Synthesis of β-CF ₂ -d-Mannopyranosides and β-CF ₂ -d-Galactopyranosides by Reformatsky Addition onto 5-Ketohexoses

Abstract

The first synthesis of β-CF ₂ -d-manno- and β-CF ₂ -d-galactopyranosylesters 1a and 1b is reported. It involves an oxidation-Reformatsky addition sequence on carbohydrate-derived diols and a dehydroxylation of the resulting cyclized compounds. The expected β-CF ₂ -d-glycoside and an undesired β-CF ₂ -l-glycoside are obtained from this sequence. An application of this methodology to the synthesis of some fluorinated pseudo-glycopeptides, potential selectin inhibitors, is also described.

Key words

fluorinated C-glycosides - CF ₂ -glycopeptides - biomimetic synthesis - addition reactions - stereoselectivity

References and Notes

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9

To a stirred solution of Wilkinson’s catalyst (0.019 g, 0.021 mmol, 0.025 equiv) in dry THF (10 mL) at 0 °C was added ethyl bromodifluoroacetate (0.144 mL, 1.22 mmol, 1.5 equiv) and a solution of dry 5-ketohexose 3a (0.437 g, 0.81 mmol, 1 equiv) in anhyd THF (13 mL). A ca. 1.0 M hexane solution of diethylzinc (2.43 mL, 2.43 mmol, 3 equiv) was then added dropwise to the mixture at 0 °C. After stirring for 1 h at this temperature, the reaction was quenched with sat. NH₄Cl (15 mL). The aqueous layer was extracted with EtOAc (3 × 15 mL) and the collected organics were washed with brine (10 mL), dried over MgSO₄ and evaporated under reduced pressure. Purification by column chromatography (6% to 10% EtOAc in cyclohexane) allowed the separation of the two diastereomers 6a (11%) and 5a (17%). R _f ( 6a) = 0.45 and R _f (5a) = 0.37 (25% EtOAc in cyclohexane).

10

To a solution of 5a (1.278 g, 1.92 mmol, 1 equiv) and Et₃SiH (6.2 mL, 38.5 mmol, 20 equiv) in CH₂Cl₂ (6 mL) was added dropwise TMSOTf (1.05 mL, 5.7 mmol, 3 equiv). The mixture was stirred at r.t. for 24 h and then neutralized with sat. NaHCO₃ (25 mL). The aqueous layer was extracted with CH₂Cl₂ (3 × 10 mL) and the collected organics were washed with brine (10 mL), dried over MgSO₄ and evaporated under reduced pressure. Purification by column chromatography (4% to 6% EtOAc in cyclohexane) afforded β-1a (54%) as a colorless oil. R _f = 0.45 (25% EtOAc in cyclohexane). [α]_D ²⁰ -21.1 (c 0.84, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 1.08 (t, 3 H, ³ J = 7.2 Hz), 3.46-3.50 (m, 1 H), 3.62 (dd, 1 H, ³ J = 9.3 Hz, ³ J = 2.4 Hz), 3.75-3.82 (m, 3 H), 3.92-4.03 (m, 2 H), 4.08 (t_app, 1 H, ³ J = 9.6 Hz), 4.17 (br s, 1 H), 4.49-4.97 (m, 8 H), 7.19-7.23 (m, 20 H). ¹³C NMR (75.5 MHz, CDCl₃): δ = 13.8, 62.9, 68.9, 72.0 (d, ³ J = 2.9 Hz), 72.4, 73.5, 74.2, 74.6, 75.4, 77.6 (t, ² J = 28.7 Hz), 81.1, 84.0, 112.7 (dd, ¹ J = 256.4 Hz, ¹ J = 252.4 Hz), 127.4, 127.5, 127.6, 127.8, 127.9, 128.0, 128.1, 128.2, 128.3, 128.4, 128.5, 138.0, 138.2, 138.3, 138.6, 162.9 (dd, ² J = 32.8 Hz, ² J = 29.9 Hz). ¹⁹F NMR (282.5 MHz, CDCl₃): δ = -117.2 (dd, ² J = 268.8 Hz, ³ J = 12.9 Hz), -111.4 (dd, ² J = 266.2 Hz, ³ J = 6.4 Hz). MS (ESI⁺): m/z = 669 [MNa⁺]. IR: 3032, 2915, 1767 cm^-1. Anal. Calcd for C₃₈H₄₀F₂0₇: C, 70.58; H, 6.19. Found: C, 70.41; H, 6.31.

