Pellegrini Moïse
email: nadia.pellegrini@univ-lorraine.fr

Keywords: C-glycoside, regioselective alkylation, 1,2-trans-diol Highlights Efficient synthesis

Functionalized carbohydrates and especially functionalized C-glycosides are useful intermediates for the synthesis of complex carbohydrates of interest. In this paper, we describe the synthesis of C-azidopropylglucopyranosides and give a full account of their regioselective acylation and alkylation. Alkylation of these C-glucosyl compounds containing 1,2-trans-diol, namely 2-and 3-OH were first optimized with benzyl bromide. The reaction has then been extended to various electrophiles thus providing 3-O-substituted C-glucosyl compounds. These results are one of the first examples of regioselective alkylation with functionalized electrophiles on glycosyl compounds featuring a trans-vicinal diol.

Furthermore, we describe some results obtained during regioselective deprotection of 4,6-Obenzylidene protecting group. This work opens the way to the synthesis of complex carbohydrate derivatives.

Introduction

The development of efficient methods for the preparation of carbohydrate derivatives is a crucial point for the synthesis of oligosaccharides, glycoconjugates or glycomimetics [1][2][START_REF] Boltje | Opportunities and challenges in synthetic oligosaccharide and glycoconjugate research[END_REF][4][5][6][7]. In this context, the access to saccharide-based building blocks requires multi-step routes and the development of regioselective strategies continues to be a field of interest in synthetic carbohydrate chemistry. In particular, regioselective protection of carbohydrates is still a challenge for chemists as attested by the number of publications dealing with mechanistic aspects nowadays, such as the recent reviews from Moitessier et al. [4] and Taylor et al. [START_REF] Dimakos | Site-Selective Functionalization of Hydroxyl Groups in Carbohydrate Derivatives[END_REF].

Regioselective protection via alkylation offers an efficient way to conveniently access protected carbohydrate derivatives. For this purpose, many metal compounds and organic small molecules have been used, such as iron [9][START_REF] Ren | An Iron(III) Catalyst with Unusually Broad Substrate Scope in Regioselective Alkylation of Diols and Polyols[END_REF][START_REF] Ren | Regioselective alkylation of carbohydrates and diols: a cheaper iron catalyst, new applications and mechanism[END_REF], boron [START_REF] Chan | Regioselective Alkylation of Carbohydrate Derivatives Catalyzed by a Diarylborinic Acid Derivative[END_REF], NaH with metal chloride, or copper derivatives (e.g. CuCl 2 ) [START_REF] Osborn | Regioselective C-3-Oacylation and O-methylation of 4,6-O-benzylidene-D-gluco-and galactopyranosides displaying a range of anomeric substituents[END_REF][START_REF] Eby | Regioselective alkylation and acylation of carbohydrates engaged in metal complexes[END_REF][START_REF] Avela | Reactions of metal chelates of hydroxyl compounds under anhydrous conditions. II. Selective substitution at the primary or secondary hydroxyl group of anomeric methyl 2,3-di-O-methyl-D-glucopyranosides via copper(II) chelates[END_REF] and other additives [4]. Organotin derivatives [START_REF] Giordano | Tin-Mediated Regioselective Benzylation and Allylation of Polyols: Applicability of a Catalytic Approach Under Solvent-Free Conditions[END_REF][START_REF] Xu | Regioselective Benzylation of Diols and Polyols by Catalytic Amounts of an Organotin Reagent[END_REF][START_REF] Zhou | Halide promoted organotin-mediated carbohydrate benzylation: mechanism and application[END_REF][START_REF] Grindley | Applications of tin-containing intermediates to carbohydrate chemistry[END_REF][START_REF] David | Regioselective manipulation of hydroxyl groups via organotin derivatives[END_REF][START_REF] Xu | Organotin-catalyzed regioselective benzylation of carbohydrate trans-diols[END_REF][START_REF] Xu | Regioselective mono and multiple alkylation of diols and polyols catalyzed by organotin and its applications on the synthesis of value-added carbohydrate intermediates[END_REF][START_REF] Murphy | Synthesis of novel HIV-1 protease inhibitors based on carbohydrate scaffolds[END_REF] have proved their efficiency and are still used today despite their toxicity [START_REF] Pekelharing | Iron, copper and zinc status in rats fed on diets containing various concentrations of tin[END_REF][START_REF] Sousa | History on organotin compounds, from snails to humans[END_REF]. Typically, these methods were employed for methylation, allylation or benzylation of carbohydrates.

Most of these approaches have been efficiently applied to carbohydrate derivatives containing 1,2-cis-diol units. For the 1,2-trans-diol found in glucopyranose derivatives for example, only a few works have described regioselective alkylations and they are generally limited to methylation and benzylation. Moreover, these alkylations on 1,2-trans-diols have usually provided poor regioselectivities [START_REF] Ren | Regioselective alkylation of carbohydrates and diols: a cheaper iron catalyst, new applications and mechanism[END_REF][START_REF] Osborn | Regioselective C-3-Oacylation and O-methylation of 4,6-O-benzylidene-D-gluco-and galactopyranosides displaying a range of anomeric substituents[END_REF][START_REF] Eby | Regioselective alkylation and acylation of carbohydrates engaged in metal complexes[END_REF][START_REF] Xu | Organotin-catalyzed regioselective benzylation of carbohydrate trans-diols[END_REF] except for particular substrates [START_REF] Osborn | Regioselective C-3-Oacylation and O-methylation of 4,6-O-benzylidene-D-gluco-and galactopyranosides displaying a range of anomeric substituents[END_REF][START_REF] Xu | Organotin-catalyzed regioselective benzylation of carbohydrate trans-diols[END_REF][START_REF] Murphy | Synthesis of novel HIV-1 protease inhibitors based on carbohydrate scaffolds[END_REF].

Hence, a regioselective synthetic plan applicable to gluco configured derivatives is a currently unmet need.

In the literature, most attention focuses on regioselective O-acylation or alkylation in order to protect carbohydrate derivatives in a regioselective manner. To go further with the preparation of complex carbohydrate intermediates, few publications have described regioselective alkylation with functional electrophiles. Lindhorst et al. have studied the alkylation of various carbohydrates with 3-bromopropyl phthalimide [START_REF] Heidecke | Regioselective Phthalimidopropyl-Modification of Carbohydrates in One Step[END_REF] and two papers from Saikam et al. and Eby et al. investigated reactions with allyl bromide [START_REF] Eby | Regioselective alkylation and acylation of carbohydrates engaged in metal complexes[END_REF][START_REF] Saikam | Dimethyltin Dichloride Catalyzed Regioselective Alkylation of cis-1,2-Diols at Room Temperature[END_REF]. To the best of our knowledge, the only example dealing with 1,2-trans-diol was described in the publication by Eby et al. related to alkylation of differently protected glucopyranosides, however they reported poor regioselectivities. Therefore, highly regioselective alkylation with functional electrophiles is unprecedented on saccharides featuring a 1,2-trans-diol.

