Stereoselective β-mannosylations and β-rhamnosylations from glycosyl hemiacetals mediated by lithium iodide

Stereoselective β-mannosylation is one of the most challenging problems in the synthesis of oligosaccharides. Herein, a highly selective synthesis of β-mannosides and β-rhamnosides from glycosyl hemi-acetals is reported, following a one-pot chlorination, iodination, glycosylation sequence employing cheap oxalyl chloride, phosphine oxide and LiI. The present protocol works excellently with a wide range of glycosyl acceptors and with armed glycosyl donors. The method doesn't require conformationally restricted donors or directing groups; it is proposed that the high β-selectivities observed are achieved via an SN2-type reaction of α-glycosyl iodide promoted by lithium iodide.


General Experimental
The reagents and solvents used in the following experiments were bought commercially and used without further purification. Oxalyl chloride from a fresh bottle was immediately stored in a Young's tube under a nitrogen atmosphere. In a glove-box, anhydrous lithium iodide beads were powdered. The powdered LiI was stored in capped vials on the bench for several weeks before use. It should be a freeflowing white solid. Dry solvents were obtained using equipment based on Grubb's design [1] and stored in Strauss flask over 4 Å molecular sieves. A Karl Fischer Titrator was used to determine the amount of water in dry solvents. For air-sensitive reactions, solvents were added via syringe through rubber septa.

2,3,4,6-Tetra-O-benzyl-α/-D-mannopyranose 1a
A solution of S2 (2.8 g, 7.1 mmol) in methanol (30 mL) was treated with Na2CO3 (222 mg, 2.09 mmol) and stirred at room temperature for 14 h. The reaction mixture was neutralised with resin IR-120, filtered and concentrated in vacuo to give a brown syrup. Under a N2 atmosphere, a solution of the syrup in anhydrous DMF (18 mL) was cooled to 0 C and NaH (60% dispersion in mineral oil) (1.6 g, 39 mmol) was added. The reaction mixture was stirred at room temperature for 30 min after which it was again cooled down to 0 C. Benzyl bromide (4.7 mL, 39 mmol) was added dropwise and the reaction mixture was left to stir at room temperature for 4 h. The reaction was quenched with MeOH and the mixture was concentrated in vacuo to give a yellow slurry. The slurry was diluted with CH2Cl2 and washed with 1 M HCl, followed by saturated NaHCO3 and brine, dried over anhydrous MgSO4 and concentrated in vacuo.

2,3,6-Tri-O-benzyl-4-O-(4-methylbenzyl)-α/-D-mannopyranose 1c
Based on the literature procedure, [8] a solution of S11 (1.3 g, 2.5 mmol) in MeCN/H2O (4:1, 13 mL) was treated with trifluoroacetic acid (2.0 mL, 26 mmol) at room temperature. After stirring for 7 h at room temperature, the reaction was quenched with saturated NaHCO3 and diluted with CH2Cl2 (150 mL). The aqueous layer was washed with CH2Cl2 (2 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo to give a bright yellow oil. The crude material was used in the next step without further purification.
Under a N2 atmosphere, a solution of crude mannopyranoside S13 in anhydrous DMF (5 mL) was cooled to 0 C and NaH (60% dispersion in mineral oil) (462 mg, 11.3 mmol) was added. The reaction mixture was stirred at room temperature for 15 min after which it was again cooled down to 0 C. Benzyl bromide (1.3 mL, 11 mmol) was added and the reaction mixture was left to stir at room temperature for 3 h. The reaction was quenched with MeOH and diluted with Et2O (100 mL). The aqueous layer was washed with Et2O (2 x 75 mL). The organic layers were combined and dried over anhydrous MgSO4 and concentrated in vacuo to give a yellow oil.
A solution of crude S14 in 9:1 acetone/water (13 mL) and treated with NBS (1.3 g, 7.5 mmol) at room temperature. After 2.5 h the reaction was quenched with saturated Na2S2O3 and diluted with CH2Cl2.

