The carbon-Ferrier rearrangement: an approach towards the synthesis of C -glycosides

The carbon-Ferrier rearrangement is the reaction of appropriately functionalised glycals, with a variety of carbon nucleophiles such as allyltrimethylsilanes, alkynyltrimethylsilanes, silyl cyanides etc. involving the corresponding nucleophilic addition at the anomeric carbon with concomitant loss of a substituent at C-3. This leads to double bond migration to give 2,3-unsaturated sugars which act as useful chiral substrates for further manipulations in organic synthesis.


Introduction
The well-known Ferrier rearrangement 1 involves the reaction of a suitably protected 1,2-glycal with an alcohol under Lewis acid catalysis to form the corresponding 2,3-unsaturated 1-Oglycosides.Such 1-O-glycosides have been transformed into a variety of useful intermediates both in organic synthesis as well as specifically in carbohydrate chemistry.Likewise, there have been reports on aza-1h and thia-1i Ferrier rearrangements.Several papers and reviews on this and allied topics have appeared in the literature. 1 Since C-glycosides are stable analogs of O-glycosides and less prone to cleavage at the anomeric carbon, they have gained considerable importance in the last few decades.Among several approaches towards C-glycosides, the Ferrier rearrangement utilising C-nucleophiles has been found to be quite useful.Several catalysts and nucleophiles have been introduced in the literature addressing α/β-selectivity, mildness of the method, effect of solvent, effect of acid (or Lewis acid) catalyst, and yields of the products.In this review, a brief account of several methods that have been reported in the literature since 1982 is presented.

Allyl silanes
Amongst the carbon nucleophiles used for C-Ferrier reactions, allyltrimethylsilanes (ATMS) have been most prominent.The first examples of such reactions were reported by Danishefsky et al. 2 where glycal acetates 1-4 (Table 1) were observed to undergo nucleophilic displacement and double bond migration in the presence of equimolar amounts of TiCl4 as a Lewis acid.The reactions were highly regioselective with allyl group addition at C1 position and shifting of double bond to C2-C3.The reaction proceeds with preference towards attack from the -side but the selectivity varied depending upon the stereochemistry of other groups on the pyranose ring.Stereoselective allylation at the C1 position in 1-alkylglucal 5 was reported by Nicolaou and group using TiCl4 (Scheme 1). 3 The nucleophile attacks from the -face of the molecule as the oxonium ion intermediate would preferentially convert into the energetically favoured half chair conformer 7 (Figure 1).

Scheme 1
Figure 1.Proposed explanation to -selectivity of allyl addition.
Isobe et al. 4 reported the use of BF3.OEt2 as a catalyst for the generation of the  and anomers 8 from acetylated glucal 1 in 94:6 ratio, which were separated by column chromatography with great difficulty (Scheme 2).

Scheme 2
The first aza-Ferrier reaction on N-carbethoxytetrahydropyridine derivative 9 with two equivalents of allyltrimethylsilane was reported by Kozikowski et al. 5 (Scheme 3).While excellent yields of the product 10 were observed in the presence of SnCl4 (90%) and TiCl4 (89%), BF3.OEt2 and TMSOTf produced the desired compound in moderate yields of 43% and 51%, respectively.

Scheme 3
Toshima and co-workers 6 reported highly stereoselective formation of allyl--C-glycosides when glycal acetates such as 1, 3, 11-13 were treated with allyltrimethylsilane in the presence of 30-50 mol% of 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) as a neutral activator (Table 2).Increase or decrease in the amount of activator caused lowering of product yield.Use of allyltributyltin under similar conditions yielded the product in 58% yield.From the same group, 10 mass % of Montmorillonite K-10 was found to be a suitable catalyst for effecting Ferrier rearrangement in acetylated glycals using allyltrimethylsilane as the source of nucleophile (Scheme 4).The reaction followed good -selectivity irrespective of the stereochemical disposition of the groups on the glycal. 7

