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Organic & Biomolecular Chemistry
1.3 eq.) in dry CH2Cl2 (9.8 mL) were added 4 Å molecular sieves corresponding amine (94 mg). To a stirred solution of the
(400 mg), hydroxybenzotriazole (239 mg, 1.77 mmol, 1.5 eq.) latter in DMF (4 mL) were added the dipeptide (109 mg,
and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (452 mg, 0.33 mmol, 1.3 eq.) and DIPEA (0.17 mL, 1.01 mmol, 4 eq.).
2.36 mmol, 2 eq.). The resulting mixture was cooled to 0 °C After 1 min, HATU (144 mg, 0.32 mmol, 1.5 eq.) was added
and Et3N (0.49 mL, 3.54 mmol, 3 eq.) was added. After being and the resulting mixture was stirred at room temperature for
stirred overnight at room temperature, the mixture was diluted 18 h. The solvent was removed and the crude product was puri-
with aqueous saturated NaHCO3 (8 mL). The aqueous phase fied by flash chromatography on silica gel (EtOAc/EtOH 99 : 1
was then extracted with EtOAc (3 × 10 mL). The organic layers to 92 : 8) to afford product 31-D (113 mg, 0.16 mmol, 65%) as a
1
were combined, dried over Na2SO4, filtered and concentrated yellow powder; [α]2D5 +14.6 (c = 1.1, MeOH). H NMR (500 MHz,
under vacuum. The residue was purified by flash chromato- CD3OD)27 δ 8.11 (d, 1H, JHAr,HAr = 7.5 Hz, HAr), 7.33–7.26 (m,
graphy on silica gel (heptane/EtOAc 80 : 20 to 60 : 40) to afford 1H, HAr), 5.77 (d, 1H, J1,2 = 9.0 Hz, H1), 4.60–4.49 (m, 1H, H7),
product 29-D (367 g, 90%) as a colorless oil. [α]2D5 −26.4 (c = 1.0, 4.10–3.53 (m, 10H, H2, H3, H4, H5, H6, H8, H9), 3.03–2.83
CHCl3); 1H NMR (300 MHz, CDCl3) δ 4.69 (m, 1H, H2), (m, 3H, NCH3), 1.56 (s, 9H, CO2C(CH3)3), 1.50–1.41 (m, 9H,
4.17–3.81 (m, 2H, H3), 3.80 (dd, 1H, J1,1′ = 9.0 Hz, J1′,1 = 3.0 Hz, OC(CH3)3), 1.20 (s, 9H, CO2C(CH3)3); 13C NMR (75 MHz,
H1), 3.72 (s, 3H, OCH3), 3.53 (dd, 1H, J1,1′ = 9.0 Hz, J1′,1
=
CD3OD)28 δ 172.1 (CvO), 163.7 (Cq), 157.0 (Cq), 156.9 (Cq),
3.0 Hz, H1), 2.93 (s, 3H, NCH3), 1.46 (s, 9H, CO2C(CH3)3), 151.9 (CvO), 144.9 (CH, CAr), 96.1 (CH, CAr), 85.2 (C1), 83.4
1.10 (s, 9H, OC(CH3)3); 13C NMR (75 MHz, CDCl3) δ 62.1 (C(CH3)3), 80.2 (CH), 75.8 (CH), 74.4 (CH2), 73.9 (C(CH3)3), 73.8
(C1), 53.4 (C3), 52.8 (C2), 52.6 (OCH3), 35.7 (NCH3), 28.5 (C(CH3)3), 71.6 (CH2), 62.8 (CH2), 56.1 (C7), 53.4 (CH), 53.1
(CO2C(CH3)3), 27.5 (OC(CH3)3); IR ν (film, cm−1) 3314 (N–H), (CH2), 36.8 (NCH3), 28.9 (C(CH3)3), 28.5 (C(CH3)3), 27.8
2975 (CH3), 2935 (CH2), 1751 (CvO), 1684 (NH–CvO); (C(CH3)3); IR ν (film, cm−1) 3264 (N–H), 2976 (CH), 2926 (CH),
ESIHRMS m/z = 347.2182 [M + H]+. C16H31N2O6 requires 1758 (CvO), 1656 (NH–CvO); ESIHRMS m/z = 687.3566
347.2191.
[M + H]+. C30H51N6O12 requires 687.3565.
