Synthesis of All Carbon Linked Glycoside Clusters Round Benzene Scaffold via Sonogashira-Heck-Cassar Cross-Coupling of Iodobenzenes with Ethynyl C-Glycosides

Abstract

The Pd-catalyzed carbon-carbon bond forming reaction between ethynyl C-glycosides and polyiodinated benzenes (Sonogashira-Heck-Cassar coupling) allows the introduction of various ethynylene glycoside chains on the phenyl ring thus creating glycoside clusters wherein the sugar moieties are linked to the benzene ring by an all carbon tether.

alkynes - clusters - cross-coupling - Sonogashira reaction - sugar acetylenes

References

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8a The C-glucoside 1 was synthesized according to the experimental procedure reported in the literature: Lowary T. Meldal M. Helmboldt A. Vasella A. Bock K. J. Org. Chem.  1998,  63:  9657 

8b

Mp 66-67 °C(pentane), [α] _D²0 = +17.3 (c 2.0, CHCl₃); lit. [9] mp 58 °C, [α]_D ²⁰ = +17.4 (c 1.6, CHCl₃)

9 Alzeer J. Vasella A. Helv. Chim. Acta  1995,  78:  177 

10

Compound 3: mp 178-180 °C (AcOEt-cyclohexane); [α]_D ²⁰ = +7.4 (c 1.0, CHCl₃); ¹H NMR selected data (C₆D₆): δ = 3.96 (dd, 1 H, J _1,3 = 2.2 Hz, J _3,4 = 9.7 Hz, H-3), 3.76 (dd, 1 H, J _4,5 = 8.8 Hz, J _5,6 = 9.7 Hz, H-5), 1.99 (d, 1 H, H-1).

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13

Compound 5: mp 150-151 °C(cyclohexane); [α]_D ²⁰ =-54.6 (c 1.0, CHCl₃); ¹H NMR (CDCl₃): δ 7.40-7.25 and 7.17-7.12 (2 m, 44 H, Ar), 5.05 and 4.87 (2 d, 4 H, J = 10.7 Hz, PhCH ₂), 4.96 and 4.87 (2 d, 4 H, J = 11.1 Hz, PhCH ₂), 4.85 and 4.55 (2 d, 4 H, J = 11.0 Hz, PhCH ₂), 4.66 and 4.57 (2 d, 4 H, J = 12.4 Hz, PhCH ₂), 4.33-4.27 (m, 2 H, 2 H-3), 3.81-3.66 (m, 10 H), 3.55-3.49 (m, 2 H); MALDI-TOF MS: 1196.1 (M + Na + 2 H), 1212.4 (M + K + 2 H). Compound 6: mp 180-181 °C (AcOEt-MeOH); [α]²⁰ _D = -33.1 (c 0.8, CH₃OH); ¹H NMR (D₂O): δ 7.12 (s, 4 H, Ar), 3.77 (dd, 2 H, J _7,8a = 0.8 Hz, J _8a,8b = 12.2 Hz, 2 H-8a), 3.58-3.51 (m, 2 H, 2 H-8b), 3.28-3.16 (m, 6 H), 3.11-3.02 (m, 4 H), 2.77-2.52, 2.03-1.90, and 1.65-1.52 (3 m, 8 H, 4 H-1, 4 H-2). Compound 7: mp 279-280 °C (CHCl₃-Et₂O); [α]_D ²⁰ =-58.5 (c 1.1, CHCl₃); ¹H NMR (C₆D₆): δ 7.12 (s, 4 H, Ar), 5.50 (dd, 2 H, J _3,4 = 9.9 Hz, J _4,5 = 9.1 Hz, 2 H-4), 5.32 (dd, 2 H, J _5,6 = 9.3 Hz, 2 H-5), 5.24 (dd, 2 H, J _6,7 = 9.6 Hz, 2 H-6), 4.22 (dd, 1 H, J _7,8a = 4.6 Hz, J _8a,8b = 12.6 Hz, 2 H-8a), 4.07 (d, 2 H, 2 H-3), 4.02 (dd, 2 H, J _7,8b = 2.0 Hz, 2 H-8b), 3.13 (ddd, 2 H, 2 H-7), 1.69, 1.68, 1.66, and 1.64 (4 s, 24 H, 8 Ac); MALDI-TOF MS: 810.2 (M + Na), 826.8 (M + K). Compound 8: mp 254-255 °C (MeOH-AcOEt); [α]_D ²⁰ = 0 (c 0.3, CH₃OH); [α]436²⁰ = -9.0 (c 0.3, CH₃OH); ¹H NMR (CD₃OD): δ 7.45 (s, 4 H, Ar), 4.21-4.15 (m, 2 H, 2 H-3), 3.90 (dd, 2 H, J _7,8a = 0.8 Hz, J _8a,8b = 12.0 Hz, 2 H-8a), 3.72-3.64 (m, 2 H, 2 H-8b), 3.43-3.27 (m, 8 H).

