Synthesis of (+)-CP-99,994 via Pd(0)-catalyzed asymmetric allylic and homoallylic C-H diamination of terminal olefin

Article abstract of DOI:10.1021/jo9015584

(Chemical Equation Presented) This paper describes an asymmetric synthesis of the potent substance P receptor antagonist (+)-CP-99,994 from 4-phenyl-1-butene via Pd(0)-catalyzed asymmetric allylic and homoallylic C-H diamination. 2009 American Chemical So

Full text of DOI:10.1021/jo9015584

pubs.acs.org/joc
catalyst derived from Pd2(dba)3 and the tetramethylpiper-
Synthesis of (+)-CP-99,994 via Pd(0)-Catalyzed
Asymmetric Allylic and Homoallylic C-H
Diamination of Terminal Olefin
idine-based phosphorus amidite ligand 5 (Scheme 1).6,7
Herein, we wish to report the extension of this diamination
process to the synthesis of (+)-CP-99,994.
Renzhong Fu, Baoguo Zhao, and Yian Shi*
Department of Chemistry, Colorado State University, Fort
Collins, Colorado 80523
yian@lamar.colostate.edu
Received July 21, 2009
FIGURE 1. The structure of (+)-CP-99,994.
SCHEME 1
This paper describes an asymmetric synthesis of the
potent substance P receptor antagonist (+)-CP-99,994
from 4-phenyl-1-butene via Pd(0)-catalyzed asymmetric
allylic and homoallylic C-H diamination.
The retrosynthetic plan for (+)-CP-99,994 is outlined in
Scheme 2. Compound 1 can be obtained from diamino acid 7
via lactam 6. Compound 7 can be derived from diamination
of 4-phenyl-1-butene (10).
(+)-CP-99,994 (1) is a potent and selective nonpeptide
substance P receptor antagonist (Figure 1).1 Its biological
activity has led to the development of various syntheses of
this molecule and related analogues.2-5 Recently, we re-
ported that terminal olefins can be enantioselectively diami-
nated at allylic and homoallylic carbons via C-H activation
using di-tert-butyldiaziridinone (3) as nitrogen source with a
The synthesis of (+)-CP-99,994 is described in Scheme 3.
Allylic and homoallylic C-H diamination of 4-phenyl-1-
butene (10) with di-tert-butyldiaziridinone (3), Pd2(dba)3,
and ligand ent-5 gave imidazolidinone 9 in 78% yield and
90% ee. Compound 9 was oxidized to aldehyde 11 in 90%
yield via dihydroxylation with OsO4-NMO, followed by
oxidativecleavage with NaIO4.8 The olefination3b of aldehyde
11, followed by hydrogenation3b gave ester 13 in high yields.
One of the tert-butyl groups on the imidazolidinone of 13
was selectively removed with CF3CO2H in CH2Cl2 to give
compound 14 along with very small amounts of 15 in 98%
yield.9 At this point, compounds 14 and 15 could not be
separated by flash column chromatography. Treating com-
pounds 14 and 15 with sodium bis(trimethylsilylamide) and
subsequently with nosyl chloride10 gave compound 16 in
72% yield after recrystallization from hexanes and ethyl
acetate. The remaining tert-butyl group of compound 16 was
removed with methanesulfonic acid to give compound 17
in 95% yield and >99% ee. Cleavage of the imidazolidinone
(1) For leading references, see: (a) Desai, M. C.; Lefkowitz, S. L.;
Thadeio, P. F.; Longo, K. P.; Snider, R. M. J. Med. Chem. 1992, 35, 4911.
(b) Rosen, T.; Seeger, T. F.; McLean, S.; Desai, M. C.; Guarino, K. J.; Bryce,
D.; Pratt, K.; Heym, J. J. Med. Chem. 1993, 36, 3197.