Our research focuses on synthetic routes to bioactive glycoconjugates, carbohydrate platforms and bioactive compounds based on C-glycosides [START_REF] Petry | Synthesis and revised stereochemistry assignment of C-allyl glucopyranosides and derivatives[END_REF][START_REF] Pellegrini-Moïse | Exo -glycals as useful tools for anomeric functionalization of sugars[END_REF][START_REF] Richard | Pellegrini-Moïse Sugaramino acids as building blocks for the synthesis of cyclic neoglycopeptides[END_REF][START_REF] Richard | Carbohydrate-based peptidomimetics targeting neuropilin-1: Synthesis, molecular docking study and in vitro biological activities[END_REF]. Indeed, C-glycosyl compounds with a robust C-C link at the anomeric position are known to be resistant to acidic and enzymatic hydrolyses and are thus stable in vivo [START_REF] Leclerc | Fluoro-C-glycosides and fluoro-carbasugars, hydrolytically stable and synthetically challenging glycomimetics[END_REF][START_REF] Levy | Strategies towards C-glycosides[END_REF][START_REF] Beau | C-Glycosyl analogs of oligosaccharides and glycosyl amino acids[END_REF][START_REF] Skrydstrup | Synthesis of C-oligosaccharides[END_REF]. In connection with these themes, we have developed the synthesis of value-added C-glycosyl building blocks via efficient regioselective functionalization. Particular attention is paid to the scope and limitations of regioselective Oalkylation of 1,2-trans-diol of C-glucosyl compounds with functional electrophiles. To the best of our knowledge, no similar example dealing with C-glycosides bearing functionalized arm at the anomeric position was documented. In this paper, we give a full account of regioselective functionalization of C-glucosyl compounds.

Results and discussion

We have recently optimized the synthesis and characterization of C-allylglucopyranoside [START_REF] Petry | Synthesis and revised stereochemistry assignment of C-allyl glucopyranosides and derivatives[END_REF] according to known methods [START_REF] Han | Concise and scalable synthesis of aspalathin, a powerful plasma sugarlowering natural product[END_REF][START_REF] Kulkarni | Efficient Synthesis of a C-Analogue of the Immunogenic Bacterial Glycolipid BbGL2[END_REF][START_REF] Thota | Synthesis of β-C-galactosyl D-and Lalanines[END_REF][START_REF] Lewis | Highly stereoselective approaches to alpha-and beta.-C-glycopyranosides[END_REF][START_REF] Martin | Synthesis of Chiral Spiroacetals from Carbohydrates[END_REF]. Briefly, 1-O-acetyl-2,3,4,6-tetra-O-benzyl-Dglucopyranose [START_REF] Han | Concise and scalable synthesis of aspalathin, a powerful plasma sugarlowering natural product[END_REF][START_REF] Kulkarni | Efficient Synthesis of a C-Analogue of the Immunogenic Bacterial Glycolipid BbGL2[END_REF] was stereoselectively converted to the corresponding β-Callylglucopyranoside 1 (Scheme 1) [START_REF] Thota | Synthesis of β-C-galactosyl D-and Lalanines[END_REF][START_REF] Lewis | Highly stereoselective approaches to alpha-and beta.-C-glycopyranosides[END_REF]. The resulting alkene was treated with 9-BBN [START_REF] Petry | Synthesis and revised stereochemistry assignment of C-allyl glucopyranosides and derivatives[END_REF][START_REF] Martin | Synthesis of Chiral Spiroacetals from Carbohydrates[END_REF] and the corresponding alcohol was converted to bromide derivative 2 (See SI) [START_REF] Petry | Synthesis and revised stereochemistry assignment of C-allyl glucopyranosides and derivatives[END_REF]. The removal of the benzyl ether protecting groups by hydrogenolysis required a meticulous optimization due to the presence of a bromide. Different parameters such as the nature of the solvent (dioxane, CH 2 Cl 2 /MeOH and THF/H 2 O), the hydrogen pressure (30 to 50 psi), the nature and quantity of catalyst (Pd/C and Pd(OH) 2 , 15 to 25% w/w) and the reaction time (4 h to 16 h) were screened in order to avoid the debromination side reaction. Catalytic hydrogenolysis under H 2 atmosphere (33 psi) with Pd(OH) 2 /C (20% w/w) in a THF/H 2 O (5/1 v/v) mixture during 13 h gave the best results. The fully deprotected derivative 3 was thus obtained in 95% yield and the formation of debrominated product was limited to 5%. An azide function, useful for late-stage functionalization via Copper-Catalyzed Azide-Alkyne Cycloaddition (CuAAC) [START_REF] Huisgen | 1.3-Dipolare Cycloadditionen, XXIII. Einige Beobachtungen zur Addition organischer Azide an CC-Dreifachbindungen[END_REF], was introduced on the anomeric arm of the C-glucosyl intermediate 3. Compound 3 was reacted with NaN 3 in an acetone/water (6/1 v/v) mixture at reflux during 12 h to afford 4 in 90% yield [START_REF] Zhang | Liver-targeted antiviral peptide nanocomplexes as potential anti-HCV therapeutics[END_REF]. Two differently protected Cazidopropylglucopyranosides were then prepared.

For clarity, atom numbering is consistent with carbohydrate numbering (scheme 1, 2) and did not correspond to IUPAC chemical name (specific nomenclature of C-glycosyl compounds).

A first protection of 6-OH was performed by reaction with trityl chloride and 1,4diazabicyclo[2.2.2]octane (DABCO) in dichloromethane for 36 h at room temperature. As expected, the protection was regioselective and compound 5 was obtained in 72% yield. The 4-and 6-OH were also protected with a benzylidene acetal, opening a second route for further functionalization. Compound 4 was reacted in a sealed tube with benzaldehyde dimethyl acetal and a catalytic amount of I 2 in acetonitrile to afford 6 in 70% yield [START_REF] Panchadhayee | Efficient Iodine-Catalyzed Preparation of Benzylidene Acetals of Carbohydrate Derivatives[END_REF]. Compared to compound 5, compound 6 only has two free hydroxyl groups, which is an advantage in case of regioselective functionalization.

We then planned to introduce a second functional arm by acylation or alkylation of remaining hydroxyl groups of compounds 5 and 6. Initially, acylation of 5 was studied (Scheme 2).

Scheme 2. Acylation of 5

It was documented that the presence of a sterically hindered group on 6-O oriented an acetylation on 3-OH for steric and electronical reasons [4,[START_REF] Moitessier | Directing-protecting groups for carbohydrates. Design, conformational study, synthesis and application to regioselective functionalization[END_REF]. We postulated that 5 bearing a trityl group should react in the same way. Acetylation of 5 was performed as previously reported [START_REF] Moitessier | Directing-protecting groups for carbohydrates. Design, conformational study, synthesis and application to regioselective functionalization[END_REF] using 0.7 equivalent of acetic anhydride (concentration of 1 mg/mL), K 2 CO 3 and a catalytic amount of DMAP in chloroform at room temperature (table 1, entry 1). A weak conversion was observed due to the default in Ac 2 O. As expected, the 3-OAc regioisomer 7 was predominantly obtained in 16% yield, 8 and 9 were also formed in low yields (approximatively 5%). To improve the conversion rate, the amount of Ac 2 O was increased to 1.1 equivalents and the concentration to 5 mg/mL (table 1, entry 2). In this case, a good conversion was achieved and 3-OAc regioisomer 7 was predominant (41% yield), 8 and 9 were recovered in 14 and 11% yield respectively. The regioselectivity was improved when the concentration of Ac 2 O was decreased to 2.5 mg/mL (table 1, entry 3) allowing access to 7 in 38% yield, with compounds 8 and 9 still formed but in lower yields (compare entries 2 and 3). Given the difficulties to isolate with convenient purities the minor isomers 8 and 9 (close Rfs), the major isomer 7 was the only one obtained with excellent purity and thus fully characterized. Nevertheless, the identification of regioisomers was unambiguously established by assignment of 1 H and 13 C signals together with 2D NMR spectroscopy.

