Synthetic Access to Hydrophilic Tetramate Derivatives of Cysteine

Abstract

The synthesis, structural and antibacterial evaluation of bicyclic tetramate derivatives of cysteine rendered hydrophilic with pendant heterocyclic substituents is reported; effective synthetic protocols and antibacterial activity for a small library of polar derivatives was found, and direct evidence for strong metal chelation in these systems was obtained. A computational study has developed a detailed understanding of the controlling factors of the key Dieckmann cyclisation step.

Mediation of metal chelation in cysteine-derived tetramate systems

“…45,[54][55][56] With these materials reliably in hand, condensation of Lcysteine esters 7a-g with aromatic aldehydes (R 2 CHO) gave the corresponding thiazolidines 8-14 as a mixture of cis/trans-2,5 diastereomers (ratio varying from 0.5 : 1 to 4.5 : 1) in good yield (Scheme 4 and Table S1, ESI †). The characteristic and highly conserved H-2 and H-5 chemical shis were consistent with those previously found in C-5 methyl ester thiazolidines, 33 both being more downeld in the trans-diastereomers.…”

“…In the NMR spectrum, complexity arose since each diastereomer appeared as a rotameric pair, and H-2 chemical shis were consistent with that observed previously in N-acylthiazolidines with C-2 aromatic substituents. 33 Thus, in the C-2 phenyl series, the H-2 chemical shis for the major trans rotamers were consistently more downeld; this trend was reversed in the minor rotamers. In the C-2 pyridyl series, the H-2 chemical shis for major trans rotamers were consistently more upeld, and this trend was preserved in the minor rotamers.…”

“…30 The metal chelating properties of tetramates are most immediately evident by post-chromatographic signal broadening in 1 H NMR spectra, which can only be removed by acid wash, [29][30][31][32] and the metal complexation behaviour of tetramates was also found to be both structure and metal-ion dependent. 33 We have described earlier that cysteinederived bicyclic tetramates 1 are excellent metal chelating agents, and established that the C-6, C-8 and/or C-9 carbonyl groups were directly involved in that metal complexation, but that it could be blocked by protection of the enolic system; 34 it seemed that modication of the C-5 ester (CO 2 R 1 , Fig. 1), along with the concave-convex shape of the bicyclic tetramate system, might be further exploited to alter the metal binding ability of the tetramate system by steric interference distal to the region of metal chelation.…”

“…1), along with the concave-convex shape of the bicyclic tetramate system, might be further exploited to alter the metal binding ability of the tetramate system by steric interference distal to the region of metal chelation. 33 Specically, target compounds were designed with increasing steric bulk at C-5, with R 1 varying from methyl to allyl, isopropyl, cyclohexyl, benzyl, nitro-benzyl and bromobenzyl esters (Fig. 2).…”

“…1 ), along with the concave-convex shape of the bicyclic tetramate system, might be further exploited to alter the metal binding ability of the tetramate system by steric interference distal to the region of metal chelation. 33 …”