Short Synthesis of Phenylpropanoid Glycosides Calceolarioside A and Syringalide B

Abstract

An efficient and practical three-step synthesis of phenylpropanoid glycosides calceolarioside A and syringalide B in >62% overall yield is disclosed. The key step involves the chemoselective and regio­selective direct O-4 cinnamoylation of unprotected 2-phenylethyl-β-d-glucosides with cinnamic anhydrides using a chiral 4-pyrrolidinopyridine organocatalyst. This approach serves as a model for the short synthesis of phenylpropanoid glycosides acylated at O-4 without protection/deprotection steps.

Keywords

phenylpropanoid glycosides - phenylethanoid glycosides - calceolarioside A - syringalide B - C₂ -symmetric chiral 4-pyrrolidino­pyridine - chemoselective - regioselective acylation

• References and Notes

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• 22 2-(4-Allyloxyphenyl)ethyl-β-d-glucopyranoside (13b): A mixture of d-glucose penta-acetate 11 (600 mg, 1.5 mmol.), phenylethanol 12b (124 mg, 0.7 mmol), and 4 Å molecular sieves (300 mg) in anhyd CH₂Cl₂ (10 mL) was stirred for 30 min under a nitrogen atmosphere at r.t. BF₃·OEt₂ (60 μL, 0.5 mmol) was added to the reaction mixture and stirring was continued for about 12 h and the reaction was monitored for complete consumption of phenylethanol 12b (TLC). Further BF₃·OEt₂ (20 μL) was added, the mixture was stirred for additional 2 h, quenched with sat. NaHCO₃ and filtered through a pad of Celite^®. The biphasic filtrate was separated and the aqueous phase was further extracted with CH₂Cl₂ (2 × 10 mL). The combined organic phases were washed with brine, dried over MgSO₄, filtered and evaporated to dryness. The residue was redissolved in MeOH (25 mL) and NaOMe (50 mg) was then added to the solution, which was stirred for 1 h before addition of Amberlite IR 120^®. The reaction mixture was stirred for additional 3 h, filtered and evaporated. The crude residue was purified by column chromatography (CH₂Cl₂–MeOH, 100:5) to give 195 mg (82% yield) of 13b as a white solid. ¹H NMR (CD₃OD): δ = 2.75 (t, J = 7.35 Hz, 2 H), 3.07 (t, J = 8.25 Hz, 1 H), 3.15–3.24 (m, 3 H, overlapping with CD₃OD signal), 3.52–3.64 (m, 2 H), 3.75 (d, J = 10.8 Hz, 1 H), 3.94 (q, J = 9.6 Hz, 1 H), 4.18 (d, J = 7.8 Hz, 1 H), 4.39 (dt, J = 1.5, 5.4 Hz, 2 H), 4.50 (s, 2 H, OH), 5.12 (dd, J = 1.5, 10.5 Hz, 1 H), 5.26 (dd, J = 1.8, 17.4 Hz, 1 H), 5.88–6.00 (m, 1 H), 6.72 (d, J = 8.7 Hz, 2 H), 7.05 (d, J = 8.4 Hz, 2 H). ¹³C NMR (CD₃OD): δ = 37.8, 64.2, 71.3, 73.1, 73.4, 76.6, 79.5, 79.6, 105.9, 117.2, 118.8, 132.5, 133.7, 136.6, 160.1. HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₇H₂₅O₇: 341.1600; found: 341.1603.
