Ring-Closing Alkyne Metathesis in the Synthesis of Alkyne-Linked Glycoamino Acids

Abstract

Synthesis of alkyne-linked glycoamino acids via ring-closing alkyne metathesis is investigated. Two different strategies are described to attach alkynylamino acids to an alkynyl sugar, either via a linker at O-4 or at O-9 of the alkynyl sugar. Ring-closing alkyne metathesis of the O-4 linked diynes failed to proceed, but alkyne-linked glycoamino acids of different chain length were effectively synthesized via attachment at O-9.

alkynes - glycopeptides - ring-closing alkyne metathesis - ring closure

References and Notes

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21

Mass analyses showed the formation of a product with m/z = 1784, which indicates [dimer + Na⁺].

22 Tietze LF. Griesbach U. Schuberth I. Bothe U. Marra A. Dondoni A. Chem. Eur. J.  2003,  9:  1296 

23

To a solution of 14 ²² (1.3 g 2.4 mmol) in Ac₂O (45 mL), H₂SO₄ (5% in Ac₂O, 10 mL) was added dropwise at -20 °C. The reaction was stirred for 10 min. The reaction was quenched with aq NaOAc, diluted with EtOAc, and washed with sat. NaHCO₃ and brine. The organic phase was dried (Na₂SO₄) and concentrated in vacuo. The crude product was purified by flash chromatography (EtOAc-heptane, 1:5) and yielded the acetolyzed product (1.0 g, 81%) as a white solid. To a solution of the acetolyzed product (1.0 g, 1.9 mmol) in MeOH (40 mL) was added KCN (15 mg, 0.23 mmol). The reaction was stirred for 24 h. The mixture was neutralized with basic Amberlyst, filtrated, and evaporated. The mixture was redissolved in EtOAc and washed with NH₄Cl, dried (MgSO₄), and evaporated. Purification by flash chromatog-raphy (EtOAc-heptane, 1:2) yielded 15 as a white solid (0.75 g, 1.6 mmol, 82%). R _f = 0.30 (EtOAc-heptane, 1:2). ¹H NMR (400 MHz, CDCl₃): δ = 7.37-7.24 (m, 15 H), 4.99 (d, J = 10.6 Hz, 1 H), 4.92 (d, J = 11.1 Hz, 1 H), 4.87-4.80 (m, 3 H), 4.65 (d, J = 10.9 Hz, 1 H), 4.05 (dd, J = 1.6, 9.5 Hz, 1 H), 3.87 (dd, J = 2.3, 12.0 Hz, 1 H), 3.70-3.50 (m, 4 H), 3.35-3.31 (m, 1 H), 2.05 (br s, 1 H), 1.88 (d, J = 1.2 Hz, 3 H). ¹³C NMR (50 MHz, CDCl₃): δ = 138.6, 138.2, 138.0, 128.6, 128.5, 128.3, 128.1, 128.0, 128.0, 127.9, 127.8, 86.0, 83.0, 82.8, 79.4, 77.6, 76.5, 75.8, 75.6, 75.3, 70.1, 62.1, 3.9. [α]_D ²⁰ -8.25 (c 0.63, CHCl₃). IR (neat): ν = 3373, 3036, 2902, 2859, 2245. HRMS (CI): m/z calcd for C₃₀H₃₃O₅ [M + H]: 473.2328; found: 473.2331.

24

Compound 15 (0.76 g, 1.6 mmol) was dissolved in anhyd THF (50 mL) and cooled to -78 °C. Then, KHMDS (0.5 M in toluene, 4.8 mL, 2.4 mmol) was added and stirred for 30 min at -78 °C. Cyclic sulfate 10 (0.64 g, 3.2 mmol)^19,27 was added. The temperature was raised overnight to r.t. After stirring for 20 h, the reaction mixture was poured into aq sat. NH₄Cl and extracted with EtOAc (2 × 100 mL). The sulfate was concentrated and redissolved in THF (100 mL). Afterwards, H₂SO₄ (0.40 mL) and H₂O (0.15 mL) were added and the reaction was stirred for 4 d. Half of the THF was evaporated and the reaction mixture was diluted with EtOAc (200 mL) and washed with H₂O (3 × 100 mL), brine, dried (MgSO₄), and evaporated. Purification by flash chromatography (EtOAc-heptane, 1:2) afforded compound 16 (0.51 g, 54%) as a white solid. R _f = 0.20 (EtOAc-heptane, 1:2). ¹H NMR (400 MHz, CDCl₃): δ = 7.42-7.20 (m, 19 H), 4.98 (d, J = 10.6 Hz, 1 H), 4.90 (d, J = 11.1 Hz, 1 H), 4.84-4.76 (m, 3 H), 4.66 (d, J = 5.3 Hz, 2 H), 4.61 (d, J = 11.5 Hz, 2 H), 4.53 (d, J = 11.1 Hz, 1 H), 3.99 (dd, J = 2.0, 9.2 Hz, 1 H), 3.72 (dd, J = 2.0, 10.6 Hz, 1 H), 3.63-3.50 (m, 4 H), 3.43-3.40 (m, 1 H), 3.10 (br t, J = 6.1 Hz, 1 H), 1.88 (d, J = 2.2 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 140.6, 138.4, 138.0, 138.0, 135.7, 130.2, 129.8, 128.9, 128.4, 128.3, 128.2, 127.9, 127.8, 127.8, 127.7, 127.6, 86.1, 83.0, 82.7, 78.4, 77.8, 76.2, 75.8, 75.5, 75.2, 72.8, 70.3, 69.0, 63.7, 4.2. [α]_D ²⁰ +6.4 (c 1.0, CHCl₃). IR (film): ν = 3480, 3062, 3027, 2905, 2868, 2250. HRMS (CI): m/z calcd for C₃₈H₄₁O₆ [M + H]: 593.2903; found: 593.2875.

