An efficient synthesis of enantiomerically pure 2-[(2R)-arylmorpholin- 2-yl]ethanols, key intermediates of tachykinin receptor antagonist

Article abstract of DOI:10.1016/S0957-4166(98)00336-X

We report herein an efficient and practical synthetic method for the preparation of enantiomerically pure 2[(2R)-arylmorpholin-2-yl]ethanols 1a- d, key intermediates of tachykinin receptor antagonist. Sharpless catalytic asymmetric dihydroxylation of 4a-d was employed to introduce the required absolute stereochemistry, and cyclization of 7a-d was accomplished by the Mitsunobu reaction.

Full text of DOI:10.1016/S0957-4166(98)00336-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 3251–3262
An efficient synthesis of enantiomerically pure
2-[(2R)-arylmorpholin-2-yl]ethanols, key intermediates of
tachykinin receptor antagonist
Takahide Nishi,∗ Koki Ishibashi, Katsuyoshi Nakajima, Yukiko Iio and Tetsuya Fukazawa
Medicinal Chemistry Research Laboratories, Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
Received 17 July 1998; accepted 10 August 1998
Abstract
We report herein an efficient and practical synthetic method for the preparation of enantiomerically pure 2-
[(2R)-arylmorpholin-2-yl]ethanols 1a–d, key intermediates of tachykinin receptor antagonist. Sharpless catalytic
asymmetric dihydroxylation of 4a–d was employed to introduce the required absolute stereochemistry, and
cyclization of 7a–d was accomplished by the Mitsunobu reaction. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
The tachykinins, a family of neuropeptides comprising substance P (SP), neurokinin A (NKA) and
neurokinin B (NKB), are involved in a variety of biological actions such as pain transmission, vaso-
dilation, smooth muscle contraction, and neurogenic inflammation. Airway inflammation and broncho-
constriction in asthma and chronic airway-obstructive disease continue to be the major foci of clinical
interest in tachykinin research. Based on the different orders of potency of natural tachykinins, three
distinct receptor types have been identified, i.e. NK1 (SP-preferring), NK2 (NKA-preferring), and NK3
(NKB-preferring).1 Among several classes of recently reported tachykinin receptor antagonists, there is
speculation that a combined NK1/NK2/NK3 receptor antagonist might be an effective drug in asthma
and chronic airway obstruction. In the course of our study to find a combined antagonist, we recently
reported morpholine analogues which had balanced binding affinities to both NK1 and NK2 receptors.2
Independently, Sanofi’s group discovered SR-144190, an NK2 receptor-selective antagonist which also
possesses the morpholine moiety.3 Preliminary studies indicated that the stereochemistry of the 2-
substituents of the morpholine ring has great impact on the binding activity to tachykinin receptor, and the
(R)-configuration has been shown to be an essential requirement for more potent binding affinities. For
∗
Corresponding author. E-mail: takahi@shina.sankyo.co.jp
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00336-X

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the synthesis of these enantiomerically pure morpholine analogues, 2-[(2R)-arylmorpholin-2-yl]ethanols
1a–d are recognized as key intermediates. In various phases of a program we have been conducting
to develop a novel tachykinin receptor antagonist, we have relied on the use of large amounts of
enantiomerically pure 1a–d. We report herein an efficient and practical method for the preparation of
homochiral 1a–d. The key features of our approach are the Sharpless asymmetric dihydroxylation (AD)
of 3-aryl-3-buten-1-ol tert-butyldimethylsilyl (TBDMS) ethers 4a–d, and the Mitsunobu reaction for
dehydration of 7a–d (Scheme 1).
Scheme 1.
2. Results and discussion
At first, we explored two complementary approaches to the conversion of bromobenzenes 2a–d
to olefins 4a–d. Methyl 3-aryl-3-butenoates 3a–d were prepared from corresponding bromobenzenes
2a–d and diketene by the palladium-catalyzed Grignard coupling reaction, followed by esterification
in the presence of conc. H2SO4 in MeOH in moderate yield.4 Compounds 4a–d were cleanly pro-
vided by reduction of esters 3a–d with LiAlH4 followed by protection of primary alcohol with tert-
butyldimethylsilyl chloride and triethylamine in DMF. Compounds 4a–d were also obtained directly
by the palladium-catalyzed cross-coupling reaction of arylmagnesium bromide with vinylbromide 55 in
good conversion yield (Scheme 2).
Scheme 2.
For the preparation of homochiral (R)-diols 6a–d, we examined Sharpless AD to olefins 4a–d. Among
the various chiral ligands for Sharpless AD, Sharpless data suggested that the phthalazine ligand (PHAL)
is recommended for the 1,1-disubstituted olefins.6 In fact, in our initial survey of the available ligands,
(DHQD)2PHAL7 (98% ee for 6a) performed better than the (DHQD)2PYR8 (66% ee for 6a). These
oxidations were carried out by treating the olefins 4a–d with AD-mix-β® [K2OsO2(OH)4 (0.004 mol%),

T. Nishi et al. / Tetrahedron: Asymmetry 9 (1998) 3251–3262
3253
(DHQD)2PHAL (0.01 mol%), K3Fe(CN)6 (3 equiv.), and K2CO3 (3 equiv.)] in t-BuOH–H2O at 0°C for
6–8 h. The results of the oxidations are summarized in Scheme 3. The homochiral (R)-diols 6a–d were
obtained as colorless oils in quantitative yield (6a: [α]D25 +11.4 (c 1.0; MeOH); 6b: [α]D25 +15.6 (c 1.1;
MeOH); 6c: [α]D25 +14.1 (c 1.5; MeOH); 6d: [α]D25 +14.0 (c 1.2; MeOH)).
Scheme 3.