(2) For leading references on racemic synthesis of CP-99,994, see: (a)
Desai, M. C.; Rosen, T. J. WO 9301170. (b) Desai, M. C.; Thadeio, P. F.;
Lefkowitz, S. L. Tetrahedron Lett. 1993, 34, 5831. (c) Reference 1b. (d) Tsai,
M.-R.; Chen, B.-F.; Cheng, C.-C.; Chang, N.-C. J. Org. Chem. 2005, 70, 1780.
(3) For leading references on chiral synthon-based asymmetric synthesis
of CP-99,994, see: (a) Reference 1a. (b) Chandrasekhar, S.; Mohanty, P. K.
Tetrahedron Lett. 1999, 40, 5071. (c) Huang, P.-Q.; Liu, L.-X.; Wei, B.-G.; Ruan,
Y.-P. Org. Lett. 2003, 5, 1927. (d) Liu, L.-X.; Huang, P.-Q. Tetrahedron:
Asymmetry 2006, 17, 3265. (e) Oshitari, T.; Mandai, T. Synlett 2006, 3395.
(4) For leading references on chiral auxiliary-based asymmetric synthesis
of CP-99,994, see: (a) Yamazaki, N.; Atobe, M.; Kibayashi, C. Tetrahedron
Lett. 2002, 43, 7979. (b) Atobe, M.; Yamazaki, N.; Kibayashi, C. J. Org.
Chem. 2004, 69, 5595. (c) Lemire, A.; Grenon, M.; Pourashraf, M.; Charette,
A. B. Org. Lett. 2004, 6, 3517. (d) Davis, F. A.; Zhang, Y.; Li, D. Tetrahedron
Lett. 2007, 48, 7838. (e) Ahari, M.; Perez, A.; Menant, C.; Vasse, J.-L.;
Szymoniak, J. Org. Lett. 2008, 10, 2473. (f) Liu, R.-H.; Fang, K.; Wang, B.;
Xu, M.-H.; Lin, G.-Q. J. Org. Chem. 2008, 73, 3307.
(5) For leading references on chiral catalyst-based asymmetric synthesis
of CP-99,994, see: (a) Tsuritani, N.; Yamada, K-i.; Yoshikawa, N.;
Shibasaki, M. Chem. Lett. 2002, 276. (b) Okada, A.; Shibuguchi, T.;
Ohshima, T.; Masu, H.; Yamaguchi, K.; Shibasaki, M. Angew. Chem., Int.
Ed. 2005, 44, 4564. (c) Takahashi, K.; Nakano, H.; Fujita, R. Tetrahedron
Lett. 2005, 46, 8927. (d) Xu, X.; Furukawa, T.; Okino, T.; Miyabe, H.;
Takemoto, Y. Chem.;Eur. J. 2006, 12, 466.
(6) Du, H.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2008, 130, 8590.
(7) For leading references on the preparation of di-tert-butyldiaziridi-
none (3), see: (a) Greene, F. D.; Stowell, J. C.; Bergmark, W. R. J. Org.
Chem. 1969, 34, 2254. (b) Du, H.; Zhao, B.; Shi, Y. Org. Synth. In press.
(8) Oshitari, T.; Akagi, R.; Mandai, T. Synthesis 2004, 1325.
(9) (a) Du, H.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 762. (b) Du,
H.; Yuan, W.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 11688.
(10) Adlington, R. M.; Baldwin, J. E.; Becker, G. W.; Chen, B.; Cheng, L.;
Cooper, S. L.; Hermann, R. B.; Howe, T. J.; McCoull, W.; McNulty, A. M.;
Neubauer, B. L.; Pritchard, G. J. J. Med. Chem. 2001, 44, 1491.
DOI: 10.1021/jo9015584
r
Published on Web 09/01/2009
J. Org. Chem. 2009, 74, 7577–7580 7577
2009 American Chemical Society

Fu et al.
