Synthesis of oxazolidinedione derived bicalutamide analogs

Abstract

The synthesis of chiral oxazolidinedione derived bicalutamide analogs has been discussed. KeywordsOxazolidinedione; Bicalutamide; Enantiomers; Androgen; ReceptorIn our earlier investigations, we developed a series of second generation androgen receptor binding ligands 1b (Fig. 1), which were analogous to bicalutamide 1a in structure. 1-4 Biological testing of these compounds exhibited high binding affinities and biological activities. 5-8 Based on the results obtained and homology modeling, we had earlier reported the binding interactions between the androgen receptor and the ligands. 9-11 Examination of torsional strain parameters and hydrogen bonding interactions revealed that the molecule adopts a conformation similar to 1c. The hydroxyl group α to the carbonyl undergoes positioning in such a manner that it enters into hydrogen bonding interaction with Aspargine705 of the receptor. The amino group forms a weak hydrogen bond with the back bone oxygen of Leucine704. The computational predictions made were in agreement with the results obtained from the binding assays. However, to convincingly establish the aforesaid interactions and the conformation adopted by the molecules, it was highly imperative to have a suitable molecular model, which did not have free hydroxyl and amide protons and above all was conformationally restricted to a structure similar to 1c. Accordingly, we decided to interlock the amide nitrogen and the hydroxyl oxygen by a carbonyl functionality, which led to the design of structure 1d, an oxazolidinedione derivative. As of this day, no literature reports are available on the synthesis of chiral oxazolidinedione derived bicalutamide analogs and hence we devised and attempted a stereoselective synthesis of this molecule, the details of which form the subject matter of the present letter.Pyrrolidine-2-carboxylic acid 2 was acylated by Schotten Baumann reaction to obtain methacryloyl pyrrolidine-2-carboxylic acid 3, which was subsequently lactonized to obtain bromolactone 4, according to the procedure that we reported recently. 12,13 Nucleophilic substitution of compound 4 with 4′-fluorobenzenethiol under alkaline conditions in 2-propanol medium afforded compound 5. However, hydrolysis of compound 5 under acidic conditions did not afford the desired chiral hydroxy acid 6. Since our initial attempt failed to give 6, we decided to reinvestigate the synthesis of chiral hydroxy acid 6 (Scheme 1), as we knew from our earlier experiments that the hydrolysis of bromolactone 4 using HBr solution under reflux conditions would give 3-bromo-2-hydroxy-2-methylpropanoic acid 7 in excellent yields. 12Corresponding author. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe hydroxy and carboxyl groups of compound 7 were then protected with tribromoacetaldehyde under acidic conditions to obtain compound 8 ,14 which was coupled with 4′-fluorobenzenethiol. Acidification of the reaction mixture with concd HCl followed by workup and isolation afforded chiral hydroxy acid 6 in good...

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