2,3,4-Tri-O-benzyl-6-O-(4-methoxybenzyl)-α-D-mannopyranose 1d
Under a N2 atmosphere, a solution of mannopyranoside S6 (0.50 g, 1.3 mmol) in anhydrous DMF (2.6 mL) was cooled to 0 C and NaH (60% dispersion in mineral oil) (0.21 g, 5.2 mmol) was added followed by benzyl bromide (0.62 mL, 5.2 mmol). After stirring the reaction mixture for 11 h, it was quenched with MeOH and diluted with Et2O (40 mL). The aqueous layer was washed with Et2O (2 x 40 mL). The organic layers were combined and neutralised with 1 M HCl. The organic layer was washed with water and brine, dried over anhydrous MgSO4 and concentrated in vacuo to give a yellow oil.
Based on the literature procedure, [8] a solution of crude S7 in MeCN/H2O (4:1, 6.5 mL) was treated with trifluoroacetic acid (0.74 mL, 10 mmol) at room temperature. After stirring for 8 h at room temperature, the reaction was quenched with saturated NaHCO3 and diluted with CH2Cl2 (50 mL). The aqueous layer was washed with CH2Cl2 (2 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo to give a yellow syrup. The crude material was used in the next step without further purification. Under a N2 atmosphere, a solution of the crude mannopyranoside in anhydrous DMF (2.5 mL) was cooled to 0 C and NaH (60% dispersion in mineral oil) (130 mg, 3.25 mmol). After 15 minutes, 4-methoxylbenzyl bromide (0.45 mL, 3.3 mmol) was added and the reaction mixture was left to stir at room temperature for 2 h. The reaction was quenched with MeOH and diluted with Et2O (100 mL). The aqueous layer was washed with Et2O (2 x 40 mL). The organic layers were combined and neutralised with 1 M HCl. The organic layer was washed with water and brine, dried over anhydrous MgSO4 and concentrated in vacuo to give a yellow oil.
Based on the literature procedure, [8] a solution of crude S7 in MeCN/H2O (4:1, 6.5 mL) was treated with trifluoroacetic acid (0.74 mL, 10 mmol) at room temperature. After stirring for 8 h at room temperature, the reaction was quenched with saturated NaHCO3 and diluted with CH2Cl2 (50 mL). The aqueous layer was washed with CH2Cl2 (2 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo to give a yellow syrup. The crude material was used in the next step without further purification. Under a N2 atmosphere, a solution of the crude mannopyranoside in anhydrous DMF (2.5 mL) was cooled to 0 C and NaH (60% dispersion in mineral oil) (130 mg, 3.25 mmol). After 5 minutes, 2-(bromomethyl)naphthalene (719 mg, 3.25 mmol) was added and the reaction mixture was left to stir at room temperature for 1 h. The reaction was quenched with MeOH and diluted with Et2O (100 mL). The aqueous layer was washed with Et2O (2 x 40 mL). The organic layers were combined and neutralised with 1 M HCl. The organic layer was washed with water and brine, dried over anhydrous MgSO4 and concentrated in vacuo to give a yellow oil.
A solution of S16 in 9:1 acetone/water (13 mL) and treated with NBS (0.69 g, 3.9 mmol) at room temperature. After 2 h the reaction was quenched with saturated Na2S2O3 and diluted with CH2Cl2. The aqueous layer was washed with CH2Cl2. The combined organic layers were washed with water and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give a colourless syrup.

2,3,4-Tri-O-benzyl-6-O-tert-butyldiphenylsilyl-α/-D-mannopyranose 1f
A solution of S2 (500 mg, 1.27 mmol) in methanol (10 mL) was treated with Na2CO3 (40 mg, 0.38 mmol) and stirred at room temperature for 1.5 h. The reaction mixture was neutralised with resin IR-120, filtered and concentrated in vacuo to give a brown paste. Under a N2 atmosphere, a solution of the crude material and imidazole (259 mg, 3.81 mmol) in anhydrous DMF (2.5 mL) was treated with TBDPSCl (0.50 mL, 1.9 mmol) and left to stir at room temperature for 2.5 h. The reaction mixture was diluted with Et2O and washed with water and brine, dried over anhydrous MgSO4 and concentrated in vacuo to give a yellow syrup.
Under a N2 atmosphere, a solution of crude mannopyranoside S17 in anhydrous DMF (2.5 mL) was cooled to 0 C and NaH (60% dispersion in mineral oil) (228 mg, 5.72 mmol) was added. The reaction mixture was stirred at room temperature for 15 min after which it was again cooled down to 0 C. Benzyl bromide (0.68 mL, 5.7 mmol) was added and the reaction mixture was left to stir at room temperature for 6 h. The reaction was quenched with MeOH and diluted with Et2O (100 mL). The aqueous layer was washed with Et2O (2 x 75 mL). The organic layers were combined and dried over anhydrous MgSO4 and concentrated in vacuo to give a yellow oil.
A solution of crude S18 in 9:1 acetone/water (13 mL) and treated with NBS (678 mg, 3.81 mmol) at room temperature. After 50 minutes the reaction was quenched with saturated Na2S2O3 and diluted with CH2Cl2. The aqueous layer was washed with CH2Cl2 (2 x 100 mL). The combined organic layers were washed with water and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give a yellow syrup. Purification by column chromatography (3:1 to 0:1; Pentane/Et2O) afforded the hydrolysed product 1f as a yellowish syrup (388 mg, 44% yield over 4 steps, / = 85:15).
The following were observed for / anomers:
The crude material was used in the next step without further purification. Under a N2 atmosphere, a solution of the crude material and DMAP (17 mg, 0.14 mmol) in anhydrous CH2Cl2 (2.9 mL) was treated with anhydrous pyridine (0.11 mL, 1.4 mmol) followed by benzoyl chloride (0.33 mL, 2.8 mmol) at room temperature. TLC (CH2Cl2) analysis of the reaction after 50 minutes showed complete consumption of starting material. The reaction was quenched with water and diluted with CH2Cl2. The organic layer was washed with 1 M HCl, saturated NaHCO3 and brine. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo to give a colourless oil. 1  The crude material S20 was dissolved in 9:1 acetone/water (14 mL) and treated with NBS (1.02 g, 5.72 mmol) at room temperature. After 3 h the reaction was quenched with saturated Na2S2O3 and diluted with CH2Cl2. The aqueous layer was washed with CH2Cl2. The combined organic layers were washed with water and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give a colourless syrup. Purification by column chromatography (2:1 to 1:1; Pentane/Et2O) afforded the hydrolysed product 1h as a colourless syrup (645 mg, 81% yield over 3 steps, / = 77:23).
The following were observed for / anomers: . NMR data were consistent with literature data. [12]

4-O-Acetyl-2,3,6-tri-O-benzyl-α/-D-mannopyranose S22
A solution of S5 (800 mg, 1.62 mmol), acetic anhydride (0.31 mL, 1.6 mmol) and DMAP (20 mg, 0.16 mmol) in pyridine (0.13 mL, 1.6 mmol) (little bit of CH2Cl2 was added to get a clear solution) was stirred at room temperature for 2 h. The reaction mixture was diluted with CH2Cl2 and washed with 1 M HCl, saturated NaHCO3 and brine. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo to give a yellowish syrup. The crude material was used in the next step without further purification. 1 15.0 (SCH2CH3). NMR data were consistent with literature data. [4] The crude material S21 was dissolved in 9:1 acetone/water (10 mL) and treated with NBS (865 mg, 4.86 mmol) at room temperature. After 5 h the reaction was quenched with saturated Na2S2O3 and diluted with CH2Cl2. The organic layer was washed with water and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by column chromatography (2:1 to 1:1, Pentane/Et2O) afforded the hydrolysed product S22 as a syrup (632 mg, 79% yield over 2 steps, / = 79:21).
The following were observed for / anomers:
Under a N2 atmosphere, 3i (200 mg, 0.37 mmol) was dissolved in anhydrous CH2Cl2 (3.7 mL) and the reaction was treated with anhydrous pyridine (0.11 mL, 1.4 mmol) followed by pivaloyl chloride (0.146 mL, 1.20 mmol) at room temperature. TLC (cyclohexane:EtOAc) analysis of the reaction after 1 h showed complete consumption of starting material. The reaction was quenched with water and diluted with CH2Cl2. The organic layer was washed with 1 M HCl, saturated NaHCO3 and brine. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo to give a colourless oil.
The following were observed for / anomers: 1

Synthesis of Rhamnosyl Donors
After stirring the reaction mixture at room temperature for 20 h, TLC analysis (cyclohexane: EtOAc; 6:4; Rf = 0.7) showed full conversion of the starting material into a single product. The reaction mixture was then carefully quenched with saturated NaHCO3. The organic layer was washed with water and brine, dried over anhydrous MgSO4 and concentrated in vacuo to give S27 as a yellow oil (9.00 g, 26.  (d,J = 6.3 Hz,3H). NMR data are consistent with the literature. [19] Thiorhamnoside S27 (9.0 g, 26.2 mmol) was dissolved in MeOH (300 mL). Na2CO3 (0.5 g, 5.0 mmol) was added to the solution and the mixture was left to stir at room temperature for 2 h, after which TLC analysis (EtOAc; Rf = 0) indicated that the reaction had gone to completion. The reaction mixture was neutralised with resin IR-120 and the mixture was filtered and was concentrated in vacuo to give S28 as a yellow oil, which was used in the next step without further purification.
Crude thiorhamnoside S31 was dissolved in CH2Cl2 (12 mL) and H2O (0.5 mL) was added. TFA (4.0 mL, 52 mmol) was then added and the reaction left to stir at RT overnight. TLC analysis (cyclohexane: EtOAc; 7:3; Rf =0.3) indicated that the reaction had gone to completion. The reaction mixture was quenched saturated NaHCO3 (20 mL), diluted with CH2Cl2 (50 mL) and the two layers were separated.
The aqueous phase was extracted with CH2Cl2 (100 mL) and the combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo.
The crude material was used in the next step without further purification. Under a N2, the crude thiorhamnoside was dissolved in anhydrous DMF (20 mL, 0.2 M). The flask was cooled to 0 °C (50:50; ice/water), and NaH (60% dispersion in mineral oil) (384 mg, 16.0 mmol) was added to the reaction flask. The ice bath was removed, and the reaction was left to stir at room temperature for 30 min. The flask was again cooled to 0 °C, and BnBr (1.2 mL, 10 mmol) was added to the reaction mixture. The ice bath was removed, and the reaction mixture was left to stir at room temperature for 4 h, after which TLC analysis (cyclohexane: EtOAc; 4:1; Rf = 0.6) showed that the starting material had been consumed. The reaction was quenched with MeOH (2 mL), and the solvents were removed using rotary evaporation.
The organic layer was dried over anhydrous Na2SO4, filtered off and concentrated in vacuo.
Crude rhamnoside S32 was dissolved in a 9:1 mixture of acetone:water (20 mL) and NBS (1.1 mg, 6.0 mmol) was added. The reaction left to stir at room temperature for 1 h when TLC analysis (cyclohexane: EtOAc; 6:4; Rf = 0.6) showed the complete conversion of the starting material to the desired product.
Crude thiorhamnoside S33 was dissolved in CH2Cl2 (12 mL) and H2O (0.5 mL) was added. TFA (4.0 mL, 52 mmol) was then added and the reaction left to stir at RT overnight. TLC analysis (cyclohexane:EtOAc; 7:3; Rf = 0.4) indicated that the reaction had gone to completion. The reaction mixture was quenched saturated NaHCO3 (20 mL), diluted with CH2Cl2 (50 mL) and the two layers were separated. The aqueous phase was extracted with CH2Cl2 (100 mL) and the combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude material was used in the next step without further purification. Under a N2, the crude thiorhamnoside was dissolved in anhydrous DMF (20 mL). The flask was cooled to 0 °C (50:50; ice/water), and NaH (60% dispersion in mineral oil) (384 mg, 16.0 mmol) was added to the reaction flask. The ice bath was removed, and the reaction was left to stir at room temperature for 30 min. The flask was again cooled to 0 °C, and BnBr (1.2 mL, 10 mmol) was added to the reaction mixture. The ice bath was removed, and the reaction mixture was left to stir at room temperature for 4 h, after which TLC analysis (cyclohexane: EtOAc; 4:1; Rf = 0.6) showed that the starting material had been consumed. The reaction was quenched with MeOH (2 mL), and the solvents were removed using rotary evaporation.
The organic layer was dried over anhydrous Na2SO4, filtered off and concentrated in vacuo.
A solution of the crude product S36 was dissolved in anhydrous DMF (100 mL) and the flask was cooled to 0 ºC. NaH (60% dispersion in mineral oil) (3.77 g, 94.3 mmol) was added to the solution and the icebath was removed. The reaction was stirred at room temperature for 1 h, after which it was again cooled to 0 ºC and treated slowly with BnBr (11.2 mL, 94.3 mmol). The ice-bath was removed, and the reaction mixture was left to stir at room temperature. TLC analysis (cyclohexane:EtOAc; 9:1) after 12 h showed complete consumption of starting material. The reaction mixture was quenched with MeOH (10 mL) and was extracted wit Et2O (3 × 200 mL). The combined organic layer was washed with 1 M HCl (100 mL) followed by saturated NaHCO3 (100 mL) and brine (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a yellow oil.
The crude product S37 was dissolved in MeOH (10 mL) and 1.25 M HCl in MeOH (10 mL) was added.

Methyl 2,3-di-O-benzyl-4,6-O-benzylidene--D-glucopyranoside S39
Under a N2 atmosphere, a solution of glucopyranoside S38 (5.0 g, 18 mmol) in anhydrous DMF (40 mL) was cooled to 0 C and NaH (60% dispersion in mineral oil) (2.3 g, 58 mmol) was added. The reaction mixture was stirred at room temperature for 30 min after which it was again cooled down to 0 C. Benzyl bromide (6.4 mL, 54 mmol) was added dropwise to the reaction mixture. The reaction mixture was left to stir at room temperature for 9 h. The reaction was quenched with MeOH and the mixture was concentrated in vacuo to give a yellow slurry. The slurry was diluted with CH2Cl2 and washed with 1 M HCl, followed by saturated NaHCO3 and brine, dried over anhydrous MgSO4 and concentrated in vacuo. Purification by column chromatography (90:10; Pentane/Et2O) gave S39 as a white solid (7.9 g, 95% yield). 1  . NMR data were consistent with literature data. [25]

Methyl 2,4,6-tri-O-benzyl--D-glucopyranoside 3c
Under a N2 atmosphere, a solution of glucopyranoside S43 (2.1 g, 5.0 mmol) in anhydrous DMF (17 mL) was cooled to 0 C and benzyl bromide (0.72 mL, 6.1 mmol) was added. After 15 minutes, NaH (60% dispersion in mineral oil) (242 g, 6.05 mmol) was added in one portion and the reaction mixture was stirred at 0 C for 30 minutes. The reaction mixture was warmed to room temperature and stirred for 3.5 h. The reaction was quenched with MeOH and the mixture was concentrated in vacuo to give a yellowish slurry. The slurry was diluted with CH2Cl2 and washed with 1 M HCl, followed by saturated NaHCO3 and brine, dried over anhydrous MgSO4 and concentrated in vacuo. A solution of the crude in MeOH was treated with MeONa (0.14 g, 2.5 mmol) and the mixture was left to stir at room temperature for 3 days. Purification by column chromatography (98:2 to 95:5; CH2Cl2/Et2O) gave 3c as a colourless syrup (1.3 g, 56% yield over 2 steps). 1  were consistent with literature data. [29]
The reaction was quenched with water (5 mL), diluted with CH2Cl2 (200 mL) and the two phases separated. The organic layer was subsequently washed with 1 M HCl, water, saturated NaHCO3 and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give a light brown syrup. The crude material was dissolved in CH3CN and water (100 mL, 7:1) and treated with TFA (16 mL, 0.21 mol). The reaction mixture was stirred at room temperature for 21 hours and monitored by TLC analysis

General Procedure A for Mannosylation Donor Scope
A 25 mL crimp-top vial charged with a stir-bar, hemiacetal (0.10 mmol, 1 eq) and Ph3PO (14 mg, 0.050 mmol, 0.5 eq) was placed under three cycles of vacuum and nitrogen. The solids were dissolved in anhydrous CHCl3 (0.2 mL, 0.5 M), treated with oxalyl chloride (10 L, 0.12 mmol, 1.2 eq) and left to stir at room temperature. After 1 h, the solvent and excess oxalyl chloride were removed by applying vacuum. Solid acceptor (0.07 mmol, 0.7 eq) and powdered LiI (53 mg, 0.40 mmol, 4 eq) were added to the vial and placed under three cycles of vacuum and nitrogen. The contents were re-dissolved in anhydrous CHCl3 (0.25 mL, 0.4 M w.r.t. donor) and treated with iPr2NEt (42 L, 0.25 mmol, 2.5 eq).
The reaction was stirred at 45 C for 24 h or 30 C for 36 h. The reaction mixture was diluted with CH2Cl2 (1 mL) and treated with 1 M HCl (1 mL). The aqueous layer was washed with CH2Cl2 (2 x 1 mL) and the combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo to give a yellow or brown syrup. The / ratio was determined by 1 H NMR spectroscopy of the crude reaction mixture.

General Procedure B for Mannosylation Acceptor Scope
A 25 mL crimp-top vial charged with a stir-bar, hemiacetal (0.10 mmol, 1 eq) and Ph3PO (28 mg, 0.10 mmol, 1 eq) was placed under three cycles of vacuum and nitrogen. The solids were dissolved in anhydrous CHCl3 (0.2 mL, 0.5 M), treated with oxalyl chloride (10 L, 0.12 mmol, 1.2 eq) and left to stir at room temperature. After 30 minutes, the solvent and excess oxalyl chloride were removed by applying vacuum. Solid acceptor (0.07 mmol, 0.7 eq) and powdered LiI (53 mg, 0.40 mmol, 4 eq) were added to the vial and placed under three cycles of vacuum and nitrogen. The contents were re-dissolved in anhydrous CHCl3 (0.25 mL, 0.4 M w.r.t. donor) and treated with iPr2NEt (69 L, 0.40 mmol, 4 eq).
The reaction was stirred at 45 C for 24 h. The reaction mixture was diluted with CH2Cl2 (1 mL) and treated with 1 M HCl (1 mL). The aqueous layer was washed with CH2Cl2 (2 x 1 mL) and the combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo to give a yellow or brown syrup. The / ratio was determined by 1 H NMR spectroscopy of the crude reaction mixture.

General Procedure C for Mannosylation Acceptor Scope
A 25 mL crimp-top vial charged with a stir-bar, hemiacetal (0.10 mmol, 1 eq) and Ph3PO (28 mg, 0.10 mmol, 1 eq) was placed under three cycles of vacuum and nitrogen. The solids were dissolved in anhydrous CHCl3 (0.2 mL, 0.5 M), treated with oxalyl chloride (10 L, 0.12 mmol, 1.2 eq) and left to stir at room temperature. After 30 minutes, the solvent and excess oxalyl chloride were removed by applying vacuum. Powdered LiI (53 mg, 0.40 mmol, 4 eq) was added to the vial and placed under three cycles of vacuum and nitrogen. A stock solution of the acceptor in anhydrous CHCl3 (0.4 M w.r.t. donor or 0.28 M w.r.t acceptor) was added followed by iPr2NEt (69 L, 0.40 mmol, 4 eq). The reaction was stirred at 45 C for 24 h. The reaction mixture was diluted with CH2Cl2 (1 mL) and treated with 1 M HCl (1 mL). The aqueous layer was washed with CH2Cl2 (2 x 1 mL) and the combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo to give a yellow or brown syrup. The / ratio was determined by 1 H NMR spectroscopy of the crude reaction mixture.

General procedure D for Rhamnosylation Donor Scope
A 25 mL crimp-top vial charged with a stir-bar, hemiacetal (0.10 mmol, 1 eq) and Ph3PO (28 mg, 0.10 mmol, 1 eq) was placed under three cycles of vacuum and nitrogen. The solids were dissolved in anhydrous CHCl3 (0.2 mL, 0.5 M), treated with oxalyl chloride (10 L, 0.12 mmol, 1.2 eq) and left to stir at room temperature. After 30 minutes, the solvent and excess oxalyl chloride were removed by applying vacuum. Solid acceptor (0.07 mmol, 0.7 eq) and powdered LiI (53 mg, 0.40 mmol, 4 eq) were added to the vial and placed under three cycles of vacuum and nitrogen. The contents were re-dissolved in anhydrous CHCl3 (0. 25 mL, 0.4 M w.r.t. donor) and treated with iPr2NEt (69 L, 0.40 mmol, 4 eq).
The reaction was stirred at 45 C or 30 °C for 24 h. The reaction mixture was diluted with CH2Cl2 (15 ml) and washed with 1M HCl (2  5 ml), brine (10 ml), dried using Na2SO4, filtered and concentrated in vacuo. The / ratio was determined by 1 H NMR spectroscopy of the crude reaction mixture.

General procedure E for Rhamnosylation Acceptor Scope
A 25 mL crimp-top vial charged with a stir-bar, hemiacetal (0.10 mmol, 1 eq) and Ph3PO (14 mg, 0.050 mmol, 0.5 eq) was placed under three cycles of vacuum and nitrogen. The solids were dissolved in anhydrous CHCl3 (0.2 mL, 0.5 M), treated with oxalyl chloride (10 L, 0.12 mmol, 1.2 eq) and left to stir at room temperature. After 1 h, the solvent and excess oxalyl chloride were removed by applying vacuum. Solid acceptor (0.07 mmol, 0.7 eq) and powdered LiI (53 mg, 0.40 mmol, 4 eq) were added to the vial and placed under three cycles of vacuum and nitrogen. The contents were re-dissolved in anhydrous CHCl3 (0. 25 mL, 0.4 M w.r.t. donor) and treated with iPr2NEt (42 L, 0.25 mmol, 2.5 eq).
The reaction was stirred at 45 C or 30 °C for 24 h. The reaction mixture was diluted with CH2Cl2 (15 ml) and washed with 1M HCl (2  5 ml), brine (10 ml), dried using Na2SO4, filtered and concentrated in vacuo. The / ratio was determined by 1 H NMR spectroscopy of the crude reaction mixture.

Donor and Acceptor Limitations
Peracetylated/4-OAc donors S22, S24 and S35, were disarmed and no glycosylation was observed. 6-OTIPS donor S23 led to the anhydro sugar. Benzylidene acceptors S40 and S46 were poor nucleophiles and no desired reaction was observed. Benzoylated acceptor S49 led to complex mixtures due to ester migration. We confirmed that ester migration occurred on benzoylated acceptor S49 with iPr2NEt in CHCl3 at 45 C in the absence of other reagents. Acceptor S43 gave a complex mixture in reactions with 1a; there were trace amounts of the desired -product (as evidenced by HSQC), and the major product was the donor elimination product. We suspect there was also acyl migration but it was difficult to be sure because of the complex mixture generated. S43 is a poor nucleophile and so observation of elimination is not that surprising. Reaction with cholesterol gave the product S50 in a very high yield but with no selectivity. When S35 used as donor in the glycosylation reaction with acceptor 3a, transesterification was observed giving product S51 (see below). [38] Entry Route Deviation from standard procedure β/α a