JOCNote
SCHEME 2
SCHEME 3
ring of 17 with potassium hydroxide solution,11 followed by
cyclization in refluxing AcOH12 led to lactam 18 in 72% yield
in two steps. It was found that the nosyl group of 18 could not
be removed with thiophenol under basic conditions. Com-
pound 18 was then transformed to compound 19 in 94% yield
by alkylation with 2-methoxybenzyl chloride. The removal of
the nosyl group was realized by treating 19 with thiophenol
and K2CO3 to give compound 6 in 79% yield.13 Based on a
known procedure,1b,2a,2b reduction of compound 6 with bor-
ane dimethyl sulfide (THF, reflux, 15 h) and subsequent
treatment with saturated HCl-Et2O gave (+)-CP-99,994 (1)
as its dihydrochloride salt in 80% yield and >99% ee. The
spectroscopic data and optical rotation were consistent with
literature data.1a,3c,3e,4b,4f The X-ray structure of (þ)-CP-
99,994 (1) dihydrochloride salt is shown in the Supporting
Information.1a
In conclusion, (þ)-CP-99,994 (2HCl) was synthesized
from 4-phenyl-1-butene in overall 20% yield and >99%
ee. The vicinal diamine moiety was introduced onto a readily
available terminal olefin with our recently developed asym-
metric allylic and homoallylic C-H diamination process.
The selective removal of one of the tert-butyl groups allows
ready differentiation of the two nitrogens. Further applica-
tion of the diamination strategy to other biologically signi-
ficant molecules is in progress.
product 9 as a colorless oil (1.75 g, 78% yield, 90% ee). The
enantioselectivity was determined by HPLC (Chiralpak AD Col-
umn, NO. AD00CE-EA001, hexanes:2-propanol = 90:10, v/v).
1
[R]20 -29.2 (c 1.0, CHCl3) (90% ee); IR (KBr) 1689 cm-1; H
D
NMR (300 MHz, CDCl3) δ 7.37-7.26 (m, 5H), 6.04 (ddd, J=17.7,
10.2, 8.4 Hz, 1H), 5.20 (d, J=17.7 Hz, 1H), 4.16 (s, 1H), 3.65 (d, J=
8.4 Hz, 1H), 1.34 (s, 9H), 1.28 (s, 9H); 13C NMR (75 MHz, CDCl3)
δ 159.1, 144.0, 140.9, 128.9, 127.8, 125.8, 115.7, 64.9, 63.3, 53.6,
53.4, 29.0, 28.8; HRMS calcd for C19H29N2O (M þ 1) 301.2274,
found 301.2279.
Experimental Section
Synthesis of Compound 9. A 50-mL flask containing Pd2(dba)3
(0.345 g, 0.38 mmol) and ligand ent-5 (0.769 g, 1.66 mmol) was
evacuated and then filled with argon three times. Upon addition of
benzene (2.0 mL, distilled from sodium), the resulting mixture was
immersed in an oil bath (65 °C), stirred for 45 min, and then
concentrated under vacuum at room temperature. 4-Phenyl-1-
butene (1.0 g, 7.6 mmol) was then added. The resulting mixture
was immersed in an oil bath (65 °C) with stirring. Then di-tert-
butyldiaziridinone (3.21 g, 18.9 mmol) was added by syringe pump
at a rate of 1.89 mmol/h. Upon completion of addition (10 h), the
reaction mixture was stirred for an additional 5 h and purified by
flash chromatography (silica gel, hexane:ethyl acetate=30:1, v/v) to
give the diamination product along with a small amount of dba,
which was further purified by flash chromatography (silica gel,
toluene then hexane:ethyl acetate=30:1, v/v) to give diamination
Synthesis of Compound 11. To a solution of compound 9 (2.33
g, 7.8 mmol) in 1,4-dioxane (140 mL)-H2O (45 mL) was added
Me3NO 2H2O (1.73 g, 15.6 mmol) and aqueous OsO4 (2.75 mL,
3
0.45 mmol, 4% w/w). Then the resulting mixture was stirred at rt
for 14 h. Upon addition of NaIO4 (5.81 g, 27.2 mmol), the
reaction mixture was stirred at rt for 4 h, quenched with
saturated aqueous Na2S2O3, and extracted with ethyl acetate
(3ꢀ50 mL), washed with brine, dried (MgSO4), filtered, con-
centrated, and recrystallized from hexane to give aldehyde 11 as
a yellow crystal (2.12 g, 90% yield). Mp 120-122 °C; [R]20
D
-10.0 (c 1.0, CHCl3); IR (KBr) 1728, 1674 cm-1; 1H NMR (300
MHz, CDCl3) δ 9.77 (d, J=3.3 Hz, 1H), 7.40-7.26 (m, 5H), 4.56
(d, J=1.8 Hz, 1H), 3.66 (dd, J=3.3, 1.8 Hz, 1H), 1.37 (s, 9H),
1.27 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 201.0, 159.0, 142.7,
129.1, 128.4, 125.8, 68.9, 57.6, 54.3, 53.8, 29.0, 28.8. Anal. Calcd
for C18H26N2O2: C, 71.49; H, 8.67; N, 9.26. Found: C, 71.29; H,
8.54; N, 9.12.
