Efficient Synthesis Of Alkyl And Aryl 2 , 3-Unsaturated Glycopyranosides via Ferrier Rearrangement

The reactions of 3,4,6-tri-O-acetyl-D-glucal with phenolic and aliphatic alcohol in various Lewis acid catalysts (namely La(NO3)3.6H2O, InCl3, ZnCl2 and BF3•OEt2) have furnished the corresponding alkyl and aryl 2,3-unsaturated glycopyranosides via Ferrier rearrangement. BF3•OEt2 showed the best Lewis acids catalysts with excellent yields and minimum reaction times. The reactions performed in CH3CN gave better yields and shorter reaction times compared to CH2Cl2. The electron withdrawing properties of aromatic ring resulting lower yields of aryl 2,3-unsaturated glycopyranosides compared to alkyl 2,3-unsaturated glycopyranosides under this condition. This study is significant in the preparation of O-glycosides via Ferrier rearrangement. | Ferrier rearrangement | Lewis acids | alcohols | glycosides | ® 2011 Ibnu Sina Institute. All rights reserved.


INTRODUCTION
Ferrier rearrangement is an attractive methodology for the synthesis of glycoside derivatives with various alcohols.It is an efficient reaction for the substitution at the anomeric position with allylic rearrangement [1,2].The Ferrier rearrangement involves the addition of nucleophile onto the intermediate allylic axycarbenium ion, preferentially in a quasi-axial orientation [1].This rearrangement leads to the formation of alkyl and aryl 2,3unsaturated-O-glycosides, which are versatile chiral intermediates in the synthesis of several biologically active natural products [1,2].2,3-unsaturated-O-glycosides are also important building blocks in the synthesis of some antibiotics [1].
In this paper, we report Lewis acid-promoted allylic rearrangement of 3,4,6-tri-O-acetyl-D-glucal with 4hydroxybenzaldehyde and aliphatic alcohols with different type of catalysts at different solvents.This study was used as model studies for the synthesis of glycosides bearing chalcone derivatives via Claisen-Schmidt condensation of aldehyde and acetophenone [11].

Materials, method and instruments
Solvents were dried using standard method.All chemicals were used as received.All reactions were performed under nitrogen atmosphere. 1 H NMR spectra were recorded on a JEOL 500 MHz instrument using TMS as an internal standard.The IR spectra were obtained on a Perkin Elmer Instruments Spectrum Gx1v5.0 using NaCl disc.Reactions were monitored by thin-layer chromatography carried out on 0.2 mm Merck pre-coated silica gel plates (60 F 254 ).
The presence of paraffinic chain was confirmed by the protons resonances at δ 1.59 (q, 2H, 8-H 2 ) and δ 0.91 (t, J = 7.4Hz, 3H, 9-H 3 ) in the 1 H NMR spectrum.The CH 3 of the acetates appeared as two singlets at δ 2.05and δ 2.04, while the protons of 3-H and 2-H were observed at δ 5.91 and δ 5.02.The resonance of C-1 appeared as a singlet at δ 5.01 (s, 1H, 1-H).The IR and 1 H NMR spectra of 3 are shown in Figure 1a and Figure 2a.
In the reaction of 1 with 2 and 4 respectively, in the presence of InCl 3 as an activator, neither afforded 3 nor 5 with higher yield.Using ZnCl 2 as an activator only showed little effect on the reaction times and yield.The choice of CH 3 CN as solvent, on the other hand, afforded 73% yield of 3 after stirring 30 min (entry 3(ii) in Table 1).
The reaction depicted in Scheme 1 afforded 3 and 5, where each compound present as a mixture of α-and βanomers.
In all cases the α isomer was produced predominantly, and the different catalysts had little influence in the anomeric ratios.On TLC, their spots completely overlapped, and their separation was not achieved.The results of the reaction are presented in Table 1.Encouraged by the initial results using La(NO 3 ) 3 .6H 2 O, InCl 3 and ZnCl 2 as activators, the choice of the Lewis acids was extended to BF 3 •OEt 2 .Interestingly, higher yields were obtained in the presence of BF 3 •OEt 2 as the activator (entries 4(i,ii) in Table 1).BF 3 •OEt 2 has taken a strong prevalence among other catalysts involved in the reactions.The reaction of 1 with 2, in the presence of BF 3 •OEt 2 in CH 3 CN afforded 92% of 3 in 15 min with α/β (98:2).The reaction of 1 with 4 however, afforded lower yields compared to that of 3.This is due to the electron withdrawing properties of the aromatic ring in benzaldehyde, which under the acidic condition become a weaker nucleophile as compared to alkyl, resulting in lower yields [12].
Notably, the solvents have an important influence on the reaction efficiencies.The effect of different types of solvents was also studied.The polarity of the solvents tends to influence the reaction kinetics.CH 3 CN gave better yields and shorter reaction times compared to CH 2 Cl 2 .The overall reactions is shown in Table 1.

CONCLUSION
The feasibility of using BF 3 •OEt 2 has been demonstrated to furnish the corresponding alkyl and aryl 2,3-unsaturated glycopyranosides via Ferrier rearrangement.BF 3 •OEt 2 exhibited excellent Lewis acids catalysts and minimum reaction times compare to other catalysts.This research is significant in the preparation of O-glycosides via Ferrier rearrangement.

Table 1
Yield of 3 and 5 in various catalysts and solvents.
a Anomeric ratios were determined by 1 H NMR spectroscopy.