6890
Y. Shishido et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6887–6890
C. A. Expert Opin. Ther. Targets 2003, 7, 342; (c± Albert,
J. S. Expert Opin. Ther. Targets 2004, 14, 1421.
18. Anwer, M. K.; Spatola, A. F. Synthesis 1980, 929.
*
*
*
*
19. (1R ,3S ,4S ,5S )-4-[(N-(2-methoxy-5-trifluoromethoxyben-
zyl)amino]-3-phenyl-2-aza-7-oxabicyclo[3.3.0]octane) (com-
2
. Hale, J. J.; Mills, S. G.; MacCoss, M.; Finke, P. E.;
Cascieri, M. A.; Sadowski, S.; Ber, E.; Chicchi, G. G.;
Kurtz, M.; Metzger, J.; Eirmann, G.; Tsou, N. N.;
Tattersall, F. D.; Rupniak, N. M. J.; Williams, A. R.;
Rycroft, W.; Hargreaves, R.; MacIntyre, D. E. J. Med.
Chem. 1998, 41, 4607.
. Ito, F.; Kondo, H.; Shimada, K.; Nakane, M.; Lowe, J. A.
III; Rosen, T. J.; Yang, B. V. WO 9221677 A1.
. Desai, M. C.; Lefkowitz, S. L.; Bryce, D. K.; McLean, S.
Bioorg. Med. Chem. Lett. 1994, 4, 1865.
1
pound (± )-1±. H NMR (600 MHz± d (CDCl
3
±: 2.05 (br s,
2H±, 2.86 (td, J = 7.8, 3.6 Hz, 1H±, 3.02 (d, J = 4.5 Hz,
1H±, 3.50 (d, J = 14.2 Hz, 1H±, 3.56 (s, 3H±, 3.69 (d,
J = 14.2 Hz, 1H±, 3.74 (dd, J = 9.5, 3.6 Hz±, 3.78 (dd,
J = 9.7, 2.7 Hz, 1H±, 3.81 (dd, J = 9.7, 5.7 Hz, 1H±, 3.85
(dd, J = 9.5, 7.8 Hz, 1H±, 4.18–4.24 (m, 1H±, 6.71 (d,
J = 8.8 Hz, 1H±, 6.90 (d, J = 2.5 Hz, 1H±, 7.04 (dd, J = 8.8,
2.5 Hz, 1H±, 7.23–7.29 (m, 3H±, 7.31–7.36 (m, 2H± ppm.
3
4
5
1
3
3
C NMR (125 MHz± d (CDCl ±: 46.4, 49.5, 55.3, 62.6,
. (a± Harrison, T.; Williams, B. J.; Swain, C. J.; Ball, R. G.
Bioorg. Med. Chem. Lett. 1994, 4, 2545; (b± Harrison, T.;
Owens, A. P.; Williams, B. J.; Swain, C. J.; Baker, R.;
Hutson, P. H.; Sadowski, S.; Cascieri, M. A. Bioorg. Med.
Chem. Lett. 1995, 5, 209; (c± Hale, J. J.; Mills, S. G.;
MacCoss, M.; Shah, S. K.; Qi, H.; Mathre, D. J.; Cascieri,
M. A.; Sadowski, S.; Strader, C. D.; MacIntyre, D. E.;
Metzger, J. M. J. Med. Chem. 1996, 39, 1760; (d±
Ashwood, M. S.; Cottrell, I. F.; Davies, A. J. Tetrahedron:
Asymmetry 1997, 8, 957; (e± Ladduwahetty, T.; Baker, R.;
Cascieri, M. A.; Chambers, M. S.; Haworth, K.; Keown,
L. E.; MacIntyre, D. E.; Metzger, J. M.; Owen, S.;
Rycroft, W.; Sadowski, S.; Seward, E. M.; Shepheard, S.
L.; Swain, C. J.; Tattersall, F. D.; Watt, A. P.; Williamson,
D. W.; Hargreaves, R. J. J. Med. Chem. 1996, 39, 2907; (f±
Williams, B. J.; Cascieri, M. A.; Chicchi, G. G.; Harrison,
T.; Owens, A. P.; Own, S. N.; Rupniak, N. M. J.;
Tattersall, D. F.; Williams, A.; Swain, C. J. Bioorg. Med.
Chem. Lett. 2002, 12, 2719.