(11) Hakogi, T.; Taichi, M.; Katsumura, S. Org. Lett. 2003, 5, 2801.
(12) (a) Elworthy, T. R.; Brill, E. R.; Caires, C. C.; Kim, W.; Lach, L. K.;
Tracy, J. L.; Chiou, S.-S. Bioorg. Med. Chem. 2005, 15, 2523. (b) Garrido, N.
ꢀ
M.; Garcıa, M.; Dıez, D.; Sanchez, M. R.; Sanz, F.; Urones, J. G. Org. Lett.
2008, 10, 1687.
(13) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36,
6373.
Synthesis of Compound 12. To a solution of aldehyde 11
(2.10 g, 6.9 mmol) in CH2Cl2 (40 mL) was added methyl
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Fu et al.
JOCNote
(triphenylphosphoranylidene)acetate (2.55 g, 7.6 mmol). Upon
stirring at rt for 4 h, the reaction mixture was concentrated and
purified by flash chromatography (silica gel, hexane:ethyl acet-
ate=8:1, v/v) to give compound 12 as a colorless oil (2.44 g, 99%
yield). [R]20D -66.9 (c 1.0, CHCl3); IR (KBr) 1728, 1690 cm-1; 1H
NMR (300 MHz, CDCl3) δ 7.38-7.25 (m, 5H), 7.04 (dd, J=15.6,
7.8 Hz, 1H), 5.97 (d, J=15.6 Hz, 1H), 4.18 (d, J=1.5 Hz, 1H), 3.81
was collected by suction filtration, dried under vacuum, and
recrystallized from hexane and EtOAc to give compound 17 as a
white solid (1.46 g, 95% yield, >99% ee) (the enantioselectivity
was determined by HPLC, Chiralpak AD-H Column, NO.
ADH0CE-FD069, hexanes:2-propanol = 85:15, v/v). Mp
123-125 °C; [R]20 þ47.9 (c 1.0, CHCl3); IR (KBr) 3314,
D
1
1730, 1532, 1351, 1175 cm-1; H NMR (300 MHz, CDCl3) δ
(dd, J=7.8, 1.5Hz, 1H), 3.78 (s, 3H), 1.32 (s, 9H), 1.27 (s, 9H); 13
C
8.25 (d, J=8.7 Hz, 2H), 8.07 (d, J=8.7 Hz, 2H), 7.36-7.22 (m,
NMR (75 MHz, CDCl3) δ 166.7, 158.9, 149.1, 143.4, 129.1, 128.2,
125.8, 121.5, 62.7, 62.3, 53.9, 53.7, 52.0, 28.7; HRMS calcd for
C21H31N2O3 (M þ 1) 359.2329, found 359.2332.
3H), 6.94 (d, J=7.5 Hz, 2H), 5.59 (s, 1H), 4.39 (s, 1H), 4.23-4.21
(m, 1H), 3.72 (s, 3H), 2.60-2.52 (m, 2H), 2.37-2.26 (m, 2H); 13
C
NMR (75 MHz, CDCl3) δ 172.8, 155.1, 150.6, 143.6, 140.5,
129.4, 129.0, 125.0, 124.1, 65.7, 58.3, 52.1, 30.6, 29.0. Anal.