11

The procedure described in ref. 10 was applied to 6a allowing the isolation of 7a (58%): R _f = 0.50 (25% EtOAc in cyclohexane). [α]_D ²⁰ +3.26 (c 1.50, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 1.10 (t, 3 H, ³ J = 7.2 Hz), 3.42-3.56 (m, 3 H), 3.60 (app t, 1 H, ³ J _app = 3.2 Hz), 3.86 (dd, ³ J = 10.0 Hz, ³ J = 2.8 Hz), 3.92-4.18 (m, 3 H), 4.21-4.59 (m, 9 H), 7.09-7.26 (m, 20 H). ¹³C NMR (75.5 MHz, CDCl₃): δ = 13.9, 62.6, 68.6, 72.0, 73.1, 73.3, 73.5, 73.6 (t, ² J = 23.9 Hz), 73.8, 74.8, 75.0, 114.2, 127.8, 127.88, 127.9, 128.0, 128.1, 128.2, 128.4, 128.5, 128.6, 137.6, 138.0, 138.1, 138.2, 163.0 (t, ² J = 31.0 Hz). ¹⁹F NMR (282.5 MHz, CDCl₃): δ = -119.2 (d, ² J = 261.7 Hz), -118.2 (d, ² J = 261.7 Hz). MS (ESI⁺): m/z = 669 [MNa⁺]. IR: 3040, 2914, 1765 cm^-1. Anal. Calcd for C₃₈H₄₀F₂0₇: C, 70.58; H, 6.19. Found: C, 70.55; H, 6.18.

13

The procedure described in ref. 9 was applied to 3b allowing the isolation of 5b and 6b as an unseparable mixture (32%). This mixture was subjected to the dehydroxylation procedure described in ref. 10 to afford β-1b (23%) and 7b (35%).
Compound β-1b: R _f = 0.43 (25% EtOAc in cyclohexane). [α]_D ²⁰ +29.09 (c 1.10, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 1.06 (t, 3 H, ³ J = 7.2 Hz), 3.48-3.55 (m, 3 H), 3.59 (dd, 1 H, ³ J = 9.2 Hz, ³ J = 2.8 Hz), 3.80-4.02 (m, 4 H), 4.09 (t_app, 1 H, ³ J = 9.8 Hz), 4.28-4.40 (m, 2 H), 4.50-4.69 (m, 4 H), 4.83-4.89 (m, 2 H), 7.15-7.28 (m, 20 H). ¹³C NMR (75.5 MHz, CDCl₃): δ = 13.7, 62.7, 68.5, 72.3, 73.1, 73.5, 73.6, 74.5, 74.8, 77.5 (t, ² J = 23.2 Hz), 77.7, 84.3, 113.5 (t, ¹ J = 255.9 Hz), 127.6, 127.75, 127.8, 127.85, 127.9, 128.15, 128.2, 128.35, 128.4, 128.5, 137.8, 137.9, 138.0, 138.5, 162.7 (t, ² J = 31.1 Hz). ¹⁹F NMR (282.5 MHz, CDCl₃): δ = -118.3 (dd, ² J = 259.0 Hz, ³ J = 9.7 Hz), -116.7 (dd, ² J = 259.0 Hz, ³ J = 12.9 Hz). MS (ESI⁺): m/z = 669 [MNa⁺]. IR: 3034, 2920, 1768 cm^-1. Anal. Calcd for C₃₈H₄₀F₂0₇: C, 70.58; H, 6.19. Found: C, 70.69; H, 6.17.
Compound 7b: R _f = 0.50 (25% EtOAc in cyclohexane). [α]_D ²⁰ -2.65 (c 2.00, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 1.18 (t, 3 H, ³ J = 7.2 Hz), 3.69-3.72 (m, 1 H), 3.74-3.77 (m, 1 H), 3.79-3.84 (m, 2 H), 3.94 (dd, 1 H, ³ J = 10.0 Hz, ³ J = 2.6 Hz), 4.02 (app dt, 1 H, ³ J = 10.0 Hz, ³ J = 2.6 Hz), 4.09-4.20 (m, 2 H), 4.27-4.74 (m, 9 H), 7.15-7.39 (m, 20 H, H_ar). ¹³C NMR (75.5 MHz, CDCl₃): δ = 13.7, 62.7, 69.0, 71.7, 71.8, 72.0, 72.7, 72.9, 73.2 (d, ³ J = 2.9 Hz), 73.4, 74.2 (t, ² J = 28.2 Hz), 76.3, 113.3 (dd, ¹ J = 257.0 Hz, ¹ J = 251.8 Hz), 127.75, 127.8, 127.85, 127.9, 128.0, 128.1, 128.3, 128.4, 137.5, 137.85, 137.9, 138.6, 163.0 (dd, ² J = 33.3 Hz, ² J = 30.5 Hz). ¹⁹F NMR (282.5 MHz, CDCl₃): δ = -117.9 (dd, ² J = 267.6 Hz, ³ J = 14.0 Hz), -111.9 (dd, ² J = 267.6 Hz, ³ J = 7.5 Hz). MS (ESI⁺): m/z = 669 [MNa⁺], 685 [MK⁺]. IR: 3032, 2915, 1768 cm^-1. Anal. Calcd for C₃₈H₄₀F₂0₇: C, 70.58; H, 6.19. Found: C, 70.45; H, 6.13.