To study the scope of regioselective acylation, the reaction with 3-butenoic acid was next investigated. After introduction on the sugar building block, this alkene could be used for further functionalization by thiol-ene coupling for example. To start with, a protocol using benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), N, Ndiisopropylethylamine (DIEA) and 3-butenoic acid in dichloromethane was carried out (table 1, entry 4). The conversion rate was moderate and unexpected compounds 10, 11 and 12 were obtained resulting from the isomerization of the terminal double bound in a more stable substituted one [START_REF] Bigley | Studies in Decarboxylation. Part 14.1 The Gas-phase Decarboxylation of But-3-enoic Acid and the Intermediacy of lsocrotonic (cis-But-2-enoic) Acid in its isomerisation to Crotonic (trans-But-2-enoic) Acid[END_REF]. The structures of compounds 10, 11 and 12 were confirmed by 1 H NMR spectra thanks to characteristic multiplicities of (E)-disubstituted double bond moiety observed around 5.95 and 7.05 ppm with a coupling constant of 15.5 Hz. The reaction performed with isobutyl chloroformate (IBCF), triethylamine (TEA), a catalytic amount of 4dimethylaminopyridine (4-DMAP) and 3-butenoic acid in dichloromethane gave approximately the same result (table 1, entry 5). In both cases, we were pleased to note that the 3-O-substituted compound 10 was predominantly obtained in 38 and 31% yields respectively, both 2-O-and 4-O-acylated derivatives 11 and 12 were also obtained in low yields. Compound 12 was clearly identified on 1 H NMR spectrum, but was tedious to isolate with an acceptable purity. A protocol avoiding the use of amine was performed with N,N'dicyclohexylcarbodiimide (DCC), a catalytic amount of 4-DMAP and 3-butenoic acid in dichloromethane. This time no isomerization of the double bond occurred. Nevertheless, the reaction was not as efficient, giving 13 in 25% yield. The formation of 15 and 14 was limited, these isomers were identified on 1 H NMR spectrum of the crude reaction mixture, but could not be isolated. Non identified by-products were also detected explaining the moderate recovered yields. These acylation reactions were regioselective, as previously described on other carbohydrate derivatives bearing a sterically hindered group on 6-O, and 3-O-susbtituted regioisomers were always predominantly obtained [4,[START_REF] Moitessier | Directing-protecting groups for carbohydrates. Design, conformational study, synthesis and application to regioselective functionalization[END_REF]. However, in our case, the regioselectivity was not satisfactory. In order to develop tools compatible with biological applications displaying strong in vivo stability; we thus planned to explore other types of links, like ether for example.

As attested by several studies, alkylations of carbohydrates with more than two free hydroxyls give complex mixtures of different regioisomers [START_REF] Giordano | Tin-Mediated Regioselective Benzylation and Allylation of Polyols: Applicability of a Catalytic Approach Under Solvent-Free Conditions[END_REF][START_REF] Zhou | Halide promoted organotin-mediated carbohydrate benzylation: mechanism and application[END_REF]. For these reasons, alkylation reactions were investigated on entry 2) according to reported method [START_REF] Osborn | Regioselective C-3-Oacylation and O-methylation of 4,6-O-benzylidene-D-gluco-and galactopyranosides displaying a range of anomeric substituents[END_REF]. Copper chelates of 4,6-O-benzylidene glycopyranoside dianions are described to react regioselectively with alkylating agents giving predominantly 3-O-alkylation in good yields, even on 1,2-trans-diol [START_REF] Osborn | Regioselective C-3-Oacylation and O-methylation of 4,6-O-benzylidene-D-gluco-and galactopyranosides displaying a range of anomeric substituents[END_REF][START_REF] Eby | Regioselective alkylation and acylation of carbohydrates engaged in metal complexes[END_REF][START_REF] Avela | Reactions of metal chelates of hydroxyl compounds under anhydrous conditions. II. Selective substitution at the primary or secondary hydroxyl group of anomeric methyl 2,3-di-O-methyl-D-glucopyranosides via copper(II) chelates[END_REF]. The carbohydrate dianions are postulated to be deactivated by the formation of the copper(II) salt, limiting the disubstitution. In our case, the reaction gave a mixture of starting compound 6, mono-and disubstituted compounds in which 3-O-monobenzylated derivative 16 preponderated (51% yield, entry 2). Regioselective procedure for alkylation via formation of 2,3-trans-stannylidene acetal intermediate was then investigated. A recent, original and green procedure was carried out with a catalytic amount of Bu 2 SnCl 2 , TBABr and K 2 CO 3 in acetonitrile [START_REF] Xu | Organotin-catalyzed regioselective benzylation of carbohydrate trans-diols[END_REF][START_REF] Xu | Regioselective mono and multiple alkylation of diols and polyols catalyzed by organotin and its applications on the synthesis of value-added carbohydrate intermediates[END_REF]. In our case, only modest conversion of compound 6 was observed and non-identified by-products were also detected despite optimizations (reaction time, equivalents of BnBr, temperature). Only 3-O-benzyl derivative 16 was obtained and isolated in a poor yield (5%, entry 3).

The classical one-pot procedure using bis-dibutyltin oxide was then investigated [18-20, 23, 49]. Bis-dibutyltin oxide has been used for a long time and its regioselective mechanism has been hypothesized to be controlled by complex stannylene structures (dimer or polymer)

giving regioselective alkylation [4,[START_REF] Grindley | Applications of tin-containing intermediates to carbohydrate chemistry[END_REF]. Different protocols could be used but it has been reported that the use of additives such as tetrabutylammonium halides or fluoride salts increase the rate of alkylation reactions of organotin derivatives [START_REF] Zhou | Halide promoted organotin-mediated carbohydrate benzylation: mechanism and application[END_REF][START_REF] Kaji | Regioselectivity shift from β-(1->6)-to β-(1->3)glycosylation of non-protected methyl β-D-galactopyranosides using the stannylene activation method[END_REF][START_REF] Danishefsky | The total synthesis of octosyl acid A: a new departure in organostannylene chemistry[END_REF][START_REF] Nagashima | Selective Monoalkylation of Acyclic Diols by Means of Dibutyltin Oxide and Fluoride Salts[END_REF] We next examined the scope and limitation of the regioselective 3-O-alkylation of compound 6 with various functional alkylating agents using Bu 2 SnO (protocol D with 2.5 equivalents of alkylating agent, Fig. 2).

Conclusion

To conclude, we investigated the regioselective functionalization of C-glycosyl compounds in order to obtain high value added building blocks. In our hands, acylation reaction has proved to be more capricious than alkylation reaction. The regioselective alkylation of Cazidopropylglucopyranosides bearing 1,2-trans-diol was carefully optimized with benzyl bromide revealing that Bu 2 SnO protocol was the most efficient. This strategy was successfully extended to functional electrophiles i.e. allyl bromide, 3-bromopropyl phthalimide and bromoacetic acid tert-butyl ester. The corresponding 3-O-substituted carbohydrates were obtained in good to moderate yields depending on the reagent and these results are one of the first examples of regioselective alkylation with functional electrophiles on trans-vicinal diol. Furthermore, the regioselective reduction of 4,6-O-benzylidene was investigated on one compound. This work opens the way to the synthesis of complex carbohydrates derivatives and the diverse functional groups enable the coupling of various moieties for biological applications.

Experimental section

General information

Solvents and liquid reagents were purified and dried according to recommended procedures.

