Practical synthesis of chiral emopamil left hand as a bioactive motif.

Article abstract of DOI:10.1021/jo020166d

An asymmetric synthesis of (2S)-2-(2-isopropyl)-5-hydroxy-2-phenylpentanenitrile (emopamil left hand, 2) has been completed by use of the MAD (methyl aluminum bis(4-methyl-2,6-di-tert-butylphenoxide)-induced rearrangement of a chiral epoxyalcohol as the key reaction. The stereochemistry of the chiral quaternary center was confirmed by transformation of 2 to (S)-noremopamil. This method requires minimal purification procedures and affords high chemical and optical yields. Acid-catalyzed isomerization of an allylaldehyde and retro-aldol type racemization at the quaternary carbon of a nitrile-alcohol were encountered.

Full text of DOI:10.1021/jo020166d

P r a ctica l Syn th esis of Ch ir a l Em op a m il
Left Ha n d a s a Bioa ctive Motif
Teiji Kimura,* Noboru Yamamoto, Yuichi Suzuki,
Koki Kawano, Yoshihiko Norimine, Koichi Ito,
Satoshi Nagato, Yoichi Iimura, and Masahiro Yonaga
Tsukuba Research Laboratories, Eisai Company, Ltd.,
5-1-3 Tokodai, Tsukuba-shi, Ibaraki 3002635, J apan
t2-kimura@hhc.eisai.co.jp
Received March 8, 2002
F IGURE 1.
Abstr a ct: An asymmetric synthesis of (2S)-2-(2-isopropyl)-
5-hydroxy-2-phenylpentanenitrile (emopamil left hand, 2)
has been completed by use of the MAD (methyl aluminum
bis(4-methyl-2,6-di-tert-butylphenoxide)-induced rearrange-
ment of a chiral epoxyalcohol as the key reaction. The stereo-
chemistry of the chiral quaternary center was confirmed by
transformation of 2 to (S)-noremopamil. This method re-
quires minimal purification procedures and affords high
chemical and optical yields. Acid-catalyzed isomerization of
an allylaldehyde and retro-aldol type racemization at the
quaternary carbon of a nitrile-alcohol were encountered.
F IGURE 2.
lic acids or amines,8 or enzymatic resolution of the
racemic compound9 could provide a solution to this
problem. However, manipulation to establish the proper
conditions is usually time-consuming and would be
difficult to standardize because of the variety of target
substrates. Although enantioselective synthesis would be
more practical, the results reported thus far have shown
low enantiomeric excesses.10 We have explored a novel
asymmetric synthesis of the phenylalkylamine locus, and,
in this paper, we report our findings on the preparation
of the chiral emopamil left hand, 2.
In tr od u ction
Progress in the use of combinatorial approaches in the
drug discovery field has enabled medicinal chemists to
search for more druglike templates. We have focused on
the phenylalkylamine motif (Figure 1) in L-type calcium
channel blockers, such as verapamil (1a ), emopamil (1b),
and noremopamil (1c), which exhibit a wide range of
biological activities.1-3 A library of compounds that
incorporate phenylalkylamine as a bioactive motif has
the potential to provide interesting new lead compounds
for biological evaluations.
Resu lts a n d Discu ssion
The phenylalkylamine moiety includes a chiral qua-
ternary carbon center, and recent research has indicated
that the optical isomers differ significantly in their
biological effects.4,5 Thus, we planned to build a library
in which this benzylic center is stereochemically defined.
