Catalytic asymmetric synthesis of (-)-ritodrine hydrochloride via silyl enol ether amination using dirhodium(II) tetrakis [tetrafluorophaloyl-(S)-tert-leucinate]

Article abstract of DOI:10.3987/COM-08-S(N)121

A catalytic asymmetric synthesis of (-)-ritodrine hydrochloride was achieved, incorporating an enantioselective amination of (Z)-silyl enol ether derived from 4-benzyloxypropiophenone with [(2-nitrophenylsulfonyl)imino]phenyliodinane (NsN=IPh) and a chelation-controlled reduction of the ketone carbonyl group with Zn(BH₄)₂ as the key steps. The use of dirhodium(II) tetrakis[tetrafluorophthaloyl-(S)-tert-leucinate] as a catalyst produced the targeted α-amino ketone in 94% yield with 91% ee.

Full text of DOI:10.3987/COM-08-S(N)121

HETEROCYCLES, Vol. 76, No. 2, 2008
1633
HETEROCYCLES, Vol. 76, No. 2, 2008, pp. 1633 - 1645. © The Japan Institute of Heterocyclic Chemistry
Received, 13th May, 2008, Accepted, 9th June, 2008, Published online, 12th June, 2008. COM-08-S(N)121
CATALYTIC ASYMMETRIC SYNTHESIS OF (–)-RITODRINE
HYDROCHLORIDE VIA SILYL ENOL ETHER AMINATION USING
DIRHODIUM(II) TETRAKIS [TETRAFLUOROPHTHALOYL-(S)-TERT-
LEUCINATE]
Masahiko Tanaka, Seiichi Nakamura, Masahiro Anada,
and Shunichi Hashimoto*
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812,
Japan
e-mail: hsmt@pharm.hokudai.ac.jp
Abstract – A catalytic asymmetric synthesis of (–)-ritodrine hydrochloride was
achieved, incorporating an enantioselective amination of (Z)-silyl enol ether
derived from 4-benzyloxypropiophenone with [(2-nitrophenylsulfonyl)imino]-
phenyliodinane (NsN=IPh) and a chelation-controlled reduction of the ketone
carbonyl group with Zn(BH4)2 as the key steps. The use of dirhodium(II)
tetrakis[tetrafluorophthaloyl-(S)-tert-leucinate] as a catalyst produced the targeted
α-amino ketone in 94% yield with 91% ee.
2-Amino-1-aryl-1-propanols (1) are important and versatile intermediates in the synthesis of a wide
1
variety of natural products and pharmaceuticals, such as ephedrine (1a),1 norephedrine (1b),2
pseudoephedrine (1c),3 norpseudoephedrine (1d),4 the α1-adrenergic receptor agonist metaraminol (1e),5
and the antianginal agent oxyfedrine (1f).6 Further interest stems from their use as chiral auxiliaries and
ligands.7 Because of their importance, several strategies have been developed to achieve the catalytic
asymmetric synthesis of 1, including asymmetric nitroaldol (Henry) reaction,8,9 dynamic kinetic
resolution of racemic α-amino ketones,10 and asymmetric reduction of α-oxoketoxime ethers.11
OH
OH
OH
OH
OMe
Me
Me
NHR
R = Me: pseudoephedrine (1c)
HO
Me
NH2
metaraminol (1e)
Me
NHR
HN
R = Me: ephedrine (1a)
R = H: norephedrine (1b)
O
oxyfedrine (1f)
R = H: norpseudoephedrine (1d)
† Dedicated to Professor Ryoji Noyori on the occasion of his 70th birthday.