The ee-values of diols 6a–d could be determined by chiral HPLC analysis [6a: column, Chiralcel
OF (4.6φ×250 mm); eluent, 99:1 n-hexane:2-propanol mixture; flow rate, 1.0 ml/min; tR(R)=15.6 min,
tR(S)=18.0 min. 6b: column, Chiralcel OD (4.6φ×250 mm); eluent, 95:5 n-hexane:2-propanol mixture;
flow rate, 0.5 ml/min; tR(R)=24.2 min, tR(S)=21.9 min. 6c: column, Chiralcel OF (4.6φ×250 mm);
eluent, 95:5 n-hexane:2-propanol mixture; flow rate, 1.0 ml/min; tR(R)=13.6 min, tR(S)=16.3 min. 6d:
column, Chiralcel OD (4.6φ×250 mm); eluent, 95:5 n-hexane:2-propanol mixture; flow rate, 0.5 ml/min;
tR(R)=22.2 min, tR(S)=19.2 min]. After selective formation of the primary tosylate, substitution with
ethanolamine was performed in the presence of LiClO4 in acetonitrile at 100°C,9 and the protection of
the resulting secondary amine with Boc2O and triethylamine cleanly provided 7a–d in good yield. In
the continued construction of the morpholine ring, mild conditions were required to retain the stereo-
chemistry of the chiral center. Although the initial efforts at dehydration with 7a–d were problematic,
the Mitsunobu reaction proved successful.10 Treatment of 7a–d with diethyl azodicarboxylate (DEAD)
and triphenylphosphine in toluene at rt cleanly provided homochiral morpholine derivatives 8a–d in
good yield without undesired stereomutation. The desired enantiomerically pure 2-[(2R)-arylmorpholin-
2-yl]ethanols 1a–d were obtained by deprotection of Boc and the TBDMS group via treatment of 4N
HCl/dioxane at 60°C followed by base treatment (Scheme 4).
Scheme 4.

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The ee-values of 1a–d could be directly determined by chiral HPLC analysis [column, Chiralpak AD
(4.6φ×250 mm); eluent, 85:15 n-hexane:2-propanol mixture; flow rate, 1.0 ml/min; tR(R)=12.5 min
(1a), 9.8 min (1b), 12.6 min (1c), 15.0 min (1d); tR(S)=19.8 min (1a), 11.6 min (1b), 18.5 min (1c), 18.7
min (1d)]. Recrystallization from a mixture of n-hexane and ethyl acetate yielded 1a–d of >99.9% ee
25
in the form of white crystals in 80–90% recovery [1a: mp 90–91°C, [α]D +19.2 (c 1.0; MeOH); 1b:
25
25
mp 170–171°C, [α]D +28.0 (c 1.0; MeOH); 1c: mp 133–134°C, [α]D +22.6 (c 1.0; MeOH); 1d: mp
139–140°C, [α]D25 +33.6 (c 1.0; MeOH)].
The stereochemistry of 1a was confirmed by X-ray analysis of α-methoxy-α-trifluoromethylphenyl-
acetic acid (MTPA) amide of 1a. A single-crystal X-ray structure determination of the (R)-MTPA amide
of 1a unambiguously established the relative configuration, and hence, the absolute stereochemistry of
1a is R, as shown in Fig. 1.11
Fig. 1. X-Ray ORTEP of (R)-MTPA amide of (R)-1a
This synthesis also led, of course, to the synthesis of 2-[(2S)-arylmorpholin-2-yl]ethanols with the
opposite configuration by using (DHQ)2PHAL instead of (DHQD)2PHAL as the chiral ligand for the
Sharpless ADs of 4a–d.
In conclusion, we have thus synthesized excellent yields of 1a–d, key intermediates of tachykinin
receptor antagonist with high enantiomeric purity, through the use of Sharpless AD and the Mitsunobu
reaction as the key steps. Further work in this area is now in progress.
3. Experimental
3.1. General
All melting points were measured on a Yanaco MP-500D micro melting point apparatus and are
uncorrected. Optical rotations were measured with a JASCO P-1030 digital polarimeter. The IR spectra
were measured on a JASCO FT/IR 8300 or JASCO FT/IR 8900 spectrophotometer as KBr plates or
1
as CHCl3 solution, and peaks are reported in cm−1. H NMR spectra were recorded on a JEOL JNM-
1
GSX 400 spectrometer in CDCl3. H NMR chemical shifts are reported in ppm downfield of internal
tetramethylsilane. Mass spectra were recorded using a JEOL JMS-BU 20 or JMS-700 spectrometer. Thin
layer chromatography (TLC) was used routinely to monitor the progress and purity of compounds and
was performed on Merck Kieselgel 60 F254 plates. For flash column chromatography, silica gel (Kieselgel
60, 230–400 mesh) was employed.
3.2. Methyl 3-(3,4-dichlorophenyl)-3-butenoate 3a
11.3 g (0.47 mol) of magnesium flakes were added to 300 ml of diethyl ether, followed by a small
amount of iodine. The mixture was then allowed to stand for 1 h, after which a solution of 1-bromo-3,4-

T. Nishi et al. / Tetrahedron: Asymmetry 9 (1998) 3251–3262
3255
dichlorobenzene 2a (102.9 g, 0.46 mol) in diethyl ether (150 ml) was slowly added dropwise. A further
150 ml of diethyl ether was added, and then anhydrous ZnCl2 (60.3 g, 0.44 mol) was slowly added and the
mixture was stirred for 1 h. Dichlorobis(triphenylphosphine)palladium(II) (3.10 g, 4.42 mmol) was then
added, and a solution of diketene (34.2 ml, 0.43 mol) in diethyl ether (600 ml) was added dropwise. The
reaction mixture was stirred at rt for 30 min, after which the mixture was poured into ice-cold 1N aqueous
HCl (1000 ml) and extracted with diethyl ether. The combined organic layer was extracted with aqueous
1N NaOH solution. The combined aqueous layer was acidified with conc. HCl, whilst ice-cooling, and
extracted with diethyl ether, and then the combined organic layer was dried over anhydrous MgSO4. The
solvent was removed in vacuo, and the residue was dissolved in MeOH (350 ml). Conc. H2SO4 (10 ml)
was added, and the solution was heated under reflux for 30 min. The reaction mixture was cooled and
neutralized with a saturated aqueous solution of NaHCO3. MeOH was then removed in vacuo, and the
residue was extracted with CH2Cl2. The combined organic layer was dried over anhydrous MgSO4, and
then the solvent was removed in vacuo. The residue was distilled under reduced pressure to obtain 3a
(69.1 g, 62% yield) as a pale yellow oil, bp 144–146°C (5 mmHg). IR (CHCl3): 1737, 1631, 1552, 1475,
1438, 1171 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.51 (1H, d, J=2.2 Hz), 7.40 (1H, d, J=8.2 Hz), 7.25
(1H, dd, J=8.2, 2.2 Hz), 5.55 (1H, s), 5.30 (1H, s), 3.67 (3H, s), 3.49 (2H, s); MS (EI) m/z: 244 (M+).
3.3. Methyl 3-(4-chlorophenyl)-3-butenoate 3b
According to a similar procedure for the preparation of 3a, 3b (18.7 g) was prepared in 34% yield
from 2b (50.0 g, 0.26 mol). The final purification by distillation under reduced pressure gave a colorless
1
oil, bp 120–123°C (4 mmHg). IR (CHCl3): 1736, 1494, 1437, 1340, 1167 cm−1; H NMR (400 MHz,
CDCl3): δ 7.36 (2H, d, J=8.7 Hz), 7.30 (2H, d, J=8.7 Hz), 5.53 (1H, s), 5.25 (1H, s), 3.66 (3H, s), 3.50
(2H, s); MS (EI) m/z: 210 (M+).
3.4. Methyl 3-(3,4-difluorophenyl)-3-butenoate 3c
According to a similar procedure for the preparation of 3a, 3c (15.9 g) was prepared in 49% yield from
2c (29.6 g, 0.15 mol). The final purification by distillation under reduced pressure gave a colorless oil,
1
bp 94–96°C (4 mmHg). IR (CHCl3): 1737, 1602, 1519, 1437, 1272, 1165 cm−1; H NMR (400 MHz,
CDCl3): δ 7.08–7.10 (2H, m), 7.12–7.15 (1H, m), 5.51 (1H, s), 5.27 (1H, s), 3.67 (3H, s), 3.49 (2H, s);
MS (EI) m/z: 212 (M+).
3.5. Methyl 3-(4-fluorophenyl)-3-butenoate 3d
According to a similar procedure for the preparation of 3a, 3d (27.7 g) was prepared in 50% yield
from 2d (50.0 g, 0.29 mol). The final purification by distillation under reduced pressure gave a colorless
1
oil, bp 100–102°C (5 mmHg). IR (CHCl3): 1736, 1604, 1512, 1437, 1162 cm−1; H NMR (400 MHz,
CDCl3): δ 7.41 (2H, d, J=8.7 Hz), 7.39 (2H, d, J=8.7 Hz), 5.49 (1H, s), 5.22 (1H, s), 3.66 (3H, s), 3.51
(2H, s); MS (EI) m/z: 194 (M+).
3.6. 3-(3,4-Dichlorophenyl)-3-butenol tert-butyldimethylsilyl ether 4a
LiAlH4 (7.50 g, 0.20 mol) was suspended in 350 ml of anhydrous THF, and a solution of methyl 3-
(3,4-dichlorophenyl)-3-butenoate 3a (48.2 g, 0.20 mol) in anhydrous THF (350 ml) was slowly added
dropwise under a nitrogen atmosphere at 0°C over a period of 15 min. The reaction mixture was stirred

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at the same temperature for 30 min, after which 350 ml of H2O and 350 ml of 10% aqueous solution
of NaOH were slowly added. The mixture was then stirred at rt for 1 h. It was then filtered through
Celite and the filtrate was extracted with AcOEt. The combined organic extracts were then dried over
anhydrous MgSO4. The solvent was removed in vacuo, and the residue was dried under reduced pressure.
The residue was then dissolved in anhydrous DMF (150 ml), and then triethylamine (32.9 ml, 0.24 mol),
4-dimethylaminopyridine (4.80 g, 0.04 mol) and tert-butyldimethylsilyl chloride (35.6 g, 0.24 mol) were
added, in that order, whilst ice-cooling. The mixture was then stirred, whilst ice-cooling, for 2 h. At the
end of this time, AcOEt (500 ml) was added to the reaction mixture, and the mixture was washed, in
turn, with ice-cooled 10% aqueous HCl and brine. It was then dried over anhydrous MgSO4. The solvent
was removed in vacuo, and the residue was purified by silica gel flash column chromatography, using a
gradient elution method, with mixtures of n-hexane and AcOEt ranging from 50:1 to 20:1 by volume as
the eluent, to obtain 4a (59.3 g, 91%) as a colorless oil. IR (CHCl3): 2956, 2930, 2858, 1472, 1257, 1096
1
cm−1; H NMR (400 MHz, CDCl3): δ 7.50 (1H, d, J=2.1 Hz), 7.38 (1H, d, J=8.1 Hz), 7.24 (1H, dd,
J=8.1, 2.1 Hz), 5.35 (1H, s), 5.16 (1H, s), 3.70 (2H, t, J=6.9 Hz), 2.67 (2H, t, J=6.9 Hz), 0.89 (9H, s),
0.00 (6H, s).
3.7. 3-(4-Chlorophenyl)-3-butenol tert-butyldimethylsilyl ether 4b
According to a similar procedure for the preparation of 4a, 4b (23.6 g) was prepared in 90% yield from
1
3b (18.6 g, 88.3 mmol) as a colorless oil. IR (CHCl3): 2957, 2931, 2859, 1493, 1094 cm−1; H NMR
(400 MHz, CDCl3): δ 7.35 (2H, d, J=8.6 Hz), 7.28 (2H, d, J=8.6 Hz), 5.32 (1H, s), 5.11 (1H, s), 3.69
(2H, t, J=7.4 Hz), 2.70 (2H, t, J=7.4 Hz), 0.89 (9H, s), 0.00 (6H, s).
3.8. 3-(3,4-Difluorophenyl)-3-butenol tert-butyldimethylsilyl ether 4c
According to a similar procedure for the preparation of 4a, 4c (15.0 g) was prepared in 71% yield from
1
3c (15.0 g, 70.7 mmol) as a colorless oil. IR (CHCl3): 2956, 2930, 2858, 1600, 1516, 1100 cm−1; H
NMR (400 MHz, CDCl3): δ 7.05–7.29 (3H, m), 5.30 (1H, s), 5.13 (1H, s), 3.70 (2H, t, J=6.6 Hz), 2.67
(2H, t, J=6.6 Hz), 0.87 (9H, s), 0.00 (6H, s).