Thin layer chromatography (TLC) analyses were performed using standard procedures on Kieselgel 60F254 plates (Merck, Kenilworth, NJ, USA). Compounds were visualized using UV light (254 nm) and a methanolic solution of sulfuric acid and charred. Column chromatography was performed on silica gel SI 60 (63-200 µm) (Merck). Melting points were determined with a Tottoli apparatus and are uncorrected. FTIR spectra were recorded on a Perkin-Elmer Spectrum 100 by using NaCl windows (film) or KBr pellets (cm -1 ). Optical rotations were measured on an Anton-Paar MCP 300 polarimeter. 1 H and 13 C NMR spectra were recorded on a Bruker spectrometer DPX250 (250 MHz and 62.9 MHz respectively) or

Avance III 400 (400 MHz and 100.6 MHz, respectively). For complete assignment of 1 H and [START_REF] Osborn | Regioselective C-3-Oacylation and O-methylation of 4,6-O-benzylidene-D-gluco-and galactopyranosides displaying a range of anomeric substituents[END_REF] C signals, two-dimensional 1 H, 1 H COSY and 1 H, 13 C correlation spectra were recorded. Mass and high resolution mass spectrometry spectra were recorded on a Bruker microTOFQ apparatus.

Chemistry

Compound 2 [START_REF] Petry | Synthesis and revised stereochemistry assignment of C-allyl glucopyranosides and derivatives[END_REF] was prepared according to previously described methods (see SI).

Physico-chemical characterization of minor isomers 11, 17, 18 and 24 is described in the supporting information.

Synthesis of 4,8-anhydro-1-bromo-1,2,3-trideoxy-D-glycero-D-gulo-nonitol (3)

Compound

Synthesis of 4,8-anhydro-1-azido-1,2,3-trideoxy-D-glycero-D-gulo-nonitol (4)

To a solution of 3 (5.0 g, 20.

4,8-anhydro-1-azido-1,2,3-trideoxy-9-O-triphenylmethyl-D-glycero-D-gulo-nonitol (5)

To a solution of 13 C NMR (100.6 MHz, CDCl 3 ): δ 24.9 (C-2), 28.9 (C-3), 51.5 (C-1), 68.9 (C-9), 70.

Procedure for regioselective acetylation

To a solution of 5 (150 mg, 0.31 mmol) in chloroform (100 mL), was added, under argon at room temperature, K 2 CO 3 (410 mg, 3.0 mmol, 9.6 equiv.), Ac 2 O (33 µL, 0.34 mmol, 1.1 equiv.) and 4-DMAP (1.89 mg, 0.016 mmol, 0.05 equiv.). The solution was stirred at room temperature for 13 h and was then diluted with water. The organic layer was washed with brine, dried over MgSO 4 , filtered and evaporated under vacuum. The crude product was purified by column chromatography on silica gel (eluent: cyclohexane/EtOAc 90/10 to 50/50) to give 7, 8 and 9.

6H, H Ar ); 13 C NMR (100.6 MHz, CD 3 OD): δ 21.2 (CH 3 ),

General procedure for regioselective alkylation with functionalized electrophiles

To a solution of 6 (150 mg, 0.4 mmol) in dry toluene (5 mL), was added under argon, dibutyltin oxide (130 mg, 0.68 mmol, 1.5 equiv.). The solution was stirred for 2 h at 110°C with a Dean-Stark apparatus. After evaporation under vacuum, the product was diluted in 3 mL of dry DMF, then CsF (100 mg, 0.68 mmol, 1.5 equiv.) and functionalized bromide (1 mmol, 2.5 equiv.) were added under argon at room temperature. The solution was then stirred for 48 h at 90°C (except for 19, 50°C). After evaporation under vacuum, the crude product was purified by flash chromatography on silica gel (eluent: cyclohexane/EtOAc 80/20 to 50/50).

Figure 2 .Scheme 4 .

 24 Figure 2. Structures of compounds 19-21

  Chemical shifts (δ) are given in parts per million relative to the solvent residual peak. For clarity, atom numbering resulting from the IUPAC naming of compounds (cf SI, fig S1) was used so atom numbering did not correspond to carbohydrate classical numbering. The following abbreviations are used for multiplicity of NMR signals: s = singlet, d = doublet, t = triplet, q = quadruplet, m = multiplet, b = broad signal and app = apparent multiplicity. The given J values refer to apparent multiplicities and do not represent the true coupling constants.

  2 mmol) in acetone/water mixture (6/1 v/v, 90 mL), NaN 3 (3.5 g, 2 equiv., 40.4 mmol) were added under argon. The mixture was stirred overnight at reflux. After evaporation under vacuum, the crude residue was purified by chromatography on silica gel (eluent: CH 2 Cl 2 /MeOH 90/10) to afford compound 4. Yield 90%; Oil; [α] D 25 -19.9 (c 0.07, CH 3 OH); IR (film); ν 3350, 3232, 2086, 1597, 1355 cm - 1 ; 1 H NMR (400 MHz, CD 3 OD): δ 1.49-1.59 (m, 1H, H-3a), 1.69-1.80 (m, 1H, H-2a), 1.86-1.96 (m, 1H, H-2b), 1.96-2.05 (m, 1H, H-3b), 3.13 (app t, 1H, J 5,4 = J 5,6 = 9.0 Hz, H-5), 3.20-3.30 (m, 2H, H-4 and H-8), 3.34 (app t, 1H, J 6,7 = J 6,5 = 9.0 Hz, H-7), 3.35-3.40 (m, 1H, H-6), 3.41 (t, 2H, J 1,2 = 7.5 Hz, H-1), 3.71 (dd, 1H, J 9a,9b = 12.0 Hz, J 9a,8 = 5.5 Hz, H-9a), 3.90 (dd, 1H, J 9b,8 = 2.5 Hz, H-9b); 13 C NMR (100.6 MHz, CD 3 OD): δ 26.0 (C-2), 29.9 (C-3), 52.6 (C-1), 63.0 (C-9), 71.9 (C-7), 75.3 (C-5), 79.6 (C-6), 80.3 (C-8), 81.4 (C-4); HRMS (ESI): calcd for C 9 H 17 N 3 BrO 5 Na [M+Na] + : 270.1066, found: 270.1080.

  2 (C-8), 74.4 (C-5), 75.1 (C-6), 79.5 (C-4), 81.1 (C-7), 101.9 (C-10), 126.4 (2C Ar ), 128.4 (2C Ar ), 129.4 (C Ar ), 137.2 (C qAr ); HRMS (ESI): calcd for C 16 H 22 N 3 O 5 [M+H] + : 336.1554, found: 336.1542.

