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A. Vermote et al. / Bioorg. Med. Chem. xxx (2016) xxx–xxx
3H), 7.77–7.86 (m, 2H). 13C NMR (75 MHz, CDCl3) d ppm 16.66,
16.71, 27.7, 27.9, 43.0, 44.0, 53.8, 75.3, 84.2, 84.4, 92.3, 113.8,
127.1, 128.8, 132.0, 133.7, 168.2. HRMS (ESI-TOF) m/z: [MꢀH]ꢀ
Calcd for C19H27N2O6Sꢀ 411.15953; Found 411.1585.
5.1 Hz, 1H), 3.17 (ddd, J = 13.6, 7.8, 5.6 Hz, 1H), 3.68 (dd, J = 14.4,
6.2 Hz, 1H), 3.75–3.89 (m, 3H), 4.12 (app. t, J = 6.3 Hz, 1H), 4.45
(d, J = 1.5 Hz, 1H), 6.23 (dd, J = 7.6, 5.0 Hz, 1H), 7.04 (t, J = 6.2 Hz,
1H), 7.30–7.53 (m, 6H), 7.73–7.83 (m, 2H), 7.96–8.03 (m, 1H). 13C
NMR (75 MHz, CDCl3) d ppm 27.6, 27.8, 43.0, 43.3, 75.1, 83.3,
84.4, 92.1, 113.7, 127.0, 127.2, 128.6, 131.0, 131.4, 131.6, 131.8,
133.6, 133.8, 137.1, 168.1. HRMS (ESI-TOF) m/z: [MꢀH]ꢀ Calcd
for C22H24ClN2O6Sꢀ 479.10491; Found 479.1055.
5.1.16. N-(((3aS,6R,6aR)-2,2-Dimethyl-6-(((trifluoromethyl)
sulfonamido)methyl)dihydrofuro[3,4-d][1,3]dioxol-3a(4H)-
yl)methyl)benzamide (14d)
General procedure 3. White foam, 16% 1H NMR (300 MHz,
CDCl3) d ppm 1.33 (s, 3H), 1.54 (s, 3H), 3.43–3.57 (m, 2H), 3.60–
3.70 (m, 1H), 3.90 (q, J = 9.7 Hz, 2H), 4.10 (dd, J = 14.9, 7.9 Hz,
1H), 4.24 (app. td, J = 4.3, 1.8 Hz, 1H), 4.36 (d, J = 1.8 Hz, 1H), 6.84
(t, J = 6.3 Hz, 1H), 7.44–7.59 (m, 3H), 7.76–7.85 (m, 2H), 7.92 (br
s, 1H). 19F NMR (282 MHz, CDCl3) d ppm ꢀ77.9 (s). 13C NMR
(75 MHz, CDCl3) d ppm 27.5, 28.3, 42.6, 45.2, 75.7, 82.9, 83.7,
92.3, 114.2, 120.0 (q, J = 321.2 Hz), 127.2, 129.1, 132.6, 133.1,
169.1. HRMS (ESI-TOF) m/z: [MꢀH]ꢀ Calcd for C17H20F3N2O6Sꢀ
437.09997; Found 437.0984.