A number of reports have described syntheses of the
individual enantiomers. However, a straightforward ap-
proach utilizing chiral substrates as starting materials
is not suitable for library preparation due to the limited
commercial availability and high price of suitable com-
pounds.6 Separation of diastereomers formed by the
introduction of a chiral side chain or with a chiral
auxiliary using column chromatography,7 classical reso-
lution of diastereomeric salts formed with chiral carboxy-
Retrosynthetic analysis guided us to a chiral aldol
(Figure 2) which could be formed by rearrangement of a
chiral epoxyalcohol using the organoaluminum reagent
reported by Yamamoto et al.11
Phenylacetonitrile was selected as the starting mate-
rial because of its commercial availability. The acryloni-
trile compound 3 was predominantly obtained as the
Z-isomer by Ladhar’s procedure.12 Reduction of the nitrile
3 using diisobutylaluminum hydride (DIBALH) followed
by acid hydrolysis and further reduction gave the allyl
alcohol 4 as a mixture of E- and Z-isomers in preliminary
experiments. Since isomerization might have occurred
during the hydrolysis step after DIBALH reduction, the
process was investigated in detail. When the reduction
of 3 by DIBALH was quenched with 3 N H2SO4 at -78
(1) Mitani, K.; Sakurai, S.; Suzuki, T.; Morikawa, K.; Koshinaka,
E.; Kato, H.; Ito, Y.; Fujita, T. Chem. Pharm. Bull. 1988, 36, 4103.
(2) Eliason, J . F.; Ramuz, H.; Kaufmann, F. Int. J . Cancer 1990,
46, 113.
(7) Gilmore, J .; Prowse, W.; Steggles, D.; Urquhart, M.; Olkowski,
J . J . Chem. Soc., Perkin Trans. 1 1996, 2845.
(3) Peroutka, S. J . Ann. Neurol. 1988, 23, 500.
(8) Bannister, R. M.; Brookes, M. H.; Evans, G. R.; Katz, R. B.;
Tyrrell, N. D. Org. Process Res. Dev. 2000, 4, 467.
(9) Im, D. S.; Cheong, C. S.; Lee, S. H.; Park, H.; Youn, B. H.
Tetrahedron Asymmetry 1999, 10, 3759.
(10) Brunner, H.; Zintl, H. Monatsch. Chem. 1991, 122, 841.
(11) Maruoka, K.; Sato, J .; Yamamoto, H. Tetrahedron 1992, 48,
3749.
(4) Longstreth, J . A.. Verapamil: A Chiral Challenge to the Phar-
macokinetic and Pharamacodynamic Assessment of Bioavailability and
Bioequivalence. In Clinical Pharmacology, 2nd ed.; Wainer, I. W.,
Drayer, D. E., Eds.; Drug Stereochemistry, Vol. 11; Dekker: New York,
1993; p 315.
(5) Stison, C. C&EN 1993, Sept 27, 38.
(6) Theodore, L. J .; Nelson, W. L. J . Org. Chem. 1987, 52, 1309.
(12) Ladhar, F.; Gharbi, R. EL. Synth. Commun. 1991, 21, 413.
10.1021/jo020166d CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/18/2002
6228
J . Org. Chem. 2002, 67, 6228-6231

SCHEME 1
SCHEME 2
°C, the E/ Z ratio of the obtained allyl aldehyde was 1:2.
Quenching at 0 °C provided a 3:1 mixture of E- and
Z-allyl aldehyde. This result indicates that formation of
the E-allyl aldehyde is thermodynamically more favor-
able than that of the Z-isomer. Finally, heating at 60 °C
for 24 h under acid hydrolysis conditions after the
reduction exclusively gave the E-allyl aldehyde. Reduc-
tion of the E-allyl aldehyde with NaBH4 gave the desired
E-allyl alcohol with the corresponding saturated alcohol
as a byproduct. Although reduction by CeCl3-NaBH4
could be carried out with 1,2-selectivity, the dimethyl-
acetal form of the allyl aldehyde was produced in 30%
yield. Complete transformation of the E-allyl aldehyde
to the E-allyl alcohol 4 was accomplished by reduction
with lithium aluminum hydride (LAH). The chiral epoxy
alcohol 5 was obtained by the standard Sharpless asym-
metric epoxidation procedure.13 This procedure gave the
optically pure epoxyalcohol 5 (>99% ee) in crystalline
form, circumventing the need for time-consuming column
chromatography. The stereochemistry of 5 was directly
determined by NOESY study and the data retrospectively
confirmed 4 as the E-isomer. Transformation from the
epoxy alcohol 5 to the corresponding aldol 7 was per-
formed essentially according to Yamamoto’s report.11 The
alcohol moiety of 5 was protected as a triphenylsilyl
ether, and the resulting epoxide 6 was treated with MAD
(methyl aluminum bis(4-methyl-2,6-di-tert-butylphenox-
ide) to provide the desired aldehyde 7 in quantitative
yield. The aldehyde 7 was derivatized to its oxime using
hydroxylamine and subsequent dehydrated by reatment
with carbonyldiimidazole (CDI) to afford the protected
nitrile compound. After desilylation with tetrabutylam-
monium fluoride (TBAF), the enantiomeric purity of the
nitrile-alcohol 8 was evaluated by HPLC using a chiral
column. Contrary to our expectation, the isolated mate-
rial 8 was racemic, although the precursors 6 and 7
showed some degree of optical rotation by polarimetry.
