3-Acyltetramic Acids: A Decades-Long Approach to a Fascinating Natural Product Family

Abstract

This account relates our quest for effective syntheses of 3-acyltetramic acids and also presents examples of our group's increasing audacity to tackle the more intricate structural varieties of this compound class. 1 Introduction 2 A New Wittig-Based Access to Tetramic Acids 3 3-Acyltetramic Acids with Linear Side Chains 4 3-Decalinoyltetramic Acids 5 Oand N-Glycosylated 3-Acyltetramic Acids 6 Macrocyclic 3-Acyltetramic Acids 7 Miscellaneous Reactions 8Whither to go from Here?

Tetramate Derivatives by Chemoselective Dieckmann Ring Closure of threo-Phenylserines and Their Antibacterial Activity

“…Nonetheless, 11 carboxamides were active at concentrations between 31.25 and 62.5μg/mL, an important outcome, as earlier findings had demonstrated that C3/C7-acyl/carboxamidotetramates in most cases suffered from either partial or complete loss of efficacy under similar conditions . As tetramic acids are well-known metal chelators, , of interest was to investigate whether this loss of activity was due to metal chelation or plasma protein binding (PPB), specifically with human serum albumin (HSA). , To answer this question, bicyclic tetramate 12a was tested against MRSA using a broth dilution assay, under standard conditions and with the addition of similar metal cations (Fe, Ca, Mg, and Zn) with concentration as that found in blood, respectively. The activity was found to be slightly improved for the latter {0.49 vs 0.24 [MIC (μg/mL) against MRSA]}, suggesting that the weaker metal chelating properties of these aryl-substituted tetramates discussed above may be important for in vivo activity in therapeutic application.…”

“…The tetramate system occurs as a scaffold in natural products which exhibit a wide range of bioactivities, − and we have previously established that bicyclic tetramates are readily available from malonyloxazolidines by highly chemoselective and stereoselective Dieckmann ring closures of oxazolidines and thiazolidines derived from serine, threonine, and cysteine; differently substituted threonines effectively gave cyclization, but thus far this approach has been limited to such readily available amino acids. Of interest was whether phenylserines could be used for similar cyclizations, especially so since such systems would also further expand the substrate scope by enabling greater functional group diversity around the bicyclic ring (Figure ).…”

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

“…The tetramate system occurs as a core skeleton in natural products which exhibit a wide range of bioactivity, [1][2][3] and we have shown that bicyclic tetramates, which are accessible by chemoselective and stereoselective Dieckmann ring closures of oxazolidine or thiazolidine templates 1 (Fig. 1), 4,5 may also exhibit potent antibacterial activity, mostly against Gram-positive bacteria.…”

Mediation of metal chelation in cysteine-derived tetramate systems

“…Tetramates 1 exhibit wide ranging antibacterial activity coupled with low levels of toxicity, 2–5 but are also well known for their metal chelating ability, 6,7 which, it has been suggested recently, should be explicitly considered during any study of their biological effects. 8 For example, metal chelates of a 3-acyltetramic acid, melophlin C, with Ga( iii ), La( iii ) and Ru( ii ), all of which were considered to be Fe( iii ) mimics, were found to be active against Micrococcus luteus ( M. luteus ).…”