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• 25 2-[3,4-Bis(tert-butyldimethylsilyloxy)phenyl]ethylβ-d-gluco­pyranoside (13a): A mixture of O-(2, 4,6-tetra-O-acetyl-α-d-glucopyranosyl)trichloroacetimidate (14; 300 mg, 0.6 mmol), phenylethanol 12a (170 mg, 0.45 mmol), and molecular sieves 4Å (300 mg) in anhyd CH₂Cl₂ (10 mL) was stirred at r.t. for 30 min. The reaction mixture was then cooled to – 78 °C and TMSOTf (8 μL, 0.045 mmol) was added. After 1 h, the reaction was allowed to warm to r.t., quenched with a sat. aq NaHCO₃ and filtered through a pad of Celite^®. The biphasic mixture was separated and the aqueous phase was further extracted with CH₂Cl₂ (2 × 10 mL). The combined organic phases were dried over MgSO₄, filtered and evaporated to dryness. The residue was redissolved in MeOH (10 mL) and NaOMe (20 mg) was then added to the solution. The resulting mixture was stirred at r.t. for 1 h. Amberlite IR 120^® was then added and the mixture stirred for an additional 2 h. The reaction was filtered and evaporated. The crude mixture was purified by column chromato­graphy (CH₂Cl₂–MeOH, 100:5) to give 225 mg (92% yield) of 13a as a white solid. ¹H NMR (CDCl₃): δ = 0.00 (s, 12 H), 0.80 (s, 18 H), 2.66 (t, J = 7.05 Hz, 2 H), 3.14 (d, J = 9.3 Hz, 1 H), 3.28 (t, J = 8.25 Hz, 1 H), 3.41 (t, J = 8.0, 7.0 Hz, 1 H), 3.51 (q, J = 9.0 Hz, 2 H), 3.59–3.67 (m, 2 H), 3.67–3.92 (m, 1 H + 4 OH), 4.19 (d, J = 7.5 Hz, 1 H), 6.44–6.56 (m, 3 H). ¹³C NMR: δ = –4.08, –4.06, 18.4, 26.0, 35.4, 61.3, 69.3, 71.4, 73.4, 75.6, 76.4, 102.9, 121.0, 121.8, 130.7, 145.4, 146.6. HRMS (ESI+): m/z [M + H]⁺ calcd for C₂₆H₄₉O₈Si₂: 545.2966; found: 545.2960.
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• 29 General Procedure for O-4 Acylation of 13a,b with Organocatalyst 16: A solution of 2-phenylethyl-d-glucopyranosides 13a,b (0.2 mmol), organocatalyst 16 (17 mg, 0.02 mmol) and s-collidine (40 μL, 0.3 mmol) in CHCl₃ (2 mL) under an inert atmosphere was cooled to –20 °C. Cinnamic anhydride (15a,b, 0.22 mmol, 1.1 equiv) was then added and the mixture was stirred for 5 d. The reaction mixture was allowed to warm to r.t. and sat. aq NH₄Cl (10 mL) was added. The resulting mixture was extracted with EtOAc (3 × 10 mL), the combined organic phases were dried over MgSO₄, filtered and evaporated under reduced pressure. The crude residue was purified by column chromatography (gradient EtOAc–hexane, 1:1 to 3:1) to give the products 17a,b. The general procedure was used to prepare:2-[3,4-Bis(tert-butyldimethylsilyloxy)phenyl]ethyl 4-Ο-(E)-3,4-Bis(tert-butyldimethylsilyloxy)caffeoyl-β-d-glucopyranoside (17a): ¹H NMR (CDCl₃): δ = 0.15 (s, 6 H), 0.16 (s, 6 H), 0.18 (s, 6 H), 0.19 (s, 6 H), 0.95 (s, 9 H), 0.956 (s, 9 H), 0.96 (s, 9 H), 0.97 (s, 9 H), 2.81 (t, J = 7.35 Hz, 2 H, OCH₂CH ₂Ar), 3.41–3.46 (m, 1 H, Glc-H5), 3.47 (t, J = 8.1 Hz, 1 H, Glc-H2), 3.56–3.75 (m, 3 H, Glc-H6, OCH _2aCH₂Ar), 3.78 (t, J = 9.0 Hz, 1 H, Glc-H3), 4.04–4.12 (m, 1 H, OCH _2bCH₂Ar), 4.32 (d, J = 3.9 Hz, 1 H, Glc-H1), 4.96 (t, J = 9.5 Hz, 1 H, Glc-H4), 6.22 (d, J = 15.9 Hz, 1 H, ArCH=CH), 6.61–6.81 (m, 4 H, ArH), 6.97–7.01 (m, 2 H, ArH), 7.60 (d, J = 15.9 Hz, 1 H, ArCH=CH). ¹³C NMR (CDCl₃): δ = –3.9, 18.6, 26.3, 35.6, 61.6, 71.0, 71.4, 74.4, 74.5, 74.7, 102.8, 114.3, 120.8, 121.1, 121.4, 121.9, 122.0, 122.9, 127.7, 131.3, 145.6, 146.9, 147.1, 147.5, 150.2, 167.8. HRMS (ESI+): m/z [M + H]⁺ calcd for C₄₇H₈₃O₁₁Si₄: 935.5013; found: 935.5009.2-(3-Methoxy-4-allyloxyphenyl)ethyl 4-Ο-(E)-4-Allyloxycaffeoyl-β-d-glucopyranoside (17b): ¹H NMR (CDCl₃): δ = 2.82 (t, J = 6.75 Hz, 2 H, OCH₂CH ₂Ar), 3.30–3.41 (m, 2 H, Glu-H2, Glu-H5), 3.45–3.52 (m, 1 H, Glc-H6a), 3.55–3.71 (m, 3 H, Glc-H3, Glc-H6b, OCH _2aCH₂Ar), 3.81 (s, 3 H, OMe), 4.03 (q, J = 9.3 Hz, 1 H, OCH _2bCH₂Ar), 4.28 (d, J = 3.9 Hz, 1 H, Glc-H1), 4.42 (dt, J = 1.35, 5.1 Hz, 2 H), 4.56 (dt, J = 1.35, 5.1 Hz, 2 H), 4.92 (t, J = 9.6 Hz, 1 H, Glc-H4), 5.18–5.37 (m, 4 H), 5.81–6.05 (m, 2 H), 6.24 (d, J = 15.9 Hz, 1 H, ArCH=CH), 6.77 (d, J = 8.4 Hz, 3 H, ArH), 6.96–7.07 (m, 4 H, ArH), 7.59 (d, J = 15.9 Hz, 1 H, ArCH=CH).¹³C NMR (CDCl₃): δ = 35.2, 56.0, 61.3, 68.9, 69.7, 70.8, 71.1, 74.1, 74.3, 74.5, 102.7, 110.15, 112.7, 114.3, 114.8, 117.6, 118.5, 122.9, 127.1, 129.9, 130.4, 132.6, 133.4, 146.8, 149.5, 150.5, 157.2, 167.6. HRMS (ESI+): m/z [M + H]⁺ calcd for C₃₀H₃₇O₁₀: 557.2387; found: 557.2383.
• 30 2-[3,4-Dihydroxyphenyl]ethyl 4-Ο-(E)-Caffeoyl-β-d-glucopyranoside (Calceolarioside A; 7): A solution of 17a (100 mg, 0.11 mmol), Et₃N (32 μL, 0.22 mmol) and Et₃N·3HF (1.56 M in pyridine, 450 μL) in pyridine (1.2 mL) was stirred at r.t. for 3 h. The reaction was then evaporated under reduced pressure. The crude mixture was purified by column chromatography (EtOAc–MeOH = 10:1) to give 43 mg (82% yield) of calceolarioside A 7; [α]_D –21 (c = 0.43, MeOH). ¹H NMR (CD₃OD): δ = 2.70 (t, J = 7.35 Hz, 2 H), 3.18–3.20 (m, 1H), 3.38–3.55 (m, 5 H), 3.95 (ms, 1 H), 4.27 (d, J = 7.8 Hz, 1 H, Glc-H1), 4.70–4.80 (1 H, ­Glc-H4, overlapping with CD₃OD signal), 6.20 (d, J = 15.9 Hz, 1 H), 6.47 (dd, J = 2.1, 8.1 Hz, 1 H), 6.57–6.70 (m, 3 H), 6.86 (dd, J = 2.1, 8.1 Hz, 1 H), 6.9 (d, J = 1.8 Hz, 1 H), 7.50 (d, J = 15.9 Hz, 1 H). ¹³C NMR (CD₃OD): δ = 36.7, 62.6, 72.3, 72.6, 75.3, 75.9, 76.2, 104.5, 114.8, 115.3, 116.4, 116.7, 117.3, 121.4, 123.2, 127.8, 131.6, 144.8, 146.2, 146.9, 147.8, 149.8, 168.8. HRMS (ESI+): m/z [M + H]⁺ calcd for C₂₃H₂₇O₁₁: 479.1553; found: 479.1563.
• 31 2-(4-Hydroxyphenyl)ethyl 4-Ο-(E)-Feruloyl-β-d-glucopyranoside (Syringalide B; 8): A mixture of 17b (100 mg, 0.18 mmol), Pd/C (200 mg) and p-TsOH·H₂O (3.4 mg, 0.018 mmol) in MeOH–H₂O (3.6 mL MeOH and 0.4 mL H₂O) was heated at 80 °C for 12 h. The crude mixture was filtered through a pad of Celite®. The filtrate was evaporated under reduced pressure. The crude product obtained was purified by column chromatography (EtOAc–MeOH, 100:5) to afford 78 mg (92% yield) of syingalide B 8; [α]_D –29 (c = 0.78, MeOH) . ¹H NMR (CD₃OD): δ = 2.78 (t, J = 7.35 Hz, 2 H), 3.18–3.20 (m, 1 H, overlapped with MeOD signal), 3.38–3.60 (m, 5 H), 3.79 (s, 3 H, –OCH3), 3.91–3.99 (m, 1 H), 4.27 (d, J = 7.5 Hz, 1 H, Glc-H1), 4.70–4.80 (1 H, Glc-H4, overlapping with CD₃OD signal), 6.30 (d, J = 15.9 Hz, 1 H), 6.61(d, J = 6.6 Hz, 2 H), 6.71 (d, J = 8.1 Hz, 1 H), 6.96–7.01 (m, 3 H), 7.09 (d, J = 1.8 Hz, 1 H), 7.56 (d, J = 15.9 Hz, 1 H). ¹³C NMR (CD₃OD): δ = 36.5, 56.6, 62.6, 72.4, 72.7, 75.4, 76.0, 76.3, 104.5, 111.9, 115.3, 116.3, 116.7, 124.4, 127.8, 130.8, 131.1, 147.7, 149.5, 150.9, 156.9, 168.7. HRMS (ESI+): m/z [M + H]⁺ calcd for C₂₄H₂₉O₁₀: 477.1761; found: 477.1772.