Thus, we speculated that compound 8 might have race-
mized through a retro-aldol type mechanism under the
TBAF deprotection conditions.
practice, the desilylation step was carried out in one pot
following transformation of the oxime to the nitrile,
because quenching of excess CDI remaining in the
reaction mixture produced sufficient imidazole to prevent
scrambling of the stereocenter. Oxidation of the nitrile
alcohol 8 followed by treatment with the Horner-
Emmons reagent provided the R,â-unsaturated ester 9,
and subsequent hydrogenation led to compound 10.
Reduction of 10 with LAH gave the target alcohol 2 in
quantitative chemical and optical yield. To confirm the
configuration of the quaternary carbon center, alcohol 2
was transformed to a known derivative, noremopamil
(1c). Since the isolated product exhibited levo-rotation,
which is consistent with that of (S)-noremopamil reported
by Gilmore et al.,7 the stereogenic center of 2 was
concluded to have the expected S configuration. This
result supports the assignments of all the stereogenic
centers of the compounds described here. A chiral phe-
nylalkylamine library was built by coupling of the me-
sylate of (S)-2 or by reductive amination of the aldehyde
of (S)-2 with various amines. The utility of this library
has already been confirmed by the discovery of E-2050,
which is a novel neuronal calcium channel blocker.14
Evaluation of this library for other biological targets is
in progress and will be reported in due course.
Su m m a r y
A versatile, high-yield process for the asymmetric
synthesis of (2S)-2-(2-isopropyl)-5-hydroxy-2-phenylpen-
tanenitrile has been developed. The minimal purification
procedures required and the ready availability of the
starting materials distinguish this efficient approach
from other routes reported to date.
Exp er im en ta l Section
Gen er a l. Melting points are uncorrected. 1H and 13C NMR
spectra were determined at 400 and 100 MHz, respectively. Mass
spectra were recorded by electron spray ionization (ESI) or FAB
ionization. Optical rotations were measured using a digital
polarimeter with a 10-cm cell. The enantiomeric purity was
determined using chiral HPLC analysis by comparison with the
To avoid the putative retro-aldol type reaction, the
desilylation was performed in the presence of a proton
donor such as imidazole. The amended conditions gave
optically pure 8 without racemization (>99% ee). In
(14) Yamamoto, N.; Suzuki, Y.; Iimura, Y.; Komatsu, M.; Kawano,
K.; Kimura, T.; Norimine, Y.; Ito, K.; Nagato, S.; Niidome, T.; Teramoto,
T.; Kimura, M.; Kaneda, Y.; Amino, H.; Ueno, M.; Hamano, T.;
Nishizawa, Y.; Yonaga, M. Presented in part at the 222nd American
Chemical Society National Meeting, Chicago, August, 2001.
(13) Gao, Y.; Hanson, R. M.; Klunder, J . M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J . Am. Chem. Soc. 1987, 109, 5765.
J . Org. Chem, Vol. 67, No. 17, 2002 6229

SCHEME 3
corresponding racemic compound (see Supporting Information).
Chiral HPLC analysis were performed on a Chiralcel OJ column
(250 × 4.6 mm, n-hexane/isopropyl alcohol/ethanol 85/10/5, 1 mL/
min) for enantiomers of 2, 5, 8, and 11, and a Chiral OD column
(250 × 4.6 mm, n-hexane/ethanol 95/5, 1 mL/min) for 1c. The
retention time of each enantiomer is given as tR. Elemental
analyses were performed at the Analytical Chemistry Section
of Eisai Tsukuba Research Laboratories.