Scheme 4
Also, stereoselective allyl -C-glycosidation using unprotected glycals 14-17 (Table 3) was successfully achieved in the presence of equimolar amounts of TMSOTf at low temperatures by the same group. 8Selective formation of C-glycosides was promoted by low temperature conditions (-78 o C).The yield of the reactions was observed to be dependent on the solvent.
Studies on pentapyranose derivatives 18 and 19 by Isobe and co-workers 9 revealed 1,4-anti diastereoselectivity (>95:5) in the addition of allyl nucleophile, giving 20 and 21 in the presence of BF3.OEt2 (Scheme 5).This observation is in contrast to the reactions of hexapyranoses which exhibit 1,5-anti diastereoselectivity.The authors have rationalised this difference by the conformations of the oxonium ion intermediates.While for the hexapyranoses the stereochemistry is guided by the equatorial orientation of the C-5 substituent, the pentapyranoses favour the transition state having quasi-axial orientation of the C-4 substituent which is 1.5 kcal/mol more stable than the quasi-equatorial conformer.C-glycosylation of acetylated glycals using allyltrimethylsilane in the presence of 1.5-2 equivalents of InCl3 in dichloromethane has been reported by Ghosh et al. 10a The reaction proceeded with 1,5-anti diastereoselectivity giving the products in good to excellent yields.Consecutively, Das et al. 10b have modified the reaction condition using 20 mol% of InCl3 to the reaction mixture in acetonitrile under microwave irradiation.The reaction was complete in 30 seconds and the products were obtained in excellent yields with very good diastereoselectivity.Later, Ghosh et al. 10c reported that addition of 2 mol% of InCl3 and 20 mol% of trimethylsilyl chloride was found to be effective in generating the desired pseudoglycals.The catalyst system was observed to be equally effective when used in neat allyltrimethylsilane. 10c These results are summarised in Scheme 6.
Yadav et al. have reported the use of several Lewis acids for C-Ferrier reactions on variously protected glycals.with allyltrimethylsilane as the nucleophile.Catalytic amounts of Sc(OTf)3, 11a molecular iodine, 11b InBr3, 11c Bi(OTf)3, 11d phosphomolybdic acid (PMA) supported on silica gel 11e have been found to be efficient in producing the C-pseudoglycosides in 85-95% yields with very high -anomeric selectivity (Table 4).Equimolar amount of LiBF4 11f has also been observed to be competent as a promoter for this reaction giving the desired products in excellent yields and selectivity.

Scheme 7
Venkateswarlu et al. 13 have reportedly used 5 mol% of ZrCl4 as catalyst for Ferrier reaction on acetylated glycals with allyltrimethylsilane as nucleophile producing the expected products in excellent yields with very good selectivity (Scheme 8).

Scheme 8
Misra and co-workers 14 have reported HClO4-SiO2 as an insoluble catalyst promoting the Ferrier rearrangement on glycals.50 mg of the solid supported catalyst was found to be effective for 1 mmol of the glycal, rapidly generating the desired products in 75-85% yields with excellent selectivity as shown in Scheme 9.

Scheme 9
Lin and coworkers 15a reported the reaction of exo-and endo-glycals with allyltrimethylsilane in the presence of 10 equivalents of trifluoroacetic acid (TFA) yielding the desired products in about 85%, with selectivity towards the -anomer 25 and 27 (Scheme 10).The same reagent was used by Gallagher et al. 15b in the synthesis of a novel laulimalide analogue via intermediate 8.

Scheme 11
Phenylsulfonylethylidene (PSE) protected glycals 28 were observed to undergo the Ferrier reaction with allyltrimethylsilane on being activated by TMSOTf to give product 29 as shown in Scheme 12. 17

Scheme 12
A catalytic amount of AuCl3 was also found to be efficient in promoting C-allyl product formation.18 The reaction produced the expected compounds in good yields with the -isomer predominating (Scheme 13).

Scheme 13
Ultrastable Y-zeolites have been reported by Gammon et al. 19 to catalyze C-allylation on acetylated glycal with formation of the corresponding -anomer selectively (Scheme 14).

Scheme 14 2.2 Substituted allylsilanes as nucleophiles
Danishefsky et al. 20 explored the selectivity of nucleophilic attack of (E)-and (Z)-crotylsilanes 30 on substituted glycals.The rearrangement was promoted by BF3.OEt2 to give the -configurated pseudoglycosides.Several glycal-like substrates were treated by the silanes.While the E-silane yielded predominantly C1-anti product, the Z-silane gave the C1-syn isomer as the major products.On incorporating a substituent at C-2 position or an electron withdrawing group at C-3 position, the anti:syn ratio increased considerably.These observations are summarised in Scheme 15.
Subsequently, Panek et al. 21reported the Lewis acid mediated attack of substituted crotylsilanes 31 and 34 on glycal 1 as shown in Scheme 16.In their work, BF3.OEt2 was found to be most effective as a Lewis acid in contrast to TMSOTf and TiCl4.Upon treatment of triacetylated glucal 1 with (R)-silane 31, the isomer 33 was obtained as the major product while the (S)-silane 32 produced 34 as the major isomer.

