Complete NMR elucidation of a novel trishomocubane hydantoin and its mono‐ and bis‐t‐Boc protected derivatives

Abstract

The syntheses of a novel trishomocubane hydantoin and its mono- and bis-protected t-Boc derivatives are described. The less nucleophilic N-3' nitrogen of the hydantoin ring is protected first when treated with di-tert-butyl dicarbonate (t-Boc anhydride), possibly owing to steric hindrance by the bulky trishomocubane cage skeleton. More basic conditions were required to form the bis-protected t-Boc hydantoin with the same reagent. The structures of these novel compounds were elucidated with 2D NMR techniques. The proton spectrum of the trishomocubane skeleton is complex owing to major overlap of proton signals. A high-level DFT calculation was used to determine some of the crucial interatomic positions, which assisted with the elucidation of the structures. The assignment of proton and carbon signals of the three structures is described and it differs significantly from each other and also from the trishomocubanol precursor. The bis-Boc hydantoin is required for a more facile hydrolysis to the corresponding trishomocubane amino acid at room temperature.

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

“…0 3,10 .0 5,9 ] undecane (trishomocubane) was first reported by Eaton et al [1]. As part of a project to synthesise pentacycloundecane derived cage amino acids [2][3][4][5], the synthesis of racemic trishomocubane hydantoin 2 [6] and the corresponding amino acid 3 was undertaken (see Fig. 1).…”

“…This method, according to literature [11], should result in an improved yield compared to the conventional hydrolysis [5,12] of the unprotected hydantoins. Mono-Boc protection of the hydantoin at N-3 was reported before [6]. Although NMR elucidation of the pentacyclo-undecane cage system is well studied 1 School of Chemistry, University of KwaZulu-Natal, Durban 4001, South Africa.…”

“…Bis-Boc protection and hydrolysis [11] of the bis-Boc protected hydantoin (±2) [6] should yield the corresponding amino acid (±3). This method, according to literature [11], should result in an improved yield compared to the conventional hydrolysis [5,12] of the unprotected hydantoins.…”

“…Although NMR elucidation of the pentacyclo-undecane cage system is well studied 1 School of Chemistry, University of KwaZulu-Natal, Durban 4001, South Africa. 2 To whom all corespondence should be addressed; e-mail: kruger@ ukzn.ac.za [2,3,5,[13][14][15][16][17], similar studies on the intrinsically chiral [8] trishomocubane systems [6,7,[18][19][20] are somehow neglected. Various authors [16,[21][22][23] have commented on the difficulty of NMR elucidation of these cage compounds.…”

Synthesis and NMR assignment of pentacycloundecane precursors of potential pharmaceutical agents

“…Protons on the cage are normally deshielded if a heteroatom of a side chain is positioned such that the electron rich heteroatom is in close proximity of the cage proton(s). [4,19,28,29] It is possible that the OH and NH 2 groups in 1 cause intramolecular hydrogen bond interactions. This will largely 'tie' the two groups together at room temperature.…”