65.3, 67.0, 72.8, 76.5, 110.4, 120.5 (q, J = 125 Hz±, 120.6,
122.6, 126.9 (two carbons±, 127.1, 128.2 (two carbons±,
129.5, 138.1, 142.3, 155.9 ppm. IR mmax (film±: 3340, 1496,
À1
1457, 1248, 1163, 1032, 917, 700 cm . MS (ESI± m/z 409
(M+H± .
+
72.8
3.56
55.3
MeO
3
.85 α/3.74 β
6.71
O
110.4
2
.86
7
6.5
2.05 br
H
155.9
7
.04
3
.81 α/3.78 β
49.5
62.6
H
1
20.6
N
129.5
142.3
6
7.0
.02
4.21H
46.4
.69/3.50
3
3
1
6
22.6
.90
OCF
HN
3
6
5.3
.45 138.1
2.05 br
120 5 (q,
56 Hz)
4
2
7.24
1
26.9
7
.27
7.34
28.4
1
27.1
1
6
. Desai, M. C.; Lefkowitz, S. L.; Thadeio, P. F.; Longo, K.
P.; Snider, R. M. J. Med. Chem. 1992, 35, 4911.
The structure of (± ±-1 including the relative stereochem-
7
8
. Padwa, A.; Ku, H. J. Org. Chem. 1979, 44, 255.
. Woller, P. B.; Cromwell, N. K. J. Org. Chem. 1970, 35,
1
13
istry was verified using H and C NMR (d, ppm, JCF-Hz±
and some key NOEs in CDCl
3
.
888.
*
*
*
*
(
1R ,3S ,4S ,5S )-4-[(N-(2-methoxy-5-trifluoromethoxy-
9
. Nakamura, I.; Harada, K. Heterocycles 1978, 9, 473.
benzyl)amino]-3-phenyl-2-aza-7-oxabicyclo[3.3.0]octane)Æ
1
0. Mori, K.; Tominaga, M.; Takigawa, T.; Matsui, M.
Synthesis 1973, 790.
1. O-protection of diol 15a using TBDMS-Cl, N-protection
using Cbz-Cl followed by O-deprotection under acidic
condition also provided 15b in a higher yield.
1
dihydrochloride (1Æ2HCl). White solid; mp 203–205 ꢂC. H
6
NMR (270 MHz± d (DMSO-d ±: 3.30–4.46 (10H, m±, 3.74
1
(
3H, s±, 4.67 (1H, br s±, 4.96 (1H, br s±, 7.08 (1H, d,
J = 9.2 Hz±, 7.32–7.82 (7H, m± ppm. IR mmax (film±: 3450,
1
6
582, 1563, 1504, 1457, 1278, 1261, 1244, 1217, 1174, 1032,
95 cm . Anal. Calcd for C H N O F Æ2HCl: C, 52.40;
1
2. Carlock, J. I.; Mack, M. P. Tetrahedron Lett. 1978, 9, 473.
3. Levin, J. I.; Turos, E.; Weinreb, S. M. Synth. Commun.
À1
1
21 23
2
3 3
H, 5.24; N, 5.82. Found: C, 52.43; H, 5.35; N, 5.75. HPLC
purity: 99.8% area at 215 mm. Conditions: Apparatus,
Alliance 2695 with 996 PDA detector, Waters; Column,
XTerra MS C18, 3.5 lm, 2.1 · 100 mm, Waters; Mobile
1
982, 12, 989.
1
4. The alkali hydrolysis of 16 using lithium hydroxide
resulted in epimerization at the C -position, as determined
4
1
by H NMR analysis after esterification of 19 using
trimethylsilyldiazomethane.
5. Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K.
B. J. Org. Chem. 1981, 46, 3936.
6. Baumgarten, H. E.; Smith, H. L.; Staklis, A. J. Org. Chem.
3 3 3 2 4
phase: A: CH CN/B: CH CN/10 mM CH CO NH (5/95,
v/v± (ca. pH7± = 5/95–95/5; Flow rate, 0.25 mL/min; Col-
umn temperature, 40 ꢂC.
The gradient program was as follows: initially A:B (5/95,
v/v±, then 8 min linear gradient to A:B (95/5, v/v± and 5
min isocratic with A:B (95/5, v/v±; then an additional
period of 7 min linear gradient to the initial conditions.
1
1
1
1
975, 40, 3554.
7. Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem.
Soc. 1971, 93, 2897.