Enol Silyl Ethers as Nucleophiles
Reaction of 1-(trimethylsilyloxy)styrene with tri-O-acetyl glucal 1 was first reportedly observed by Dawe and Fraser-Reid. 22The reaction proceeded in presence of 1.4 equivalents of BF3.OEt2 at -40 o C producing the C-pseudoglycoside 35 in 99% yield with -anomeric selectivity (Table 5).Although the authors expected an increment in the ratio of selectivity in acetonitrile as solvent due to formation of nitrilium ion that would adopt a -orientation, changing the solvent from dichloromethane to acetonitrile failed to provide any improvement.An Aza-Ferrier reaction on the N-carbethoxytetrahydropyridine derivative 9 with two equivalents of silyl enol ether in presence of 1.5 equivalents of TMSOTf to give the 1-acetyl-2oxopropyl derivative 36 in 84% yield has been reported by Kozikowski and Park, 5 as shown in Scheme 17.

Scheme 17
Lithium perchlorate has been identified as an effective promoter for the Ferrier reaction on acetylated glucal with silyl enol ether (ketene acetal) by Pearson and Schkeryantz. 23The anomer of the ester 37 so formed was observed to be the major product (Scheme 18).

Scheme 18
Isobe et al. 9 have reported the reaction of enol silyl ether on acetylated xylal 18 in presence of BF3.OEt2 to form the C-C coupling product 38 in 65% yield.The reaction was observed to follow 1,4-anti selectivity in the ratio of 85:15 as shown in Scheme 19.

Scheme 19
Yb(OTf)3 has been found to be a good catalyst for reaction of several enol silyl ethers on acetylated glucal by Schmidt et al. 12a The reaction proceeded with good selectivity and excellent yields.Subsequently, Grée et al. 12c have reported the utilisation of Yb(OTf)3 in ionic liquid in the reaction of similar silyl enol ethers with glucal forming the desired products in moderate yields and good diastereoselectivity.These observations are summarized in Table 6.
Exo-Ferrier reaction on 39 with a silyl enol ether in the presence of trifluoroacetic acid, resulting in the formation of compound 40, containing a quaternary anomeric carbon, in 65% yield, has been reported by Lin and co-workers (Scheme 20).15a Scheme 20

Organometallic Nucleophiles
In 1986, Nicolaou and his group 3 reported trialkylaluminium and alkylaluminium chloride as sources of the carbon nucleophile in Ferrier rearrangements of the triacetylated 1-methyl glucal 5 (Table 7).The reaction was promoted by TiCl4 and successfully yielded 1,1-dialkylated pseudoglycals 6 and 7 stereospecifically.The reaction proceeded via the transition state as described in Figure 1.
Orsini and Pelizzoni 24 reportedly used the Reformatsky reagent tert-butoxycarbonylmethylzinc bromide 41 on acetylated glycals to bring about formation of pseudoglycosides in the presence of TMSOTf at 0 o C. While the D-glucose derived olefin produced the -anomer as the major product, the selectivity was reversed in the D-galactose and L-rhamnose derived olefins 11 as shown in Table 8.The reactions produced the desired products in poor to moderate yields only.9).Attempts to utilise Zn(Cu) couple with alkyl halides for similar organometallic reaction in presence of Lewis acids resulted in the formation of C-3 substituted glycals.The authors have subsequently reported 25b that alkylated zinc halides react with a -selectivity similar to that earlier reported by Isobe et al.

Scheme 21
Cossy and Rakotoarisoa 27 reported efficient nucleophilic attack by alkyl copper reagents on C-2-formylated tri-O-benzyl-D-glucal 49 in the presence of BF3.OEt2.The reactions were observed to be stereospecific, yielding only the  anomer of the Ferrier products 50 (Scheme 22).On the contrary, the glycals underwent a 1,4-Michael addition in the presence of lithium dialkyl cuprates with no elimination of the C-3 substituent to form adducts 51 without the activation with a Lewis acid.

Scheme 22
Several-aryl-Pd compexes synthesized via transmetalation reaction between boronic acid and palladium (II) salt were observed to be efficient in carrying out Ferrier rearrangements on acetylated glycals.The reagent system, developed by Maddaford et al., 28 produced the desired product with -selectivity on the D-glycal substrates (Scheme 23).