3.9. 3-(4-Fluorophenyl)-3-butenol tert-butyldimethylsilyl ether 4d
According to a similar procedure for the preparation of 4a, 4d (27.2 g) was prepared in 68% yield from
3d (27.6 g, 0.14 mol) as a colorless oil. IR (CHCl3): 2957, 2931, 2859, 1509, 1094 cm−1; 1H NMR (400
MHz, CDCl3): δ 7.37 (1H, d, J=8.7 Hz), 7.35 (1H, d, J=8.7 Hz), 6.99 (1H, d, J=8.7 Hz), 6.97 (1H, d,
J=8.7 Hz), 5.26 (1H, s), 5.06 (1H, s), 3.68 (2H, t, J=7.3 Hz), 2.69 (2H, t, J=7.3 Hz), 0.85 (9H, s), −0.02
(6H, s).
3.10. 3-(3,4-Dichlorophenyl)-3-butenol tert-butyldimethylsilyl ether 4a
Magnesium flakes (6.50 g, 0.27 mol) were added to 100 ml of diethyl ether, and a small amount of io-
dine was added to the mixture. Diethyl ether solution (150 ml) containing 1-bromo-3,4-dichlorobenzene
2a (55.2 g, 0.24 mol) was then added dropwise over a period of 30 min, and the mixture was stirred
for 15 min at room temperature under a nitrogen atmosphere to give a Grignard reagent. A THF
solution (250 ml) containing 3-bromo-3-butenol tert-butyldimethylsilyl ether 55 (20.3 g, 81.4 mmol)
and dichlorobis(triphenylphosphine)palladium(II) (1.70 g, 2.42 mmol) was added to the mixture, and the

T. Nishi et al. / Tetrahedron: Asymmetry 9 (1998) 3251–3262
3257
reaction mixture was stirred for 3 h at rt under a nitrogen atmosphere. At the end of this time, the reaction
mixture was poured into an aqueous solution of NH4Cl and extracted with AcOEt. The organic layer was
washed with brine and dried over anhydrous MgSO4. The solvent was removed in vacuo, and the residue
was purified by silica gel flash column chromatography, using n-hexane as the eluent, to give 4a (20.7
g, 77% yield). The physicochemical properties of this compound were the same as those of the product
produced as described in Section 3.6.
3.11. 3-(4-Chlorophenyl)-3-butenol tert-butyldimethylsilyl ether 4b
According to a similar procedure for the preparation of 4a, 4b (2.18 g) was prepared in 80% yield from
2b (5.00 g, 26.1 mmol) and 5 (2.30 g, 9.23 mmol). The physicochemical properties of this compound
were the same as those of the product produced as described in Section 3.7.
3.12. 3-(3,4-Difluorophenyl)-3-butenol tert-butyldimethylsilyl ether 4c
According to a similar procedure for the preparation of 4a, 4c (0.41 g) was prepared in 74% yield from
2c (1.00 g, 5.18 mmol) and 5 (0.46 g, 1.85 mmol). The physicochemical properties of this compound were
the same as those of the product produced as described in Section 3.8.
3.13. 3-(4-Fluorophenyl)-3-butenol tert-butyldimethylsilyl ether 4d
According to a similar procedure for the preparation of 4a, 4d (8.30 g) was prepared in 73% yield
from 2d (20.0 g, 0.11 mol) and 5 (10.2 g, 0.41 mol). The physicochemical properties of this compound
were the same as those of the product produced as described in Section 3.9.
3.14. 4-tert-Butyldimethylsilyloxy-(2R)-(3,4-dichlorophenyl)butane-1,2-diol 6a
AD-mix-β (80.0 g) was dissolved in 300 ml of t-butanol and 300 ml of water, and 3-(3,4-dichloro-
phenyl)-3-butenol tert-butyldimethylsilyl ether 4a (19.1 g, 57.6 mmol) was added, whilst cooling, at
0°C. The mixture was then stirred at 0°C for 8 h. At the end of this time, 90.0 g of sodium sulfite was
added, and the mixture was stirred at rt for 1 h. It was then extracted with AcOEt, and the combined
organic extracts were dried over anhydrous MgSO4. The solvent was then removed in vacuo, and the
residue was purified by silica gel flash column chromatography, using a gradient elution method, with
mixtures of n-hexane and AcOEt ranging from 5:1 to 1:1 by volume as the eluent to obtain 6a (19.8 g,
94% yield) as a colorless oil of optical purity 98% ee. The ee-value of 6a was determined by chiral HPLC
analysis [column, Chiralcel OF (4.6φ×250 mm); eluent, 99:1 n-hexane:2-propanol mixture; flow rate,
25
1.0 ml/min; tR(R)=15.6 min, tR(S)=18.0 min]. [α]D +11.4 (c 1.0; MeOH); IR (CHCl3): 3421, 2957,
1
2932, 1471, 1390, 1261 cm−1; H NMR (400 MHz, CDCl3): δ 7.57 (1H, d, J=2.1 Hz), 7.43 (1H, d,
J=8.1 Hz), 7.24 (1H, dd, J=8.1, 2.1 Hz), 5.00 (1H, s), 3.80 (1H, ddd, J=10.4, 3.8, 3.8), 3.5–3.7 (3H, m),
2.51 (1H, dd, J=8.0, 5.2 Hz), 2.37 (1H, ddd, J=15.0, 11.1, 4.0 Hz), 1.86 (1H, ddd, J=15.0, 2.9, 2.9 Hz),
0.89 (9H, s), 0.04 (3H, s), −0.01 (3H, s); MS (FAB) m/z: 365 (M+H)+.
