Efficient Regio- and Stereoselective Synthesis of 1-β-O-Glucuronyl Carba­mates and Carbonates from Unprotected 1,2,3,4-Hydroxyl Glucuronates

Abstract

The coupling of either isocyanates or chloroformates with hydroxyl-unprotected glucuronates in the presence of N-methylmorpholine allowed the preparation of a range of 1-β-O-glucuronyl carbamates and carbonates with high regio- and stereo­selectivity.

Key words

glucuronide - carbamate - carbonate - regioselectivity - stereoselectivity

References and Notes

• 1 Müller T. Schneider R. Schmidt RR. Tetrahedron Lett.  1994,  35:  4763 
• 2 For a review, see: Stachulski AV. Jenkins GN. Nat. Prod. Rep.  1998,  39:  173 
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• 4 For a review, see: Schaefer WH. Curr. Drug Metab.  2006,  7:  873 
• 5a de Graaf M. Nevalainen TJ. Scheeren HW. Pinedo HM. Haisma HJ. Boven E. Biochem. Pharmacol.  2004,  68:  2273 
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• 7 Leenders RGG. Damen EWP. Bijsterveld EJA. Schereen HW. Houba PHJ. van der Meulen-Muileman IH. Boven E. Haisma HJ. Bioorg. Med. Chem.  1999,  7:  1597 
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11

General Procedure for the Synthesis of 1-β- O -Glucuronyl Carbamates and Carbonates: To a stirred solution of glucuronate 1 (1.5 mmol) and N-methyl-morpholine (5 equiv) in dry MeCN (15 mL) under nitrogen at 0 °C was added a solution of either isocyanate or chloroformate (1 mmol in 2 mL of MeCN) over a period of 1 h. The reaction mixture was then allowed to warm to r.t. and stirring was continued for 1 h. The solvent was removed under reduced pressure and the resulting crude product subjected to flash column chromatography.
Selected Data
Compound 2a: ¹H NMR [(CD₃)₂SO]: δ = 7.46 (d, 2 H, J = 7.8 Hz), 7.28 (t, 2 H, J = 7.5 Hz), 7.03 (t, 1 H, J = 7.3 Hz), 5.91 (m, 1 H), 5.46 (m, 2 H), 5.37 (m, 2 H), 5.21 (d, 1 H, J = 10.4 Hz), 4.61 (d, 2 H, J = 5.6 Hz), 3.92 (d, 1 H, J = 9.2 Hz), 3.23 (m, 1 H) ppm. ¹³C NMR [(CD₃)₂SO]: δ = 168.51, 152.19, 138.87, 132.43, 129.18, 123.27, 118.77, 118.53, 95.26, 79.51, 76.11, 72.49, 71.72, 65.47.
Compound 2g: ¹H NMR [(CD₃)₂CO]: δ = 8.93 (br s, 1 H), 7.50 (d, 2 H, J = 8.2 Hz), 7.22 (d, 2 H, J = 8.5 Hz), 5.57 (d, 1 H, J = 9.1 Hz), 4.82 (br s, 3 H), 4.01 (d, 1 H, J = 8.4 Hz), 3.68 (s, 3 H), 3.62 (m, 2 H), 3.45 (br s, 1 H), 2.42 (s, 3 H) ppm. ¹³C NMR [(CD₃)₂CO]: δ = 170.15, 153.14, 137.59, 133.66, 129.03, 120.60, 96.53, 77.58, 77.19, 73.77, 73.03, 52.92, 16.86 ppm.
Compound 3a: ¹H NMR (CDCl₃): δ = 7.06 (d, 2 H, J = 6.9 Hz), 6.80 (d, 2 H, J = 7.0 Hz), 5.82 (m, 1 H), 5.56 (d, 1 H, J = 6.9 Hz), 5.44 (br s, 1 H), 5.32 (d, 1 H, J = 17.0 Hz), 5.26 (d, 1 H, J = 10.4 Hz), 4.97 (br s, 1 H), 4.74 (br s, 1 H), 4.62 (d, 2 H, J = 5.8 Hz), 4.12 (d, 1 H, J = 8.7 Hz), 4.00 (m, 3 H), 3.72 (s, 3 H) ppm. ¹³C NMR (CDCl₃): δ = 168.63, 157.53, 152.63, 144.40, 131.20, 121.88, 119.36, 114.42, 97.66, 75.43, 75.04, 71.84, 71.12, 66.69, 55.54 ppm.
Compound 3e: ¹H NMR (CDCl₃): δ = 5.45 (d, 1 H, J = 7.7 Hz), 5.31 (br s, 1 H), 4.75 (br s, 1 H), 4.69 (br s, 1 H), 4.08 (d, 1 H, J = 9.0 Hz), 3.98 (d, 2 H, J = 6.8 Hz), 3.81 (s, 3 H), 3.70 (m, 3 H), 2.00 (m, 1 H), 0.95 (s, 3 H), 0.93 (s, 3 H) ppm. ¹³C NMR (CDCl₃): δ = 169.33, 153.85, 97.06, 77.04, 75.38, 74.95, 71.74, 71.08, 52.95, 27.60, 18.88 ppm.