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HETEROCYCLES, Vol. 76, No. 2, 2008
Ritodrine, (±)-(1R*,2S*)-1-(4-hydroxyphenyl)-2-[N-[2-(4-hydroxyphenyl)ethyl]amino]-1-propanol, is a
selective β2-adrenergic receptor agonist, and its hydrochloride is currently one of the most commonly
used drugs for the treatment of preterm labor.12 Ritodrine binds to β2-receptors located on the outer
surface of the myometrium, triggering the conversion of adenosine 5'-triphosphate (ATP) to cyclic
adenosine 3',5'-monophosphate (cAMP), which leads to relaxation of myometrial tissues. Although
ritodrine is used as a racemate, it has been disclosed that the
OH
(1R,2S)-(–)-enantiomer (1g) is primarily responsible for the
Me
pharmacological effects.13 Very recently, Shibasaki and
HN
HO
co-workers described the first highly efficient, catalytic
·HCl
OH
asymmetric synthesis of (–)-ritodrine (1g) hydrochloride by
(–)-ritodrine (1g) hydrochloride
developing an anti- and enantio-selective nitroaldol reaction
catalyzed by a heterobimetallic Pd/La/Schiff base complex.14
We have recently documented the utility of Rh2(S-TFPTTL)4 (2a) and Rh2(S-TCPTTL)4 (2b),15
characterized by the substitution of fluorine or chlorine atoms for four hydrogen atoms on the
phthalimido group in the parent dirhodium(II) complex, [Rh2(S-PTTL)4] (2c),16,17 in the catalysis of
enantioselective nitrene transfer reactions18 such as C–H amination19,20 and olefin aziridination.21 More
recently, we have reported that Rh2(S-TFPTTL)4-catalyzed enantioselective amination of silyl enol ethers
with [(2-nitrophenylsulfonyl)imino]phenyliodinane (NsN=IPh) (4) provides N-(2-nitrophenylsulfonyl)-α-
amino ketones with enantioselectivities of up to 95% ee,22 the effectiveness of which has been
demonstrated by an asymmetric formal synthesis of (–)-metazocine (6), a benzomorphan analgesic
(Scheme 1). In this process, the use of NsN=IPh (4) as a nitrene precursor is not only crucial for high
levels of enantioselection but also synthetically advantageous since the alkylation of resultant N-
1. Rh2(S-TFPTTL)4
OSiEt3
(3 mol %)
NMe
O
Me
CH2Cl2, –40 °C, 8 h
Me
Me
NHNs
Me
+
NsN=IPh
2. aq. TFA, 0 °C
MeO
4
MeO
5a
3a (Z:E = 87:13)
HO
(–)-metazocine (6)
Ns = 2-NO2C6H4SO2
82% (90% ee)
1. Rh2(S-TFPTTL)4
(3 mol %)
CH2Cl2, –40 °C, 5–7 h
X
O
N
X
OSiEt3
O
X
Me
+
Me
H
NsN=IPh
X
O
2. aq. TFA, 0 °C
X
NHNs
O
O
4
X
Z:E = >99:1
Rh Rh
3b (X = H)
3c (X = Cl)
3d (X = MeO)
5b (X = H): 97% (93% ee)
5c (X = Cl): 94% (90% ee)
5d (X = MeO): 98% (95% ee)
X = F: Rh2(S-TFPTTL)4 (2a)
X = Cl: Rh2(S-TCPTTL)4 (2b)
X = H: Rh2(S-PTTL)4 (2c)
Scheme 1

HETEROCYCLES, Vol. 76, No. 2, 2008
1635
monosubstituted Ns-amides and deprotection proceed under mild conditions.23 In order to further broaden
the utility of this catalytic protocol, we envisioned that stereocontrolled reduction of the
1-phenyl-2-[N-(2-nitrophenylsulfonyl)amino]propan-1-one derivatives thus obtained would provide facile
access to optically active 2-amino-1-aryl-1-propanols (1).24,25 Based on this scenario, we have now
addressed the catalytic asymmetric synthesis of (–)-ritodrine (1g) hydrochloride.