5.1.21. N-(((3aS,6R,6aR)-6-(([1,10-Biphenyl]-4-sulfonamido)
methyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-3a(4H)-
yl)methyl)benzamide (14i)
General procedure 3. White foam, 67% 1H NMR (300 MHz,
CDCl3) d ppm 1.35 (s, 3H), 1.48 (s, 3H), 3.13 (dt, J = 13.8, 5.6 Hz,
1H), 3.25 (ddd, J = 13.6, 7.8, 5.3 Hz, 1H), 3.73 (dd, J = 14.4, 6.2 Hz,
1H), 3.78–3.91 (m, 3H), 4.16 (app. td, J = 5.6, 1.5 Hz, 1H), 4.47 (d,
J = 1.8 Hz, 1H), 6.22 (dd, J = 7.3, 5.3 Hz, 1H), 6.98 (t, J = 6.3 Hz,
1H), 7.31–7.52 (m, 6H), 7.52–7.60 (m, 2H), 7.61–7.71 (m, 2H),
7.75–7.85 (m, 2H), 7.85–7.96 (m, 2H). 13C NMR (75 MHz, CDCl3)
d ppm 27.7, 27.9, 43.1, 43.7, 75.3, 83.6, 84.5, 92.2, 113.8, 127.1,
127.4, 127.6, 127.8, 128.5, 128.7, 129.1, 132.0, 133.7, 138.7,
5.1.17. N-(((3aS,6R,6aR)-2,2-Dimethyl-6-(phenylsulfonamidom-
ethyl)dihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)benzamide
(14e)
139.4, 145.5, 168.3. HRMS (ESI-TOF) m/z: [MꢀH]ꢀ Calcd for C28H29
-
General procedure 3. White foam, 60% 1H NMR (300 MHz,
CDCl3) d ppm 1.35 (s, 3H), 1.48 (s, 3H), 3.07 (app. dt, J = 13.6,
5.6 Hz, 1H), 3.21 (ddd, J = 13.6, 8.0, 5.4 Hz, 1H), 3.65–3.88 (m,
4H), 4.13 (app. td, J = 5.6, 1.5 Hz, 1H), 4.44 (d, J = 1.8 Hz, 1H), 6.11
(dd, J = 7.8, 5.1 Hz, 1H), 6.96 (t, J = 6.2 Hz, 1H), 7.34–7.59 (m, 6H),
7.72–7.93 (m, 4H). 13C NMR (75 MHz, CDCl3) d ppm 27.7, 27.9,
43.0, 43.6, 75.3, 83.6, 84.5, 92.2, 113.8, 127.0, 127.1, 128.8, 129.2,
132.0, 132.7, 133.7, 140.1, 168.3. HRMS (ESI-TOF) m/z: [MꢀH]ꢀ
Calcd for C22H25N2O6Sꢀ 445.14388; Found 445.1421.
N2O6Sꢀ 521.17518; Found 521.1768.
5.1.22. N-(((3aS,6R,6aR)-2,2-Dimethyl-6-((3-phenylureido)
methyl) dihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)
benzamide (15a)
A flask containing a solution of the crude amine 13 (originating
from 0.540 mmol of azide 12 via general procedure 1) in 5 mL of
pyridine was purged with nitrogen gas and treated with phenyliso-
cyanate (65.0 lL, 0.590 mmol). After 3 h, TLC (CH2Cl2/MeOH 97:3)
showed no starting material. Evaporation of pyridine and
purification of the residue via flash column chromatography
(CH2Cl2/MeOH 98:2) afforded the final compound in 76% yield.
1H NMR (300 MHz, CDCl3) d ppm 1.32 (s, 3H), 1.49 (s, 3H), 3.14
(app. dt, J = 14.2, 4.5 Hz, 1H), 3.62 (app. dt, J = 14.3, 7.1 Hz, 1H),
3.74 (dd, J = 14.4, 5.6 Hz, 1H), 3.81 (app. s, 2H), 3.93 (dd, J = 14.4,
7.3 Hz, 1H), 4.11 (app. t, J = 5.13 Hz, 1H), 4.51 (d, J = 1.2 Hz, 1H),
6.39 (dd, J = 7.2, 4.83 Hz, 1H), 6.96 (app. t, J = 7.3 Hz, 1H), 7.21
(app. t, J = 7.9 Hz, 2H), 7.30–7.44 (m, 4H), 7.46–7.54 (m, 1H), 7.78
(t, J = 6.3 Hz, 1H), 7.85–7.95 (m, 2H), 8.06 (s, 1H). 13C NMR
(75 MHz, CDCl3) d ppm 27.4, 27.9, 40.1, 42.6, 75.0, 84.0, 84.4,
92.0, 113.5, 119.6, 122.6, 127.3, 128.7, 128.9, 132.0, 133.5, 139.3,
156.8, 168.6. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C23H28N3O+5
426.20235; Found 426.2041.
