1
828
D. S. Radchenko et al.
LETTER
Santini, A.; Saviano, M.; Kamphuis, J. J. Pept. Sci. 1997, 3,
110. (b) Jiménez-Osés, G.; Corzana, F.; Busto, J. H.; Pérez-
Fernández, M.; Peregrina, J. M.; Avenoza, A. J. Org. Chem.
2006, 71, 1869.
O
O
O
O
O
a
b
i-PrO2C
CO2i-Pr
10
i-PrO2C
53%
quant.
Br Br
CO2i-Pr
(
3) Robins, L. I.; Dixon, S. M.; Wilson, D. K.; Kurth, M. J.
Bioorg. Med. Chem. 2006, 14, 7728.
(4) Wrobleski, M. L.; Reichard, G. A.; Paliwal, S.; Shah, S.;
Tsui, H.-C.; Duffy, R. A.; Lachowicz, J. E.; Morgan, C. A.;
Varty, G. B.; Shih, N.-Y. Bioorg. Med. Chem. Lett. 2006, 16,
8
9
H
H
O
N
O
N
c
O
d
O
NH
NH
93%
91%
3859.
i-PrO2C
HOOC
(
5) Gaoni, Y.; Chapman, A. G.; Parvez, N.; Pook, P. C.-K.;
Jane, D. E.; Watkins, J. C. J. Med. Chem. 1994, 37, 4288.
6) Allan, R. D.; Hanrahan, J. R.; Hambley, T. W.; Johnston,
G. A. R.; Mewett, K. N.; Mitrovic, A. D. J. Med. Chem.
CO2i-Pr
COOH
11
12
(
H
N
O
COOH
NH2
1990, 33, 2905.
e
0%
f
O
(7) Kabalka, G. W.; Yao, M.-L. J. Org. Chem. 2004, 69, 8280.
NH
6
65%
F3C
(8) (a) Martarello, L.; McConathy, J.; Camp, V. M.; Malveaux,
E. J.; Simpson, N. E.; Simpson, C. P.; Olson, J. J.; Bowers,
G. D.; Goodman, M. M. J. Med. Chem. 2002, 45, 2250.
F3C
⋅HCl
CF3
CF3
13
6
(
b) Shoup, T. M.; Goodman, M. M. J. Labelled Compd.
Radiopharm. 1999, 42, 215. (c) Goodman, M. M.
WO 2007001940 A2 20070104, 2007.
9) (a) O’Hagan, D.; Rzepa, H. S. Chem. Commun. 1997, 645.
Scheme 1 Reagents and conditions: (a) CH (CO i-Pr) (2.2 equiv),
2
2
2
NaH (2.0 equiv), DMF, 140 °C, 48 h; (b) HCl , acetone, r.t., 24 h; (c)
aq
(
(
(
NH ) CO (3.0 equiv), KCN (1.5 equiv), H O–EtOH, 60 °C, 24 h;
4
2
3
2
(
b) Kirsch, P. In Modern Fluoroorganic Chemistry; Wiley-
d) (i) NaOH (8 equiv), H O r.t., 10 h; (ii) HCl ; (e) SF (6 equiv),
2
aq
4
VCH: Weinheim, 2004.
HF, 90 °C, 24 h; (f) (i) NaOH (10 equiv), H O, reflux, 24 h; (ii) HCl .
2
aq
(
(
10) Gallucci, R. R.; Going, R. J. Org. Chem. 1981, 46, 2532.
11) (a) Perkin, W. H. Ber. Dtsch. Chem. Ges. 1883, 16, 1787.
(b) Perkin, W. H. Ber. Dtsch. Chem. Ges. 1884, 17, 54.
(c) Pigou, P. E.; Schiesser, C. H. J. Org. Chem. 1988, 53,
3841.
12) (a) Bergs, H. DE 566094, 1929; Chem. Abstr. 1933, 27:
1001. (b) Bucherer, H. R.; Barsch, H. J. Prakt. Chem. 1934,
H
O
O
O
N
O
a
b
O
NH
i-PrO2C
95%
45%
(
HOOC
CO2i-Pr
HOOC
9
14
15a,b
140, 151.