Toward this end, we selected (Z)-1-(4-benzyloxyphenyl)-1-triethylsiloxy-1-propene (3e) as a substrate on
the basis of our previous finding that only (Z)-silyl enol ethers are responsible for the formation of
α-amino ketones.22,26 (Z)-Silyl enol ether (3e) was readily prepared from 4-benzyloxypropiophenone (7)27
by treatment with LDA at –78 °C followed by the addition of Et3SiCl (Scheme 2).28 The
1
(Z)-stereochemistry of 3e was established by the H NOE between C2–H and ortho protons on the
benzene ring. The reaction of 3e with NsN=IPh (4) in CH2Cl2 in the presence of 3 mol % of
Rh2(S-TFPTTL)4 proceeded at –40 °C to completion in 5 h, and, after treatment with 90% aqueous
23
trifluoroacetic acid, gave α-amino ketone (5e), [α]D +4.65° (c 1.27, CHCl3), in 92% yield. The
enantioselectivity of this reaction was determined to be 82% ee by HPLC analysis (Daicel Chiralpak IA
column). The preferred absolute configuration of 5e was assigned as S by its conversion to 1g·HCl (vide
infra). Gratifyingly, the enantioselectivity was further enhanced up to 91% ee by lowering the reaction
temperature to –60 °C without affecting product yield, although much longer reaction times (36 h) were
necessary to reach completion. Chelation-controlled reduction of the ketone carbonyl group in 5e with
Zn(BH4)2 led to the exclusive formation of the desired anti-amino alcohol (8) in 95% yield.25b,c,29 The
anti-stereochemistry of 8 was established by its transformation to the 1,3-oxazolidin-2-one (9),30 which
1. Rh2(S-TFPTTL)4 (2a)
(3 mol %)
NsN=IPh (4) (1.05 equiv)
O
O
OSiEt3
Me
LDA, THF
–78 °C, 30 min
Me
Me
5.5%
CH2Cl2, –60 °C, 36 h
2. aq. TFA, 0 °C
then Et3SiCl
23 °C, 2 h
NHNs
H
BnO
BnO
BnO
H
7
5.2%
5e
94% (91% ee)
87%
3e (Z:E = >99:1)
: NOE
OH
Me
OAc
Me
Zn(BH4)2
Ac2O
THF, 0 °C
95%
NHNs
NHNs
DMAP, pyridine
91%
BnO
BnO
10
8
(Cl3CO)2C=O
Et3N, CH2Cl2
0 °C
91% ee
recryst.
85%
>99% ee
O
N
92%
O
Ns
7.6%
Me
BnO
H
10.2%
9
Scheme 2

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HETEROCYCLES, Vol. 76, No. 2, 2008
showed an NOE correlation between the C4-methyl group and ortho protons on the benzene ring. No
signs of the syn-amino alcohol could be detected in the crude reaction mixture by NMR spectroscopy.31
Acetylation of 8 under standard conditions provided amino acetate (10) in 93% yield as a white solid.
Fortunately, we found that a single recrystallization of 10 from MeOH gave crystals with 3% ee {11%,
mp 130.5–131.5 °C, [α]D23 –1.46° (c 1.12, CHCl3)}, while the mother liquor contained 10 with >99% ee
{84%, mp 50.0–51.0 °C, [α]D23 –41.2° (c 1.05, CHCl3)}.
With enantioenriched amino acetate (10) (>99% ee) in hand, we proceeded to the elaboration of the target
molecule (Scheme 3). N-Alkylation of 10 with 2-(4-benzyloxyphenyl)ethanol32 under Mitsunobu
conditions gave the N,N-disubstituted amine derivative (11) in 82% yield.33,34 Removal of the Ns group
under standard Fukuyama conditions23 followed by removal of the acetyl group with K2CO3 in MeOH
gave β-amino alcohol (12) in 83% yield. Hydrogenolysis of the benzyl ethers over 10% Pd/C in EtOH
21
furnished (–)-ritodrine (1g), [α]D –5.33° (c 1.43, EtOH), in 96% yield, which upon treatment with HCl
in EtOH afforded (–)-ritodrine (1g) hydrochloride13,14 in 89% yield. The synthetic material (1g·HCl) had
23
an optical rotation, [α]D –13.6° (c 0.30, EtOH), in good agreement with the literature value {lit.,13
20
[α]D –13.2° (c 0.24, EtOH)}. Thus, the preferred absolute configuration of α-amino ketone (5e) was
established as S.
