Substance P Inhibitors
1372 1376
containing 2,6-lutidine (600 mL, 5.2 mol). HPLC analysis indicated com-
plete consumption of diol. After addition of 2-aminoethanol (1 L), the
acetonitrile and 2,6-lutidine were removed by reduced pressure distillation
at 908C over 3 hours. The remaining oil was partitioned between 10%
aqueous sodium carbonate (1 L) and ethyl acetate (1.2 L). The organic
layer was washed with water (3 Â 300 mL) and then with brine (1 Â
300 mL). After drying with MgSO4, the solvent was removed to afford an
143.9, 132.9 (d, J 3.1 Hz), 131.7 (q, J 33.2 Hz), 129.4 (d, J 8.0 Hz),
126.0 (q, J 2.5 Hz), 123.1 (q, J 272.6 Hz), 121.6 (m), 115.4 (d, J
20.9Hz), 89.0, 71.5, 61.2, 56.8, 52.7, 52.6; IR (KBr): nÄ 3073, 2976, 1016,
935 cmÀ1; elemental analysis calcd (%) for C20H16F7NO2: C 55.18, H 3.70, F
30.55, N 3.22; found: C 55.10, H 3.60, F 30.66, N 3.20.
Preparation of bicyclic acetal quaternary ammonium iodide 5: Benzyl
chloride (0.7 mL, 6.08 mmol) was added to a solution of sodium iodide
(880 mg, 587 mmol) in acetone (10 mL), and the reaction mixture stirred in
the dark for 18 hours. The resulting slurry was filtered, bicyclic acetal (15)
(2.00 g, 4.60 mmol) was added, and the resulting solution was heated at
508C for 8 hours. The solvent was switched into cyclohexane (10 mL), and
oil. Crystallization from MBTE/heptane afforded 59% of (S)-7 as a white
25
solid (205 g, 0.647 mol). M.p. 80 828C; [a] 34.48 (c 2.64 in MeOH);
589
1H NMR (400.13 MHz, [D6]DMSO): d 8.03 (s, 2H), 7.93 (s, 1H), 5.71
(brs, 1H), 4.85 (m, 1H), 4.46 (brs, 1H), 3.43 (t, J 5.6 Hz, 2H), 2.75 (m,
1H), 2.69(m, 1H), 2.59(m, 2H), 1.95 (brs, 1H); 13C NMR (100.61 MHz,
[D6]DMSO): d 148.7, 130.1 (q, J 32.0 Hz), 127.1 (q, J 3.2 Hz), 123.8 (q,
J 272.3 Hz), 120.7 (m), 70.8, 60.8, 57.2, 51.8; IR (KBr): nÄ 2973, 2868,
1427, 1029cm À1; elemental analysis calcd (%) for C12H13F6NO2: C 45.43, H
4.13, F 35.93, N 4.42; found: C 45.15, H 3.77, F 35.89, N 4.12.
the product was removed by filtration to afford quaternary salt 5 as a pale
25
yellow solid (2.76 g, 89%). M.p. 169 171 8C; [a] À0.868 (c 2.05 in
589
1
MeOH); H NMR (500.13 MHz, CD3CN): d 8.25 (m, 2H), 8.15 (s, 2H),
8.09(s, 1H), 7.55 (m, 2H), 7.51 (m, 1H), 7.44 (m 2H), 7.32 (m, 2H), 6.03 (s,
1H), 5.91 (dd, J 11.9, 3.6 Hz, 1H), 5.77 (s, 1H), 5.62 (d, J 12.3 Hz,), 4.82
(m, 1H), 4.70 (m, 1H), 4.45 (m, 1H), 3.75 (d, J 12.3 Hz, 1H), 3.68 (m,
2H), 3.57 (t, J ꢀ 12 Hz, 1H); 13C NMR (125.77 MHz, CD3CN): d 165.3 (q,
J 249.8 Hz), 140.1, 136.5 (vbr), 134.6, 132.6 (q, J 33.8 Hz), 131.7, 130.0,
128.3 (q, J 3.7 Hz), 126.8, 124.8 (d, J 3.7 Hz), 124.4 (q, J 272.0 Hz),
124.0 (m), 117.2 (d, J 22.1 Hz), 94.7, 69.3, 67.1, 65.0, 60.2, 58.2, 57.8; IR
Preparation of lactol 12: A 40% aqueous glyoxal solution (0.46 mL,
2 equiv) were added to a solution of aminodiol (S)-7 (632 mg, 2.00 mmol) in
tert-amylalcohol (10 mL). After
a 1 hour, 4-fluorophenylboronic acid
(335 mg, 2.54 mmol) was added, and the reaction mixture was heated to
408C for 15 hours. The reaction mixture was diluted with cyclohexane
(80 mL) and washed with water (3 Â 30 mL). Drying (MgSO4) and
evaporation gave a glassy solid, consisting of the diastereomeric mixture
6, 11, 12, 13, and 14 (1.06 g), which partially crystallized on standing. After
addition of methylcyclohexane (4 mL) and EtOAc (0.15 mL), the resulting
(KBr): nÄ 3278, 3059, 1098, 959 cmÀ1
.