(Z)-2-P h en yl-3-isop r op yla cr ylon itr ile (3) was essentially
prepared according to the literature procedure12 and was purified
by distillation under reduced pressure (yield 95%. bp 75 °C/0.3
mmHg).
(E)-2-P h en yl-3-isop r op yla llyl a lcoh ol (4). To a solution of
3 (27.4 g, 160 mmol) in hexane (200 mL) at -30 °C was added
DIBALH (1.5 M toluene solution, 100 mL) over 20 min. After 2
h at 0 °C, the reaction mixture was slowly poured into ice cold
3 N H2SO4 (100 mL), ensuring the mixture remained below 10
°C. The resulting solution was stirred at 0 °C for 0.7 h and then
at 60 °C for 19 h. The organic layer was separated, and the
aqueous phase was extracted with EtOAc. The combined organic
layer was washed with saturated NaHCO3 and dried, filtered,
and concentrated in vacuo.
The residue in THF (100 mL) was treated with LiAlH4 (3.1 g,
81.6 mmol) at -78 °C for 30 min. After the reaction was
quenched with water and 5 N NaOH, the resulting precipitate
was filtered off, and the filtrate was evaporated in vacuo. The
residue oil was distilled under reduced pressure to yield 4 (E/ Z
93:7) as a colorless oil (23.6 g, 83.7%). The E/ Z ratio was
determined by integration of both vinylic proton signals (Z-
isomer δ 5.71 ppm).
the aqueous phase was extracted twice with Et2O. The combined
organic phases were washed with brine, dried, filtered, and then
concentrated in vacuo. The residue was crystallized from hexane
to afford the epoxy alcohol (5) as colorless crystals (18.4 g, 84.1%,
>99% ee): mp 63 °C. 1H NMR (400 MHz, DMSO): δ (ppm) 0.72
(d, 3H, J ) 6.4 Hz), 0.76-0.88 (m, 1H), 0.94 (d, 3H, J ) 6.4 Hz),
2.90 (d, 1H, J ) 8.8 Hz), 3.68 (dd, 1H, J ) 12.4, 6.0 Hz), 3.78
(dd, 1H, J ) 12.4, 6.0 Hz), 4.91 (t, 1H, J ) 6.0), 7.25-7.40 (m,
5H). 13C NMR (100 MHz, CDCl3): δ (ppm) 18.1, 20.1, 27.3, 64.9,
66.6, 67.0, 126.9, 128.0, 128.5, 136.2. LRMS (ESI) m/e: 247 (M
+ Na + MeOH)+. [R]28 ) -50.1 (c 0.78, CHCl3). Anal. Calcd
D
for C12H16O2 (192.25): C, 74.97; H, 8.39. Found: C, 74.62; H,
8.38. (2S,3S)-enantiomer of 5: tR ) 5.0 min. (2R,3R)-enantiomer
of 5: tR ) 6.5 min.
(2S,3S)-3-Isop r op yl-2-p h en yl-2,3-ep oxyp r op a n -1-t r ip h -
en ylsilyl Eth er (6). To a solution of 5 (5.0 g, 26.0 mmol) in
DMF (50 mL) were added imidazole (3.5 g, 51.5 mmol) and
triphenylchlorosilane (7.7 g, 26.1 mmol) at 0 °C, and the reaction
mixture was stirred at room temperature for 6 h. After water
and hexane were added to the reaction mixture, the organic layer
was separated, and the aqueous layer was extracted with
hexane. The combined organic layer was dried, filtered, and
concentrated in vacuo. The compound 6 (11.8 g, 100%) was
enough pure to use in the next reaction without further
purification: 1H NMR (400 MHz, CDCl3): δ (ppm) 0.73 (d, 3H,
J ) 6.4 Hz), 0.90-0.98 (m, 1H), 0.98 (brs, 3H), 2.93 (d, 1H, J )
8.6 Hz), 4.07 (s, 2H), 7.27-7.58 (m, 20H). 13C NMR (100 MHz,
CDCl3): δ (ppm) 18.2, 20.1, 27.5, 66.5, 67.5, 67.6, 127.6, 127.7,
128.1, 128.2, 130.3, 134.0, 135.7, 136.9. LRMS (ESI) m/e: 473
(M + Na)+ [R]26 ) -24.8 (c 1.83, CHCl3).