Calcd for C19H19N3O7S: C, 52.65; H, 4.42; N, 9.69. Found: C,
52.42; H, 4.65; N, 9.68.
Synthesis of Compound 13. A suspension of compound 12
(2.40 g, 6.7 mmol) and palladium on activated carbon (10 wt %)
(0.24 g) in MeOH (100 mL) was stirred under H2 atmosphere
(ballon) at rt for 2 h. The reaction mixture was filtered through
Celite and concentrated to give compound 13 as a colorless oil
(2.41 g, 99% yield). [R]20D þ6.0 (c 1.0, CHCl3); IR (KBr) 1739,
1686 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.36-7.21 (m, 5H),
4.18 (s, 1H), 3.69 (s, 3H), 3.21 (dd, J = 7.5, 2.4 Hz, 1H),
2.58-2.36 (m, 2H), 2.06-1.84 (m, 2H), 1.36 (s, 9H), 1.28 (s,
9H); 13C NMR (75 MHz, CDCl3) δ 173.6, 158.7, 144.2, 128.9,
127.8, 125.6, 61.1, 60.9, 53.5, 52.9, 52.0, 30.7, 29.0; HRMS calcd
for C21H33N2O3 (M þ 1) 361.2486, found 361.2490.
Synthesis of Compound 18. A suspension of compound 17
(1.38 g, 3.2 mmol) in 60% (w/w) aqueous KOH (50 mL) was
stirred at room temperature for 36 h. The resulting clear solution
was diluted with water (20 mL) and adjusted to pH 5-6 with
12 N HC1. The yellow precipitate was collected by suction
filtration, washed with water, and dried under vacuum to give
a yellow solid (0.985 g, 79% yield). A suspension of the above
yellow solid (0.860 g, 2.2 mmol) in AcOH (50 mL) was heated at
reflux for 3 h. The resulting clear solution was concentrated
under vacuum to give the crude product, which was recrystal-
lized from EtOAc and MeOH to give compound 18 as a yellow
solid (0.751 g, 91% yield) (72% yield for two steps). Mp
Synthesis of Compounds 14 and 15. To a solution of com-
pound 13 (2.30 g, 6.4 mmol) in CH2Cl2 (25 mL) at 0 °C was
added CF3CO2H (25 mL) dropwise over 30 min. The reaction
mixture was then warmed to room temperature slowly, stirred at
room temperature for 10 h, and concentrated. The resulting
residue was dissolved in CH2Cl2 (100 mL), washed with satu-
rated aqueous Na2CO3 and brine, dried (MgSO4), filtered, and
concentrated to give a mixture of compounds 14 and 15 as a
colorless oil (1.91 g, 98% yield) (the ratio of compound 14 to 15
is 15 to 1 based on 1H NMR). [R]20D -13.4 (c 1.0, CHCl3); IR
149-151 °C; [R]20 -7.75 (c 0.40, CH3OH); IR (KBr) 3103,
D
1653, 1527, 1350, 1162 cm-1; 1H NMR (300 MHz, CD3OD) δ
8.18 (d, J=9.0 Hz, 2H), 7.76 (d, J=9.0 Hz, 2H), 7.26-7.14 (m,
5H), 4.78 (d, J=4.2 Hz, 1H), 3.93-3.87 (m, 1H), 2.64-2.37 (m,
2H), 2.04-1.78 (m, 2H); 13C NMR (75 MHz, CD3OD) δ 174.5,
151.0, 148.2, 139.0, 129.3, 128.9, 128.8, 125.3, 60.6, 52.8, 28.5,
26.6; HRMS calcd for C17H18N3O5S (M þ 1) 376.0962, found
376.0964.
