J. Dong et al. / Bioorg. Med. Chem. 22 (2014) 1383–1393
1391
J2 = 2.5 Hz, 1H), 5.56 (d, J = 10.0 Hz, 1H), 5.7 (br s, 1H), 7.1 (br s, 1H).
4.3.4. (R)-N-Boc-3-hydroxyadamantylglycine-D-cis-4,5-
methanoprolinenitrile (19d)
13C NMR (125 MHz, CDCl3): d 173.8, 171.9, 156.9, 80.3, 68.4, 65.5,
59.9, 46.3, 44.4, 37.6, 35.2, 30.2, 28.3, 22.0, 18.3. ESI-MS m/z 434
[M+H]+. HRMS for C23H36N3O5 calcd 434.2655, found 434.2660
[M+H]+.
Compound 19d was prepared starting with 18d (340 mg,
0.79 mmol): white foam, 180 mg, 55% yield. ½a D25
ꢁ1.0 (c 0.48, CH3-
ꢃ
OH). 1H NMR (300 MHz, CDCl3): d 1.05–1.09 (m, 2H), 1.44 (s, 9H),
1.44–1.69 (m, 13H), 2.26 (br s, 2H), 2.35–2.40 (m, 1H), 2.51–2.55
(m, 1H), 3.84–3.86 (m, 1H), 4.46 (d, J = 9.0 Hz, 1H), 5.04 (dd,
J1 = 10.0 Hz, J2 = 3.0 Hz, 1H), 5.36 (d, J = 9.0 Hz, 1H): 13C NMR
(75 MHz, CDCl3): d 171.5, 155.5, 119.2, 68.8, 58.7, 46.2, 45.2,
44.3, 41.2, 37.4, 35.1, 30.4, 30.2, 28.3, 17.8, 13.5. ESI-MS m/z 416
[M+H]+. HRMS for C23H34N3O4 calcd 416.2549, found 416.2553
[M+H]+.
4.2.8. (R)-N-Boc-3-hydroxyadamantylglycine-D-trans-4,5-
methanoprolinamide (18h)
Compound 18h was prepared starting with 8b (0.45 g,
1.38 mmol) and 15d (0.32 g, 1.45 mmol): white solids, 0.35 g,
57% yield. ½a 2D5
ꢃ
72.3 (c 0.34, EtOAc). 1H NMR (500 MHz, CDCl3): d
0.59–0.61 (m, 1H), 1.14–1.17 (m, 1H), 1.50 (s, 9H), 1.59–1.65 (m,
12H), 1.88–1.90 (m, 1H), 1.99–2.01 (m, 1H), 2.24 (br s, 2H), 2.72–
2.75 (m, 1H), 3.37–3.40 (m, 1H), 4.62–4.67 (m, 1H), 5.2 (d,
J = 10.0 Hz, 1H), 5.6 (br s, 1H), 6.7 (br s, 1H). 13C NMR (125 MHz,
CDCl3): d 172.8, 170.2, 155.4, 79.8, 68.6, 64.6, 58.9, 46.0, 44.5,
37.5, 35.3, 30.2, 29.0, 28.3, 21.2, 19.4. ESI-MS m/z 434 [M+H]+.
HRMS for C23H36N3O5 calcd 434.2655, found 434.2659 [M+H]+.
4.3.5. (S)-N-Boc-3-hydroxyadamantylglycine-L-trans-4,5-
methanoprolinenitrile (19e)
Compound 19e was prepared starting with 18e (430 mg,
1.0 mmol): white foam, 250 mg, 60% yield. ½a D25
ꢁ90.3 (c 0.35, CH3-
ꢃ
OH). 1H NMR (300 MHz, CDCl3): d 0.67–0.72 (m, 1H), 1.23–1.25 (m,
1H), 1.43 (s, 9H), 1.43–1.74 (m, 12H), 2.00–2.05 (m, 1H), 2.27 (br s,
2H), 2.54–2.60 (m, 2H), 3.50–3.55 (m, 1H), 4.57 (d, J = 12.0 Hz, 1H),
4.83–4.87 (m, 1H), 5.24 (d, J = 12.0 Hz, 1H). 13C NMR (75 MHz,
CDCl3): d 172.2, 155.8, 118.2, 68.8, 58.8, 51.1, 46.0, 44.3, 37.3,
37.0, 35.1, 32.7, 30.2, 28.3, 27.3, 21.5, 18.9. ESI-MS m/z 416
[M+H]+. HRMS for C23H34N3O4 calcd 416.2549, found 416.2552
[M+H]+.
