Tetrahedron Letters
3
Fisher, D.A.; Smith, J.F.; Zagouras, P.; Magna, H.A.;
Saltarelli, M.J.; Johnson, K.S.; Nelms, L.F.; Des Etages, S.G.;
Hayes, L.S.; Kawabta, T.T.; Finco–Kent, D.; Baker, D.L.;
Larson, M.; Si, M.–S.; Paniagua, R.; Higgins, J.; Holm, B.;
Reitz, B.; Zhou, Y.–J.; Morris, R.E.; O’Shea, J.J.; Borie, D.C.
Science 2003, 302, 875–878.
Shia, S.; Steffek, M.; Ubhayakar, S.; Ultsch, M.; Van
Abbema, A.; Ward, S.I.; Waszkowycz, B.; Zak, M. J. Med.
Chem. 2012, 55, 5901–5921.
3. Jiang, J.–K.; Ghoreschi, K.; Deflorian, F.; Chen, Z.; Perreira,
M.; Pesu, M.; Smith, J.; Nguyen, D.–T.; Liu, E.H.; Leister,
W.; Costanzi, S.; O’Shea, J.J.; Thomas, C.J. J. Med. Chem.
2008, 51, 8012–8018.
2. Kulagowski, J.J; Blair, W; Bull, R.J.; Chang ,C.; Deshmukh,
G.; Dyke, H.J.; Eigenbrot, C.; Ghilardi, N.; Gibbons, P.;
Harrison, T.K.; Hewitt, P.R.; Liimatta, M.; Hurley, C.A.;
Johnson, A.; Johnson, T.; Kenny, J.R.; Bir Kohli, P.; Maxey,
R.J.; Mendonca, R.; Mortara, K.; Murray, J.; Narukulla, R.;
BuLi, DABCO,
1. HMDS
OH
TBDPSCl
O
tBu Boc2O, -78˚C
O
tBu
OTBDPS
BuLi
PhSeCl
-78˚C
THF
2. H2O2
60%
Si
Si
THF
Ph
Ph
Ph
Ph
imidazole
DMF
96%
85%
O
N
H
O
N
H
O
N
O
N
Boc
Boc
2
3
4
NHMe
DIAD-Ph3P
Dioxane
100 oC, 2 h
68%
Boc
N
MeMgBr
CuBr.S(CH3)2
(CH3)3SiCl
Et2O
OTBDPS
OH
a. AlH3, THF, 78%
b. TBAF/THF, 75%
N
NMe
N
N
O
N
N
N
H
Boc
Boc
-78˚C, 62%
5
6b
7
1-Boc
N
N
H
CN
HN
ZnBr2
CH2Cl2
EDC/HOBt
CH2Cl2
N
NMe
N
O
NC
CO2H
80%
95%
NMe
N
N
N
N
H
N
H
1
1-NH
Scheme 1. Proposed synthetic route for the total synthesis of CP-690,550.
1.05 (s, 9H), 1.75-1.95 (m, 2H), 2.23 (ddd, J 17.2, 6.1, 6.1
Hz, 1H), 2.66 (ddd, J 17.2, 9.0, 6.1 Hz, 1H), 3.16-3.23 (m,
2H), 4.03-4.10 (m, 1H), 6.08 (s, 1H, NH), 7.30-7.50 (m, 6H),
7.60-7.70 (m, 2H). 13C NMR (100 MHz, CDCl3), : 19.0,
27.0, 27.6, 28.5, 48.8, 64.5, 127.8 (4xC), 129.9 (4xC), 130.2
(2xC), 135.5 (2xC), 172.3. HRMS (ESI): m/z calc. for
[C21H27NO2Si + H]+ 354.1889; found: 354.1893. Anal. calcd
for C21H27NO2Si: C, 71.34; H, 7.70; N, 3.96; O, 9.05. Found:
C, 71.42; H, 7.68; N, 3.94; O, 9.08.
4. Vijayakrishnan, L.; Venkataramana, R.; Gulati, P. Trends
Pharmacol. Sci. 2011, 32, 25–34.
5. Seavey, M.M.; Dobrzanski, P. Biochem. Pharmacol. 2012,
83, 1136–1145.
6. Matsumura, Y.; Ogino, T.; Libendi, S.S.; Onomura, O. 209th
ECS Meeting, Abstract #952, 2006.
7. Cabello-Sanchez, N.; Jean, L.; Maddaluno, J.; Lasne, M.-C.;
Rouden, J. J. Org. Chem. 2007, 72, 2030–2039.
8. Analytical data for compound 2: []D = -12.9 (c 1.0,
CH3OH). >96% ee determined by HPLC using a Chiralpack
OD column. m.p. 120-121 oC, white solid. 1H NMR (400
MHz, CD3OD), : 1.82-2.01 (m, 2H), 2.28 (ddd, J 16.0, 7.0,
7.0 Hz, 1H), 2.51 (ddd, J 16.0, 7.0, 7.0 Hz, 1H), 3.19 (dd, J
12.0, 5.0, 1H), 3.40 (dd, J 12.0 Hz, 4.0 Hz, 1H), 4.09 (m, 1H).
13C NMR (100 MHz, CD3OD), : 28.0, 28.9, 49.0, 63.5,
172.3. HRMS (ESI): m/z calc. for [C5H10NO2 + H]+ 116.0712;
found: 116.0710. Anal. calcd for C21H27NO2Si: C, 71.34; H,
7.70; N, 3.96; O, 9.05. Found: C, 71.42; H, 7.68; N, 3.94; O,
9.08.
11. Kaiser, E. M.; Yun, H. H. J. Org. Chem. 1970, 35, 1348-
1351.
12. Analytical data for compound 3: []D = -21.9 (c 1.0,
EtOAc). Colourless oil. FT-IR (KBr cell): 1775 and 1720
cm-1. 1H NMR (400 MHz, CDCl3), : 1.05 (s, 9H), 1.47 (s,
9H), 1.80-1-90 (m, 2H), 2.40 (ddd, J 17.0, 6.0, 6.0 Hz, 1H),
2.71 (ddd, J 17.0, 9.0, 6.0 Hz, 1H), 3.39 (dd, J 13.0, 3.0 Hz,
1H), 3.70 (dd, J 13.0, 4.0 Hz, 1H), 4.12-4.18 (m, 1H), 7.30-
7.46 (m, 6H), 7.63-7.70 (m, 4H). 13C NMR (100 MHz,
CDCl3), : 18.5, 26.8, 27.6, 28.1, 30.6, 51.6, 64.9, 82.1,
127.5, 129.6, 133.0, 135.0, 152.1, 170.3. HRMS (ESI): m/z
calc. for [C26H34NO4Si + H]+ 453.2335; found: 453.2333.
Anal. calcd for C26H34NO4Si: C, 68.84; H, 7.78; N, 3.09; O,
14.11. Found: C, 68.88; H, 7.81; N, 3.10; O, 14.13.
9. Herdeis, C. Synthesis 1986, 3, 232–233.
10. Analytical data for compound 2-OTBDPS: []D = -14.9 (c
1.0, EtOAc). m.p. 79-80 oC, colorless crystal. FT-IR (KBr
1
cell): 3210 and 1675 cm-1. H NMR (400 MHz, CDCl3), :