Indium trichloride catalyzed Ferrier rearrangement – facile synthesis of 2,3-unsaturated glycosides

Treatment of tri-O -acetyl-D-glucal 1 with various alcohols and phenols in the presence of InCl 3 / CH 2 Cl 2 at ambient temperature furnished the corresponding alkyl and aryl 2,3-unsaturated glycopyranosides in excellent yields in short reaction times and good anomeric selectivity.


Introduction
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-unsaturatedglucosides are accessible by acid catalyzed nucleophilic substitution with allylic rearrangement of tri-O-acetylglucal while it is not that easy to prepare the 2,3-unsaturated galactosides by this route.This reaction, often referred to as the "Ferrier rearrangement", 1 has found wide application.This reaction continues to receive wide attention and various glycosidation methodologies using it have been extensively reviewed. 2he requirement of an acid catalyst to bring about the Ferrier rearrangement precludes its applicability to substrates that are sensitive to acidic conditions.This has led to the development of essentially non-acidic alternative method viz., iodonium reagents (NIS or iodonium dicollidinium perchlorate as promoter) by Fraser-Reid. 3Furthermore, Toshima etal 4 reported a novel method for the glycosidation of glycals under neutral conditions by using a catalytic amount of 2,3-dichloro-5, 6-dicyano-p-benzoquinone (DDQ) to furnish 2,3-unsaturated glycosides in high yields.Mereyala etal 5  Indium(III) chloride InCl 3 , which is a relatively strong Lewis acid, has been used as a catalyst for a wide variety of organic reactions. 12However, Indium trichloride has hardly been used in the carbohydrate field.We have found an interesting application for InCl 3 as an efficient and versatile catalyst for the expeditious synthesis of alkyl and aryl 2,3-unsaturated glycopyranosides via Ferrier rearrangement. 13Recently a few papers have appeared on the InCl 3 catalyzed, microwave assisted Ferrier rearrangement of glycals leading to 2,3-unsaturated O-and C-glycosides in good to excellent yields. 14

Results and Discussion
Synthesis of 2,3-unsaturated alkyl and aryl glycosides using InCl 3 .When 1 equiv. of tri-Oacetyl-D-glucal 1 was treated with 1.2 equiv. of benzyl alcohol and anhydrous InCl 3 in CH 2 Cl 2 for 10 minutes at ambient temperature, a mixture of benzyl 2,3-unsaturated glucopyranosides 3a and 3b was obtained in 86% yield with the α-anomer as the major product.The product showed two close moving spots in TLC (almost identical R f ), corresponding to the α and β-anomers.The complete assignment of signals in the 1 H NMR spectrum was possible based on irradiation studies and the stereochemistry at the anomeric center was established unambiguously as α based on our earlier NOE studies 9c .When the signal due to H-1 of the alpha anomer was irradiated, there was no significant enhancement in the intensity of the signal due to H-5, and vice versa.Based on the integration values of signals due to anomeric protons (α and β anomeric protons come without overlapping and can be integrated without difficulty) in the 1 H NMR (400 MHz) spectrum of the mixture, the ratio of the anomers was calculated.Likewise, a few other alcohols (Scheme 2) and phenols (Scheme 3) also underwent the Ferrier rearrangement catalyzed by InCl 3 in shorter reaction time furnishing the 2,3-unsaturated glycosides in excellent yields with high selectivity in favor of the α-anomer.This procedure worked equally well for the synthesis of a disaccharide viz.methyl 6-O-[4,6di-O-acetyl-2, 3-dideoxy-D-erythro-hex-2-enopyranosyl]-2,3,4-tri-O-methyl-α-D-glucopyranoside 13a and β-anomer 13b (Scheme 4).Thus, reaction of methyl 2,3,4-tri-O-methyl-α-Dglucopyranoside 12 with 1 in dichloromethane/acetonitrile in the presence of InCl 3 led to the known disaccharide 6a 13a and 13b in 80% yield with α-anomer as the major product (α:β= 9:1).