Scheme 23
The proposed mechanism involves syn addition of the in situ generated PhPdOAc from the -face of the glycal followed by anti elimination which results in the formation of Pd(OAc)2.When L-rhamnal diacetate 11 was subjected to the reagent system, the -anomer 52 was obtained as the only product, thus supporting the proposed mechanism where the metal complex approaches from the less hindered face of the glycal.The reaction was successful with 10 mol% of Pd(OAc)2 and electron withdrawing groups on the boronic acid reduced the yield of the reactions considerably. Du Bois and co workers 29 have demonstrated the use of alkyl and aryl zinc reagents as efficient nucleophiles on 1,2-dihydropyranylacetate derivatives.Several phenyl and heteroarylzinc reagents were synthesized smoothly from the in situ generated lithiated aryl intermediates via transmetallation with ZnCl2 at -78 o C as shown in Table 10.The Ferrier rearrangement proceeded with good stereoselectivity with preference for the -anomers at 25 o C.
Both electron donating and withdrawing groups on the phenyl ring furnished the desired products in comparable rates and yield.Correspondingly, the authors have generated alkylated zinc reagents using Zn(Cu) couple, ZnCl2, with DMA as an additive with alkyl iodides.The 1,2dihydropyranyl acetates reportedly underwent Ferrier rearrangement with these zinc intermediates to furnish trans-2,6-dialkyl-substituted pyrans.Lubin-Germain et al. 31 reported the synthesis of alkynated pseudoglycosides catalysed by indium metal from the corresponding alkyne iodide in more than 9:1 stereoselectivity favoring the -anomer as shown in Table 12.The presence of the iodide functionality on the alkynes was found to be essential for the Ferrier reaction to occur.Indium metal was observed to be superior to other metals like zinc, manganese or their salts for product formation with better yields and selectivity.The trimethylsilylethynyl-C-glycoside was treated with silver nitrate and Niodosuccinimide to obtain the corresponding iodide which in turn was reacted with substituted

  
The above mentioned protocol has been employed by the same authors with Garner's aldehyde-derived alkynyl iodide but failed to provide the desired pseudoglycal (Scheme 24). 32A bicyclic alkene 53 was obtained, the formation of which has been suggested to be via indium mediated carbamate reduction followed by cyclization.On changing the amine protection from Boc to o-diphenylamide, Ferrier-rearranged products 54 were obtained in good yields.

Propargyl or Alkynyl Silanes
In a manner analogous to the allylsilane addition to the anomeric centre of D-hexopyranose rings, silylacetylenes were found to be reactive enough to generate the corresponding 'sugar acetylenes'.As mentioned earlier, Nicolaou et al. have explored the reaction of various nucleophiles on 1-substituted glycals 5 and 56 using 1 equiv. of TiCl4. 3 On reacting methyl trimethylsilyl acetylene with these substrates, they obtained products in good yields in a highly stereospecific manner (Scheme 25).Utilising this protocol, many 1,1-disubstituted glycosides 55 and 57 respectively have been obtained.

Scheme 25
During the course of their study towards the synthesis of okadaic acid, Isobe et al. 4 explored the C-glycosidation on glycals with silyl acetylenes instead of the usual allylsilanes using TiCl4 (Scheme 26).Interestingly, the stereoselectivity of this reaction was observed to be excellent, yielding only the -anomer 58, as compared to the 16:1 ratio of isomers in the case of allylsilanes. 2Other nucleophiles such as trimethylphenylsilane, trimethylvinylsilane, ethynyltrimethylsilane and dihydropyran failed to react owing to the rapid polymerisation of glucal 1.In their next report, Isobe et al. 33a out the glycosylation studies on D-glucal 1 with bistrimethylacetylenes, under the influence of SnCl4, to obtain the product 58 in quantitative yield.The same reaction was performed with tributylstannyl-and trimethylsilylacetylene using TiCl4 in high yields.The noteworthy fact is the observation of complete stereoselectivity in all examples.

Scheme 26
Similar C-glycosidation on 2-acetoxy-D-glucal 59 with SnCl4 proceeded to give products 60 which were unstable (Scheme 27) and were converted into -unsaturated ketones 61 on aqueous workup, and reduced using NaBH4 or LiAlH4 to give allylic alcohols 62 for analysis.
Isobe et al. were able to isolate some of the doubly glycosidated product 65 (Scheme 28), from the reaction of the ene diyne nucleophile 63 with glucal 1, albeit in only 10% yield with 20% conversion of the starting monoglycosylated compound 64.Moreover, the reaction was unsuccessful in other cases.

Scheme 28
Later, the same group attempted double glycosidation using bistrimethylsilylacetylene on glucal triacetate 1 in the presence of SnCl4, but failed. 34However, glucal 1 on reaction with 1,4bis(trimethylsilyl)-1,3-butadiyne 66 with 1% SnCl4 at 0 o C in 3 hours led to the second glycosidation product 68 in 55% yield along with 19% of the monoglycosylated product 67 (Scheme 29).Bis-glycosylated product 68, on the other hand, was obtained in one pot without isolating the intermediate in 54% yield by further treatment with 1 in presence of SnCl4.The same reaction was observed with the glucal derivative 59 but the yields were not very encouraging.Furthermore, similar reaction employing 1,6-bis(trimethylsilyl)-hex-3-en-1,5-diyne 63 and glucal acetate 1 gave the monoglycosylated product 64 in just 1.25 h in 79% yield , and the bis-glycosylated product 65 in 68%, without isolating the intermediate.The second glycosidation took place faster in this case.In all the reactions, the acetylenic group entered in  orientation with exclusive regio-and stereoselectivity.

