Complete NMR Elucidation of Two N-Protected Trishomocubane Hydantoins and the Ethyl Ester of the Corresponding Amino Acid

Abstract

In an attempt to resolve a racemic mixture of a trishomocubane hydantoin, the synthesis of a pair of novel diastereomers was obtained by protecting the racemic hydantoin with chlorocarbonic acid-(−)(R)-sec-butyl ester. An achiral i-propyl ester was first used to establish the procedure. The NMR elucidation of both the chiral and achiral N-protected hydantoins is described. Some proton and carbon NMR shifts on the cage are reversed when relative small changes on the protection group are introduced. The chiral centre on the protective group induced splitting of some carbon signals in the 13 C spectrum on the cage skeleton, but effective separation of the diastereomers could not be obtained. In a further attempt to demonstrate the potential use of the trishomocubane amino acid in peptide synthesis, the ethyl ester of the cage amino acid was synthesised. The structures of the amino acid derivatives were elucidated with 2D NMR techniques and the assignment of the NMR data is presented.

Regioselective protection of hydantoins – essential for hydantoin based anti-epileptic drugs

“…The racemic hydantoins (3)(4)(5) are synthesized from acetaldehyde, acetone and PCU monoketone [16,17] under normal Bucherer-Bergs [18,19] conditions. Mono-and bis-Boc protection of the hydantoins have not been reported before.…”

“…In a recent study [4], it was demonstrated that the trishomocubane hydantoin 1 is selectively protected at N-3 . It appears as if competition between N-1 (more steric hindrance but stronger nucleophile) and N-3 (less steric hindrance but less nucleophilic) influence the course of the reaction.…”

“…This investigation forms part of a programme to investigate regioselective protection of lactams and hydantoins [1][2][3][4]. Protection of the trishomocubane hydantoin ring at N-3 and NMR elucidation of 1 was recently reported in this journal [4].…”

“…Protection of the trishomocubane hydantoin ring at N-3 and NMR elucidation of 1 was recently reported in this journal [4]. Hydantoins were first applied as anti-epileptic drugs in the 1950s [5].…”

Analysis of the conformational profile of trishomocubane amino acid dipeptide

“…[4][5][6][7] The synthesis of the first trishomocubane amino acid (3) was recently reported. 8,9 To understand the function of peptides and proteins in biological processes, knowledge of their molecular structure is an essential prerequisite. Therefore, structural investigations on novel constrained amino acids are relevant areas of study.…”