OR2
OAc
EtO2CN=NCO2Et
Me 4-BnOC6H4CH2CH2OH
Me
NHNs
N
PPh3, THF
82%
R1
BnO
BnO
10
OBn
11: R1 = Ns, R2 = Ac
12: R1 = R2 = H
1. Cs2CO3, PhSH
2. K2CO3, MeOH
83%
OH
H2, Pd/C
Me
HCl(g)
EtOH
1g·HCl
EtOH, 0 °C
96%
HN
(–)-ritodrine (1g)
HO
89%
OH
Scheme 3
In summary, we have achieved the catalytic asymmetric synthesis of (–)-ritodrine hydrochloride in 10
steps and with 35% overall yield from 4-benzyloxypropiophenone. The present protocol provides ready
access to its novel analogues for biological and pharmacological investigations.
EXPERIMENTAL
General. Melting points were determined on a Büchi 535 digital melting point apparatus and are
uncorrected. IR spectra were recorded on a JASCO FT/IR-4100 spectrometer and absorbance bands are

HETEROCYCLES, Vol. 76, No. 2, 2008
1637
reported in wavenumber (cm–1). 1H NMR spectra were recorded on JEOL JNM-ECX 400 (400 MHz)
spectrometer or JEOL JNM-ECA 500 (500 MHz) spectrometer. Chemical shifts are reported relative to
the internal standard (tetramethylsilane; δH 0.00, CDCl3; δH 7.26 or DMSO-d6; δH 2.50). Data are
presented as follows: chemical shift (δ, ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,
13
m = multiplet, br = broad), coupling constant and integration. C NMR spectra were recorded on JEOL
JNM-ECX 400 (100 MHz) spectrometer or JEOL JNM-ECA 500 (125 MHz) spectrometer. The
following internal references were used (CDCl3; δ 77.0, CD3OD; δ 49.8 or DMSO-d6; δ 39.7). Optical
rotations were measured on a JASCO P-1030 digital polarimeter at the sodium D line (589 nm). EI-MS
spectra were obtained on a JEOL JMS-FABmate spectrometer, operating with ionization energy of 70 eV.
FAB-MS spectra were obtained on a JEOL JMS-HX 110 spectrometer. Column chromatography was
carried out on Kanto silica gel 60 N (63–210 mesh) or Wakogel® C-200 (75–150 mesh). Analytical thin
layer chromatography (TLC) was carried out on Merck Kieselgel 60 F254 plates with visualization by UV
light, anisaldehyde stain solution or phosphomolybdic acid stain solution. Analytical high performance
liquid chromatography (HPLC) was performed on a JASCO PU-1580 intelligent HPLC pump with
JASCO UV-1575 intelligent UV/vis detector. Detection was performed at 254 nm. Chiralpak AD-H (0.46
cm × 25 cm) or Chiralpak IA column (0.46 cm × 25 cm) from Daicel were used. Retention times (tR) and
peak ratios were determined with JASCO-Borwin analysis system.
All non-aqueous reactions were carried out in flame-dried glassware under an argon atmosphere unless
otherwise noted. Reagents and solvents were purified by standard means. Dehydrated stabilizer-free
CH2Cl2 and THF were purchased from Kanto Chemical Co., Inc. Diisopropylamine and
N,N-dimethylformamide (DMF) were distilled from calcium hydride prior to use.
Rh2(S-TFPTTL)4·2EtOAc (2) was prepared from L-tert-leucine according to literature procedure.15,17
[N-(2-nitrophenylsulfonyl)imino]phenyliodinane (4) was prepared from the corresponding sulfonamide
according to literature procedure.35 Diethyl azodicarboxylate (2.2 M in toluene) was purchased from
Tokyo Chemical Industry Co., Ltd. Cesium carbonate was purchased from Wako Pure Chemical
Industries, Ltd.