Scheme 29
Isobe et al. 9 went on to expand the scope of acetylenic glycosylations on pentopyranose derivatives such as di-O-acetyl-D-xylal 18 and di-O-acetyl-D-arabinal 19 (Scheme 30).The reaction was carried out with bistrimethylsilylacetylene using TiCl4 at -40 o C. In striking contrast to the observations for glucal 1, the product in these cases bore predominantly 1,4-anti stereochemistry.The products 69 and 70 exhibited the same optical rotation with opposite sign proving that they were enantiomers of each other.Several other nucleophiles such as Me3Si-C≡C-R, where R = Me, SPh, etc. were also used.

Scheme 30
The stereochemical outcome was rationalised as a consequence of the stereoelectronic effect, as discussed earlier, vide supra (see Figure 2), while dealing with similar reactions using allyl trimethylsilane.
the same year, Vogel 35a and Isobe 35b reported for the first time the reaction of glucal 1 with propargyltrimethylsilane and obtained -C-allenyl product 71.Vogel et al. performed the reaction in CH3CN using TMSOTf as a catalyst, as part of a disaccharide synthesis (Scheme 31).

Scheme 31
Isobe's group carried out the same reaction with 1.5 equiv. of propargyltrimethylsilane in dichloromethane at -20 o C (Scheme 32).By using SnCl4 as a catalyst, they reported 83.3% yield, whereas by using TiCl4, the yield increased slightly to 88.5%.Reaction of propargyl silane with tri-O-acetyl-D-galactal 3 under the influence of SnCl4 or TiCl4, gave the -C-allenyl product 72 in 81.6 or 75.7% yield respectively.Surprisingly the same reaction with 2,3,4,5-tetra-O-acetyl-Dgalactal 59, followed by reduction gave a mixture of and -allenyl products 73 and 74 in 7.3:1 ratio with SnCl4 and 5.2:1 in the case of TiCl4 (Scheme 33).

Scheme 32 Scheme 33
Yadav et al. 36 reported C-alkynylation of glycals 75 with the much milder Lewis acid InBr3 (Scheme 34).Employing only 5 mol% of the catalyst, they obtained very good yields of 76 in shorter reaction time, with high anomeric selectivity, and recoverability of the catalyst.Other Lewis acids were also tried, such as InCl3, In(OTf)3, Sc(OTf)3, Tb(OTf)3, YCl3 and YbCl3, but InBr3 gave the best results in terms of conversion and selectivity.As earlier, 1,4-anti selectivity was observed in the case of pentose sugars.

Scheme 34
Iodine was found to catalyse the C-glycosidation of tri-O-acetyl-D-glucal 1 with various silylacetylenes at room temperature, in high yield (Scheme 35). 37Optimum conditions for this reaction were investigated and it was found that 1 equiv. of I2 in dry CH2Cl2, with 2 equiv. of

Scheme 35
acetylene nucleophile was effective for this reaction.In agreement with previous observations, the stereochemistry at the C-1 position in the product 77 was exclusively orientation.
Isobe et al. 38 then carried out a comparative study of the reactivity of alkynyl and propargyl silanes.The nucleophile 78 containing both propargyl and alkynyl moieties was of interest since it is suitable for the evaluation of reactivities of both groups under the same conditions.In the reaction between 1,3-bis(trimethylsilyl)propyne 78 and glucal 1, a mixture of allene 79 and alkyne 80 was obtained in 1:2.5 ratio (Scheme 36) using SnCl4 as a Lewis acid.The ratio was found inverted to 4:1, on changing the solvent from dichloromethane to acetonitrile.The reason for the reversal of ratio was proposed to be due to the stabilisation of the cationic intermediate by acetonitrile (Figure 3).Different substrates with different silyl groups were investigated.In the silyl nucleophile with 2 triisopropylsilyl groups, no reaction took place.With triisopropylsilyl group in the propargylic position, the alkyne product 81 was obtained exclusively.When the triisopropylsilyl group was in the acetylenic position, the major product was found to be the propargylic compound 83, along with a small amount of allenic product 82.On changing the medium of reaction from dichloromethane to acetonitrile, the formation of 83 was favoured.
A new nucleophile, 1,4-bis(trimethylsilyl)-2-butyne 84 was introduced by Isobe et al. 39 that reacted with glucal 1 in the presence of BF3.Et2O, to give silylallene glycoside 85 with orientation (Scheme 38).On reacting 2 equiv. of the glucal with 1 equiv. of nucleophile using BF3.Et2O provided a new symmetrical diene glycoside 86 along with monoglycosidation product 85.Changing the Lewis acid to TMSOTf or SnCl4 did not improve yields of the reaction.However, when 3 equiv.of 1 were used under the influence of SnCl4, the diene 86 was obtained in 92% yield in just 15 minutes.In a similar manner, other symmetrical and unsymmetrical diene glycosides were prepared using this method.