(KBr) 1737, 1688 cm-1 1H NMR (300 MHz, CDCl3) δ
;
7.38-7.26 (m, 5H), 4.64 (br s, 1H), 4.37 (d, J=3.3 Hz, 1H),
3.67 (s, 3H), 3.23-3.16 (m, 1H), 2.45-2.36 (m, 2H), 1.99-1.81
(m, 2H), 1.28 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 173.5,
161.7, 144.2, 128.9, 127.8, 125.9, 65.4, 58.2, 54.0, 51.8, 31.5, 29.7,
28.8; HRMS calcd for C17H25N2O3 (M þ 1) 305.1860, found
305.1861.
Synthesis of Compound 19. A suspension of compound 18
(0.60 g, 1.6 mmol), 2-methoxybenzyl chloride (0.376 g,
2.4 mmol), sodium iodide (0.024 g, 0.16 mmol), and cesium
carbonate (0.78 g, 2.4 mmol) in DMF (4 mL) was heated at 80 °C
for 5 h. The resulting reaction mixture was diluted with water
(50 mL), extracted with EtOAc (3 ꢀ 50 mL), washed with brine,
dried (MgSO4), filtered, concentrated, and purified by flash
chromatography (silica gel, CH2Cl2:MeOH=100:1, v/v) to give
compound 19 as a yellow solid (0.751 g, 94% yield). Mp
Synthesis of Compound 16. To a stirred solution of com-
pounds 14 and 15 (1.76 g, 5.8 mmol) in THF (12 mL) at -78 °C
was added dropwise sodium bis(trimethylsilyl)amide (1.0 M
solution in THF, 6.1 mL, 6.1 mmol) over 10 min. After 15 min
of stirring at -78 °C, a solution of 4-nitrobenzenesulfonyl
chloride (1.54 g, 6.9 mmol) in THF (8 mL) was added dropwise
at -78 °C over 10 min. The reaction mixture was stirred at
-78 °C for another 2 h and allowed to warm to 0 °C slowly.
Upon addition of water (30 mL), the mixture was extracted with
ethyl acetate (3 ꢀ 50 mL), washed with brine, dried (MgSO4),
filtered, concentrated, and purified by flash chromatography
(silica gel, hexane:ethyl acetate=6:1, v/v) to give a white solid
(2.45 g, 86% yield) that was recrystallized from hexanes (15 mL)
and ethyl acetate (10 mL) to give compound 16 as a white crystal
(2.05 g, 72%). Mp 131-132 °C; [R]20D þ37.6 (c 1.0, CHCl3); IR
(KBr) 1727, 1532, 1397, 1350, 1174 cm-1; 1H NMR (300 MHz,
CDCl3) δ 8.35 (d, J=9.0 Hz, 2H), 8.19 (d, J=9.0 Hz, 2H),
7.34-7.22 (m, 3H), 6.92 (d, J = 6.9 Hz, 2H), 4.42 (s, 1H),
3.98-3.93 (m, 1H), 3.71 (s, 3H), 2.49 (t, J = 7.5 Hz, 2H),
2.25-2.12 (m, 2H), 1.24 (s, 9H); 13C NMR (75 MHz, CDCl3)
δ 172.9, 152.1, 150.6, 144.6, 141.3, 129.8, 129.4, 128.8, 125.1,
124.1, 62.6, 62.2, 55.6, 52.1, 30.6, 29.0, 28.2. Anal. Calcd for
C23H27N3O7S: C, 56.43; H, 5.56; N, 8.58. Found: C, 56.66; H,
5.68; N, 8.72.
