Tetramate derivatives by chemoselective Dieckmann ring closure ofallo-phenylserines, and their antibacterial activity

Abstract

A general route which provides direct access to substituted bicyclic tetramates, making use of Dieckmann cyclisation of oxazolidines derivatives derived from allo-phenylserines, is reported. Of interest is the high level...

Synthesis of fused tetramate-oxazolidine and -imidazolidine derivatives and their antibacterial activity

“…This outcome further confirmed that the C5-ethyl ester was most likely to be on the same face as the C2 and C4-aryl substituents, which is consistent with Dieckmann cyclisations of similar bicyclic tetramate derivatives. 4,5 Moreover, this work also showed that -NCH(Ar)Naminal systems are accessible, and whose better stability relative to -NCH(Ar)Ohemiaminal ether systems was likely assisted by the electronic withdrawing properties of the tetramate ring.…”

“…8 Such a process is not dissimilar to the biosynthesis of tetramate natural products. 9,10 We have also shown that allo -arylserines 1f close by the conventional route A pathway 5 to give tetramate 4e via the Dieckmann cyclisation of the major malonamide diastereomer 2g , but interestingly, the minor 2,5- trans malonamide 2e diastereomer derived from threo -aryl serines 1e has been found to ring close by route B to give tetramate 5e . The exclusive chemoselective formation of tetramates 4e and 5e can be explained via steric effects, in which the bulky C2- t -Bu and C4-aryl groups prefer to reside on the less hindered exo -face of the bicyclic lactam.…”

“…It was assumed that reaction with 1-adamantylamine would proceed by chemoselective attack at the C7-ethyl ester but in the event, indiscriminate attack at both the C5 and C7-ethyl ester positions was observed to form both C5-23a and C7-24a carboxamides (Scheme 4). The assignment of structure to these by NMR analysis using NOESY or HMBC analysis was difficult, but a comparison of chemical shift information with the structures of previously reported analogues 4,5 enabled tentative assignment of the C5-carboxamide 23a and C7-carboxamide 24a (Fig. S8, ESI †) as the C7-ethyl ester tetra-Scheme 5 Dieckmann ring closures in malonylimidazolidines.…”

“…3 Bicyclic derivatives may be accessed by a highly chemo-, diastereo- and enantioselective Dieckmann cyclisation of oxazolidine/thiazolidine templates 2a–g derived from hydroxyalkyl- and thioalkyl side chain amino acids (serine 1a , threonine 1b , allo -threonine 1c , cysteine 1d , or threo 1e and allo -phenylserines 1f , Scheme 1). 4,5 Of importance is the identity of the aldehyde which is used to condense the amino acids to form the oxazolidine/thiazolidine heterocycle, which has generally been limited to pivaldehyde; this aldehyde gives a relatively stable oxazolidine/thiazolidine template 2a–g , in which the bulky t -butyl group favours the most stable ring form in a ring-chain tautomeric equilibrium, and plays a significant role in the control of a subsequent diastereoselective N -acylation reaction and also directs the mode of the Dieckmann cyclisation towards bicyclic tetramates. 6…”

“…3 Bicyclic derivatives may be accessed by a highly chemo-, diastereo-and enantioselective Dieckmann cyclisation of oxazolidine/thiazolidine templates 2a-g derived from hydroxyalkyl-and thioalkyl side chain amino acids (serine 1a, threonine 1b, allo-threonine 1c, cysteine 1d, or threo 1e and allophenylserines 1f, Scheme 1). 4,5 Of importance is the identity of the aldehyde which is used to condense the amino acids to form the oxazolidine/thiazolidine heterocycle, which has generally been limited to pivaldehyde; this aldehyde gives a relatively stable oxazolidine/thiazolidine template 2a-g, in which the bulky t-butyl group favours the most stable ring form in a ring-chain tautomeric equilibrium, and plays a significant role in the control of a subsequent diastereoselective N-acylation reaction and also directs the mode of the Dieckmann cyclisation towards bicyclic tetramates. 6 For serine 1a, threonines 1b,c and cysteine 1d, the Dieckmann cyclisation usually occurs from the 2,5-cis-malonyloxa(or thia)zolidines 2a-dwhich forms as the major product after N-acylation of oxazolidinesby closure from the C-5 enolate onto the side chain ethyl ester giving tetramates 4a-d as the major product (Scheme 1, route A and inset A), placing the C-2 t-butyl group on the exo-face (that is, the less hindered convex face) of the newly generated bicyclic ring system.…”