Palladium-catalysed allylic amination for the direct synthesis of epi-4-alkylamino-N-acetylneuraminic acid derivatives Ricardo Resende, Christian Glover, Andrew G. Watts * Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom article info Article history: Received 13 February 2009 Revised 14 March 2009 Accepted 24 March 2009 Available online 28 March 2009 Keywords: Allylic amination Neuraminidase inhibitors 4-epi-Alkylamino-N-acetylneuraminic acids Palladium abstract A simple and efficient procedure has been developed for the direct formation of epi-4-alkylamino-N-acet- ylneuraminic acid derivatives as potential inhibitors of influenza neuraminidases. The allylic amination of oxazoline 6 has been effected with a series of primary and secondary amines in the presence of catalytic Pd(p-allyl) 2 (Et 3 P) 2 to give the corresponding 4-epi-alkylamino products in a stereoselective and regio- specific manner. Ó 2009 Elsevier Ltd. All rights reserved. Influenza neuraminidase is an exo-glycosidase responsible for the cleavage of terminal N-acetylneuraminic acid residues from a host of oligosaccharide substrates which decorate a range of glyco- proteins and glycolipids. 1 This enzyme is required by the influenza virus to degrade cell-surface receptor molecules, a process which facilitates the effective release of newly formed viral particles from the surface of infected cells. 2,3 As such, inhibitors of influenza neu- raminidases such as Zanamivir 1 and the prodrug Oseltamivir ethyl ester 2, have proved themselves as effective drugs for the clinical treatment of influenza. 4,5 O CO 2 H HO AcHN OH OH HN CO 2 Et O AcHN H 2 N H 2 N NH 1 2 Compounds 1 and 2 act as competitive inhibitors and were designed to mimic the ‘transition-state analogue’ 2-deoxy-2,3- didehydro-N-acetylneuraminic acid (DANA) 3, itself a potent inhib- itor of influenza neuraminidases (K m 4 lM). 6 At the heart of the potent inhibitory activity of both 1 and 2 is the introduction of a basic nitrogen at the C-4 position, which is capable of forming an important binding interaction with an anionic aspartate residue in the active site of the enzyme. 7 The importance of this modifica- tion was first reported by von Itzstein et al., where 4-amino-2,4- dideoxy-2,3-didehydro-N-acetylneuraminic acid 4 (K m 40 nM) was found to have 100-fold greater inhibitory potency against influenza neuraminidase than DANA 3. 8 Interestingly, von Itzstein also found that the introduction of an amino group axial at C-4 also improved inhibition, with epi-4-amino-2,4-dideoxy-2,3-didehy- dro-N-acetylneuraminic acid 5 showing 10-fold greater inhibitory activity (K m 300 nM) than 3. 6 This improvement in inhibition was ascribed to potential binding interactions between the axial C-4 amino group and an active-site glutamate residue located above the sugar ring. However, no further studies regarding either the synthesis or biological evaluation of derivatives of 5 have been reported. As part of our interest in the development of novel potent inhibitors of influenza neuraminidases, we have developed a sim- ple and efficient method for the synthesis of epi-4-alkylamino derivatives of DANA, to explore further the inhibitory activities of this interesting class of N-acetylneuraminic acids. We have examined the allylic amination of the oxazoline 6 with methylamine using several palladium/phosphine catalysts. Our initial screening revealed that catalysts generated from Pd 2 (dba) 3 and a variety of phosphine ligands (Et 3 P, Me 3 P and Ph 3 P) did not catalyse the desired amination in reasonable yields. On the other hand, the catalyst generated from (Pd(p-allyl)Cl) 2 and Et 3 P was found to act as a very efficient catalyst with a variety of amine nucleophiles (Table 1). Treatment of 6 with methylamine in the presence of the catalyst (5 mol %) generated from (Pd(p-allyl)Cl) 2 and Et 3 P under standard reaction conditions (dichloromethane, room temperature, 2 h) 9 resulted in stereospecific and regioselec- tive formation of the 4-epi-methylamino-N-acetylneuraminic acid 0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2009.03.166 * Corresponding author. Tel.: +44 (0)1225 386788; fax: +44 (0)1225 386114. E-mail address: aw270@bath.ac.uk (A.G. Watts). Tetrahedron Letters 50 (2009) 4009–4011 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet