(2-Benzyloxyphenyl)acetyl (BnPAc): A Participating Relay Protecting Group for Diastereoselective Glycosylation and the Synthesis of 1,2-trans Glycosyl Esters

Abstract

The (2-benzyloxyphenyl)acetyl group has been identified as a new protecting group for hydroxyl functions. Various alcohols could be easily protected with high yields, and deprotection was achieved by a relay approach using Pd/H₂ in combination with 1,8-bis(dimethylamino)naphthalene, conditions that are orthogonal to ester groups. The new protecting group is stable in glycosylation reactions demonstrating an effective neighboring group participation leading to the exclusive formation of 1,2-trans glycosides and glycosyl esters.

Key words

protecting groups - relay deprotection - neighboring group participation - anchimeric assistance - glycosides - glycosyl esters

• References and Notes

• 1 The Organic Chemistry of Sugars . Levy D. Fügedi P. CRC Press; Boca Raton, FL: 2005
• 2 Guo J. Ye X.-S. Molecules 2010; 15: 7235
• 3 Ágoston K. Streicher H. Fügedi P. Tetrahedron: Asymmetry 2016; 27: 707
• 4 Kocienski PJ. Protecting Groups . Kocieński PJ. Thieme; Stuttgart: 2005. 3rd ed.
• 5 Wuts PG. M. Greene TW. Greene’s Protective Groups in Organic Synthesis . John Wiley and Sons; Hoboken, NJ: 2006. 4th ed.
• 6 Wada T. Ohkubo A. Mochizuki A. Sekine M. Tetrahedron Lett. 2001; 42: 1069
• 7 Xu J. Guo Z. Carbohydr. Res. 2002; 337: 87
• 8 Arranz E. Boons G.-J. Tetrahedron Lett. 2001; 42: 6469
• 9 Vatèle J.-M. Tetrahedron Lett. 2005; 46: 2299
• 10 Ziegler T. Pantkowski G. Liebigs Ann. Chem. 1994; 659
• 11 Daragics K. Fügedi P. Org. Lett. 2010; 12: 2076
• 12 Watanabe Y. Ishimaru M. Ozaki S. Chem. Lett. 1994; 23: 2163
• 13 Crich D. Cai F. Org. Lett. 2007; 9: 1613
• 14 General Procedure A: Introduction of BnPAc Alcohol (0.5 mmol, 1 equiv), BnPAcOH (0.6 mmol, 1.2 equiv), and DMAP (0.05 mmol, 0.1 equiv) were dissolved in dry CH₂Cl₂ (3 mL) and the mixture cooled to 0 °C. After addition of EDCI (0.6 mmol, 1.2 equiv), the reaction mixture was stirred at r.t. until completion of the reaction. The reaction mixture was diluted with CH₂Cl₂ (10 mL) and washed with 1 M HCl (2 × 10 mL), saturated NaHCO₃ solution (2 × 10 mL), and brine (10 mL). The aqueous phases were extracted with CH₂Cl₂ (5 mL) after each washing step. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (gradient elution hexanes/EtOAc) to yield the desired product.
• 15 (2-Benzyloxyphenyl) Acetic Acid, Cyclohexyl Ester 7 Starting from cyclohexanol (100 mg, 0.1 mmol) and following general procedure A BnPAc ester 7 was obtained as a white solid (306 mg, 94%). For analytical data see Supporting Information.
• 16 (2-Benzyloxyphenyl) Acetic Acid, Cyclohexylmethyl Ester 8 Starting from cyclohexyl methanol (114 mg, 0.1 mmol) and following general procedure A BnPAc ester 8 was obtained as a white solid (315 mg, 93%). For analytical data see Supporting Information.
• 17 (2-Benzyloxyphenyl) Acetic Acid, 3,4-di-O-Benzyl Glucuronal Ester 9 Starting from 3,4-di-O-benzyl glucuronal (200 mg, 0.61 mmol) and following general procedure A BnPAc ester 9 was obtained (276 mg, 82%). For analytical data see Supporting Information.
• 18 (2-Benzyloxyphenyl) Acetic Acid, 1,2,5,6-Diisopropylidene Glucosyl Ester 10 Starting from diacetone-d-glucose (50 mg, 0.19 mmol) and following general procedure A BnPAc ester 10 was obtained (80 mg, 86%). For analytical data see Supporting Information.
• 19 Ethyl 3,4,6-Tri-O-benzyl-2-O-[(2-benzyloxyphenyl)acetyl]-1-thio-β,d-glucoside (11) Starting from ethyl 3,4,6-tri-O-benzyl-1-thio-β,d-glucoside (4.4 g, 9 mmol) and following general procedure A glucosyl donor 11 was obtained as a white solid (5.2 g, 88%). For analytical data see Supporting Information.
• 20 General Procedure B1: Deprotection of BnPAc via Catalytic Hydrogenation To a solution of the respective BnPAc-protected compound (0.07 mmol, 1 equiv) in dry ethanol (1.5 mL) one small tip of a spatula of Pd/C was added under an argon atmosphere. The argon balloon was changed for a H₂ balloon, and the reaction mixture was stirred for 3–6 h at r.t. The reaction mixture was filtered through a syringe filter, proton sponge (1 equiv) was added to the filtrate, and the reaction solution was heated up to 80 °C until completion of the reaction (4–8 h). The reaction mixture was concentrated, and the residue was purified either by flash chromatography (gradient elution hexanes/EtOAc) or by preparative HPLC (H₂O/MeCN) to yield the corresponding product.
• 21 General Procedure B2: Deprotection of BnPAc via basic hydrolysis To a solution of the respective BnPAc-protected compound in dry methanol K₂CO₃ (0.5 equiv) was added. The reaction mixture was stirred for 16 h at room temperature. In some cases, further addition of 0.5 equiv NaOMe was necessary for completion of the reaction. The reaction mixture was filtered, concentrated and the residue was purified by flash chromatography (gradient elution hexanes/EtOAc) or by preparative-HPLC (H₂O/MeCN) to obtain the desired product.
• 22 Mikula H. Matscheko D. Schwarz M. Hametner C. Fröhlich J. Carbohydr. Res. 2013; 370: 19
• 23 General Procedure C: Glycosylation with Donor 11 To a solution of the acceptor (680 μmol, 2.5 equiv) and glucosyl donor 11 (200 mg, 272 μmol, 1 equiv) in dry CH₂Cl₂ (5 mL) molecular sieves (3 Å, 100 mg/mL) were added, and the reaction mixture was stirred for 2 h at r.t. After cooling to –10 °C, N-iodo­succinimide (133 mg, 544 μmol, 2 equiv), followed by trifluoromethanesulfonic acid (5 μL, 54 μmol, 0.2 equiv) were added, and stirring was continued for 16 h. The reaction was quenched by addition of saturated aqueous NaHCO₃ and Na₂SO₃ solutions (1:1, 1 mL), then the reaction solution was diluted with CH₂Cl₂ (4 mL) and filtered through Celite^®. The filtrate was washed with water (5 mL) and brine (3 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (hexanes/EtOAc gradient elution) to obtain the desired product.
• 24 2-Phenylethyl 3,4,6-Tri-O-benzyl-2-O-[(2-benzyloxy-phenyl)acetyl]-β,d-glucoside (12) General procedure C; starting from phenylethanol (83 mg, 0.68 mmol) and glucosyl donor 11 (200 mg, 0.27 mmol) 12 was obtained as a white solid (90 mg, 88%). For analytical data see Supporting Information.
• 25 Methyl 2,3,4,9,10,12-Hexa-O-benzyl-8-O-[(2-benzyloxy-phenyl)acetyl]-α,d-gentiobioside (15) General procedure C; starting from glucosyl donor 11 (60 mg, 0.08 mmol) and acceptor 14 (93 mg, 0.2 mmol) 15 (83 mg, 91%) was obtained. For analytical data see Supporting Information.
• 26 2-Phenylethyl-β,d-glucoside (13) Starting from compound 12 (36 mg, 0.05 mmol) and following general procedure B1 13 was obtained as a white solid (12 mg, 84%). Analytical data matched those reported in the literature.³⁰
• 27 Methyl 2,3,4,9,10,12-Hexa-O-benzyl-α,d-gentiobioside (16) Starting from compound 15 (50 mg, 0.04 mmol) and following general procedure B2 16 was obtained as a white solid (37 mg, 95%). For analytical data see Supporting Information.
• 28 trans-N-(tert-Butoxycarbonyl)-4-acetoxy-l-proline, 3,4,6-Tri-O-benzyl-2-O-[(2-benzyloxyphenyl) Acetyl]-β,d-glucosyl Ester (18) General procedure C; starting from glucosyl donor 11 (100 mg, 0.14 mmol) and acceptor 17 (57 mg, 0.21 mmol) 18 (80 mg, 62%) was obtained. For analytical data see Supporting Information.
• 29 trans-N-(tert-Butoxycarbonyl)-4-acetoxy-l-proline, β,d-Glucosyl Ester (19) Starting from compound 18 (35 mg, 0.04 mmol) and following general procedure B1 19 was obtained as a colourless solid (11 mg, 68%).
• 30 Guo Y. Zhao Y. Zheng C. Meng Y. Yang Y. Chem. Pharm. Bull. 2010; 58: 1627