135-137 °C; [R]20 -100.2 (c 1.0, CHCl3); IR (KBr) 3206,
D
1666 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.10 (d, J=8.7 Hz,
2H), 7.59 (d, J=8.7 Hz, 2H), 7.50-7.36 (m, 5H), 7.05 (t, J=7.2
Hz, 1H), 6.85 (d, J=7.5 Hz, 1H), 6.66 (t, J=7.5 Hz, 1H), 6.37 (d,
J=7.8 Hz, 1H), 6.21 (s, 1H), 5.09-5.07 (m, 1H), 4.77-4.72 (m,
1H), 3.66 (d, J=15.6 Hz, 1H), 3.46 (s, 3H), 3.26 (d, J=15.6 Hz,
1H), 2.67-2.63 (m, 2H), 2.26-2.15 (m, 1H), 2.00-1.85 (m, 1H);
13C NMR (75 MHz, CDCl3) δ 170.5, 156.8, 149.4, 147.2, 137.8,
131.3, 129.4, 128.9, 128.8, 127.9, 123.7, 123.0, 120.0, 109.6, 59.6,
58.6, 54.7, 44.4, 31.4, 20.4; HRMS calcd for C25H26N3O6S
(M þ 1) 496.1537, found 496.1541.
Synthesis of Compound 6. A mixture of compound 19 (0.731 g,
1.5 mmol), PhSH (0.25 g, 2.3 mmol), K2CO3 (0.21 g, 1.5 mmol),
and DMSO (4 mL) was stirred at room temperature for 3 h. The
reaction mixture was diluted with water (20 mL), extracted with
EtOAc (3 ꢀ 30 mL), washed with brine, dried (MgSO4), filtered,
concentrated, and purified by flash chromatography (silica gel,
CH2Cl2:MeOH=25:1, v/v) to give compound 6 as a yellow oil
(0.368 g, 79% yield). [R]20D þ40.5 (c 1.0, CHCl3); IR (KBr) 3201,
3063, 1660 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.42-7.25 (m,
5H), 7.19 (td, J=8.1, 1.5 Hz, 1H), 7.07 (d, J=7.5 Hz, 1H), 6.85 (t,
J=7.2 Hz, 1H), 6.73 (d, J=8.1 Hz, 1H), 5.90 (br s, 1H), 4.74 (d,
J=3.3 Hz, 1H), 3.77 (d, J=13.8 Hz, 1H), 3.56 (d, J=13.8 Hz,
1H), 3.50 (s, 3H), 3.08-3.00 (m, 1H), 2.79-2.66 (m, 1H),
2.43-2.33 (m, 1H), 2.10-2.00 (m, 1H), 1.91-1.80 (m, 1H);
Synthesis of Compound 17. To MeSO3H (5 mL) was added
compound 16 (1.69 g, 3.5 mmol) at rt. After being stirred for 1 h,
the reaction mixture was added dropwise to saturated aqueous
Na2CO3 (30 mL) with vigorous stirring. The white precipitate
J. Org. Chem. Vol. 74, No. 19, 2009 7579

Fu et al.
JOCNote
13C NMR (75 MHz, CDCl3) δ 172.8, 157.5, 138.6, 129.5, 128.7,
128.3, 128.1, 127.6, 127.0, 120.3, 110.0, 60.7, 54.9, 52.9, 46.4,
27.5, 23.5. Anal. Calcd for C19H22N2O2: C, 73.52; H, 7.14; N,
9.03. Found: C, 73.80; H, 6.97; N, 9.19.
A suspension of the 2HCl salt of (þ)-CP-99,994 (1) (0.105 g,
0.28 mmol) in CH2Cl2 (5 mL) and 1 N NaOH (10 mL) was
stirred at room temperature for 15 min. Then the mixture
was extracted with CH2Cl2 (3 ꢀ 10 mL). The combined
organic layers were washed with brine, dried (MgSO4), fil-
tered, and concentrated to give (þ)-CP-99,994 as a yellow oil
(0.075 g, 89% yield, >99% ee) (the enantioselectivity
was determined by HPLC, Chiralcel OD-H Column, NO.
Synthesis of (þ)-CP-99,994. To a solution of compound 6
(0.328 g, 1.06 mmol) in THF (3 mL) was added borane dimethyl
sulfide in THF (2.0 M, 2.8 mL, 5.6 mmol) under argon. The
reaction mixture was heated at reflux for 18 h. After the reaction
mixture was cooled to room temperature, MeOH (5 mL) was
added dropwise (cautiously) to decompose the excess borane
dimethyl sulfide. The resulting mixture was then concentrated.