( 7 )

 7 Yield: vide supra; Colorless oil; [α] D 25 -13.2 (c 0.

4. 2 . 7 . 5 . 4 , 8 - 2 (

 275482 anhydro-1-azido-6-O-benzyl-1,2,3-trideoxy-7,9-O-phenylmethylene-Dglycero-D-gulo-nonitol (16) Yield: 33%; Gum; [α] D 25 -19.9 (c 0.1, CHCl 3 ); IR (film); ν 3443, 2922, 2868, 2091, 1497, 1452, 1368 cm -1 ; 1 H NMR (400 MHz, CDCl 3 ): δ 1.48-1.57 (m, 1H, H-3a), 1.62-1.73 (m, 1H, H-2a), 1.77-1.87 (m, 1H, H-2b), 1.91-1.99 (m, 1H, H-3b), 3.29 (td, 2H, J 1,2 = 7.0 Hz, J 1,3a = 1.5 Hz, H-1), 3.33-3.37 (m, 2H, H-4 and H-5), 3.45 (ddd, 1H, J 8,9a = 10.0 Hz, J 8,7 = 9.5 Hz, J 8,9b = 5.0 Hz, H-8), 3.60 (app t, 1H, J 5,4 = J 5,6 = 9.0 Hz, H-6), 3.67 (app t, 1H, J 7,6 = J 7,8 = 9.5 Hz, H-7), 3.72 (app t, 1H, J 9a,9b = J 9a,8 = 10.0 Hz, H-9a), 4.33 (dd, 1H, J 9b,9a = 10.0 Hz, J 9b,8 = 5.0 Hz, H-9b), 4.71 (d, 1H, J = 11.5 Hz, CH 2 Bn), 5.04 (d, 1H, J = 11.5 Hz, CH 2 Bn), 5.58 (s, 1H, H-10), 7.35-7.40 (m, 8H, H Ar ), 7.49-7.52 (m, 2H, H Ar ); 13 C NMR (100.6 MHz, CDCl 3 ): δ 25.0 (C-2), 29.2 (C-3), 51.6 (C-1), 69.1 (C-9), 70.6 (C-8), 73.7 (C-5), 74.7 (CH 2 Bn), 79.6 (C-4), 82.4 (C-7 or C-6), 82.4 (C-6 or C-7), 101.3 (C-10), 126.1 (2C Ar ), 128.1 (C Ar ), 128.2C Ar ), 128.4 (2C Ar ), 128.7 (2C Ar ), 129.1 (C Ar ), 137.5 (C qAr ), 138.4 (C qAr ); HRMS (ESI): calcd for C 23 H 28 N 3 O 5 [M+H] + : 426.2023, found: 426.2018.

4. 2 . 8 . 1 . 4 , 8 - 9 (

 281489 anhydro-1-azido-1,2,3-trideoxy-7,9-O-phenylmethylene-6-O-(2-propen-1-yl)-D-glycero-D-gulo-nonitol (19) Yield: 53%; White solid; mp 50-52°C (diethyl ether); [α] D 25 -27.6 (c 0.1, CHCl 3 ); IR (KBr); ν 3337, 2961, 2914, 2859, 2091, 1726, 1452, 1385, 1360, 1346 cm -1 ; 1 H NMR (400 MHz, CDCl 3 ): δ 1.49-1.58 (m, 1H, H-3a), 1.64-1.74 (m, 1H, H-2b), 1.76-1.90 (m, 1H, H-2b), 1.94-2.02 (m, 1H, H-3b), 3.25 (td, 2H, J 1,2 = 7.0 Hz, J 1,3a = 1.5 Hz, H-1), 3.33-3.38 (m, 2H, H-4 and H-5), 3.43 (ddd, 1H, J 8,9b = 5.0 Hz, J 8,7 = 9.0 Hz, J 8,9a = 10.0 Hz, H-8), 3.52 (app t, 1H, J 6,7 = J 6,5 = 9.0 Hz, H-6), 3.59 (app t, 1H, J 7,8 = J 7,6 = 9.0 Hz, H7-), 3.70 (app t, 1H, J 9a,9b = J 9a,8 =10.0 Hz, H-9a), 4.20 (app ddt, 1H, J 11a,11b = 12.5 Hz, J 11a,12 = 6.5 Hz, J 11a,13a = J 11a,13b = 1.5 Hz, H-11a), 4.31 (dd, 1H, J 9b,8 = 5.0 Hz, H-9b), 4.50 (app ddt, 1H, J 11b,12 = 5.5 Hz, J 11b,13a = J 11b,13b = 1.5 Hz, H-11b), 5.20 (b dddd, J 13a,12 = 10.5 Hz, J 13a,13b = 2.5 Hz, H-13a), 5.29 (b dddd, J 13b,12 = 17.5 Hz, H-13b), 5.54 (s, 1H, H-10), 5.90-6.00 (m, 1H, H-12), 7.35-7.40 (m, 8H, H Ar ), 7.46-7.50 (m, 2H, H Ar ); 13 C NMR (100.6 MHz, CDCl 3 ): δ = 24.9 (C-2), 29.2 (C-3), 51.6 (C-1), 69.0 (C-9), 70.6 (C-8), 73.6 (C-11), 73.7 (C-5), 79.6 (C-4), 82.3 (C-7 or C-6), 82.3 (C-7 or C-6), 101.2 (C-10), 117.6 (C-13), 126.1 (2C Ar ), 128.4 (2C Ar ), 129.1 (C Ar ), 134.C12), 137.5 (C qAr ); HRMS (ESI): calcd for C 19 H 25 NaN 3 O 5 [M+Na] + : 398.1686, found: 398.1700. 4.2.8.2. 4,8-anhydro-1-azido-1,2,3-trideoxy-6-O-[2-(1,1-dimethylethoxy)-2-oxoethyl]-7,9-O-phenylmethylene-D-glycero-D-gulo-nonitol (20)

Table 1 . Scope and limitation of 5 acylation

 1 DMAP cat., 3-butenoic acid, CH 2 Cl 2 . d DCC, 4-DMAP cat., 3-butenoic acid, CH 2 Cl 2 /MeCN. e isolated yield. f estimated on 1 H NMR spectra.

	Entry	Reagent	Equiv. of reagent	Starting cpd (%) 5 e	O-substituted cpds (yield %) 3-O e 2-O f 4-O f
	1	Ac 2 O a	0.7	54	7 (16)	8 (5)	9 (5)
	2	Ac 2 O a	1.1	12	7 (41)	8 (14)	9 (11)
	3	Ac 2 O a	1.1	31	7 (38)	8 (8)	9 (<5)
	4	3-butenoic acid b	1.2	37	10 (38)	11 (8) e	12 (<5)
	5	3-butenoic acid c	1.2	25	10 (31)	11 (10) e	12 (<5)
	6	3-butenoic acid d	1.2	10	13 (25)	14 (8)	15 (<5)
	a K 2 CO 3 , 4-DMAP cat, Ac 2 O, CHCl 3 ; [Ac 2 O] = 1mg/mL for entry 1; [Ac 2 O] = 5mg/mL for
	entry 2; [Ac 2 O] = 2.5mg/mL for entry 3. b PyBOP, DIEA, 3-butenoic acid, CH 2 Cl 2 . c IBCF,

Table 2 .

 2 Taken together, these results suggested that the use of 2.5 equivalents of alkylating agent was the most efficient in terms of regioselectivity and yield. Scope and limitation of 6 benzylation trans-diol and were the first example with a C-glucosyl derivative. Indeed, most of regioselective 3-O-alkylations have been efficiently applied to carbohydrate bearing a 1,2-cisdiol composed of one axial hydroxyl and one equatorial hydroxyl, but they have rarely provided good regioselectivities for glucopyranose presenting 1,2-trans-diol, i.e. two equatorial hydroxy groups.

	in toluene was refluxed during 2 h (entry 4). Infra-red spectrometry enabled monitoring of the
	disappearance of the absorption band of the hydroxyl groups and thus the stannylidene acetal
	intermediate formation. Dimethylformamide, BnBr (1.2 equiv.) and cesium fluoride (1.5
	equiv.) were then added and the mixture was stirred at 90°C for 48 h. Regioselective 3-O-
	benzylation of 6 occurred and only regioisomer 16 was obtained in 33% yield. In these
	conditions, the conversion rate was about 60%, 39% of compound 6 being recovered. To
	improve the conversion rate, the amount of BnBr was increased (entries 5 and 6). With 2.5

. Regioselective alkylation of diols is usually documented with catalytic amount of Bu 2 SnO

[START_REF] Giordano | Tin-Mediated Regioselective Benzylation and Allylation of Polyols: Applicability of a Catalytic Approach Under Solvent-Free Conditions[END_REF][START_REF] Xu | Regioselective Benzylation of Diols and Polyols by Catalytic Amounts of an Organotin Reagent[END_REF]

.

