LETTER ▌ 1325 letter Copper(II) Triflate as a Mild and Efficient Catalyst for Ferrier Glycosylation: Synthesis of 2,3-Unsaturated O-Glycosides 2,3-Unsaturated O-Glycosides Batthula Srinivas, Thurpu Raghavender Reddy, Palakodety Radha Krishna,* Sudhir Kashyap* D-207, Discovery Laboratory, Organic and Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad-500 007, India Fax +91(40)27160387; E-mail: skashyap@iict.res.in Received: 20.02.2014; Accepted after revision: 24.03.2014 Abstract: Various acceptors including carbohydrates, amino acids, natural products, and hydroxylamine derivatives were coupled with 3,4,6-tri-O-acetyl-D-glucal in the presence of Cu(OTf) 2 as catalyst. The protocol offers facile and efficient Ferrier glycosylation for the synthesis of 2,3-unsaturaed O-glycosides in good yields and high anomeric selectivity. Key words: glycosides, glycosylation, glycoconjugates, Ferrier re- action, Lewis acid Sugar scaffolds are crucial for the development of thera- peutic agents due to the role played by saccharides and glycoconjugates in many biological processes. 1 Owing to the presence of enol ether functionality, glycals are among the most utilized chiral intermediates for the synthesis of carbohydrate derivatives and they serve as building blocks for various molecules of biological significance. 2 The synthetic potential of the stereochemically rigid structure of glycal systems has been demonstrated in di- versity-oriented synthesis of small molecules with com- plex structures 2a,b and Danishefsky’s glycal assembly for the preparation of various biologically active molecules and glycoconjugates. 2c However, Ferrier glycosylation 3 remains the most investigated chemical transformation on glycals. The Ferrier reaction is an allylic rearrangement that involves displacement of a leaving group at the C-3 position of a glycal ester in the presence of a Lewis acid catalyst. Subsequently, the nucleophile attacks at the ano- meric position of the cyclic allylic oxocarbenium ion in a quasi-axial orientation leading to the formation of 2,3-un- saturated glycosides or ‘pseudo-glycals’. The stereoselective synthesis of 2,3-unsaturated glyco- sides is of particularly importance due to their usefulness as key intermediates in the synthesis of several biological- ly important molecules such as antibiotics, 4 oligosaccha- rides, 5 uronic acids, 6 and complex carbohydrates, 7 various natural products, 8a glycopeptides, 9 nucleosides, 7,8b and modified carbohydrate derivatives. 7 The presence of a 2,3-olefinic group in ‘pseudo-glycals’ has further added to the diversity, hence, they are employed in various com- plexity-generating reactions. 10 So far, a large number of catalysts including Lewis ac- ids, 11 Brønsted acids, 12 and oxidants 13 have been reported to effect the Ferrier rearrangement. However, many of the existing protocols suffer from lack of generality because strong acidic conditions restrict the use of acid-labile sub- strates. In addition, many of these methods have limita- tions such as high reaction temperature, extensive workup, use of expensive, moisture-sensitive, toxic met- als, and strong oxidizing reagents, require excess loading of reagents and nucleophiles, offer low anomeric selectiv- ity, or provide poor yields of the desired products. Over the years, a variety of metal triflates have been used to ef- fect the Ferrier reaction 3c of glycals with various nucleo- philes. However, the use of toxic metals is limited for the synthesis of active pharmaceutical ingredients (APIs) be- cause tedious workup and metal-scavenging is required to reduce the amount of residual metals to acceptable limits in the desired products. 14 Therefore, the development of mild protocols that use low quantities of environmental friendly, non-toxic catalysts, is of crucial importance for the synthesis of glycoside and saccharide functionalized molecules. In recent years, Cu(OTf) 2 has become a valuable reagent for various reactions such as trifluoromethylation, 15a cya- notrifluoromethylation, 15b and hydroalkoxylation of al- kenes. 15c In a recent report, a combination of Cu(OTf) 2 and ascorbic acid has been employed to effect the C-gly- cosylation of glycals with unactivated alkynes. 15d The success of Cu(OTf) 2 as a non-toxic, moisture- and air-sta- ble catalyst encouraged us to use this reagent as a Lewis acid in Ferrier glycosylation. In a continuation of our in- terest in the development of new glycosylation methods and synthesis of glycosides, 16 herein, we report the use of Cu(II) triflate as an efficient catalyst for the synthesis of 2,3-unsaturated O-glycosides. As a first step, Ferrier glycosylation was performed with 3,4,6-tri-O-acetyl glucal (1) as glycosyl donor and benzyl alcohol (2a) as a model acceptor, being a relatively fast reactant. Initially, we observed only 50% conversion at room temperature after 16 hours in the presence 10 mol% Cu(OTf) 2 and dichloromethane as solvent. Notably, the rate of reaction was accelerated with incremental rise in temperature, and 90% conversion of 1 was observed after 8 hours at 40 °C to obtain benzyl glycoside 3a in 76% yield. The temperature and solvent played an important role in this transformation in terms of yield and stereo- chemistry. Optimization of reaction conditions was then carried out in different solvents; the results are summarized in Table SYNLETT 2014, 25, 1325–1330 Advanced online publication: 10.04.20140936-52141437-2096 DOI: 10.1055/s-0033-1341232; Art ID: st-2014-d0145-l © Georg Thieme Verlag Stuttgart · New York This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.