EtOH (9 mL) and powdered K2CO3 (0.311 g, 2.25 mmol) were
added. The resulting mixture was heated at reflux for 18 h,
cooled, and concentrated. Water (20 mL) was added to the
resulting residue. The mixture was extracted with CH2Cl2 (4 ꢀ
20 mL), dried (MgSO4), filtered, and concentrated. Then the
residue was dissolved in a minimum amount of CH2Cl2 (2 mL),
followed by addition of saturated HCl-ether (50 mL). After the
solution was stirred for 2 h, white solids were collected by
filtration and recrystallized from hot MeOH-EtOH (1:1, v/v)
to give the 2HCl salt of (þ)-CP-99,994 (1) as a white crystalline
solid (0.31 g, 80% yield). Mp 253-255 °C; [R]20D þ77.3 (c 1.0,
MeOH); IR (KBr) 3461, 3386, 1603, 1491, 1440 cm-1; 1H NMR
(300 MHz, CD3OD) δ 7.76-7.68 (m, 2H), 7.62-7.52 (m, 3H),
7.40 (td, J=7.8, 1.5 Hz, 1H), 7.21 (dd, J=7.8, 1.5 Hz, 1H),
6.98-6.92 (m, 2H), 5.03 (d, J=3.6 Hz, 1H), 4.14 (d, J=13.2 Hz,
1H), 4.06-3.98 (m, 1H), 3.87 (d, J=13.2 Hz, 1H), 3.70 (s, 3H),
3.72-3.62 (m, 1H), 3.38-3.28 (m, 1H), 2.55-2.40 (m, 2H),
2.34-2.22 (m, 1H), 2.06-1.94 (m, 1H); 13C NMR (75 MHz,
CD3OD) δ 159.0, 133.0, 132.84, 132.80, 131.2, 130.9, 128.4,
122.0, 119.0, 111.9, 60.4, 58.4, 56.1, 49.1, 45.6, 25.3, 17.8. Anal.
Calcd for C19H26Cl2N2O: C, 61.79; H, 7.10; N, 7.58. Found: C,
61.53; H, 6.96; N, 7.74.
ODHOCE-ME069, hexanes:2-propanol =90:10). [R]20
þ
D
69.8 (c 1.0, CHCl3); IR (KBr) 3329, 1492, 1461, 1241 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.34-7.18 (m, 5H), 7.15 (td, J=
8.1, 1.5 Hz, 1H), 6.97 (dd, J=7.2, 1.2 Hz, 1H), 6.80 (t, J=7.8
Hz, 1H), 6.67 (d, J=8.1 Hz, 1H), 3.87 (d, J=2.1 Hz, 1H), 3.68
(d, J=13.8 Hz, 1H), 3,43 (s, 3H), 3.41 (d, J=13.8 Hz, 1H),
3.31-3.24 (m, 1H), 2.85-2.73 (m, 2H), 2.19-2.10 (m, 1H),
2.01-1.82 (m, 3H), 1.65-1.53 (m, 1H), 1.44-1.34 (m, 1H); 13
C
NMR (75 MHz, CDCl3) δ 157.6, 142.3, 129.7, 128.2, 127.9,
126.6, 126.3, 120.0, 109.8, 64.0, 54.8, 54.6, 47.8, 46.8, 28.1,
20.3; HRMS calcd for C19H25N2O (M þ 1) 297.1961, found
297.1965.
Acknowledgment. We are grateful to the generous finan-
cial support from the General Medical Sciences of the
National Institutes of Health (GM083944-02).
Supporting Information Available: The synthetic procedure
for ligand ent-5, the X-ray structure of (þ)-CP-99,994 (1)
(2HCl), and the data for the determination of the enantiomeric
excess of compounds 9, 17, and 1 along with the NMR spectra
for ligand ent-5 and compounds 1, 6, 9, and 11-19. This
material is available free of charge via the Internet at http://
pubs.acs.org.
7580 J. Org. Chem. Vol. 74, No. 19, 2009