D
bp 85 °C/0.4 mmHg. 1H NMR (400 MHz, CDCl3): δ (ppm) 0.94
(d, 6H, J ) 6.6 Hz), 1.45 (brt, 1H), 2.31-2.43 (m, 1H), 4.29 (d,
2H, J ) 5.5 Hz), 5.52 (d, 1H, J ) 10.1 Hz), 7.19-7.39 (m, 5H).
13C NMR (100 MHz, CDCl3): δ (ppm) 23.4, 27.8, 68.4, 127.3,
128.5, 128.8, 136.4, 138.1, 139.1. LRMS (ESI) m/e: 231 (M +
Na + MeOH)+.
(2S)-2-Isopr opyl-2-ph en yl-3-(tr iph en ylsiloxy)pr opan al (7).
To a solution of 6 (9.0 g, 20.0 mmol) in dichloromethane (100
mL) was added methyl aluminum bis(4-methyl-2,6-di-tert-bu-
tylphenoxide) (0.4 M in toluene, 100 mL) at -78 °C. After being
stirred at -78 °C for 1 h, the reaction mixture was poured into
cold 2 N HCl (200 mL). The organic layer was separated, and
the aqueous layer was extracted with dichloromethane. The
combined organic layer was passed through a silica gel bed and
concentrated in vacuo to give 7 (8.90 g, 99%) as a colorless oil:
1H NMR (400 MHz, CDCl3): δ (ppm) 0.80 (d, 3H, J ) 6.8 Hz),
0.88 (d, 3H, J ) 6.8 Hz), 2.75 (septet, 1H, J ) 6.8 Hz), 4.24 (d,
1H, J ) 10.4 Hz), 4.27 (d, 1H, J ) 10.4 Hz), 7.05-7.53 (m, 20H),
9.79 (s, 1H). 13C NMR (100 MHz, CDCl3): δ (ppm) 18.0, 18.6,
29.2, 62.5, 64.5, 127.4, 128.1, 128.6, 128.9, 130.4, 133.7, 135.6,
136.8, 203.9. HRMS (FAB) m/e calcd for C30H31O2Si 451.2094;
(2S,3S)-3-Isop r op yl-2-p h en yl-2,3-ep oxyp r op a n -1-ol (5).
Diethyl L-(+)-tartrate (2.52 mL, 14.8 mmol) and titanium
tetraisopropoxide (3.38 mL, 11.4 mmol) were added sequentially
to a mixture of powdered activated 4 Å molecular sieves (9 g)
and dichloromethane (200 mL) at 0 °C with stirring. The reaction
mixture was cooled to -20 °C, tert-butyl hydroperoxide (2.7 M
in dichloromethane, 109.4 mL, 296.4 mmol) was added dropwise
over 0.2 h, and the resulting mixture was stirred at -20 °C for
1 h. Compound 4 (20 g, 114 mmol) dissolved in dichloromethane
(100 mL) was then added dropwise over 0.2 h. After stirring for
15 h at -20 °C, the reaction mixture was poured into a freshly
prepared ferrous sulfate solution (66 g of FeSO4‚7H2O and 22 g
of citric acid in 200 mL of H2O) at -20 °C and stirred for 1 h.
The organic layer was separated, and the aqueous layer was
extracted with Et2O. The combined organic layer was dried,
filtered, and concentrated in vacuo. To the residue in Et2O (300
mL) was added 30% NaOH (20 mL), and the resultant mixture
was stirred at 0 °C for 1 h. The two phases were separated, and
found 451.2110. [R]26 ) -28.5 (c 0.29, CHCl3).
D
(2R)-2-Hydr oxym eth yl-2-isopr opylph en ylaceton itr ile (8).
To a solution of 7 (8.90 g, 19.8 mmol) in ethanol (50 mL) were
added hydroxylamine hydrochloride (2.06 g, 28.8 mmol) and
sodium acetate (2.44 g, 29.8 mmol), and the reaction mixture
was stirred at room temperature for 2 h. After concentration of
the reaction mixture in vacuo, EtOAc was added, and the organic
phase was washed twice with water, dried, and evaporated in
vacuo.