(Z)-1-(4-Benzyloxyphenyl)-1-triethylsiloxy-1-propene (3e). BuLi (1.6 M in hexane, 6.8 mL, 11.0
mmol) was added to a solution of diisopropylamine (1.31 g, 1.82 mL, 12.0 mmol) in THF (20 mL) at
–78 °C. After stirring at this temperature for 0.5 h, 4-benzyloxypropiophenone27 (2.40 g, 10.0 mmol) in
THF (15 mL) was added to the mixture over a period of 1 h. The solution was stirred for 0.5 h and
chlorotriethylsilane (1.85 mL, 11.0 mmol) was added. The mixture was allowed to warm to rt over 0.5 h
and stirred for 1 h. The mixture was diluted with 5% triethylamine in hexane (60 mL), and the mixture
was washed with saturated aqueous NaHCO3 (3 × 30 mL) and brine (2 × 30 mL), and dried over

1638
HETEROCYCLES, Vol. 76, No. 2, 2008
anhydrous Na2SO4. Filtration and evaporation in vacuo furnished the crude product, which was purified
by Kugelrohr distillation (3 mmHg, 180 °C) to provide 3e (2.81 g, 81% yield, Z/E = >99:1) as a colorless
oil; Rf = 0.48 (19:1 hexane/EtOAc); IR (neat) ν: 2954, 1651, 1606, 1508, 1240, 1065, 1008, 835 cm-1; 1H
NMR (400 MHz, CDCl3) δ 0.61 (q, J = 8.2 Hz, 6H, CH3CH2Si), 0.93 (t, J = 8.2 Hz, 9H, CH3CH2Si), 1.73
(d, J = 6.9 Hz, 3H, CH3CH=C), 5.06 (s, 2H, PhCH2O), 5.10 (q, J = 6.9 Hz, 1H, CH3CH=C), 6.88–6.92 (m,
13
2H, ortho proton of 4-benzyloxyphenyl group), 7.31–7.45 (m, 7H, Ar); C NMR (125 MHz, CDCl3) δ
5.34 (CH2), 6.70 (CH3), 11.47 (CH3), 69.95 (CH2), 103.73 (CH), 114.18 (CH), 126.62 (CH), 127.50 (CH),
127.92 (CH), 128.53 (CH), 132.68 (C), 136.96 (C), 149.96 (C), 158.17 (C); HRMS (EI) C22H30O2Si (M+)
354.2015, found 354.2027.
(S)-1-(4-Benzyloxyphenyl)-2-[(2-nitrophenylsulfonyl)amino]-1-propanone (5e). [N-(2-nitrophenyl-
sulfonyl)imino]phenyliodinane (4) (806.4 mg, 2.0 mmol, 1.05 equiv) was added in one portion to a
solution of 3e (673.6 mg, 1.90 mmol, Z/E = >99:1) and Rh2(S-TFPTTL)4·2EtOAc (2a) (90.4 mg, 0.057
mmol, 3 mol %) in CH2Cl2 (15 mL) at –60 °C. After stirring at this temperature for 36 h, the reaction
mixture was treated with 90% aqueous TFA (ca. 0.5 mL) followed by stirring for 0.5 h at rt. The mixture
was partitioned between EtOAc (50 mL) and pH 7.0 phosphate buffer (15 mL). The separated organic
layer was washed with water (2 × 20 mL) and brine (2 × 20 mL), and dried over anhydrous Na2SO4.