H
H
N
(13) Dmowski, W. Houben–Weyl Methods of Organic
Chemistry, Vol. E10a; Baasner, B.; Hagemann, H.; Tatlow,
J. C., Eds.; Thieme: Stuttgart, 1999, 321.
O
N
O
COOH
NH2
c
5%
O
d
61%
e
O
NH
NH
6
62%
(
14) Spectral and Analytical Data for New Compounds
*HCl
Diisopropyl 3-Oxo-1,1-cyclobutanedicarboxylate (10)
CF3
CF3
CF3
1
1
6a,b
16a
7
H NMR (400 MHz, CDCl ): d = 5.10 [m, J = 6.4 Hz, 2 H,
3
CH(CH ) ], 3.58 (s, 4 H, CH ), 1.26 [d, J = 6.4 Hz, 12 H,
CH(CH ) ]. C NMR (100 MHz, CDCl ): d = 200.95 (s,
CH CO), 169.64 (s, COO), 69.66 [s, CH(CH ) ], 54.98 (s,
3
2
2
Scheme 2 Reagents and conditions: (a) 12 N HCl , reflux, 72 h; (b)
13
aq
3
2
3
(
(
i) (NH ) CO (3.0 equiv), KCN (1.5 equiv), H O–EtOH, 60 °C, 24 h;
4
2
3
2
2
3 2
ii) HClaq (c) SF (3 equiv), HF, 90 °C, 24 h; (d) crystallization from
4
CH CO), 43.54 [s, C(COOi-Pr) ], 21.14 [s, CH(CH ) ]. MS:
2
2
3 2
MeCN; (e) (i) NaOH (10 equiv), H O, reflux, 24 h; (ii) HCl .
2
aq
m/z = 243 [M + 1].
Diisopropyl 6,8-Dioxo-5,7-diazaspiro[3.4]octane-2,2-
O
dicarboxylate (11)
Mp 142–143 °C. H NMR (400 MHz, CDCl ): d = 8.75 (br
s, 1 H, NH), 6.69 (s, 1 H, NH), 5.03 [m, 2 H, CH(CH ) ],
H
1
NH
3
H
strong NOE
weak NOE
F3C
3 2
N
O
3.14 (d, J = 13.6 Hz, 2 H, CH ), 2.63 (d, J = 13.6 Hz, 2 H,
2
H
H
CH ), 1.18 [2 overlapped d, J = 6.4 Hz, 12 H, CH(CH ) ].
2
3 2
1
3
16a
C NMR (100 MHz, CDCl ): d = 175.70 (s, CCONH),
72.22 (s, COO), 169.20 (s, COO), 156.08 (s, NHCONH),
3
1
Figure 3 Determination of the stereochemistry of 16a by H,H-
7
0.64 [s, CH(CH ) ], 69.55 [s, CH(CH ) ], 58.16 (s,
3
2
3 2
NOESY experiments
NHCCO), 46.72 (s, CH ), 41.98 [s, C(COOi-Pr) ], 39.14 (s,
2
2
CH ), 21.68 [s, CH(CH ) ], 21.63 [s, CH(CH ) ]. MS: m/z =
2
3
2
3 2
313 [M + 1].
2
,2-Bis(trifluoromethyl)-5,7-diazaspiro[3.4]octane-6,8-
References and Notes
dione (13)
1
Mp >230 °C. H NMR [500 MHz, (CD ) SO]: d = 10.88 (s,
(
1) (a) Tsang, J. W.; Schmied, B.; Nyfeler, R.; Goodman, M.
J. Med. Chem. 1984, 27, 1663. (b) Gershonov, E.; Granoth,
R.; Tzehoval, E.; Gaoni, Y.; Fridkin, M. J. Med. Chem.
3 2
1
2
H, NH), 8.59 (s, 1 H, NH), 3.14 (d, J = 12.0 Hz, 2 H, CH ),
2
1
9
.69 (d, J = 12.0 Hz, 2 H, CH ). F NMR [377 MHz,
2
4
(
CD ) SO]: d = –71.72 (q, J = 7.4 Hz, CF ), –73.13 (q,
3 2 F–F 3
13
1
996, 39, 4833.
4
JF–F = 7.4 Hz, CF3). C NMR [125 MHz, (CD ) SO]: d =
1
(
2) (a) Gatos, M.; Formaggio, F.; Crisma, M.; Toniolo, C.;
Bonora, G. M.; Benedetti, Z.; Di Blasio, B.; Iacovino, R.;
3 2
1
76.23 (s, CCONH), 157.14 (s, NHCONH), 126.87 (q, J
C–
1
=
280.0 Hz, CF ), 125.15 (q, J = 277.5 Hz, CF ), 55.52
F
3 C–F 3
(
s, NHCCO), 42.73 [m, C(CF ) ], 33.79 (s, CH ). MS: m/z =
3 2 2
277 [M + 1].
Synlett 2009, No. 11, 1827–1829 © Thieme Stuttgart · New York