14 Godt A. Franzen C. Veit S. Enkelmann V. Pannier M. Jeschke G. J. Org. Chem.  2000,  65:  7575 

15

Compound 10: mp 133-134 °C (AcOEt-MeOH); [α]_D ²⁰ =
-48.5 (c 1.2, CHCl₃); ¹H NMR (CDCl₃): δ 7.43 (s, 3 H, Ar), 7.39-7.22 and 7.18-7.13 (2 m, 60 H, 12 Ph), 4.96 and 4.82 (2 d, 6 H, J = 10.7 Hz, PhCH ₂), 4.95 and 4.86 (2 d, 6 H, J = 11.0 Hz, PhCH ₂), 4.85 and 4.56 (2 d, 6 H, J = 11.0 Hz, PhCH ₂), 4.65 and 4.56 (2 d, 6 H, J = 12.3 Hz, PhCH ₂), 4.30-4.24 (m, 3 H, 3 H-3), 3.81-3.66 (m, 15 H), 3.54-3.48 (m, 3 H); MALDI-TOF MS: 1742.0 (M + Na), 1758.4 (M + K). Compound 11: mp 234-236 °C (AcOEt); [α]_D ²⁰ = -58.4 (c 0.9, CHCl₃); ¹H NMR (C₆D₆): δ 7.33 (s, 3 H, Ar), 5.46 (dd, 3 H, J _3,4 = 9.8 Hz, J _4,5 = 9.2 Hz, 3 H-4), 5.32 (dd, 3 H, J _5,6 = 9.1 Hz, 3 H-5), 5.24 (dd, 3 H, J _6,7 = 9.6 Hz, 3 H-6), 4.23 (dd, 3 H, J _7,8a = 4.5 Hz, J _8a,8b = 12.5 Hz, 3 H-8a), 4.03 (dd, 3 H, J _7,8b = 2.0 Hz, 3 H-8b), 4.00 (d, 3 H, 3 H-3), 3.14 (ddd, 3 H, 3 H-7), 1.79, 1.68, 1.66, and 1.65 (4 s, 36 H, 12 Ac); MALDI-TOF MS: 1164.3 (M + Na), 1180.7 (M + K). Compound 12: mp 178-180 °C, dec. (MeOH); [α]_D ²⁰ = +5.5 (c 0.2, CH₃OH); ¹H NMR (D₂O): δ 7.55 (s, 3 H, Ar), 4.24-4.17 (m, 3 H, 3 H-3), 3.80 (dd, 3 H, J _7,8a = 0.9 Hz, J _8a,8b = 12.5 Hz, 3 H-8a), 3.60 (dd, 3 H, J _7,8b = 5.0 Hz, 3 H-8b), 3.45-3.28 (m, 12 H). Compound 13: [α]_D ²⁰ = -39.6 (c 0.8, CH₃OH); ¹H NMR (D₂O): δ 6.93 (s, 3 H, Ar), 3.80 (dd, 3 H, J _7,8a = 0.9 Hz, J _8a,8b = 12.2 Hz, 3 H-8a), 3.58 (dd, 3 H, J _7,8b = 5.0 Hz, 3 H-8b), 3.28-3.16 (m, 9 H), 3.13-2.98 (m, 6 H), 2.77-2.54, 2.05-1.91, and 1.69-1.55 (3 m, 12 H, 6 H-1, 6 H-2). Compound 14: mp 116 °C, softening 86 °C(cyclohexane); [α]_D ²⁰ = -10.8 (c 0.5, CHCl₃); ¹H NMR (CDCl₃) selected data: δ 7.41 (s, 3 H, Ar), 7.35-7.15 (m, 105 H, 21 Ph), 4.23-4.18 (m, 3 H, 3 H-3), 3.71-3.59 (m, 18 H), 3.42-3.18 (m, 15 H), 2.22-2.15 and 1.55-1.46 (2 m, 12 H, 6 H-8, 6 H-9); MALDI-TOF MS: 3035.7 (M + Na + 3 H), 3051.7 (M + K + 3 H). Compound 15Ac: mp 245-246 °C (EtOAc); [α]_D ²⁰ =-13.0 (c 0.4, CHCl₃); ¹H NMR (CDCl₃): δ 6.79 (s, 3 H, Ar), 5.20 (dd, 3 H, J _11,12 = J _12,13 = 9.4 Hz, 3 H-12), 5.14 (dd, 3 H, J _4,5 = J _5,6 = 9.3 Hz, 3 H-5), 5.06 (dd, 3 H, J _13,14 = 10.0 Hz, 3 H-13), 4.91 (dd, 3 H, J _10,11 = 9.9 Hz, 3 H-11), 4.86 (dd, 3 H, J _3,4 = 9.9 Hz, 3 H-4), 4.86 (dd, 3 H, J _6,7 = 9.9 Hz, 3 H-6), 4.29 (dd, 3 H, J _14,15a = 5.0, J _15a,15b = 12.2 Hz, 3 H-15a), 4.11 (dd, 3 H, J _14,15b = 2.2 Hz, 3 H-15b), 3.67 (ddd, 3 H, 3 H-14), 3.46-3.33 (m, 9 H, 3 H-3, 3 H-7, 3 H-10), 2.87-2.76, 2.51-2.40, 1.94-1.85, 1.77-1.68, and 1.52-1.39 (5 m, 24 H), 2.12, 2.08, 2.06, 2.02, 2.01, and 1.98 (6 s, 63 H, 21 Ac).

