect is observed on the equilibrium [32?]/[22?], where substitution of H by methyl increases K 600-fold. In vitro the kinetic regioselectivity for acid catalyzed cyclization of N-carbamoylaspartic to hydantoinacetic acid against dihydroorotic acid is only 10 : 1. This, together with the weaker acidity of the remote carboxyl group, favours cyclization to dihydroorotic acid under biological conditions.

Graphical abstract: Thorpe–Ingold effects in cyclizations to five-membered and six-membered rings containing planar segments. The rearrangement of N(1)-alkyl-substituted dihydroorotic acids to hydantoinacetic acids in base
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