Scheme 38
In a detailed investigation of acid-catalysed glycosidation of endo-and exo-glycals using TFA, 15a different nucleophiles were allowed to attack glycal, among which propargylsilane reacted with the galactal 87 to give sugar allene 88 in 79% yield (Scheme 39).

Silyl Cyanides
Glycosyl cyanides are important intermediates in the synthesis of C-glycosyl derivatives, since the cyano group can be easily converted into other functional groups.The first Lewis-catalysed addition of trimethylsilyl cyanide (TMSCN) on glycals was reported by De Las Heras et al. in 1983. 40The reaction on 1 was carried out in nitromethane as a solvent in the presence of a catalytic amount of BF3.OEt2, yielding a and 89b in and respectively (Scheme 41).The same reaction on glucal derivative 59 afforded a mixture of and anomers 90a and 90b in 46 and 34% yields respectively.The reaction was better than that using Lewis acid and sodium cyanide, in terms of yields and reaction conditions.

Scheme 42
During the synthesis of streptazolin, Kozikowski and Park 5 investigated a Ferrier-type reaction on piperidinol 9 with various nucleophiles.The reaction of 9 with 6 equiv. of TMSCN, in the presence of TMSOTf (1.5 equiv.) at -78 o C afforded the product 93 in 3 hours in 70% yield (Scheme 43).As expected, nucleophilic attack on the pyridinium ion occurred at the site to the ring nitrogen atom.

Scheme 43
The first example of a C-Ferrier rearrangement on acetylated and unprotected glycals without a catalyst, under thermal conditions, was reported by Hayashi's group. 41The reaction of TMSCN on glucal 1 at 80 o C, remarkably gave 95% yield of a 58:42 mixture of  and glycosyl cyanides 89a and 89b (Scheme 44).Similarly, unprotected glucal 15 in the absence of solvent and catalyst was found to react with TMSCN to give products 94a and 94b in 74:26 ratio, in 84% yield.2-bromo-D-glucal 95 reacted under the same conditions yield 72% of a 4:1 ratio of 96a and 96b.

Scheme 44
Yadav et al. 11a reported the treatment of glycals with various silyl nucleophiles in the presence of only 3 mol% of Sc(OTf)3, to afford the corresponding 2,3-unsaturated C-glycosides in excellent yields with -selectivity.Thus, for example, TMSCN reacted with 1 leading to 89 in 90% yield and the anomers were formed in 6:4 ratio (cf.Table 13, entry 1).Several glycals were successfully employed for this reaction.Sc(OTf)3 proved to be an efficient and reusable catalyst for this reaction, along with milder reaction conditions, lower catalyst usage and simple experimental procedure.Again the same group investigated the catalytic action of iodine on the addition of cyanide to glycals.11b Only 8 mol% of iodine was found to be sufficient to catalyse the reaction of glucal 3 with TMSCN in 12 hours, yielding a 6:4 mixture of and -cyanides in 80% yield, while galactal 18 gave 7:3 ratio of and -cyanides in 72% yield (Table 13, entries 2 and 3).The same group 11c later explored the InBr3-catalysed Ferrier rearrangement of glucal 3 with TMSCN at ambient temperature and obtained high yields and good selectivity (Table 13, entries 4 and 5) of the cyano product.In a similar manner, Bi(OTf)3 was employed in the C-Ferrier rearrangement of glycals.11d Bi(OTf)3, being inexpensive and easy to prepare on gramscale in laboratory conditions, provided a convenient alternative to other lanthanide-based Lewis acids used for this reaction.Only 2 mol% of the catalyst with 1.25 equiv. of TMSCN afforded a 7:3 mixture of cyanides in excellent yields (Table 13 An eco-friendly and rapid microwave-assisted method, using 6 equiv. of TMSCN and 20 mol% of InCl3 (Scheme 45), was developed by Das et al. 10b The reactants were taken in CH3CN in an open vessel and irradiated for a few seconds.High yields of glycosyl cyanides 89 and 98 were obtained from acetyl glycals 1 and 19 respectively.The yields and selectivities were comparable to usual reflux methods.