6230 J . Org. Chem., Vol. 67, No. 17, 2002

To a solution of the residue in THF (50 mL) was added 1,1′-
carbonyldiimidazole (16.0 g, 98.8 mmol). The reaction mixture
was refluxed for 2 h and then cooled to 0 °C. After water (1.8
mL) was slowly added, the resulted mixture was stirred until
dissipation of gas evolution, and tetrabutylammonium fluoride
(1 M solution in THF, 43.6 mL) was added. The reaction mixture
was stirred for 1 h at room temperature, and then EtOAc and
water were added. The organic phase was washed twice with
water, and the aqueous phase was extracted with EtOAc. The
combined organic phases were passed through a silica gel bed
and evaporated in vacuo. The residue was crystallized from
hexane to furnish 8 (2.88 g, 78%, >99% ee) as a white crystalline
J ) 13.5, 12.1, 4.6 Hz), 2.13 (septet, 1H, J ) 6.8 Hz), 2.24 (ddd,
1H, J ) 13.5, 12.1, 4.6 Hz), 3.59 (q, 2H, J ) 5.5 Hz), 7.27-7.40
(m, 5H). 13C NMR (100 MHz, CDCl3): δ (ppm) 18.6, 19.0, 28.9,
34.2, 37.9, 53.6, 62.3, 121.3, 126.4, 127.6, 128.8, 138.0. LRMS
(ESI) m/e: 240 (M + Na)+, 272 (M + Na + MeOH)+, 457 (2M +
Na)+. [R]26 ) -12.4 (c 1.2, CHCl3). (2S)-enantiomer of 2: tR
)
D
7.6 min. (2R)-enantiomer of 2: tR ) 9.5 min.
1-[(4S)-(4-Cya n o-5-m et h yl-4-p h en yl)h exyl]-4-[2-(4-flu o-
r op h en oxy)eth yl]p ip er a zin e d ih yd r och lor id e (E2050; 11).
To a solution of 2 (2.10 g, 9.68 mmol) in acetonitrile (20 mL)
were added triethylamine (2.15 g, 21.3 mmol) and methane-
sulfonyl chloride (1.22 g, 10.7 mmol) at 0 °C. After stirring for
2 h, the reaction mixture was concentrated in vacuo, and Et2O
and brine were added. The organic layer was separated, dried,
and evaporated in vacuo.
1
solid: mp 76-77 °C. H NMR (400 MHz, CDCl3): δ (ppm) 0.83
(d, 3H, J ) 6.8 Hz), 1.21 (d, 3H, J ) 6.8 Hz), 1.64 (dd, 1H, J )
8.4, 5.5 Hz), 2.30 (septet, 1H, J ) 6.8 Hz), 3.99 (dd, 1H, J )
11.2, 5.5 Hz), 4.12 (dd, 1H, J ) 11.2, 8.4 Hz), 7.32-7.49 (m, 5H).
13C NMR (100 MHz, CDCl3): δ (ppm) 18.7, 19.0, 33.9, 56.6, 67.6,
120.4, 127.0, 128.4, 129.3, 136.2. LRMS (ESI) m/e: 190 (M+H)+.
To a solution of the residue in acetonitrile (30 mL) were added
4-fluorophenoxypiperazine (2.4 g, 10.7 mmol), NaI (1.6 g, 10.7
mmol), and triethylamine (1.08 g, 10.7 mmol), and the resulting
mixture was stirred at 70 °C for 3 h. After the reaction mixture
was cooled to room temperature, Et2O and 5 N HCl were added,
and the quenched reaction was stirred vigorously for 10 min.