Boc-sarcosinyl-O-tert-butyl-D-serine 30-D. To a stirred solu-
Peptidonucleoside 32-D. To a stirred solution of 31-D (90 mg,
tion of 29-D (367 mg, 1.06 mmol, 1 eq.) in a THF/H2O mixture 0.131 mmol, 1 eq.) in CH2Cl2/MeOH (2 : 1 v/v, 1.3 mL) was
(8.8 mL/1.8 mL 5 : 1) was added lithium hydroxide (33 mg, added a solution of 4 M HCl in dioxane (0.23 mL, 0.92 mmol,
1.38 mmol, 1.3 eq.). The resulting mixture was stirred for 1 h 7 eq.). The resulting mixture was stirred at room temperature
at room temperature and then concentrated under vacuum for 2 days and then diluted with H2O and then neutralized
until THF was evaporated. 1 N HCl was then added until the with DOWEX® MONOSPHERE® 550A (OH) anion exchange
pH value was 2. The aqueous layer was extracted with EtOAc resin. The mixture was filtered on Celite and then concentrated
(3 × 10 mL). The organic layers were combined, dried over under vacuum. The crude product was purified by preparative
Na2SO4 and concentrated under vacuum to afford the clean TLC (H2O/EtOH/EtOAc 4 : 4 : 2, pH 9) to afford 32-D as a white
product 30-D (351 mg, 1.06 mmol, quantitative). The product powder (21 mg, 0.05 mmol, 37%). [α]D25 −31.3 (c = 1.1, H2O);
was used without further purification. [α]2D5 −32.8 (c = 1.0, 1H NMR (300 MHz, D2O) δ 7.73 (d, 1H, JHAr,HAr = 7.5 Hz, HAr),
1
CHCl3); H NMR (300 MHz, CDCl3) δ 6.90 (d, 1H, JNH,H2 = 8.0 6.07 (bs, 1H, HAr), 5.64 (d, 1H, J1,2 = 9.5 Hz, H1), 4.45 (t, 1H,
Hz, NH), 4.68 (m, 1H, H2), 4.07–3.64 (m, 2H, H3, H3′), 3.85 J7,8 = J7,8′ = 5.5 Hz, H7), 3.94 (s, 2H, H9), 3.91–3.80 (m, 1H, H4),
(dd, 1H, J1,1′ = 9.0 Hz, J1,2 = 3.0 Hz, H1), 3.55 (dd, 1H, J1,1′
=
3.86 (d, 2H, J8,7 = 5.5 Hz, H8), 3.80–3.71 (m, 3H, H2, H3, H5),
9.0 Hz, J1′,2 = 4.0 Hz, H1′), 2.92 (s, 3H, NCH3), 1.44 (s, 9H, 3.68 (dd, 1H, J6,6′ = 12.5 Hz, J6,5 = 1.5 Hz, H6), 3.57 (dd, 1H,
CO2C(CH3)3), 1.12 (s, 9H, OC(CH3)3); 13C NMR (75 MHz, J6′,6 = 12.5 Hz, J6′,5 = 5.5 Hz, H6′), 2.74 (s, 3H, NCH3); 13C NMR
CDCl3) δ 173.7 (CvO), 169.9 (CvO), 81.2 (CqCO C(CH ) ), 74.1 (75 MHz, D2O) δ 172.0 (CvO), 166.7 (CvO), 166.0 (CvO),
2
3 3
(CqOC(CH ) ), 61.7 (C1), 53.3 (C3), 52.7 (C2), 35.8 (NCH3), 28.5 157.9 (CqAr), 141.7 (CHAr), 97.0 (CHAr), 83.3 (C1), 77.5 (C5),
3
3
(CO2C(CH3)3), 27.5 (OC(CH3)3); IR ν (film, cm−1) 3320 (O–H), 73.7 (C3), 71.7 (C2), 61.0 (C8), 60.6 (C6), 55.9 (C7), 51.3 (C4),
2975 (CH3), 2935 (CH2), 1739 (CvO), 1670 (NH–CvO); 49.4 (C9), 32.8 (NCH3); IR ν (film, cm−1) 3310 (O–H), 3282 (N–
ESIHRMS m/z = 355.1842 [M + Na]+. C15H28N2O6Na requires H), 2976 (CH3), 2933 (CH2), 1744 (CvO), 1653 (NH–CvO);
355.1845.
ESIHRMS m/z = 431.3424 [M + H]+. C16H28N6O8 requires
Peptidonucleoside 31-D. The solution 1 was prepared with 431.1890.
Na (10 mg) in dry MeOH (2 mL, C = 0.22 M). To a stirred solu-
tion of the protected nucleoside 27 (147 mg, 0.28 mmol) in dry
MeOH (5 mL) was added the solution 1 (0.26 mL, 20 mol%).
Conflicts of interest
and then neutralized with Dowex® H+, filtered on Celite and There are no conflicts to declare.
The resulting mixture was stirred at room temperature for 1 h
concentrated under reduced pressure to afford the clean
product without further purification. The obtained product
(105 mg) was then hydrogenated at atmospheric pressure in
the presence of Pd(OH)2 (40% w/w, 42 mg) in MeOH (2.6 mL)
Acknowledgements
for 12 h. The resulting mixture was then filtered on Celite® We gratefully acknowledge the financial support from CNRS
and concentrated under reduced pressure to afford the clean and from Bayer CropScience (PhD thesis of MB).
Org. Biomol. Chem.
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