4.3. General procedure for the preparation of 19a–h
To a solution of 18a–h (1.0 equiv), pyridine (5.0 equiv) in dry
THF, trifluoroacetic anhydride (2.5 equiv) was added dropwise at
0 °C. After stirred for 0.5 h, TLC plate indicated the conversion
was finished. The solvent was removed under vacuum. To the res-
idue were added 10% aqueous K2CO3 solution and methol. The
mixture was stirred for 18 h at room temperature. After removal
of MeOH, the remaining aqueous layer was extracted with EtOAc.
The combined organic extract was washed with 1 N HCl, 1 N NaOH
and brine, dried over Na2SO4, purified by flash chromatography.
4.3.6. (R)-N-Boc-3-hydroxyadamantylglycine-L-trans-4,5-
methanoprolinenitrile (19f)
Compound 19f was prepared starting with 18f (300 mg,
0.69 mmol): white foam, 200 mg, 70% yield.
½
a 2D5
ꢃ
ꢁ84.2 (c
0.41, CH3OH). 1H NMR (300 MHz, CDCl3): d 0.61–0.66 (m, 1H),
1.16–1.23 (m, 1H), 1.46 (s, 9H), 1.41–1.74 (m, 12H), 2.00–2.02
(m, 1H), 2.23 (br s, 2H), 2.31–2.33 (m, 1H), 2.58–2.66 (m, 1H),
3.82–3.84 (m, 1H), 4.47 (d, J = 9.0 Hz, 1H), 4.58 (dd, J1 = 9.0 Hz,
J2 = 3.0 Hz, 1H), 5.25 (d, J = 12.0 Hz, 1H). 13C NMR (75 MHz,
4.3.1. (S)-N-Boc-3-hydroxyadamantylglycine-L-cis-4,5-
methanoprolinenitrile (19a)
Compound 19a was prepared starting with 18a (264 mg,
0.64 mmol): white foam, 200 mg, 79% yield. ½a D25
ꢃ
1.8 (c 0.25,
CH3OH). 1H NMR (300 MHz, CDCl3): d 1.05–1.09 (m, 2H), 1.44
(s, 9H), 1.44–1.93 (m, 13H), 2.26 (br s, 2H), 2.37 (dd, J1 = 11.5 Hz,
J2 = 2.0 Hz, 1H), 2.58 (ddd, J1 = 13.4 Hz, J2 = 9.3 Hz, J3 = 5.9 Hz, 1H),
3.82–3.83 (m, 1H), 4.46 (d, J = 9.8 Hz, 1H), 5.04 (dd, J1 = 10.6 Hz,
J2 = 2.1 Hz, 1H), 5.30 (d, J = 9.8 Hz, 1H). ESI-MS m/z 416 [M+H]+.
CDCl3): d 171.2, 155.5, 117.8, 79.9, 68.5, 58.9, 51.1, 44.5,
37.3, 37.0, 35.1, 32.9, 30.2, 28.3, 21.6, 18.6. ESI-MS m/z 416
[M+H]+. HRMS for C23H34N3O4 calcd 416.2549, found 416.2554
[M+H]+.
4.3.7. (S)-N-Boc-3-hydroxyadamantylglycine-D-trans-4,5-
4.3.2. (R)-N-Boc-3-hydroxyadamantylglycine-
L-cis-4,5-
methanoprolinenitrile (19g)
methanoprolinenitrile (19b)
Compound 19g was prepared starting with 18g (430 mg,
Compound 19b was prepared starting with 18b (250 mg,
1.0 mmol): white foam, 250 mg, 61% yield. ½a D25
ꢃ
98.5 (c 0.33,
0.60 mmol): white foam, 130 mg, 54% yield. ½a D25
ꢃ
ꢁ9.5 (c 0.26,
EtOAc). 1H NMR (300 MHz, CDCl3):
d 0.64–0.66 (m, 1H),
CH3OH). 1H NMR (300 MHz, CDCl3): d 0.97–0.99 (m, 1H), 1.13–
1.15 (m, 1H), 1.41 (s, 9H), 1.41–1.86 (m, 13H), 2.23 (br s, 2H),
2.38–2.42 (m, 1H), 2.53–2.58 (m, 1H), 3.63–3.66 (m, 1H), 4.50
(d, J = 9.0 Hz, 1H), 4.88 (dd, J1 = 12.0 Hz, J2 = 3.0 Hz, 1H), 5.29
(d, J = 9.0 Hz, 1H). 13C NMR (75 MHz, CDCl3): d 171.9, 155.2,
119.1, 68.7, 58.9, 46.1, 45.2, 44.5, 40.8, 35.1, 30.7, 30.2, 28.3,
27.3, 16.8, 12.7. ESI-MS m/z 416 [M+H]+. HRMS for C23H34N3O4
calcd 416.2549, found 416.2553 [M+H]+.