Scheme 46
In a bid to enhance the catalytic activity and also lower the catalytic loading of InCl3 in C-Ferrier reactions, TMSCl was evaluated for its synergistic effect, 10c (vide supra).Thus, glucal 1 reacted with 1.5 equiv. of TMSCN in 1 hour in dichloromethane over molecular sieves, to give 90% of 11:5 mixture of -and-glycosyl cyanides 89 (Scheme 47). 3 and rhamnal 11 also underwent reaction in good yields of 97 and 99 respectively.The catalytic system was also observed to be effective in solvent-free conditions.

Scheme 47
The proposed reaction mechanism for the regeneration of InCl3 by TMSCl is illustrated in Figure 4. Glucal 1 and galactal 3 also underwent Ferrier rearrangement with TMSCN in the presence of HClO4-SiO2 catalyst to form the corresponding cyano products 89 and 97 respectively, although the  ratio (2:1) was only marginally favoring the -anomer. 14Likewise, Er(OTf)3 also catalysed the reaction of glycals with TMSCN affording 95% of glycosyl cyanides (6:4) in the case of glucal 1 and 76% of cyanides (7:3) in the case of galactal 3 favoring -anomers. 16

Scheme 50
Marcaurelle et al. 44 investigated the reaction of glucal 1 with ketene acetal 112 under various conditions, and found the reaction to be best carried out in the presence of TMSOTf in dichloromethane, yielding 73% of a 1:1.5 mixture of 108, favouring the -anomer (Scheme 51).
However on changing the solvent to CH3CN, the ratio of isomers reversed (= 1.5:1) but the yield of 108 lowered to 65%.See also ref. 23.

Scheme 51 7.2
Aromatic nucleophiles Synthetic routes towards C-aryl glycosides have gained considerable importance over the past few years since they are part of many biologically active molecules.Hence, the task of coupling the aryl moiety into glycosides is now a challenge in organic synthesis.As early as 1987, Isobe and co-workers carried out glycosidation with furan using glucal 1 in the presence of BF3.Et2O, and a mixture of 1-and 3-substituted products 113 and 114 respectively (Scheme 52).

Scheme 52
In the ZrCl4-catalysed Ferrier rearrangement, which was mentioned earlier, 13 the reaction was also carried out with aromatic nucleophiles such as furan, pyrrole and thiophene, in good yields (Scheme 53) of the corresponding products 113, 115a and 115b respectively.Scheme 53

Scheme 54
Ethyl acetoacetate (120) has also been utilised in the Ferrier rearrangement on 1 using only 0.5 mol% of AuCl3, giving 80% of the product 121 in just 15 minutes (Scheme 55). 18Scheme 55

Olefins
Peracetylated glycals underwent Ferrier rearrangement with olefins in the presence of Lewis acids such as SnBr4 and BF3.Et2O with complete regioselectivity and high diastereoselectivity, with the -anomer being the major product. 28Thus, glucal 1 reacted with olefin 122 to give exclusively -anomer the C-glycosylated 123 in 94% in the presence of SnBr4 (Scheme 56).In the same way, glucal 59 gave 70% of only -anomer 124.In the case of methylenecyclobutane 125 and open-chain olefins such as 127, some halogeno derivatives 126 and 128 were obtained when the reaction was carried out in the presence of EtAlCl2.

Scheme 56
More recently, Osborn et al. 46 prepared the olefin 129 to carry out a similar Ferrier reaction on glycals using BF3.Et2O or I2 as a promoter (Scheme 57), leading to the 1-deoxy-C-linked disaccharide 130.The reaction was optimised with 2:1 ratio of glycal and olefin.Anomeric methoxide undergoes cleavage which also reacts with glycal, hence 2 equiv of glucal is required.The oxonium ion formed by cleavage of the acetal at the anomeric carbon of 129 is reduced by the transfer of hydride from the benzylidene acetal, leading to the subsequent removal of the benzylidene group.Reaction of glucal 1 with olefin 131 under the same conditions led to disaccharide 132 in 51% yield.Likewise, some other glucal and galactal derivatives also underwent analogous reactions.Scheme 57 7.5 Isocyanides Yadav et al. 47 reported Ferrier rearrangements with isocyanides as nucleophiles using a catalytic amount of FeCl3 at room temperature.Under mild reaction conditions, amides 133 were obtained in good yields with high selectivity (Scheme 58).Several differently protected glucals reacted efficiently with the isonitriles in the presence of only 10 mol% FeCl3 at room temperature.