5.1.18. N-(((3aS,6R,6aR)-2,2-Dimethyl-6-(((4-methylphenyl)
sulfonamido)methyl)dihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)
methyl)benzamide (14f)
General procedure 3. White powder, 86% 1H NMR (300 MHz,
CDCl3) d ppm 1.34 (s, 3H), 1.47 (s, 3H), 2.38 (s, 3H), 2.98–3.21
(m, 2H), 3.67–3.85 (m, 4H), 4.12 (app. td, J = 5.9, 1.3 Hz, 1H), 4.47
(d, J = 1.5 Hz, 1H), 6.10 (dd, J = 7.6, 5.3 Hz, 1H), 7.09 (t, J = 6.2 Hz,
1H), 7.23 (d, J = 8.2 Hz, 2H), 7.35–7.43 (m, 2H), 7.45–7.52 (m,
1H), 7.70 (d, J = 8.2 Hz, 2H), 7.76–7.83 (m, 2H). 13C NMR (75 MHz,
CDCl3) d ppm 21.6, 27.8, 27.9, 43.2, 43.7, 75.4, 83.6, 84.6, 92.3,
113.9, 127.14 (2 C), 128.8, 129.9, 132.0, 133.8, 137.1, 143.5,
168.2. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C23H29N2O6S+
461.17408; Found 461.1738.
5.1.19. N-(((3aS,6R,6aR)-6-(((4-Chlorophenyl)sulfonamido)
methyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-3a(4H)-
yl)methyl)benzamide (14g)
5.1.23. N-(((3aS,6R,6aR)-2,2-Dimethyl-6-((3-phenylthioureido)
methyl)dihydrofuro[3,4-d][1,3]dioxol-3a(4H)-yl)methyl)benz-
amide (15b)
General procedure 3. White foam, 91% 1H NMR (300 MHz,
CDCl3) d ppm 1.35 (s, 3H), 1.48 (s, 3H), 3.09 (app. dt, J = 13.7,
5.5 Hz, 1H), 3.22 (ddd, J = 13.6, 8.0, 5.4 Hz, 1H), 3.69 (dd, J = 14.4,
6.2 Hz, 1H), 3.75–3.90 (m, 3H), 4.13 (app. td, J = 5.5, 1.6 Hz, 1H),
4.42 (d, J = 1.8 Hz, 1H), 6.37 (dd, J = 7.8, 5.1 Hz, 1H), 6.95 (t,
J = 6.2 Hz, 1H), 7.36–7.56 (m, 5H), 7.71–7.86 (m, 4H). 13C NMR
(75 MHz, CDCl3) d ppm 27.7, 27.9, 43.0, 43.7, 75.3, 83.5, 84.4,
92.2, 113.9, 127.1, 128.5, 128.8, 129.4, 132.1, 133.6, 138.8, 139.0,
168.4. HRMS (ESI-TOF) m/z: [MꢀH]ꢀ Calcd for C22H24ClN2O6Sꢀ
479.10491; Found 479.1047.
A flask containing a solution of the crude amine 13 (originat-
ing from 0.560 mmol of azide 12 via general procedure 1) in 5 mL
of pyridine was purged with nitrogen gas and treated with
phenylisothiocyanate (74.0 mL, 0.620 mmol). After 3 h, TLC (CH2-
Cl2/MeOH 97:3) showed no starting material. Evaporation of pyr-
idine and purification of the residue via flash column
chromatography (CH2Cl2/MeOH 95:5) afforded the final com-
pound in 65% yield. 1H NMR (300 MHz, CDCl3) d ppm 1.37 (s,
3H), 1.48 (s, 3H), 3.63–3.80 (m, 3H), 3.83 (app. s, 2H), 3.97–
4.07 (m, 1H), 4.30 (app. t, J = 6.0 Hz, 1H), 4.48 (d, J = 1.8 Hz,
1H), 6.84 (br s, 1H), 7.09 (br s, 1H), 7.16–7.53 (m, 8H), 7.70–
7.83 (m, 2H), 8.61 (br s, 1H). 13C NMR (75 MHz, CDCl3) d ppm
27.7, 27.8, 43.1, 45.1, 75.0, 83.3, 84.4, 92.1, 113.8, 124.8, 126.6,
127.1, 128.6, 129.7, 131.9, 133.5, 136.9, 168.2, 181.2. HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C23H28N3O4S+ 442.17950; Found
442.1802.
5.1.20. N-(((3aS,6R,6aR)-6-(((2-Chlorophenyl)sulfonamido)
methyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-3a(4H)-
yl)methyl)benzamide (14h)
General procedure 3. White foam, 76% 1H NMR (300 MHz,
CDCl3) d ppm 1.34 (s, 3H), 1.46 (s, 3H), 3.04 (ddd, J = 13.7, 7.0,