25

A solution of 2-butynyl glycine 11 (18 mg, 79 µmol) and alcohol 16 (34 mg, 56 µmol) in CH₂Cl₂ (1 mL) was stirred at 0 °C. Then, DMAP (0.7 mg, 6 mol) and DCC (15 mg, 73 µmol) in CH₂Cl₂ (1 mL) were added and the reaction was stirred overnight at r.t. The reaction mixture was filtered and the residue was washed with CH₂Cl₂. The organic layer was evaporated. Flash chromatography afforded dialkyne 17 (42 mg, 94%) as a white solid. R _f = 0.43 (EtOAc-heptane, 1:2). ¹H NMR (400 MHz, CDCl₃): δ = 7.41-7.12 (m, 19 H), 5.34-5.25 (m, 3 H), 5.00 (d, J = 10.6 Hz, 1 H), 4.91 (d, J = 11.0 Hz, 1 H), 4.82-4.79 (m, 3 H), 4.64 (d, J = 12.4 Hz, 2 H), 4.50 (d, J = 10.8 Hz, 1 H), 4.45-4.42 (m, 1 H), 4.00 (dd, J = 1.7, 9.2 Hz, 1 H), 3.73 (d, J = 10.8 Hz, 1 H), 3.67 (dd, J = 4.5, 10.8 Hz, 1 H), 3.63-3.53 (m, 3 H), 3.43 (dd, J = 2.9, 9.2 Hz, 1 H), 2.72-2.56 (m, 2 H), 1.88 (d, J = 1.8 Hz, 3 H), 1.67 (t, J = 2.2 Hz, 3 H), 1.44 (s, 9 H). ¹³C NMR (75 MHz, CDCl₃): δ = 170.5, 154.9, 138.4, 138.1, 137.9, 136.4, 133.7, 129.3, 129.0, 128.3, 128.3, 128.1, 127.9, 127.8, 127.8, 127.7, 127.7, 127.6, 86.1, 82.7, 82.7, 80.1, 79.4, 78.9, 78.0, 76.6, 75.8, 75.5, 75.2, 73.2, 71.1, 70.2, 69.3, 64.9, 52.6, 28.6, 23.4, 4.2, 3.9. [α]_D ²⁰ +6.6 (c 0.8, CHCl₃). IR (film): ν = 3723, 3425, 3058, 3028, 2967, 2911, 2855, 2250, 1740, 1722. ESI-HRMS: m/z calcd for C₄₉H₅₅NNaO₉ [M + Na]: 824.3775; found: 824.3774.

26

Dialkyne 17 (108 mg, 0.135 mmol) was coevaporated with toluene (2 × 10 mL) and subsequently (t-BuO)₃W≡Ct-Bu (13, 22 mg, 47 µmol) was added. This was dissolved in toluene (2 mL) and stirred for 30 min at 80 °C. The reaction was concentrated and purified by flash chromatography (EtOAc-heptane, 1:4) to yield cyclized product 18 (81 mg, 80%) as a white solid. R _f = 0.43 (EtOAc-heptane, 1:2). ¹H NMR (400 MHz, CDCl₃): δ = 7.35-7.26 (m, 19 H), 5.34-5.23 (m, 3 H), 4.94-4.77 (m, 6 H), 4.71 (d, J = 11.7 Hz, 1 H), 4.62-4.58 (m, 2 H), 3.92 (d, J = 9.6 Hz, 2 H), 3.61-3.43 (m, 5 H), 2.96 (d, J = 16.4 Hz, 1 H), 2.56 (ddd, J = 2.1, 5.5, 16.6 Hz, 1 H), 1.39 (s, 9 H). ¹³C NMR (50 MHz, CDCl₃): δ = 171.1, 155.2, 138.5, 138.1, 138.0, 138.0, 137.5, 132.8, 130.2, 128.9, 128.6, 128.6, 128.5, 128.4, 128.2, 128.1, 128.0, 128.0, 127.9, 127.8, 85.9, 82.2, 81.9, 81.4, 80.4, 79.5, 78.3, 75.9, 75.3, 75.3, 71.8, 69.7, 69.3, 65.2, 53.5, 28.4, 23.9. [α]_D ²⁰ -30.0 (c 0.26, CHCl₃). IR (film): ν = 3321, 3062, 3032, 2967, 2907, 2868, 2258, 1701. ESI-HRMS: m/z calcd for C₄₅H₄₉NNaO₉ [M + Na]: 770.3305; found: 770.3366.

27 Leone A. Consiglio G. Helv. Chim. Acta  2005,  88:  210