Scheme 58 7.6 Allenyl silanes
Very recently, enantio-enriched allenyl silane 134 has been used for C-glycosidation under the influence of TMSOTf. 48The products 135 and 136 displayed very good diastereoselectivity, favouring the -isomer (Scheme 59).Additions on glucal were considerably higher yielding than the analogous galactal additions.Even achiral allenyl silane 137 was used for this reaction, giving similar results forming 138.Moreover, the 2,3-dihydrofuran 139, prepared from D-ribose, underwent reaction with both enantiomers of 134, affording trans dihydrofuran products 140a and 140b, albeit in lower yields (Scheme 60).Again, addition of 137 on dihydrofuran 139 gave moderate to high yield of 2,5-trans-dihydrofuran 141.Organoboron compounds Potassium alkynyltrifluoroborates have been successfully employed in the C-glycosidation of Dglucal 1 using BF3.OEt2. 48These salts are stable in air and moisture, and more nucleophilic as compared to organoboron compounds.The reaction was performed under 2 sets of conditionsusing 4 equiv. of BF3.OEt2 at -45 o C in acetonitrile gave products 142 in 20 min or using 2 equiv. of BF3.OEt2 at 0 o C allowed the reaction to complete within 10 minutes (Scheme 61).Both methods gave good yields with high -selectivity, with the former method giving higher selectivity in some cases.

Scheme 61
BF3.Et2O is believed to convert the trifluoroborate into the organoboron difluoride 143, which is able to activate the acetate of the glucal 1, generating a [R-B(OAc)F2] -kind of nucleophilic species, which attacks the C-1 oxonium ion, ultimately giving rise to 142 (Figure 5).

Conclusions
From the foregoing discussion, it is clear that a wide range of carbon nucleophiles and a great number of catalysts have been studied to bring about the carbon-Ferrier rearrangement leading to C-glycosides.Although a good amount of progress in terms of improvements in yield, selectivity etc. has been reported, there is still in many reactions room for improvement.It is expected that this review will give sufficient impetus to readers to embark on the development of new catalysts and introduction of new nucleophiles in the carbon-Ferrier rearrangement.

Alafia Ali
Scheme 21. -Selectivity for both nucleophilic substitution at C-3 giving 46a, and Ferrier rearrangement at C-1 resulting in 46b was observed.Several amino acid derived alkanes have been used as nucleophiles.Also, glutamic acid derived zinc reagent 47 when reacted with tri-Oacetyl-D-glucal 1 produced the C-1 adduct only 48 with -selectivity in the presence of BF3.OEt2.
Ansari has received her B.Sc and M.Sc.degrees in 2005 and 2007, from Aligarh Muslim University, India.She is currently pursuing her Ph.D. under the supervision of Prof. Y. D. Vankar, Department of Chemistry, IIT Kanpur, India since 2008.Her research work includes the synthesis of glycosidase inhibitors and development of newer synthetic methodologies in carbohydrate chemistry.Rima Lahiri obtained her Bachelor's Degree from Presidency College, Kolkata, India in 2005 and joined M.Sc. in IIT Kanpur, India.After completion of her master's programme she joined as a Ph.D. Student under the supervision of Prof. Y. D. Vankar in IIT Kanpur, India in 2007.She has been working in the area of synthetic organic chemistry and her research involves multistep syntheses towards natural and unnatural iminosugars as potential glycosidase inhibitors.Yashwant D. Vankar was born in 1950 in Varanasi, India.He obtained his M.Sc.(Organic Chemistry) degree from the Banaras Hindu University, Varanasi in 1971.He obtained his Ph.D. degree at the National Chemical Laboratory, Pune, India under the guidance of Professor B. D. Tilak.He then worked as a post-doctoral fellow at King's College, London (with Professor David I. Davies, 1976-1977), at the University of Southern California, Los Angeles (with Nobel

Table 2 .
Reactivity and selectivity in various glycals with allyltrimethylsilane and DDQ

Table 3 .
Reaction of unprotected glycals with TMSOTf

Table 4 .
Lewis acids used for carbon-Ferrier reactions with ATMS as nucleophile

glycosides 8 or 23 in
80% yield.The reaction was observed to be highly stereoselective with preference towards the -anomer.12c

Table 8 .
TMSOTf-mediated addition of Reformatsky reagent on glycals Alkylated zinc reagents have been reported by Gallagher et al. 25a for the Ferrier rearrangements on various protected glycals in the presence of BF3.OEt2 or TMSOTf as a Lewis acid.The reaction yielded the  anomer predominantly (Table

Table 9 .
Alkylated zincs as nucleophiles in the presence of BF3.OEt2

Table 10 .
Alkyl and aryl iodides in the presence of ZnCl2