Preparation of cis-vinyl ether 4: A slurry of quaternary salt 5 (2.00 g,
2.98 mmol) in ethanol (3 mL) was heated at 408C. Sodium hydroxide (2n,
1.64 mL, 3.28 mmol) was added and heating was continued until dissolution
occurred. After 20 minutes the reaction was seeded with 4 (20 mg). After
40 minutes at 408C precipitation of 4 occurred. The reaction was heated at
758C for a further 4 hours and then allowed to cool. An ethanol/water
mixture (4:3, 7 mL) was added over 45 minutes. After 1 hour the product 4
was isolated by filtration and washed twice with 1:1 ethanol/water. After
drying 1.46 g 4 was obtained as a white powder (90%). Supercritical-fluid
slurry was aged for 18 hours in a 458C bath to give the crystalline cis-lactol
25
12 (775 mg, 95 A%, 86% yield). M.p. 130 1328C; [a] 1.148 (c 1.075
589
in MeOH); 1H NMR (600.13 MHz, CD3CN): d 7.83 (s, 1H), 7.78 (s, 2H),
7.40 (m, 2H), 7.05 (m, 2H), 4.96 (dd, J 9.8, 3.4 Hz, 1H), 4.80 (dd, J 7.9,
1.9Hz, 1H), 4.29(d, J 7.9Hz, 1H), 4.19(td, J 11.7, 2.6 Hz, 1H), 3.87
(brs, 1H), 3.63 (m, 1H), 3.59(d, J 1.9Hz, 1H), 3.17 (dt, J 11.7, 2.6 Hz,
1H), 2.53 (td, J 11.3, 3.8 Hz, 1H), 2.38 (dd, J 12.8, 9.8 Hz, 1H), 2.21 (dd,
J 12.8, 3.4 Hz, 1H); 13C NMR (150.90 MHz, CD3CN; selected data): d
chromatographic analysis (OD column, 3% MeOH isocratic) indicated
25
ꢁ99% ee of the desired enantiomer. M.p. 101 1038C; [a] 114.18
589
94.0, 70.5, 68.8, 62.4, 59.8, 52.2; IR (KBr): nÄ 3395, 1029, 800 cmÀ1
;
(c 1.18 in MeOH); IR (KBr): nÄ 3028, 2882, 1466, 753 cmÀ1; elemental
analysis calcd (%) for C27H22F7NO2: C 61.72, H 4.22, F 25.31, N 2.67; found:
C 61.22, H 4.13, F 25.09, N 2.61.
elemental analysis calcd (%) for C20H18F7NO3: C 52.99, H 4.00, F 29.33, N
3.09; found: C 52.62, H 3.91, F 29.25, N 3.03.
Preparation of 6 ¥ HCl salt: A solution of the cis-lactol 12 (705 mg,
1.57 mmol) in EtOAc (10 mL) was heated to reflux. After cooling to room
temperature, the solution was saturated with HCl gas. To the clear solution
of the salt, methylcyclohexane (10 mL) was added. The slow crystallization
was allowed to take place over 18 hours, hen the slurry was concentrated to
[1] U. S. von Euler, J. H. Gaddum, J. Physiol. (London) 1931, 72, 74 78.
[2] a) R. M. Snider, J. W. Constantine, J. A. Lowe, K. P. Longo, W. S.
Lebel, H. A. Woody, S. E. Droda, M. C. Desai, F. J. Vinick, R. W.
Spencer, H. J. Hess, Science 1991, 251, 435 437; b) Z. Gao, N. P. Peet,
Curr. Med. Chem. 1999, 6, 375 388.
[3] a) M. S. Kramer, N. Cutler, J. Feighner, R. Shrivastava, J. Carman, J. J.
Sraek, S. A. Reines, G. Liu, D. Snavely, E. Wyatt-Knowles, J. J. Hale,
S. G. Mills, M. MacCoss, C. J. Swain, T. Harrison, R. G. Hill, F. Hefti,
E. M. Scolnick, M. A. Cascieri, G. G. Chicchi, S. Sadowski, A. R.
Williams, L. Hewson, D. Smith, E. J. Carlson, R. J. Hargreaves, N. M.
Rupniak, Science 1998, 281, 1640 1645; b) K. A. Maubach, N. M. J.
Rupniak, M. S. Kramer, R. G. Hill, Curr. Opin. Chem. Biol. 1999, 3,
481 488.
[4] a) J. J. Hale, S. G. Mills, M. MacCoss, P. E. Finke, M. A. Cascieri, S.
Sadowski, E. Ber, G. G. Chicchi, M. Kurtz, J. Metzger, G. Eiermann,
N. N. Tsou, F. D. Tattersall, N. M. Rupniak, A. R. Williams, W.
Rycroft, R. Hargreaves, D. E. MacIntyre, J. Med. Chem. 1998, 41,
4607 4614; b) R. J. Alabaster, A. W. Gibson, S. A. Johnson, J. S.