However, it has been observed by Pei et al.

[START_REF] Xu | Regioselective Benzylation of Diols and Polyols by Catalytic Amounts of an Organotin Reagent[END_REF]

that benzylation of methyl 4,6-Obenzylidene--D-glucopyranoside requires a stoichiometric amount of dibutyltin oxide to predominantly form one regioisomer. They postulated that the dibutylstannylene acetal formed with catalytic amounts of Bu 2 SnO cannot be regenerated with trans-diol, leading to poor regioselectivity. Following these observations, a solution of 6 and Bu 2 SnO (1.2 equiv.) equivalents of BnBr the conversion rate reached 80% and 3-O-Bn substituted compound 16 was isolated in 40% yield. The use of 4 equivalents of BnBr did not improve the conversion and the yield of 16. a isolated yield; Protocol A: Bu 4 NHSO 4 , BnBr, NaOH, dichloromethane; Protocol B: NaH, dry THF then CuCl 2 , BnBr; Protocol C: Bu 2 SnCl 2 , TBABr, K 2 CO 3 , BnBr, acetonitrile; Protocol D: Bu 2 SnO, toluene, then dimethylformamide, BnBr, CsF. Regioisomers 16, 17 and 18 were purified by column chromatography on silica gel and their structures were established by 1D and 2D NMR spectroscopy. Some overlap of carbohydrate protons signal conducted us to further confirm these assignments and NOESY spectra of 16 and 17 were recorded (Fig. 1). The NOESY spectrum of the first eluted product showed several correlations of CH 2 Bn with H-1, H-2 and H-3 and also with protons of the anomeric arm corroborating the structure of 2-O-benzyl derivative 17. For the second eluted compound, a correlation between CH 2 Bn and H-3 and H-4 confirmed the structure of 3-O-benzyl isomer 16.

Figure 1. NOESY correlations in 16 and 17.

This regioselective 3-O-alkylation is in accordance with the literature on gluco substrates

[START_REF] Osborn | Regioselective C-3-Oacylation and O-methylation of 4,6-O-benzylidene-D-gluco-and galactopyranosides displaying a range of anomeric substituents[END_REF][START_REF] Xu | Organotin-catalyzed regioselective benzylation of carbohydrate trans-diols[END_REF]

. Particularly, the Bu 2 SnO protocol (protocol D) was totally regioselective. These results provided a new example of regioselective benzylation of glucosyl compounds bearing 1,2-

  2 (5.0 g, 7.76 mmol) and Pd(OH) 2 /C (1 g, 20 mol%) were added in THF/H 2 O mixture (5/1 v/v, 110 mL). The reaction mixture was stirred under hydrogen atmosphere at 33 psi for 13 h (Paar apparatus). After completion of the reaction, the mixture was diluted with MeOH and the catalyst was filtered off through a Celite ® pad. The filtrate was concentrated under reduced pressure to give 3 which was used without further purification.

	Yield 95%; Oil; [α] D 25 -6.5 (c 0.1, CH 3 OH); IR (film); ν 3306, 2924, 2872, 1636, 1406, 1370,
	1314, 1258 cm -1 ; 1 H NMR (400 MHz, D 2 O): δ 1.53-1.65 (m, 1H, H-3a), 1.93-2.18 (m, 3H, H-
	3b and H-2), 3.24 (app t, 1H, J 5,4 = J 5,6 = 9.5 Hz, H-5), 3.33-3.44 (m, 3H, H-4, H-7 and H-8),
	3.48 (app t, 1H, J 6,5 = J 6,7 = 9.5 Hz, H-6), 3.49 (app td, 2H, J 1,3a = 7.0 Hz, J 1,3b = 1.0 Hz, H-1),
	3.71 (dd, 1H, J 9a,8 = 5.5 Hz, J 9a,9b = 12.0 Hz, H-9a), 3.92 (dd, 1H, J 9b,8 = 2.0 Hz, H-9b); 13 C
	NMR (100.6 MHz, D 2 O): δ 27.6 (C-2), 28.6 (C-3), 33.8 (C-1), 60.1 (C-9), 69.2 (C-7), 72.5
	(C-5), 76.5 (C-8), 77.6 (C-6), 78.7 (C-4); HRMS (ESI): calcd for C 9 H 17 BrO 5 Na [M+Na] + :
	307.0157, found: 307.0153.

  The solution was diluted with CH 2 Cl 2 , washed with an aqueous solution of HCl (0.5 N), an aqueous saturated solution of NaHCO 3 and brine. The organic layer was dried over MgSO 4 , filtered and evaporated under vacuum.

	The crude product was purified by column chromatography on silica gel (eluent:
	cyclohexane/EtOAc 60/40 to 0/100) to give 5.
	Yield 72%; White solid; mp 86-87°C (cyclohexane); [α] D 25 -15.2 (c 0.1, CH 3 OH); IR (KBr); ν
	3337, 2988, 2901, 2091, 1489, 1447, 1395, 1250 cm -1 ; 1 H NMR (400 MHz, CD 3 OD): δ 1.53-
	1.62 (m, 1H, H-3a), 1.76-1.86 (m, 1H, H-2a), 1.93-2.10 (m, 2H, H-2b and H-3b), 3.13 (app t,
	1H, J 5,4 = J 5,6 = 9.0 Hz, H-5), 3.22-3.28 (m, 2H, H-9a and H-4), 3.31-3.37 (m, 2H, H-8 and H-
	6), 3.38-3.46 (m, 4H, H-1, H-9b and H-7), 7.23 (bt, 3H, J = 7.5 Hz, H Ar ), 7.30 (bt, 6H, J = 7.5
	Hz, H Ar ), 7.51 (bd, 6H, J = 7.5 Hz, H Ar ); 13 C NMR (100.6 MHz, CD 3 OD): δ 26.4 (C-2), 30.1
	(C-3), 52.6 (C-1), 65.2 (C-9), 72.3 (C-8), 75.5 (C-5), 80.0 (C-6), 80.3 (C-4), 80.6 (C-7), 87.6
	(C Tr ), 127.9 (3C Ar ), 128.7 (6C Ar ), 129.9 (6C Ar ), 145.6 (3C qAr ); HRMS (ESI): calcd for
	C 28 H 31 N 3 NaO 5 [M+Na] Yield: 70%; Colorless oil; [α] D 25 -19.5 (c 0.1, CHCl 3 ); IR (film); ν 3385, 2920, 2866, 2091,
	1452, 1375, 1350 cm -1 ; 1 H NMR (400 MHz, CDCl 3 ): δ 1.36-1.45 (m,1H, H-3a), 1.55-1.66 (m,
	1H, H-2a), 1.70-1.89 (m, 2H, H-3b, H-2b), 3.14-3.24 (m, 2H, H-4, H-5), 3.26 (t, 2H, J 1,2 = 7.0
	Hz, H-1), 3.27-3.35 (m, 1H, H-8), 3.37 (app t, 1H, J 6,7 = J 6,5 = 9.0 Hz, H-7), 3.57-3.66 (m, 3H,
	H-6, H-9a, OH), 4.00 (bs, 1H, OH), 4.26 (dd, 1H, J 9a,9b = 10.0 Hz, J 9b,8 = 4.5 Hz, H-9b), 5.46
	(s, 1H, H-10), 7.32-7.43 (m, 3H, H Ar ), 7.45-7.53 (m, 2H, H Ar );

4

(1.3g, 5.26 mmol) in dry CH 2 Cl 2 (25 mL), was added, under argon at room temperature TrCl (4.4 g, 15.78 mmol, 3 equiv.) and DABCO (1.77 g, 15.78 mmol, 3 equiv.).

