U. K. Bandarage, R. J. Davies / Tetrahedron Letters 51 (2010) 6415–6417
6417
Bn
Boc
Bn
N
N
N
1. (COCl)2 , DCM, DMF
RT, 1 hr
F
F
10% Pd / C, H2
F
6N HCl
9
reflux, 18 hr
100%
2. AlCl3, DCM
RT, 1 hr
(Boc)2O, EtOH
RT, 18 hr
66%
CO2H
O
O
81%
13
14
15
Scheme 3. Formation of Spiropyrrolidine-tetralones.
Boc
N
Boc
N
Boc
N
F
MgBr
NC
CO2C2H5
NH4OAc, C6H6
reflux, 48 hr
76%
CuCN, THF
RT, 6 hr
F
CN
O
C2H5O2C
CN
91%
CO2C2H5
16
17
Boc
N
Boc
1. LiCl, DMSO, H2O
160 oC , 3 hr
N
1. Eaton's reagent, RT, 18 hr
F
F
2. NaOH, EtOH, H2O
reflux, 48 hr
55%
2. NaOH,(Boc)2O, RT, 18 hr
83%
OH
O
O
1b
18
Scheme 4. Second route to synthesis of spiropiperidine–indanone.
R.; Stearns, R. A.; Chen, H. Y.; Chen, A. S.; Fong, T. M.; Wyvratt, M. J., Jr.;
Nargund, R. P. Bioorg. Med. Chem. Lett. 2010, 20, 4305–4399.
3. He, S.; Ye, Z.; Dobbelaar, P. H.; Sebhat, I. K.; Guo, L.; Liu, J.; Jian, T.; Lai, Y.;
Franklin, C. L.; Bakshi, R. K.; Dellureficio, J. P.; Hong, Q.; Tsou, N. N.; Ball, R. G.;
Cashen, D. E.; Martin, W. J.; Weinberg, D. H.; MacNeil, T.; Tang, R.;
Tamvakopoulos, C.; Peng, Q.; Miller, R. R.; Stearns, R. A.; Chen, H. Y.; Chen, A.
S.; Strack, A. M.; Fong, T. M.; MacIntyre, D. E.; Wyvratt, M. J.; Nargued, R. P.
Bioorg. Med. Chem. Lett. 2010, 20, 2106–2110.
1.97, and 1.55 ppm corresponding to the desired piperidine ring
system and at 2.74 ppm a two proton singlet for the indanone
methylene group.
In conclusion, we have developed an efficient, high yielding
reaction sequence to generate novel spiropyrrolidine–tetralone
ring systems via an unexpected ring opening of a bridged bicyclic
ammonium salt intermediate with a nitrile nucleophile. These
new spiropyrrolidine–tetralones have the potential to be utilized
as key building blocks for a variety of drug discovery programs in
medicinal chemistry.
4. Chu, G.; Le Bourdonnec, B.; Gu, M.; Saeui, C. T.; Dolle, R. E. Tetrahedron 2009, 65,
5161–5167.
5. Makings, L. R.; Garcia-Guzman B. M.; Hurley, D. J.; Drutu, I.; Raffai, G.; Bergeron,
D. M.; Nakatani, A.; Termin, A. P.; Silina, A. U.S. 2007043023.
6. For the recent review see Hagmann, W. K. J. Med. Chem. 2008, 51, 359–4368.
7. Weng, Z.; Li, J. Bioorg. Med. Chem. Lett. 2010, 20, 1256–1259.
8.
Acknowledgment
Boc
N
Boc
N
The authors acknowledge Dr. Michael Clark, Dr. Youssef Bennani
and Dr. Katrina Jackson at Vertex Pharmaceuticals for valuable
comments, suggestions and corrections.
F
F
1. MsCl, Et3N, DCM
2. NaCN, DMSO
100 oC
Supplementary data
OH
CN
Supplementary data associated with this article can be found, in
9. Della, E. W.; Smith, P. A. J. Org. Chem. 1999, 64, 1798–1806.
10. Guo, L.; Hf, S.; Jian, T.; Lai, Y.; Liu, J.; Nargund, R. P.; Sebhat, I.K.; Ujjinwalla, F.;
Yf, Z.; PCT 2004089307.
11. Compound 15 1H NMR (CD3OD, 500 MHz) d 8.05–8.08 (m, 1H), 7.07–7.14 (m,
2H), 3.68 (m, 1H), 3.58 (m, 1H), 3.50–3.53 (m, 2H), 2.68–2.78 (m, 2H), 2.21–
2.25 (m, 3H), 2.08–2.19 (m, 1H), 150 (s, 9H).
References and notes
1. Limanto, J.; Shultz, C. S.; Dorner, B.; Desmond, R. A.; Devine, P. N.; Krska, S. W. J.
Org. Chem. 2008, 73, 1639–1642. and references therein.
2. He, S.; Ye, Z.; Dobbelaar, P. H.; Sebhat, I. K.; Guo, L.; Liu, J.; Jian, T.; Lai, Y.;
Franklin, C. L.; Bakshi, R. K.; Dellureficio, J. P.; Hong, Q.; Tsou, N. N.; Weinberg,
D. H.; MacNeil, T.; Tang, R’; Strack, A. M.; Tamvakopoulos, C.; Peng, Q.; Miller, R.
12. Compound 1b 1H NMR (CD3OD, 500 MHz) d 7.73 (dd, J = 8.5, 5.3 Hz, 1H), 7.39
(dd, J = 9.1, 2.2 Hz, 1H), 7.19 (t m, 1H), 4.18 (m, 2H), 2.94 (s, 2H), 2.74 (s, 2H),
1.97 (m, 2H), 1.55 (m, 2H), 1.49 (s, 9H).