Stereoselective synthesis of novel (R)- and (S)-5-azidomethyl- 2-oxazolidinones from (S)-epichlorohydrin: a key precursor for the oxazolidinone class of antibacterial agents q G. Madhusudhan a,b, * , G. Om Reddy a , T. Rajesh a , J. Ramanatham a , P. K. Dubey b a Technology Development Center, Dr. Reddy’s Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500 049, AP, India b Department of Chemistry, College of Engineering, J.N.T University, Kukatpally, Hyderabad 500 872, AP, India Received 24 December 2007; revised 10 March 2008; accepted 12 March 2008 Available online 15 March 2008 Abstract A facile synthesis of novel (R)- and (S)-5-azidomethyl-2-oxazolidinones starting from (S)-epichlorohydrin is described. The (R)-azide was utilized for the preparation of Linezolid. Ó 2008 Elsevier Ltd. All rights reserved. Oxazolidinones have shown various pharmacological activities in the areas of drug development, antibacterials, 1 inhibitors of monoamine oxidase, 2 cytokine modulators, 3 sigma receptors, 4 pschyotropics, 5 antiallergy agents, 6 anti- biotics, 7 intermediates in the synthesis of renin inhibitors, 8 b-lactam and macrolide antibiotics, 9 immunosuppres- sants 10 and in many other applications. 11 Oxazolidinones are the first new class of synthetic anti- bacterial agents introduced since the discovery of quino- lones more than 30 years ago. Linezolid 1 was the first drug of this class possessing antibacterial activity, having an N-aryl-5-aminomethyl-2-oxazolidinone moiety. To access a large number of derivatives to be screened in biological assays, we required a general and efficient method for the synthesis of analogues containing N-aryl- 5-aminomethyl-2-oxazolidinone without using (n-BuLi), epoxides and phenylisocyanates which are used in the clas- sical synthesis of this class of compounds. 3,4 The prepara- tion of aryl isocyanates is cumbersome from multi- substituted aryl amines. Moreover, these strategies require further steps to convert the 5-hydroxymethyl group into a 5-aminomethyl functionality. The latest analogues have common functionalities on the 5-aminomethyl group such as acetamides carbamates, thiocarbamates, ureas and thio- ureas. 12 During the conversion of amines to carbamates, thiocarbamates, ureas and thioureas, there is a higher chance of obtaining the corresponding symmetrical deriva- tives. In view of these limitations, we focused our attention to prepare the useful chiral synthons (R)- and (S)-5-azido- methyl-2-oxazolidinone starting from commercially avail- able (S)-epichlorohydrin using a new methodology. These moieties can be derivatized on both ends to develop new oxazolidinone antibacterial analogues, as well as MAO-B inhibitors used in the treatment of Parkinson’s disease. 13 In the present synthetic strategy, we have developed facile conditions for the one-pot synthesis of 2-oxazolidinones from azido alcohols using Ph 3 P/CO 2 via the generation of an intermediate isocyanate followed by cyclization. This is an attractive application of aza-Wittig reactions of iminophosphoranes 14 and should find general utility in the synthesis of 2-oxazolidinones (Fig. 1). (S)-Epichlorohydrin 1 was stereoselectively ring-opened with NaN 3 in a mixture of H 2 O/EtOH, whilst maintaining mild acidic conditions using NH 4 Cl, to give (2S)-1-azido-3- chloropropan-2-ol 2 without racemization. The azido 0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2008.03.061 q DRL Publication No. 402A. * Corresponding author at present address: Inogent Laboratories Pvt. Ltd (A BVK BIO Company), 28A, IDA, Nacharam, Hyderabad 500 076, India. Tel.: +91 4066281215; fax: +91 40 2715 1270. E-mail address: madhusudhan.gutta@inogent.com (G. Madhusudhan). Available online at www.sciencedirect.com Tetrahedron Letters 49 (2008) 3060–3062