The solution was stirred for 36 h at room temperature. + : 512.2161, found: 512.2194.

4.2.4. 4,8-anhydro-1-azido-1,2,3-trideoxy-7,9-O-phenylmethylene-D-glycero-D-gulononitol (6)

To a solution of 4 (500 mg, 2.03 mmol) in acetonitrile (4 mL), was added at room temperature, benzaldehyde dimethyl acetal (395 µL, 2.63 mmol, 1.3 equiv.) and I 2 (50 mg, 0.2 mmol, 0.1 equiv.) in a sealed tube. The solution was stirred for 13 h at 85°C. After evaporation under vacuum, the crude product was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 /MeOH 100/0 to 80/20) to give 6.

  J 9a,9b = 10.0 Hz, J 9a,8 = 5.5 Hz, H-9a), 3.26 (app t, 1H, J 5,6 = J 5,4 = 9.5 Hz, H-5), 3.33 (ddd, 1H, J 4,3a = 7.5 Hz, J 4,3b = 2.0 Hz, H-4), 3.40 (t, 2H, J 1,2 = 7.5 Hz, H-1), 3.41-3.45 (m, 1H, H-9b), 3.47 (ddd, 1H, J 8,7 = 9.5 Hz, J 8,9b = 1.5 Hz, H-8), 3.52 (app t, 1H, J 7,6 =

	1, MeOH); IR (film); ν 3370, 2922, 2853,
	2091, 1738, 1651, 1595, 1489, 1449, 1371, 1225 cm -1 ; 1 H NMR (400 MHz, CD 3 OD): δ 1.54-
	1.63 (m, 1H, H-3a), 1.76-1.86 (m, 1H, H-2a), 1.91-2.09 (m, 2H, H-3b and H-2b), 2.12 (s, 3H,
	CH 3 ), 3.23 (dd, 1H,

J 7,8 = 9.5 Hz, H-7), 4.90 (app t, 1H, H-6), 7.22 (t, 3H, J = 7.5 Hz, H Ar ), 7.28 (t, 6H, J =

Procedures for acylation 4.2.6.1. Protocol using PyBOP:

  To a solution of 5 (100 mg, 0.2 mmol) in CH 2 Cl 2 (5 mL), was added dropwise under argon at room temperature 3-butenoic acid (26 µL, 0.3 mmol, 1.5 equiv.) and DIEA (105 µL, 0.3 mmol, 3 equiv.). The solution was cooled at 0°C and PyBOP (188 mg, 0.36 mmol, 1.8 equiv.) was added dropwise. The solution was stirred for 48 h at room temperature, then an aqueous saturated solution of NH 4 Cl was added. The aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO 4 , and the solution was stirred at 0°C for 1 h. A freshly prepared solution of 5 (100 mg, 0.2 mmol) and 4-DMAP (3 mg, 0.024 mmol, 0.12 equiv.) in CH 2 Cl 2 (10 mL) was added dropwise under argon at 0°C. The solution was stirred at room temperature overnight. The organic layer was washed with an aqueous solution of NaHCO 3 (5%), an aqueous solution of citric acid (5%) and brine. The organic layer was dried over MgSO 4 , filtered and evaporated under vacuum.were added to give a dark blue solution. The organic layer was separated and the aqueous layer extracted with EtOAc. The organic layer was dried over MgSO 4 , filtered and evaporated under vacuum. The crude product was purified by column chromatography on silica gel (eluent: cyclohexane/EtOAc 95/5 to 50/50) to give 16, 17 and 18.