Efficacy of various acid catalysts towards the Ferrier rearrangement of 1
We have examined the efficacy of a few catalysts viz., LiClO 4 , LiBF 4 , BF 3 .Et 2 O and SnCl 4 for the Ferrier rearrangement of 1 with selected alcohols.We have observed that among all these catalysts, InCl 3 is found to be the best (Table 1).In all the cases studied, the reaction was fastest with InCl 3 as compared to other catalysts.It was observed that InCl 3 is better than SnCl 4 .Besides anomeric selectivity; the yield was greatest with InCl 3 .We have examined a few other catalysts such as TaCl 5 , PsCl 3 , and LnCl3 also in dichloromethane.However, none of these Lewis acids was found to catalyze the Ferrier rearrangement.
The low yield of 2,3-unsaturated aryl glucopyranosides (Scheme 3) obtained in the case of phenols is due to further 'O' to 'C' rearrangement catalyzed by InCl 3 .There is precedence for such a rearrangement from our own earlier work.9a  The intermediate O-arylglycoside 9a and 9b could be isolated by quenching the reaction mixture with cold aq.NaOH at the end of 10 min.The 'O' to 'C' rearrangement pathway for the formation of 14a and 14b was confirmed by taking the pure O-arylglycosides 9a and 9b and subjecting them to the action of InCl 3 in dichloroethane which led to the C-arylglycoside 14a and 14b.This is an indication of a cleavage-recombination mechanism involving the intermediacy of highly stabilized allyl cation.It is worth mentioning that products of allylic attack at C-3 are not observed which is in agreement with the high electrophilic nature of the anomeric center in these glycals.While this method provides a convenient one-pot synthesis of C-aryl glycosides and also a rapid entry to 2,3-unsaturated-C-aryl glucopyranosides, it is not diastereoselective (Scheme 5).The reaction was successfully tested on p-methoxyphenol, which afforded a mixture of corresponding C-arylglycoside 15a and 15b in 63% yield albeit with poor anomeric selectivity.The diastereoselectivity observed however, was comparable to that reported with BF 3 .Et 2 O as catalyst 9a .
The reaction underwent by 3,4-di-O-acetyl-L-rhamnal 16 also, which furnished the corresponding 2,3-unsaturated C-arylrhamnosides in moderate yields but without any significant anomeric selectivity.17-18(Scheme 6).From this limited data, it appears that the presence of the substituent at C-6 does not have any influence on the anomeric selectivity in this reaction.
Strangely, under identical conditions tri-O-acetyl-D-galactal 2 yielded a complex mixture of products.All new compounds were thoroughly characterized by spectral means.
It should be emphasized that indium chloride has to be extremely anhydrous to effect the Ferrier rearrangement of 1 and 16 with various aglycons.Use of hydrated indium trichloride (InCl 3 .3H 2 O) on 1 led to the formation of substantial amount of 14c even in the presence of aglycon.Since anhydrous InCl 3 was found to be an efficient catalyst for Ferrier rearrangement it appeared worthwhile to examine its behavior towards free glycals.In the event, it led to a facile transformation affording the 2-(D-glycero-1', 2'-dihydroxyethyl) furan 21, a very useful and important chiral intermediate in organic synthesis. 18 The reaction proceeded with good anomeric selectivity, furnishing high isolated yields of the products.The reaction is amenable for scale-up.The quantity of the nucleophile used for glycosylation by this method is only 1.2 equiv.as compared to 10 equiv.used in the conventional thermal Ferrier rearrangement.The medium is compatible with the ester group, thus avoiding the attendant problem of transesterification.The reaction has been extended to Lrhamnal also, but in the case of tri-O-acetyl-D-galactal, the reaction was not clean and led to a mixture of products.

Experimental Section
Tri-O-acetyl-D-glucal 1, tri-O-acetyl-D-galactal 2 and 3,4-di-O-acetyl-L-rhamnal 16 were prepared according to the literature procedures. 15 General Procedures.To a mixture of tri-O-acetyl-D-glucal 1 (1 mmol) and the aglycone (1.1 mmol), was added anhydrous InCl 3 (0.2mmol; 20 mol%) in dry CH 2 Cl 2 (1-2 mL) (For Caryl glycosides, ClCH 2 CH 2 Cl was used as the solvent and heated the reaction mixture at 50 o C for the required time) at ambient temperature.The contents were stirred for the required time and the reaction monitored by TLC.The reaction mixture was quenched by the addition of aqueous sodium hydrogen carbonate (10%, 25 mL), extracted with dichloromethane (3 x 25 mL), dried over anhydrous sodium sulphate, filtered and concentrated.The residue was purified by flash column chromatography on silica gel to obtain the products using hexane: EtOAc as eluents.
The product showed two close moving spots in TLC (almost identical R f ), corresponding to the α and β-anomers.The mixture of anomers was not separated but characterized as such by HRMS and NMR spectroscopy.Based on the integration values of signals due to anomeric protons in the 1 H NMR spectrum of mixture, the ratio of the anomers was calculated.

Table 1 .
Study of various acid catalysts in the Ferrier rearrangement of 1 with alcohols *Anomeric ratios were determined by1H NMR (200/400 MHz) spectroscopy.