3.15. 4-tert-Butyldimethylsilyloxy-(2R)-(4-chlorophenyl)butane-1,2-diol 6b
According to a similar procedure for the preparation of 6a, 6b (24.8 g) was prepared in 95% yield
from 4b (23.5 g, 79.1 mmol) as a colorless oil of optical purity 98% ee. The ee-value of 6b was

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determined by chiral HPLC analysis [column, Chiralcel OD (4.6φ×250 mm); eluent, 95:5 n-hexane:2-
propanol mixture; flow rate, 0.5 ml/min; tR(R)=24.2 min, tR(S)=21.9 min]. [α]D25 +15.6 (c 1.1; MeOH);
1
IR (CHCl3): 3430, 2957, 2932, 1491, 1391, 1261 cm−1; H NMR (400 MHz, CDCl3): δ 7.35 (2H, d,
J=8.7 Hz), 7.31 (2H, d, J=8.7 Hz), 4.90 (1H, s), 3.76 (1H, ddd, J=10.4, 4.0, 3.9 Hz), 3.5–3.7 (3H, m),
2.48 (1H, dd, J=8.4, 5.2 Hz), 2.36 (1H, ddd, J=14.9, 11.3, 4.0 Hz), 1.86 (1H, ddd, J=14.9, 2.9, 2.9 Hz),
0.86 (9H, s), 0.00 (3H, s), −0.05 (3H, s); MS (FAB) m/z: 331 (M+H)+.
3.16. 4-tert-Butyldimethylsilyloxy-(2R)-(3,4-difluorophenyl)butane-1,2-diol 6c
According to a similar procedure for the preparation of 6a, 6c (16.3 g) was prepared in 98% yield from
4c (15.0 g, 50.3 mmol) as a colorless oil of optical purity 99% ee. The ee-value of 6c was determined by
chiral HPLC analysis [column, Chiralcel OF (4.6φ×250 mm); eluent, 95:5 n-hexane:2-propanol mixture;
flow rate, 1.0 ml/min; tR(R)=13.6 min, tR(S)=16.3 min]. [α]D25 +14.1 (c 1.5; MeOH); IR (CHCl3): 3423,
2957, 2932, 1609, 1515, 1290 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.05–7.35 (3H, m), 4.98 (1H, s),
3.80 (1H, ddd, J=10.4, 4.0, 4.0 Hz), 3.5–3.7 (3H, m), 2.54 (1H, dd, J=8.2, 5.2 Hz), 2.37 (1H, ddd, J=14.9,
11.0, 4.0 Hz), 1.86 (1H, ddd, J=14.9, 2.9, 2.9 Hz), 0.89 (9H, s), 0.04 (3H, s), −0.02 (3H, s); MS (FAB)
m/z: 333 (M+H)+.
3.17. 4-tert-Butyldimethylsilyloxy-(2R)-(4-fluorophenyl)butane-1,2-diol 6d
According to a similar procedure for the preparation of 6a, 6d (3.44 g) was prepared in 96% yield
from 4d (3.20 g, 11.4 mmol) as a colorless oil of optical purity 97% ee. The ee-value of 6d was
determined by chiral HPLC analysis [column, Chiralcel OD (4.6φ×250 mm); eluent, 95:5 n-hexane:2-
propanol mixture; flow rate, 0.5 ml/min; tR(R)=22.2 min, tR(S)=19.2 min]. [α]D25 +14.0 (c 1.2; MeOH);
1
IR (CHCl3): 3433, 2957, 2932, 1605, 1509, 1261 cm−1; H NMR (400 MHz, CDCl3): δ 7.41 (1H, d,
J=8.7 Hz), 7.39 (1H, d, J=8.7 Hz), 7.05 (1H, d, J=8.7 Hz), 7.03 (1H, d, J=8.7 Hz), 4.91 (1H, s), 3.78
(1H, ddd, J=10.3, 3.8, 3.7 Hz), 3.5–3.7 (3H, m), 2.53 (1H, dd, J=8.0, 5.1 Hz), 2.39 (1H, ddd, J=14.7,
11.0, 4.1 Hz), 1.89 (1H, ddd, J=14.7, 2.8, 2.8 Hz), 0.88 (9H, s), 0.02 (3H, s), −0.04 (3H, s); MS (FAB)
m/z: 315 (M+H)+.
3.18. 4-tert-Butyldimethylsilyloxy-(2R)-(3,4-dichlorophenyl)-1-[N-(tert-butoxycarbonyl)-N-(2-hydroxy-
ethyl)amino]-2-butanol 7a
4-tert-Butyldimethylsilyloxy-(2R)-(3,4-dichlorophenyl)butane-1,2-diol 6a (39.9 g, 0.11 mol) was dis-
solved in pyridine (80 ml), and p-toluenesulfonyl chloride (31.3 g, 0.16 mol) was added to the resulting
solution. The mixture was then stirred overnight at rt under a nitrogen atmosphere. At the end of this
time, the reaction mixture was diluted with water and extracted with AcOEt. The organic extract was
washed with water and brine, after which it was dried over anhydrous MgSO4. The solvent was then
removed in vacuo. The residue was dissolved in acetonitrile, and lithium perchlorate (35.0 g, 0.33 mol)
and 2-aminoethanol (33.4 g, 0.55 mol) were added to the resulting solution. The mixture was then heated
at 100°C for 16 h. At the end of this time, the reaction mixture was cooled to rt, diluted with AcOEt, and
washed with brine. The organic layer was then separated and dried over anhydrous MgSO4. The solvent
was removed in vacuo, and the residue was dissolved in CH2Cl2 (700 ml). Triethylamine (22.8 ml, 0.16
mol) and 26.3 g (0.12 mol) of di-t-butyl dicarbonate were added to the resulting solution, and the mixture
was stirred at rt for 12 h. The reaction mixture was then poured into water and extracted with CH2Cl2.
The organic extract was washed with brine and then dried over anhydrous MgSO4. The solvent was

T. Nishi et al. / Tetrahedron: Asymmetry 9 (1998) 3251–3262
3259
then removed in vacuo, and the residue was purified by silica gel flash column chromatography, using a
gradient elution method, with mixtures of n-hexane and AcOEt ranging from 4:1 to 7:3 by volume as the
25
eluent, to give 7a (47.8 g, 86% yield) as a colorless oil. [α]D +3.9 (c 0.7; MeOH); IR (CHCl3): 3420,
2957, 2933, 1687, 1471 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.15–7.65 (3H, m), 5.19 and 5.46 (total
1H, each broad s), 2.9–4.0 (9H, m), 1.9–2.3 (2H, m), 1.42 (9H, s), 0.83 (9H, s), −0.04 (3H, s), −0.11
(3H, s); MS (FAB) m/z: 508 (M+H)+.
