Ferrier rearrangement for the synthesis of PEG-bound 2,3-unsaturated glycopyranosyl-amino acids I Bilal A. Bhat, Syed Shafi, Basant Purnima, Abid Hussain Banday and H. M. Sampath Kumar * Synthetic Chemistry Section, Regional Research Laboratory, Jammu-Tawi 180 001, India Received 16 June 2006; revised 17 November 2006; accepted 29 November 2006 Available online 22 December 2006 Abstract—Amino acid 2,3-unsaturated glycopyranosyls have been prepared by the Ferrier rearrangement of acetyl protected glucals and PEG-bound amino acids in the presence of a catalytic quantity of BF 3 ÆEt 2 O in CH 2 Cl 2 at ambient temperature. Ó 2006 Elsevier Ltd. All rights reserved. Ever since the development of combinatorial chemistry, 1 new protocols adaptable to polymeric matrices have been developed from time to time, 2 to cater for the new challenges associated with polymer-supported syn- thesis. Cross-linked polymer supports are now ubiqui- tous throughout the fields of combinatorial chemistry, organic synthesis, catalysis and reagents. 3 However, problems associated with the heterogeneous nature of the ensuing chemistry together with the difficulties asso- ciated with ‘on-bead’ spectroscopic characterization have prompted the development of soluble polymers as alternative matrices for the production of combinato- rial libraries. 4 The lower reactivity of polystyrene-bound substrates, attributed to pseudo-dilution effects, can be circumvented in the case of soluble polymer-bound sub- strates and unbound reactants show the same kinetics, with the additional advantage of being able to separate the unbound by-products and excess reagents by prefer- ential precipitation of PEG in solvents. 2,3-Unsaturated glycosides have received wide attention in recent years, particularly in the synthesis of several biologically active natural products and also as chiral synthons. Aryl and alkyl 2,3-unsaturated glucosides are accessible by acid catalyzed nucleophilic substitution with allylic rear- rangement of tri-O-acetylglucal, however, it is not that easy to prepare 2,3-unsaturated galactosides by this route. This reaction, often referred to as the ‘Ferrier rearrangement’ 5 has found wide application and thus continues to be important in the chemistry of the 2,3- unsaturated sugars. The fact that tri-O-acetyl glucal 6 can be easily synthesized from glucose, adds to its importance. The Ferrier rearrangement continues to re- ceive wide attention and various glycosidation method- ologies that utilize it have been extensively reviewed. 7 In continuation of our interest in the development of novel liquid phase methodologies 8 for combinatorial synthesis, herein we report a liquid phase synthesis of 2,3-unsaturated glycosidic amino acid conjugates employing polyethylene glycol as a soluble support. 9 Various PEG-bound L-amino acids 4 were obtained by coupling Fmoc-amino acids with monomethoxy-PEG (Aldrich, average Mn ca. 2000). Formation of the amino acid ester was found to be quantitative as revealed by Fmoc analysis. Initial loading of the Fmoc-amino acid was determined by cleavage of a small amount (2 mg) of PEG-bound Fmoc-amino acid by treatment with piperidine (20%) in dichloromethane (3 ml) and subse- quent quantitative UV analysis by measuring the rela- tive absorbance at 289 nm. Fmoc cleavage was then effected by treatment with a solution of piperidine in dichloromethane (20%) and the resulting PEG-bound amino acid 4, isolated after routine precipitation, was al- lowed to react with acetyl protected glucals derived from various sugars in the presence of a catalytic quantity of BF 3 ÆEt 2 O. All the reactions were conducted at ambient temperature in CH 2 Cl 2 for 6 h. Glycosylation of PEG- bound amino acid 4 takes place via the delocalized allyl- oxocarbenium ion 3 generated by reaction of BF 3 ÆEt 2 O 0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2006.11.173 Keywords: Ferrier rearrangement; PEG-bound amino acids; Glycopyranosides. q RRL Communication No. T 2518. * Corresponding author. Tel.: +91 01912572002x292; fax: +91 0191 2548607; e-mail: hmskumar@yahoo.com Tetrahedron Letters 48 (2007) 1041–1043