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Synlett 2008(1): 111-115  
DOI: 10.1055/s-2007-990920
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Stan Groothuys, S. A. M. W. van den Broek, Brian H. M. Kuijpers, Maarten IJsselstijn, Floris L. van Delft*, Floris P. J. T. Rutjes*
Institute for Molecules and Materials, Radboud University Nijmegen, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
Fax: +31(24)3653393; e-Mail: F.Rutjes@science.ru.nl;
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Publikationsverlauf

Received 9 October 2008
Publikationsdatum:
11. Dezember 2007 (online)

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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.

Key words

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

1

Schrock, R. R. Nobel lecture. http://nobelprize.org/nobel_prizes/chemistry/laureates/2005/schrock-lecture.pdf (accessed 26.10.2007).

2

Grubbs, R. H. Nobel lecture. http://nobelprize.org/nobel_prizes/chemistry/laureates/2005/grubbs-lecture.pdf (accessed 26.10.2007).

21

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

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.