3.19. 4-tert-Butyldimethylsilyloxy-(2R)-(4-chlorophenyl)-1-[N-(tert-butoxycarbonyl)-N-(2-hydroxy-
ethyl)amino]-2-butanol 7b
According to a similar procedure for the preparation of 7a, 7b (12.0 g) was prepared in 83% yield
25
from 6b (10.0 g, 30.2 mmol) as a colorless oil. [α]D +5.7 (c 1.1; MeOH); IR (CHCl3): 3421, 2956,
2932, 1685, 1463, 1411, 1367, 1256 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.2–7.5 (4H, m), 5.13 and
5.41 (total 1H, each broad s), 3.1–4.0 (9H, m), 1.9–2.3 (2H, m), 1.44 (9H, s), 0.84 (9H, s), −0.03 (3H,
s), −0.11 (3H, s); MS (FAB) m/z: 474 (M+H)+.
3.20. 4-tert-Butyldimethylsilyloxy-(2R)-(3,4-difluorophenyl)-1-[N-(tert-butoxycarbonyl)-N-(2-hydroxy-
ethyl)amino]-2-butanol 7c
According to a similar procedure for the preparation of 7a, 7c (19.2 g) was prepared in 82% yield from
25
6c (16.1 g, 48.4 mmol) as a colorless oil. [α]D +2.4 (c 0.3; MeOH); IR (CHCl3): 3423, 2957, 2933,
1686, 1514, 1369, 1282 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.15–7.50 (3H, m), 5.27 and 5.54 (total
1H, each broad s), 3.1–4.0 (9H, m), 2.0–2.4 (2H, m), 1.53 (9H, s), 0.94 (9H, s), 0.09 (3H, s), 0.07 (3H,
s); MS (FAB) m/z: 476 (M+H)+.
3.21. 4-tert-Butyldimethylsilyloxy-(2R)-(4-fluorophenyl)-1-[N-(tert-butoxycarbonyl)-N-(2-hydroxy-
ethyl)amino]-2-butanol 7d
According to a similar procedure for the preparation of 7a, 7d (4.12 g) was prepared in 83% yield from
25
6d (3.43 g, 10.9 mmol) as a colorless oil. [α]D +2.0 (c 0.5; MeOH); IR (CHCl3): 3425, 2957, 2933,
1684, 1509, 1369, 1152 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.3–7.5 (2H, m), 7.0–7.1 (2H, m), 5.13
and 5.40 (total 1H, each broad s), 3.1–4.0 (9H, m), 2.0–2.4 (2H, m), 1.45 (9H, s), 0.84 (9H, s), −0.03
(3H, s), −0.11 (3H, s); MS (FAB) m/z: 458 (M+H)+.
3.22. 2-[4-tert-Butoxycarbonyl-(2R)-(3,4-dichlorophenyl)morpholin-2-yl]ethanol
silyl ether 8a
tert-butyldimethyl-
4-tert-Butyldimethylsilyloxy-(2R)-(3,4-dichlorophenyl)-1-[N-(tert-butoxycarbonyl)-N-(2-hydroxy-
ethyl)amino]-2-butanol 7a (43.5 g, 85.5 mmol) and triphenylphosphine (26.9 g, 0.10 mol) were
dissolved in toluene (450 ml). Toluene solution (44.7 g of 40% w/v) containing 0.10 mol of diethyl
azodicarboxylate was added dropwise to the resulting solution at rt under a nitrogen atmosphere, and the
mixture was stirred overnight. At the end of this time, the solvent was then removed in vacuo, and the
residue was purified by silica gel flash column chromatography, using a gradient elution method, with
mixtures of n-hexane and AcOEt ranging from 20:1 to 10:1 by volume as the eluent, to give 8a (38.6 g,
25
92% yield) as a colorless oil. [α]D +32.7 (c 0.6; MeOH); IR (CHCl3): 2957, 2931, 1687, 1473, 1462,
1
1428 cm−1; H NMR (400 MHz, CDCl3): δ 7.56 (1H, broad s), 7.43 (1H, d, J=8.8 Hz), 7.28 (1H, dd,

3260
T. Nishi et al. / Tetrahedron: Asymmetry 9 (1998) 3251–3262
J=8.8, 2.2 Hz), 3.00–4.55 (8H, m), 1.80–2.10 (2H, m), 1.43 and 1.52 (total 9H, each broad s), 0.85 (9H,
s), −0.01 (6H, s); MS (FAB) m/z: 490 (M+H)+.
3.23. 2-[4-tert-Butoxycarbonyl-(2R)-(4-chlorophenyl)morpholin-2-yl]ethanol
ether 8b
tert-butyldimethylsilyl
According to a similar procedure for the preparation of 8a, 8b (9.49 g) was prepared in 83% yield
25
from 7b (11.9 g, 25.0 mmol) as a colorless oil. [α]D +40.0 (c 1.2; MeOH); IR (CHCl3): 2956, 2930,
1686, 1428, 1256 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.38 (2H, d, J=8.7 Hz), 7.32 (2H, d, J=8.7 Hz),
3.0–4.5 (8H, m), 1.8–2.1 (2H, m), 1.43 and 1.49 (total 9H, each broad s), 0.85 (9H, s), −0.03 (6H, s);
MS (FAB) m/z: 456 (M+H)+.
3.24. 2-[4-tert-Butoxycarbonyl-(2R)-(3,4-difluorophenyl)morpholin-2-yl]ethanol tert-butyldimethylsilyl
ether 8c
According to a similar procedure for the preparation of 8a, 8c (16.2 g) was prepared in 89% yield from
25
7c (19.0 g, 39.9 mmol) as a colorless oil. [α]D +33.6 (c 0.2; MeOH); IR (CHCl3): 2958, 2931, 1687,
1519, 1428, 1276 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.1–7.4 (3H, m), 3.0–4.5 (8H, m), 1.8–2.1 (2H,
m), 1.51 (9H, broad s), 0.87 (9H, s), 0.02 (6H, s); MS (FAB) m/z: 458 (M+H)+.