The aqueous layer was separated, and the organic layer was
extracted with 5 N HCl. The combined aqueous layer was
neutralized with NaHCO3 and extracted with EtOAc. The
organic layer was separated, dried, and evaporated in vacuo to
obtain the oily product (3.51 g, 86%, >99% ee): 1H NMR (400
MHz, CDCl3); δ (ppm) 0.77 (d, 3H, J ) 6.8 Hz), 1.05-1.17 (m,
1H), 1.20 (d, 3H, J ) 6.8 Hz), 1.50-1.60 (m, 1H), 1.88 (dt, 1H,
J ) 4.4, 12.4 Hz), 2.06-2.19 (m, 2H), 2.24-2.30 (m, 2H), 2.30-
2.43 (m, 4H), 2.46-2.62 (m, 4H), 2.77 (t, 2H, J ) 5.8 Hz), 4.04
(t, 2H, J ) 5.8 Hz), 6.80-6.85 (m, 2H), 6.91-6.99 (m, 2H), 7.25-
[R]29 ) -25.5 (c 0.99, CHCl3). Anal. Calcd for C12H15NO
D
(189.25): C, 76.16; H, 7.99; N, 7.40. Found: C, 75.96; H,8.15;
N, 7.35. (2S)-enantiomer of 8: tR ) 5.2 min. (2R)-enantiomer of
8: tR ) 7.6 min.
Eth yl
(4R)-4-Cya n o-4-p h en yl-5-m eth yl-tr a n s-2-h en x-
en oa te (9). To a solution of 8 (2.77 g, 14.7 mmol) in DMSO (15
mL) were added triethylamine (13.3 mL) and sulfur trioxide-
pyridine complex (6.99 g, 44.0 mmol). The reaction mixture was
stirred at room temperature for 2 h, and then hexane and 1 N
HCl were added. The organic phase was separated, and the
aqueous phase was extracted with hexane. The combined organic
phases were washed with saturated NaHCO3, dried, and evapo-
rated in vacuo to obtain the crude aldehyde product.
To a suspension of NaH (882 mg of 60% oil suspension washed
with hexane three times) in THF (20 mL) was added triethyl
phosphonoacetate (4.94 g, 22.1 mmol) at room temperature. After
stirring for 3 h, a solution of the above aldehyde in THF (30
mL) was added to the reaction mixture. The resultant mixture
was stirred for 1 h and then concentrated to dryness. 10% EtOAc
in hexane and water were added to the reaction mixture, and
the organic phase was separated. The aqueous phase was
extracted with the same solvent system, and the combined
organic phases were filtered through a silica gel bed (SiO2, 5 g).
The filtrate was evaporated in vacuo to give 9 as a colorless oil
(2.72 g, 72%): 1H NMR (400 MHz, CDCl3): δ (ppm) 0.90 (d, 3H,
J ) 6.8 Hz), 1.13 (d, 3H, J ) 6.8 Hz), 1.29 (t, 3H, J ) 7.1 Hz),
2.40 (septet, 1H, J ) 6.8 Hz), 4.20 (q, 2H, J ) 7.1 Hz), 6.31 (d,
1H, J ) 15.6 Hz), 7.02 (d, 1H, J ) 15.6 Hz), 7.31-7.47 (m, 5H).
13C NMR (100 MHz, CDCl3): δ (ppm) 14.4, 18.4, 18.8, 37.3, 56.5,
61.1, 118.5, 122.9, 126.3, 128.6, 129.5, 137.4, 145.6, 165.9. LRMS
7.32 (m, 1H), 7.32-7.40 (m, 4H). [a]26 ) -6.5 (c 0.93, CHCl3).
D
(S)-enantiomer of 11 (free salt): tR ) 5.2 min. (R)-enantiomer
of 11 (free salt): tR ) 6.3 min.
Dissolution of the oil in EtOAc and acidification with 2
equivalents of 1N HCl in EtOAc gave a solid. Recrystallization
from 1-propanol provided the hydrochloride salt of 11 as white
crystals: mp 184-186 °C. 1H NMR (400 MHz, DMSO-d6); δ
(ppm) 0.68 (d, 3H, J ) 6.6 Hz), 1.11 (d, 3H, J ) 6.6 Hz), 1.22-
1.34 (m, 1H), 1.58-1.62 (m, 1H), 2.06-2.30 (m, 3H), 3.00-3.25
(m, 2H), 3.30-3.80 (m, 10H), 4.36 (brs, 2H), 6.98-7.07 (m, 2H),
7.11-7.20 (m, 2H), 7.32-7.40 (m, 1H), 7.40-7.50 (m, 4H).13
C
NMR (100 MHz, CD3OD): δ (ppm) 18.8, 19.1, 21.0, 35.0, 38.4,
48.6, 49.6, 54.2, 56.6, 56.9, 63.5, 116.5, 116.6, 121.3, 126.9, 128.7,
(ESI) m/e: 312 (M + Na + MeOH)+. [R]26 ) +11.3 (c 0.63,
D
129.7, 137.6, 154.1, 158.7. LRMS (ESI) m/e: 424 (M + H)+. [R]26
D
CHCl3).