	4.2.6.5 4,8-anhydro-1-azido-6-(3-butenoate)-1,2,3-trideoxy-9-O-triphenylmethyl-D-
	glycero-D-gulo-nonitol (13)
	Yield: vide supra; White solid; mp 47-48°C (cyclohexane); [α] D 25 -7.6 (c 0.18, MeOH); IR
	The crude (KBr); ν 3401, 2970, 2922, 2093, 1699, 1651, 1489, 1447, 1373, 1290, 1242 cm -1 ; 1 H NMR
	product was purified by column chromatography on silica gel previously neutralized with (400 MHz, CD 3 OD): δ 1.55-1.66 (m, 1H, H-3a), 1.70-1.77 (m, 1H, H-2a), 1.83 -1.92 (m, 1H, 4.2.7.3. Protocol C: To a solution of 6 (150 mg, 0.45 mmol) in dry acetonitrile (5 mL), was
	cyclohexane/Et 3 N 95/5 (eluent: cyclohexane/EtOAc 90/10 to 60/40) to give 10, 11 and 12. H-2b), 1.95-2.08 (m, 1H, H-3b), 3.21-3.26 (m, 3H, H-10 and H-9a), 3.27 (app t, 1H, J 5,4 = J 5,6 added under argon, Bu 2 SnCl 2 (10 μL, 0.045 mmol, 0.1 equiv.), TBABr (14.5 mg, 0.045
	= 9.0 Hz, H-5), 3.31-3.36 (m, 1H, H-4), 3.44 (t, 2H, J 1,2 = 6.5 Hz, H-1), 3.45-3.52 (m, 2H, H-mmol, 0.1 equiv.), K 2 CO 3 (93 mg, 0.68 mmol, 1.5 equiv.) and BnBr (65 μL, 0.68 mmol, 1.2
	4.2.6.3. 4,8-anhydro-1-azido-6-[(2E)-2-butenoate]-1,2,3-trideoxy-9-O-triphenylmethyl-D-9b and H-8), 3.52 (app t, 1H, J 7,6 = J 7,8 = 9.5 Hz, H-7), 4.93 (app t, 1H, J 6,5 = J 6,7 = 9.0 Hz, H-equiv.). The solution was stirred for 72 h at 80 °C in a sealed tube. After evaporation under
	glycero-D-gulo-nonitol (10) 6), 5.17 (app dq, 1H, J 12a,11 = 10.0 Hz, J 12a,12b = J 12a,10 = 1.5 Hz, H-12a), 5.20 (app dq, 1H, vacuum, the crude product was purified by flash chromatography on silica gel (eluent:
	Yield: vide supra; White solid; mp 70-71°C (cyclohexane); [α] D 25 -11.3 (c 0.08, MeOH); IR J 12b,11 = 17.0 Hz, J 12b,12a = J 12b,10 = 1.5 Hz, H-12b), 5.94-6.04 (m, 1H, H-11), 7.24 (bt, 3H, J = cyclohexane/EtOAc 95/5 to 50/50) to give 16.
	(KBr); ν 3337, 2968, 2924, 2874, 2093, 1701, 1653, 1489, 1447, 1310, 1290 cm -1 ; 1 H NMR 7.0 Hz, H Ar ), 7.31 (bt, 6H, J = 7.0 Hz, H Ar ), 7.51 (bd, 3H, J = 7.0 Hz, H Ar ); 13 C NMR (62.9
	(400 MHz, CD 3 OD): δ 1.54-1.64 (m, 1H, H-3a), 1.79-1.86 (m, 1H, H-2a), 1.89 (dd, 3H, J 12,11 MHz, CD 3 OD): δ 26.0 (C-2), 30.1 (C-3), 34.7 (C-10), 52.6 (C-1), 65.2 (C-9), 72.3 (C-8), 75.6
	= 7.0 Hz, J 12,10 = 1.5 Hz, H-12), 1.94-2.09 (m, 2H, H-3b and H-2b), 3.23 (dd, 1H, J 9a,9b = 10.0 (C-5), 80.0 (C-7), 80.4 (C-4), 80.6 (C-6), 87.6 (C qTr ), 116.1 (C-12), 125.4 (C-11), 127.9
	Hz, J 9a,8 = 5.5 Hz, H-9a), 3.28 (app t, 1H, J 5,4 = J 5,6 = 9.5 Hz, H-5), 3.31-3.37 (m, 1H, H-4), (3C Ar ), 128.6 (6C Ar ), 129.9 (6C Ar ), 145.6 (3C qAr ), 159.9 (C=O); HRMS (ESI): calcd for
	3.43 (t, 2H, J 1,2 = 7.0 Hz, H-1), 3.44-3.50 (m, 1H, H-8), 3.48 (dd, 1H, J 9b,8 = 1.5 Hz, H-9b), C 32 H 35 N 3 NaO 6 [M+Na] + : 580.2424, found: 580.2452.
	3.52 (app t, 1H, J 7,6 = J 7,8 = 9.5 Hz, H-7), 4.95 (app t, 1H, H-6), 5.95 (dq, 1H, J 10,11 = 15.5 Hz,
	C qTr ), 128.0 (3C Ar ), 128.7 (6C Ar ), 129.9 (6C Ar ), 145.5 (3C qAr ), 172.9 (C=O); HRMS (ESI): J 10,12 = 1.5 Hz, H-10), 7.03 (dq, 1H, J 11,12 = 7.0 Hz, H-11), 7.23 (bt, 3H, J = 7.5 Hz, H Ar ), 7.30 4.2.7. Procedures for regioselective benzylation
	calcd for C 30 H 33 N 3 NaO 6 [M+Na] + : 554.2267, found: 554.2219. (bt, 6H, J = 7.5 Hz, H Ar ), 7.50 (bd, 6H, J = 7.5 Hz, H Ar ); 13 C NMR (100.6 MHz, CD 3 OD): δ 4.2.7.1. Protocol A: To a solution of 6 (150 mg, 0.45 mmol) in CH 2 Cl 2 (5 mL), was added
	18.1 (C-12), 26.3 (C-2), 30.1 (C-3), 52.6 (C-1), 64.9 (C-9), 70.5 (C-8), 73.8 (C-5), 80.4 (C-4), dropwise, under argon at 0°C, Bu 4 NHSO 4 (43 mg, 0.14 mmol, 0.3 equiv.) and benzyl bromide
	80.6 (C-7), 80.9 (C-6), 87.6 (C qTr ), 123.8 (C-10), 128.0 (3C Ar ), 128.7 (6C Ar ), 130.0 (6C Ar ), 145.5 (3C qAr ), 146.2 (C11), 168.2 (C=O); HRMS (ESI): calcd for C 32 H 35 N 3 NaO 6 [M+Na] + : 580.2424, found: 580.2453. 4.2.6.4. Protocol using DCC: To a solution of 5 (100 mg, 0.2 mmol) in dichloromethane/acetonitrile mixture (1/1 v/v, 1 mL), was added dropwise under argon at mmol, 0.65 equiv.). DCC (58 mg, 0.28 mmol, 1.4 equiv.) in CH 2 Cl 2 (3 mL) was then added (52 L, 0.54 mmol, 1.2 equiv.). Then, an aqueous solution of NaOH (80 mg in 0.65 mL of water) was added at room temperature. The solution was stirred for 35 h at 60°C. After evaporation under vacuum, the crude product was diluted in EtOAc. The organic layer was washed with an aqueous solution of HCl (1N), a saturated aqueous solution of Na 2 CO 3 and water. The organic layer was dried over MgSO 4 , filtered and evaporated under vacuum. The crude product was purified by column chromatography on silica gel (eluent: 4.2.6. filtered and evaporated under vacuum. The crude product was purified by column room temperature 3-butenoic acid (20 µL, 0.24 mmol, 1.2 equiv.) and 4-DMAP (16 mg, 0.13 cyclohexane/EtOAc 95/5 to 50/50) to give 16, 17 and 18.
	chromatography on silica gel (eluent: cyclohexane/EtOAc 90/10 to 50/50) to give 10, 11 and dropwise and the resulting solution was stirred for 24 h at room temperature. The solution was 4.2.7.2. Protocol B: To a solution of 6 (150 mg, 0.45 mmol, 1 equiv.) in dry THF (15 mL)
	12. filtered and the organic layer was washed with water, an aqueous solution of HCl (1N) and was added, under argon at 0°C, NaH in mineral oil (60%) (11 mg, 0.90 mmol, 2 equiv.). The
	water. The organic layer was further washed with a saturated aqueous solution of Na 2 CO 3 and formation of the disodium alcoholate was complete in 1 h at room temperature. Anhydrous
	water. The organic layer was dried over MgSO 4 , filtered and evaporated under vacuum. The
	crude product was purified by column chromatography on silica gel (eluent:
	cyclohexane/EtOAc 90/10 to 50/50) to give 13, 14 and 15.

4.2.6.2. Protocol using IBCF:

To a solution of 3-butenoic acid (20 µL, 0.24 mmol, 1.2 equiv.) in CH 2 Cl 2 (5 mL) was added dropwise TEA (33 µL, 0.24 mmol, 1.2 equiv.) under argon at 0°C, then IBCF (27 µL, 0.24 mmol, 1.2 equiv.) was added copper(II) chloride (6 mg, 0.45 mmol, 1 equiv.) was added, affording a green solution. BnBr (215 μL, 1.8 mmol, 4.0 equiv.) was added and the reaction was refluxed for 24 h. The solution was cooled to room temperature, then water (6 mL) and a 50% aqueous NH 3 solution (6 mL)

4.2.7.4. Protocol D:

To a solution of 6 (150 mg, 0.45 mmol) in dry toluene (5 mL), was added under argon, dibutyltin oxide (130 mg, 0.68 mmol, 1.5 equiv.). The solution was stirred for 2 h at 110 °C with a Dean-Stark apparatus. After evaporation under vacuum, the product was diluted in 3 mL of dry DMF, then CsF (100 mg, 0.68 mmol, 1.5 equiv.) and benzyl bromide (95 L, 1 mmol, 2.5 equiv.) were added under argon at room temperature. The solution was then stirred for 48 h at 90 °C. After evaporation under vacuum, the crude product was purified by flash chromatography on silica gel (eluent: cyclohexane/EtOAc 95/5 to 50/50) to give 16.

Acknowledgments

This work was supported by Institut Jean Barriol. We acknowledge The Ministère de l'Enseignement Supérieur et de la Recherche for PhD funding to T. Vucko. We acknowledge the financial support from Agence Nationale de la Recherche (grant: ANR-17-CE18-0018-03). We thank S. Adach and F. Lachaud for technical assistance.