3.25. 2-[4-tert-Butoxycarbonyl-(2R)-(4-fluorophenyl)morpholin-2-yl]ethanol
ether 8d
tert-butyldimethylsilyl
According to a similar procedure for the preparation of 8a, 8d (3.38 g) was prepared in 85% yield from
25
7d (4.12 g, 9.00 mmol) as a colorless oil. [α]D +37.4 (c 0.6; MeOH); IR (CHCl3): 2956, 2930, 1699,
1511, 1426, 1256 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.41 (1H, d, J=8.7 Hz), 7.40 (1H, d, J=8.7 Hz),
7.04 (1H, d, J=8.7 Hz), 7.02 (1H, d, J=8.7 Hz), 3.0–4.5 (8H, m), 1.9–2.1 (2H, m), 1.43 and 1.50 (total
9H, each broad s), 0.85 (9H, s), −0.03 (6H, s); MS (FAB) m/z: 440 (M+H)+.
3.26. 2-[(2R)-(3,4-Dichlorophenyl)morpholin-2-yl]ethanol 1a
2-[4-tert-Butoxycarbonyl-(2R)-(3,4-dichlorophenyl)morpholin-2-yl]ethanol tert-butyldimethylsilyl
ether 8a (38.6 g, 78.7 mmol) was dissolved in 500 ml of a 4N solution of hydrogen chloride in dioxane,
and the mixture was stirred at 60°C for 3 h. At the end of this time, the solvent was removed in vacuo, a
1N aqueous HCl solution (500 ml) was added to the resulting residue, and the mixture was washed with
diethyl ether. The aqueous layer was adjusted to pH 14 by the addition of 2N aqueous NaOH solution,
and extracted with CH2Cl2. The organic layer was washed with brine and dried over MgSO4. The
solvent was removed in vacuo, and the residue was recrystallized from AcOEt (175 ml) and n-hexane
(210 ml), to obtain 1a (18.0 g, 83% yield) as white crystals of optical purity >99.9% ee. The ee-value
of 1a was determined by chiral HPLC analysis [column, Chiralpak AD (4.6φ×250 mm); eluent, 85:15
n-hexane:2-propanol mixture; flow rate, 1.0 ml/min; tR(R)=12.5 min, tR(S)=19.8 min]. Mp 90–91°C.
[α]D25 +19.2 (c 1.0; MeOH); IR (KBr): 3261, 3098, 1471, 1383, 1085, 1047 cm−1; 1H NMR (400 MHz,
CDCl3): δ 7.51 (1H, d, J=2.1 Hz), 7.48 (1H, d, J=8.2 Hz), 7.24 (1H, dd, J=8.2, 2.1 Hz), 3.76 (1H, ddd,
J=11.7, 3.3, 3.3 Hz), 3.66 (1H, ddd, J=11.7, 9.5, 3.3 Hz), 3.58 (2H, dd, J=6.0, 6.0 Hz), 3.36 (1H, d,
J=13.2 Hz), 3.11 (1H, d, J=13.2 Hz), 2.97 (1H, ddd, J=12.8, 9.5, 3.3 Hz), 2.79 (1H, ddd, J=12.8, 3.3,
3.3 Hz), 2.15 (1H, ddd, J=14.4, 6.0, 6.0 Hz), 1.79 (1H, ddd, J=14.4, 6.0, 6.0 Hz); MS (EI) m/z: 275

T. Nishi et al. / Tetrahedron: Asymmetry 9 (1998) 3251–3262
3261
(M+). Anal. calcd for C12H15NO2Cl2: C, 52.19; H, 5.48; N, 5.07; Cl, 25.68. Found: C, 52.13; H, 5.48;
N, 5.09; Cl, 25.67.
3.27. 2-[(2R)-(4-Chlorophenyl)morpholin-2-yl]ethanol 1b
According to a similar procedure for the preparation of 1a, 1b (53 mg) was prepared in 68% yield from
8b (148 mg, 0.32 mmol) as white crystals of optical purity >99.9% ee. The ee-value of 1b was determined
by chiral HPLC analysis [column, Chiralpak AD (4.6φ×250 mm); eluent, 85:15 n-hexane:2-propanol
25
mixture; flow rate, 1.0 ml/min; tR(R)=9.8 min, tR(S)=11.6 min]. Mp 170–171°C. [α]D +28.0 (c 1.0;
1
MeOH); IR (KBr): 3270, 3085, 2913, 1484, 1364, 1083, 1044 cm−1; H NMR (400 MHz, CDCl3): δ
7.39 (2H, d, J=8.7 Hz), 7.35 (2H, d, J=8.7 Hz), 3.73 (1H, ddd, J=11.6, 3.4, 3.4 Hz), 3.65 (1H, ddd,
J=11.6, 9.6, 3.0 Hz), 3.57 (2H, m), 3.42 (1H, d, J=13.3 Hz), 3.12 (1H, d, J=13.3 Hz), 2.97 (1H, ddd,
J=12.8, 9.6, 3.4 Hz), 2.77 (1H, ddd, J=12.8, 3.4, 3.0 Hz), 2.11 (1H, ddd, J=14.5, 7.0, 5.1 Hz), 1.77 (1H,
ddd, J=14.5, 6.2, 4.8 Hz); MS (EI) m/z: 241 (M+). Anal. calcd for C12H16NO2Cl: C, 59.63; H, 6.67; N,
5.80; Cl, 14.67. Found: C, 59.25; H, 6.72; N, 5.66; Cl, 14.63.