16 Dondoni A. Giovannini PP. Marra A. J. Chem. Soc., Perkin Trans. 1  2001,  2380 

17 Mattern DL. J. Org. Chem.  1984,  49:  3051 

18

A solution of 2 (157 mg, 0.44 mmol) and 16 (58 mg, 0.10 mmol) in anhydrous DMF (1.6 mL) and Et₃N (1.6 mL) was degassed by bubbling argon at r.t. for 20 min. To the solution was added commercially available Pd(PPh₃)₄ (23 mg, 0.02 mmol) and the suspension was stirred at 60 °C in an argon atmosphere. After an additional 24 h at 60 °C the red-brown solution was concentrated, then diluted with CH₂Cl₂ (50 mL), washed with 1 M phosphate buffer at pH = 7 (20 mL), dried (Na₂SO₄), and concentrated. The residue was eluted from a column of silica gel with EtOAc-cyclohexane (from 2:1 to 3:1) to give 17 (94 mg) slightly contaminated by uncharacterized byproducts. Trituration of this material with Et₂O (ca. 2 mL) afforded pure 17 (74 mg, 49%) as a white solid; mp 119-120 °C (MeOH); [α]_D ²⁰ = -70.0 (c 1.0, CHCl₃); ¹H NMR (C₆D₆): δ 7.30 (s, 2 H, Ar), 5.58-5.51 (m, 4 H, 4 H-4), 5.42-5.31 (m, 8 H, 4 H-5, 4 H-6), 4.31 (d, 4 H, J _3,4 = 9.8 Hz, 4 H-3), 4.30 (dd, 4 H, J _7,8a = 4.5 Hz, J _8a,8b = 12.3 Hz, 4 H-8a), 4.14 (dd, 4 H, J _7,8b = 1.8 Hz, 4 H-8b), 3.35-3.29 (m, 4 H, 4 H-7), 1.84, 1.74, 1.72, and 1.64 (4 s, 48 H, 16 Ac); MALDI-TOF MS: 1519.3 (M + Na), 1535.8 (M + K).

19

Compound 18: mp 292-294 °C, dec. (MeOH); [α]_D ²⁰ = -4.1 (c 0.3, H₂O); ¹H NMR (D₂O): δ 7.65 (s, 2 H, Ar), 4.29-4.24 (m, 4 H, 4 H-3), 3.81 (dd, 4 H, J _7,8a = 1.1 Hz, J _8a,8b = 12.5 Hz, 4 H-8a), 3.63 (dd, 4 H, J _7,8b = 5.1 Hz, 4 H-8b), 3.48-3.30 (m, 16 H). Compound 19: [α]_D ²⁰ = -39.6 (c 0.6, H₂O); ¹H NMR (D₂O): δ 6.98 (s, 2 H, Ar), 3.75 (dd, 4 H, J _7,8a = 0.8 Hz,
J _8a,8b = 12.5 Hz, 4 H-8a), 3.54 (dd, 4 H, J _7,8b = 3.8 Hz,
4 H-8b), 3.23-3.12 (m, 12 H), 3.03-2.98 (m, 8 H), 2.71-2.56 (m, 8 H), 1.95-1.83 (m, 4 H), 1.60-1.46 (m, 4 H).