Edwards, I. F. Cottrell, Tetrahedron: Asymmetry 1997, 8, 447 450.
[5] For condensations of organoboronic acids with imines see: a) N. A.
Petasis, I. A. Zavialov, I. A J. Am. Chem. Soc. 1997, 119, 445 446;
b) N. A. Petasis, I. A. Zavialov, J. Am. Chem. Soc. 1998, 120, 1179 8
11799; c) L. M. Harwood, G. S. Currie, M. G. B. Drew, R. W. A. Luke,
Chem. Commun. 1996, 1953 1954; d) G. S. Currie, M. G. B. Drew,
L. M. Harwood, D. J. Hughes, R. W. A. Richard, R. J. Vickers, Perkin I
2000, 2982 2990; for a related strategy, see: e) C. Agami, F. Couty, M.
Poursoulis, J. Vaissermann, Tetrahedron 1992, 48, 431.
[6] a) B. S. Green, R. Arad-Yellin, M. D. Cohen, Top. Stereochem. 1986,
16, 131 218; b) E. Vedejs, R. W. Chapman, S. Lin, M. M¸ller, D. R.
Powell, J. Am. Chem. Soc. 2000, 122, 3047 3052; c) Y. J. Shi, K. M.
Wells, P. J. Pye, W. B. Choi, H. R. O. Churchill, J. E. Lynch, A.
Maliakal, J. W. Sager, K. Rossen, R. P. Volante, P. J. Reider, Tetrahe-
dron, 1999, 55, 909 918; d) R. S. Ward, Tetrahedron Asymmetry 1995,
about half its volume and filtered to give the desired 6 ¥ HCl salt (747 mg,
25
94 A%, 98% yield). M.p. 176 1788C; [a] 778 (c 4.7 in MeOH);
589
1H NMR (600.13 MHz, CD3CN): d 12.01 (brs, 1H), 7.89(s, 1H), 7.86 (s,
2H), 7.80 (brm, 2H), 7.21(m, 2H), 6.26 (br, 1H), 5.39(d, J 10.2 Hz, 1H),
5.26 (d, J 7.9Hz, 1H), 5.08 (br, 1H), 4.63 (t, J 12.5 Hz, 1H), 4.21 (dd,
J 13.2, 2.6 Hz, 1H), 3.98 (d, J 12.5 Hz, 1H), 3.89(d, J 7.9Hz, 1H),
3.32 (m, 1H), 3.12 (d, J 13.2 Hz, 1H), 2.98 (dd, J 13.2, 10.2 Hz, 1H);
13C NMR (150.90 MHz, CD3CN): d 164.4 (d, J 247.8 Hz), 143.5, 133.2
(br), 132.0 (q, J 33.6 Hz), 127.8 (q, J 3.1 Hz), 124.5 (q, J 271.6 Hz),
122.8 (m), 117.0 (d, J 22.0 Hz), 95.4, 72.6, 66.1, 64.3, 61.8, 53.4; IR (KBr):
nÄ 3278, 3059, 1098, 959 cmÀ1
; elemental analysis calcd (%) for
C20H19ClF7NO3: C 49.04, H 3.91, Cl 7.24, F 27.15, N 2.86; found: C 48.65,
H 3.77, Cl 7.36, F 26.9, N 2.81.
Preparation of bicyclic acetal 15: A slurry of lactol HCl salt 6 (4.25 g,
8.68 mmol) in ethyl acetate (50 mL) was washed with dilute aqueous
potassium carbonate (0.7 g in 70 mL water). The organic layer was further
washed with water and dried over MgSO4. The solvent was switched into
THF (40 mL), and the solution cooled to À308C. Tributylphosphine
(2.65 mL, 10.4 mmol) was added followed by the addition of DIAD
(2.0 mL, 9.98 mmol) over 30 minutes, while a temperature below À258C
was maintained. After the addition, the reaction was allowed to warm to
158C over 3 hours, and the solvent was removed in vacuo. The residue was
filtered through a short silica gel column (20% ethylacetate in hexane) and
recrystallized from EtOH/water (1:1) to afford bicyclic acetal 15 as a white
25
solid (3.23 g, 7.43 mmol, 86% yield). M.p. 99 1018C; [a] 23.58 (c
589
1
1.36 in MeOH); H NMR (500.13 MHz, CDCl3): d 7.72 (s, 1H), 7.58 (m,
4H), 7.11 (m, 2H), 5.61 (s, 1H), 5.58 (dd, J 10.3, 6.4 Hz, 1H), 4.46 (ddd,
J 11.9, 10.0, 6.0 Hz, 1H), 4.22 (s, 1H), 3.98 (ddd, J 11.9, 7.0, 3.4 Hz, 1H),
3.91 (ddd, J 13.9, 10.0, 7.0 Hz, 1H), 3.47 (ddd, J 13.9, 6.0, 3.4 Hz, 1H),
2.90 (m, 2H); 13C NMR (125.77 MHz, CDCl3): d 161.1 (d, J 247.2 Hz),
Chem. Eur. J. 2002, 8, No. 6
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0806-1375 $ 17.50+.50/0
1375