Synthetic Access to 3-Substituted Pyroglutamic Acids from Tetramate Derivatives of Serine, Threonine, allo-Threonine, and Cysteine

Abstract

A general route which provides direct access to pyroglutamates from tetramates, making use of Suzuki coupling on an enol mesylate, followed by reduction, is reported. This work permits direct scaffold hopping from tetramate to substituted pyroglutamates. Some compounds in the library showed modest antibacterial activity against Gram-positive bacteria. _______________________________________________________________________________4a 1.4:1 86 80 75 4b 1.0:1 88 67 73 4c 2.5:1 71 66 75 4d 1.5:1

Functionalised Nitrogen Heterocycles and the Search for New Antibacterials and Bioactives

“…By extending the aldol ring closure described above, we established that Dieckmann cyclisation of oxazolidine/thiazolidine templates 58a-d derived from pivaldehyde along with serine, 104 threonine, 75 allo-threonine 105 or cysteine 77,106 readily gave enantiopure tetramates 59a-d (Scheme 7). Although this key cyclisation is highly chemo-, diastereo-and enantioselective, it was limited to the use of pivaldehyde as the initial condensing species, since this both gives relatively stable oxazolidine/thiazolidine intermediates 58a-d and makes for a system in which the bulky tert-butyl group exerts a controlling steric influence in a ring-chain tautomeric equilibrium that strongly favours the ring form.…”

“…Thus, conversion of 59a-d into mesylates 79a-d was effected, and Pd(0) couplings provided access to the substituted systems 80a-d; these could be readily reduced under mild hydrogenation conditions, giving diastereoselective access to pyroglutamates 81a-c, and bringing us full circle back to where our journey had started, with the de-velopment of approaches to functionalised pyroglutamates (Scheme 11). 105,125 Of interest was that this approach also permitted access to similarly functionalised sulfones 84 by conversion of mesylate 82 into enones 83a-e and sulfones 84a-e (Scheme 12).…”

“…130 Of interest is that the hydroxylated pyroglutamates of type 28, 32 and 36 showed better Gram-negative activity, 56,57,[121][122][123] and broader activity was found for spiro systems 48 although alkylated and arylated pyroglutamates were fully inactive. 105,125 It is clear that these systems offer considerable promise for the development of antibacterial agents. Some tetramate compounds showed activity in pine wood nematode whole organism assays.…”

Synthesis and Derivatization of 3‐Aroyl Pyroglutamic Acids

“…The synthetic protocols for the preparation of 3‐(het)aryl or 3‐alkyl‐substituted pyroglutamic acids were developed based on the Michael addition of nucleophilic glycine complexes or organometallics to the corresponding Michael acceptors. Synthesis of 3‐substituted pyroglutamates from tetramates as well as multicomponent approach to 3‐aryl pyroglutamic acids has been recently reported. To our surprise, despite the numerous synthetic approaches towards substituted pyroglutamic acid derivatives and widely recognized importance and utility of these compounds, synthesis of 3‐acyl substituted analogs is still relatively unexplored…”

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

“…The chemoselectivity of this cyclisation depends upon the identity of R 1 , R 2 , X, along with the 2,5-relative stereochemistry of the N-acyloxazolidine or thiazolidine starting material 1. Normally, Path A mode of cyclisation is preferred and predominates for 2,5-cis-malonyloxazolidines (X=O, R 1 = t Bu, R 2 =H/Me) derived from serine 5,6 and threonines 7,8 leading to tetramates 2, although 2,5-trans-malonyloxazolidines (X=O) if formed, usually close by Path B leading to tetramates 3. This intrinsic chemoselectivity may be controlled in some cases by adjusting the conditions for the Dieckmann cyclisation, thus tetramates (X=O, R 2 =H) arising by Path A were most readily accessed in good yield using the reaction conditions (KO t Bu (1.1 eq), dry t BuOH, reflux), while those from Path B were available by the use of alternate conditions (KO t Bu (2.2 eq), wet t BuOH, reflux).…”