1.16–1.20 (m, 1H), 1.45 (s, 9H), 1.43–1.69 (m, 12H), 2.00–2.05
(m, 1H), 2.23 (br s, 2H), 2.36–2.38 (m, 1H), 2.55–2.59 (m, 1 H),
3.83–3.85 (m, 1H), 4.48 (d, J = 12.0 Hz, 1H), 4.58 (dd,
J1 = 9.0 Hz, J2 = 3.0 Hz, 1H), 5.30 (d, J = 9.0 Hz, 1H). 13C NMR
(75 MHz, CDCl3): d 171.2, 155.9, 117.8, 80.3, 68.9, 58.9, 51.1,
44.3, 37.3, 37.0, 35.1, 32.8, 30.2, 28.3, 21.5, 18.6. ESI-MS m/z
416 [M+H]+. HRMS for C23H34N3O4 calcd 416.2549, found
416.2553 [M+H]+.
4.3.3. (S)-N-Boc-3-hydroxyadamantylglycine-
D
-cis-4,5-
4.3.8. (R)-N-Boc-3-hydroxyadamantylglycine-D-trans-4,5-
methanoprolinenitrile (19c)
methanoprolinenitrile (19h)
Compound 19c was prepared starting with 18c (1.51 g,
Compound 19h was prepared starting with 18h (280 mg,
3.5 mmol): white foam, 1.40 g, 97% yield. ½a D25
ꢃ
16.1 (c 0.54, EtOAc).
0.69 mmol): white foam, 170 mg, 63% yield. ½a D25
ꢃ
76.2 (c 0.49,
1H NMR (300 MHz, CDCl3): d 0.96–0.99 (m, 1H), 1.11–1.13 (m, 1H),
1.41 (s, 9H), 1.41–1.86 (m, 13H), 2.23 (br s, 2H), 2.36–2.38 (m, 1H),
2.53–2.63 (m, 1H), 3.64–3.66 (m, 1H), 4.50 (d, J = 9.0 Hz, 1H), 4.88
(dd, J1 = 12.0 Hz, J2 = 3.0 Hz, 1H), 5.29 (d, J = 9.0 Hz, 1H). 13C NMR
(75 MHz, CDCl3): d 170.3, 155.5, 119.1, 68.9, 58.9, 45.8, 45.3,
44.3, 44.2, 40.8, 35.1, 30.2, 30.1, 28.3, 27.3, 16.8, 12.7. ESI-MS m/z
416 [M+H]+. HRMS for C23H34N3O4 calcd 416.2549, found
416.2554 [M+H]+.
EtOAc). 1H NMR (300 MHz, CDCl3): d 0.67–0.72 (m, 1H), 1.22–
1.25 (m, 1H), 1.43 (s, 9H), 1.43–1.69 (m, 12H), 1.99–2.01 (m, 1H),
2.25 (br s, 2H), 2.24–2.27 (m, 1H), 2.54–2.59 (m, 1H), 3.51–3.56
(m, 1H), 4.57 (d, J = 9.0 Hz, 1H), 4.83–4.87 (m, 1H), 5.27 (d,
J = 9.0 Hz, 1H). 13C NMR (75 MHz, CDCl3): d 171.9, 155.5, 118.2,
68.9, 58.8, 51.1, 44.2, 40.9, 37.1, 32.7, 30.2, 28.3, 27.3, 21.4, 18.9.
ESI-MS m/z 416 [M+H]+. HRMS for C23H34N3O4 calcd 416.2549,
found 416.2552 [M+H]+.