Diastereoselective intramolecular aldol ring closures of threonine derivatives leading to densely functionalised pyroglutamates related to oxazolomycin

Abstract

Intramolecular aldol reactions on oxazolidine templates derived from threonine may be used to generate libraries of densely functionalised pyroglutamates with a high level of diastereoselectivity.

Intramolecular Aldol Ring Closures of Cysteine Derivatives Leading to Densely Functionalised Pyroglutamates

“…The stereochemistry of the newly created stereogenic centre for the major diastereomer was established as 7R (that is, hydroxyl group endo) by NOE analysis (Figure 1), and the stereochemistry of the others was assumed by the similarity of chemical shift values of H-6 exo and H-6 endo with this NOE-assigned structure (H-6 = 3.04 and 2.45 ppm for 7a). This was similar to reported chemical shifts of the H-6 protons for the serine (H-6 endo ( = 3.2 ppm) and H-6 exo ( = 2.5 ppm) 3 ) and threonine (H-6 exo ( = 3.1 ppm) and H-6 endo ( = 2.4 ppm) 6 ). This earlier work had shown those chemical shifts were conserved in similar diastereomers, generally regardless of substitution, and in the systems reported here, the chemical shift values for H-1 H. Almahli et al…”

“…(Scheme 2); 5,6 coupling of these with thiazolidines 4a-e gave acetoacetylthiazolidines 6a-m in good yield (Scheme 2 and Table 2). These compounds existed as rotamers in several cases, as evidenced by broad signals in the 1 H NMR spectrum, as keto-enol mixtures, and as a mixture of diastereomers, leading to complex NMR spectra, but were nonetheless used directly for further reaction.…”

“…Of interest is that enantioselective aldol reactions of malonic acid half thioesters with aldehydes have recently been reported. 14 An examination of more substituted systems was made, and to this end, malonamides 10a-b were prepared from the corresponding carboxylic acid 9 6 and thiazolidine 4a, by DCC coupling (Scheme 2). Aldol reaction using base (NaOMe) gave the corresponding pyroglutamates 11a-b in good yield as single diastereomers, the stereochemistry of which was assigned on the basis of the chemical shift information outlined above; thus, the H-1 geminal set showed a difference of Δ = 0.5 and 0.1 ppm, corresponding to the 7R (endo-hydroxyl) configuration, in keeping with that observed in the simpler systems, and in close correspondence to equivalent reported analogues in the serine 4,5 and threonine 6 series.…”

“…We have reported that malonyloxazolidines and malonylthiazolidines derived from serine and threonine, or cysteine, respectively, are suitable for highly chemoselective Dieckmann ring closures, [1][2][3] and that the serine-and threonine-derived oxazolidine systems 1 are, moreover, suitable for diastereoselective aldol ring closures after conversion into their ketoamide derivatives 2, [4][5][6] giving highly functionalised pyroglutamates 3 (Scheme 1), 7 which are closely related to the lactam moiety of oxazolomycin. 8,9 Related aldol ring closures have been reported 10 and it has been suggested that such processes are biomimetic.…”

Functionalised Nitrogen Heterocycles and the Search for New Antibacterials and Bioactives

“…71 We wondered if we could apply the elegant 'Self-Regeneration of Stereocenters' concept of Seebach 72 in an intramolecular manner, and found that highly functionalised pyroglutamates 48a were directly available by diastereoselective aldol ring closures of ketoacyloxazolidines 47a derived from serine 46a. 73 This reaction also later proved to be suitable for threonine-derived oxazolidine 47b 74,75 and cysteine-derived thiazolidine 47c templates giving pyroglutamates 48b,c (Scheme 5), 76,77 although these aldol reactions may be reversible. 78 Similar stereoselective intramolecular aldol reactions of (4R)-3-(3oxobutanoyl)-1,3-thiazolidine-4-carboxylates have been reported and are believed to be directed by 'self-induced' axial chirality.…”