) -5.5 (c 1.1, EtOH). Anal. Calcd for C26H36N3OCl2F (496.49):
E t h yl (4S)-4-Cya n o-4-p h en yl-5-m et h yl-h exa n oa t e (10).
Compound 9 (2.6 g, 10.1 mmol) was dissolved in EtOAc (50 mL)
and stirred in the presence of 10% Pd on carbon under an
atmosphere of hydrogen (1 atm) for 16 h. The mixture was
filtered through Celite and concentrated in vacuo to obtain 10
as a colorless oil (2.54 g, 97%): 1H NMR (400 MHz, CDCl3): δ
(ppm) 0.79 (d, 3H, J ) 6.8 Hz), 1.20 (t, 3H, J ) 7.1 Hz), 1.23 (d,
3H, J ) 6.8 Hz), 1.94 (ddd, 1H, J ) 16.5, 11.9, 4.6 Hz), 2.15
(septet, 1H, J ) 6.8 Hz), 2.19 (ddd, 1H, J ) 16.5, 11.9, 4.8 Hz),
2.40 (ddd, 1H, J ) 16.3, 11.9, 4.6 Hz), 2.50 (ddd, 1H, J ) 16.3,
11.9, 4.8 Hz), 3.98-4.12 (m, 2H), 7.29-7.42 (m, 5H). 13C NMR
(100 MHz, CDCl3): δ (ppm) 14.3, 18.8, 19.2, 30.9, 33.0, 38.1, 53.4,
60.8, 120.8, 126.6, 128.1, 129.2, 137.4, 172.7. LRMS (ESI) m/e:
C, 62.90; H, 7.31; N, 8.46. Found: C, 63.22; H,7.55; N, 8.51.
Ack n ow led gm en t. We wish to thank members of
the Analytical Chemistry Section of Eisai Tsukuba
Research Laboratories for interpretation of the NMR
and mass spectra and elemental analysis data. We are
grateful to Dr. A. D. Wentworth for her invaluable
advice in preparing the manuscript.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for compounds 1c, (DL)- 2, (DL)-5, and (DL)-8; spectral
data (1H NMR including NOE) for 3; spectral data (1H NMR,
13C NMR, and LRMS) for 4, 6, 9, and 10; spectral data (1H
NMR including NOESY, 13C NMR, and LRMS) and HPLC data
for 5; spectral data (1H NMR, 13C NMR, LRMS, and HRMS)
for 7; spectral data (1H NMR, 13C NMR, and LRMS) and HPLC
data for 1c, 2, 8, and 11. This material is available free of
charge via the Internet at http://pubs.acs.org.
282 (M + Na)+, 542 (2M + Na)+. [R]26 ) -37.2 (c 0.83, CHCl3).
D
(2S)-2-(2-Isop r op yl)-5-h yd r oxy-2-p h en ylp en t a n en it r ile
(2). To a solution of 10 (2.51 g, 9.69 mmol) in THF (20 mL) was
added LiAlH4 (740 mg, 19.5 mmol) portionwise at 0 °C, and the
reaction mixture was stirred at the same temperature. After 1
h, water (0.8 mL), 5 N NaOH (0.8 mL), and water (2.4 mL) was
added into the reaction mixture sequentially. The precipitate
was filtered off, and the filtrate was concentrated in vacuo to
give 2 as a colorless oil (2.54 g, 97%, >99% ee): 1H NMR (400
MHz, CDCl3): δ (ppm) 0.79 (d, 3H, J ) 6.8 Hz), 1.18-1.28 (m,
1H), 1.21 (d, 3H, J ) 6.8 Hz), 1.55-1.66 (m, 2H), 1.98 (ddd, 1H,
J O020166D
J . Org. Chem, Vol. 67, No. 17, 2002 6231