3.28. 2-[(2R)-(3,4-Difluorophenyl)morpholin-2-yl]ethanol 1c
According to a similar procedure for the preparation of 1a, 1c (6.90 g) was prepared in 81% yield from
8c (16.0 g, 35.0 mmol) as white crystals of optical purity >99.9% ee. The ee-value of 1c was determined
by chiral HPLC analysis [column, Chiralpak AD (4.6φ×250 mm); eluent, 85:15 n-hexane:2-propanol
25
mixture; flow rate, 1.0 ml/min; tR(R)=12.6 min, tR(S)=18.5 min]. Mp 133–134°C. [α]D +22.6 (c 1.0;
MeOH); IR (KBr): 3264, 3078, 1608, 1518, 1275, 1121 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.1–7.3
(3H, m), 3.75 (1H, ddd, J=11.7, 3.5, 3.5 Hz), 3.67 (1H, ddd, J=11.7, 9.5, 3.1 Hz), 3.58 (2H, m), 3.36
(1H, d, J=13.2 Hz), 3.11 (1H, d, J=13.2 Hz), 2.97 (1H, ddd, J=12.6, 9.5, 3.5 Hz), 2.78 (1H, ddd, J=12.6,
3.5, 3.1 Hz), 2.14 (1H, ddd, J=14.3, 6.6, 5.8 Hz), 1.78 (1H, ddd, J=14.3, 5.7, 5.2 Hz); MS (EI) m/z: 243
(M+). Anal. calcd for C12H15NO2F2: C, 59.25; H, 6.22; N, 5.76; F, 15.62. Found: C, 59.21; H, 6.25; N,
5.71; F, 15.37.
3.29. 2-[(2R)-(4-Fluorophenyl)morpholin-2-yl]ethanol 1d
According to a similar procedure for the preparation of 1a, 1d (1.34 g) was prepared in 78% yield from
8d (3.36 g, 7.65 mmol) as white crystals of optical purity >99.9% ee. The ee-value of 1d was determined
by chiral HPLC analysis [column, Chiralpak AD (4.6φ×250 mm); eluent, 85:15 n-hexane:2-propanol
25
mixture; flow rate, 1.0 ml/min; tR(R)=15.0 min, tR(S)=18.7 min]. Mp 139–140°C. [α]D +33.6 (c 1.0;
1
MeOH); IR (KBr): 3268, 3080, 1509, 1225, 1160, 1081, 1058 cm−1; H NMR (400 MHz, CDCl3): δ
7.38 (1H, d, J=8.7 Hz), 7.37 (1H, d, J=8.7 Hz), 7.11 (1H, d, J=8.7 Hz), 7.09 (1H, d, J=8.7 Hz), 3.73 (1H,
ddd, J=11.6, 3.4, 3.1 Hz), 3.66 (1H, ddd, J=11.6, 9.8, 3.1 Hz), 3.56 (2H, m), 3.42 (1H, d, J=13.4 Hz),
3.11 (1H, d, J=13.4 Hz), 2.96 (1H, ddd, J=13.0, 9.8, 3.4 Hz), 2.76 (1H, ddd, J=13.0, 3.1, 3.1 Hz), 2.11
(1H, ddd, J=14.6, 7.1, 4.9 Hz), 1.78 (1H, ddd, J=14.6, 6.5, 4.5 Hz); MS (EI) m/z: 225 (M+). Anal. calcd
for C12H16NO2F: C, 63.98; H, 7.16; N, 6.22; F, 8.43. Found: C, 63.86; H, 7.19; N, 6.12; F, 8.27.
Acknowledgements
We are grateful to Mr. Yoji Furukawa for the X-ray analysis.

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References
1. Regoli, D.; Boudon, A.; Fauchere, J.-L. Pharmacol. Rev. 1994, 46, 551–599 and references cited therein.
2. Nishi, T.; Fukazawa, T.; Kurata, H.; Ishibashi, K.; Nakajima, K.; Yamaguchi, T.; Ito, K. EP-776893-A1, 1996, Sankyo Co.,
Ltd.
3. Emonds-Alt, X.; Advenier, C.; Cognon, C.; Croci, T.; Daoui, S.; Ducoux, J. P.; Landi, M.; Naline, E.; Neliat, G.; Poncelet,
M.; Proietto, V.; Van Broeck, D.; Vilain, P.; Soubrié, P.; Le Fur, G.; Maffrand, J. P.; Brelière, J. C. Tachykinins in Health
and Disease, September 7–11, 1997 in Cairns, Australia, abstract p5. Emonds-Alt, X.; Grossriether, I.; Gueule, P.; Proietto,
V.; Van Broeck, D. EP-2729952-A1, 1995, Sanofi, SA.
4. Itoh, K.; Harada, T.; Nagashima, H. Bull. Chem. Soc. Jpn. 1991, 64, 3746–3748.
5. Magnus, P.; Quagliato, D. J. Org. Chem. 1985, 50, 1621–1626.
6. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483–2547.
7. Sharpless, K. B.; Amberg, W.; Bennari, Y. L.; Crispino, G. A.; Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.;
Wang, Z.-M.; Xu, D.; Zhang, X.-L. J. Org. Chem. 1992, 57, 2768–2771.
8. Crispino, G. A.; Jeong, K.-S.; Kolb, H. C.; Wang, Z.-M.; Xu, D.; Sharpless, K. B. J. Org. Chem, 1993, 58, 3785–3786.
9. Chini, M.; Crotti, P.; Macchia, F. Tetrahedron Lett. 1990, 31, 4661–4664. The reaction proceeds through the aminolysis of
the epoxide.
10. Mitsunobu, O. Synthesis 1981, 1–28. For examples of dehydrocyclization of diol by the Mitsunobu reaction, see: (a)
Tsunoda, T.; Ozaki, F.; Shirakata, N.; Tamaoka, Y.; Yamamoto, H.; Itô, S. Tetrahedron Lett. 1996, 37, 2463–2466. (b) Lee,
B. H.; Biswas, A.; Miller, M. J. J. Org. Chem. 1986, 51, 106–109.
11. Crystal data of (R)-MTPA amide of (R)-1a: C22H22NO4Cl2F3, MW=492.3, T=298 K, CuKα radiation, λ=1.5418 Å;
monoclinic, space group P21, a=12.462(2) Å, b=7.440(2) Å, c=13.395(2) Å, β=110.6(1) Å, V=1162.3(3) Å3, Z=2,
Dc=1.41 g/cm3, R=0.043. Full X-ray crystallographic data will be deposited with the Cambridge Crystallographic Data
Centre.