Filtration and evaporation furnished the crude product, which was purified by column chromatography
(silica gel, 3:1 hexane/EtOAc). Rh2(S-TFPTTL)4 (2a) {75.0 mg, 83%, Rf = 0.71 (2:1 hexane/EtOAc)}
was eluted first through the column. The fractions containing the product were collected and concentrated
23
to provide 5e (786.1 mg, 94% yield) as a colorless viscous oil; Rf = 0.23 (2:1 hexane/EtOAc); [α]D
+5.33° (c 1.51, CHCl3) for 91% ee; IR (neat) ν: 3330, 1679, 1544, 1378, 1359, 1222, 1174, 972 cm–1;1H
NMR (400 MHz, CDCl3) δ 1.49 (d, J = 7.2 Hz, 3H, CH3CHN), 5.13 (s, 2H, PhCH2O), 5.17 (dq, J = 8.2,
7.2 Hz, 1H, CH3CHN), 6.65 (d, J = 8.2 Hz, 1H, NH), 6.98–7.02 (m, 2H, Ar), 7.33–7.43 (m, 5H, Ar), 7.56
(dt, J = 1.4, 7.7 Hz, 1H, Ar), 7.64 (dt, J = 1.4, 7.7 Hz, 1H, Ar), 7.79–7.83 (m, 2H, Ar), 7.86 (dd, J = 1.4,
7.7 Hz, 1H, Ar), 7.99 (dd, J = 1.4, 7.7 Hz, 1H, Ar); 13C NMR (125 MHz, CDCl3) δ 21.16 (CH3), 54.12
(CH), 70.19 (CH2), 114.95 (CH), 125.49 (CH), 126.28 (C), 127.43 (CH), 128.32 (CH), 128.68 (CH),
130.01 (CH), 130.91 (CH), 132.71 (CH), 133.49 (CH), 134.33 (C), 135.75 (C), 147.56 (C), 163.41 (C),
195.63 (C=O); HRMS (FAB) calcd for C22H21N2O6S (M+H+) 441.1120, found 441.1126. The
enantiomeric excess of 5e was determined to be 91% by HPLC with a Daicel Chiralpak IA column (3:1
hexane/i-PrOH, 1.0 mL/min): tR (major) = 30.5 min for (S)-enantiomer; tR (minor) = 33.9 min for
(R)-enantiomer.
(1R,2S)-1-(4-Benzyloxyphenyl)-2-[(2-nitrophenylsulfonyl)amino]-1-propanol (8). Zn(BH4)236 (0.64 M
in THF, 3.2 mL, 2.06 mmol) was added to a solution of 5e (603.9 mg, 1.37 mmol) in THF (15 mL) at

HETEROCYCLES, Vol. 76, No. 2, 2008
1639
0 °C. After stirring at 0 °C for 0.5 h, the reaction was quenched with 10% aqueous HCl (5 mL) and the
whole was extracted with EtOAc (40 mL). The organic layer was washed with water (2 × 10 mL) and
brine (2 × 10 mL), and dried over anhydrous Na2SO4. Filtration and concentration in vacuo furnished the
crude product, which was purified by column chromatography (silica gel, 2:1 hexane/EtOAc) to give 8
(576 mg, 95%) as colorless needles; Rf = 0.53 (1:1 hexane/EtOAc); mp 54.0–56.0 °C (2:1
23
hexane/EtOAc); [α]D –57.6° (c 1.14, MeOH) for 91% ee; IR (KBr) ν: 3528, 3321, 1540, 1356, 1332,
1227, 1054 cm–1; 1H NMR (500 MHz, CDCl3) δ 1.01 (d, J = 6.9 Hz, 3H, CH3CHN), 2.16 (br-s, 1H, OH),
3.78 (ddq, J = 3.9, 8.3, 6.9 Hz, 1 H, CH3CHN), 4.73 (d, J = 3.9 Hz, 1 H, CHOH), 5.04 (s, 2H, PhCH2O),
5.51 (d, J = 8.3 Hz, 1H, NH), 6.88–6.91 (m, 2H, Ar), 7.16–7.19 (m, 2H, Ar), 7.34 (m, 1H, Ar), 7.38–7.44
(m, 4H, Ar), 7.70 (dt, J = 1.7, 7.4 Hz, 1H, Ar), 7.73 (dt, J = 1.7, 7.4 Hz, 1H, Ar), 7.84 (m, 1H, Ar), 8.14
13
(m, 1H, Ar); C NMR (125 MHz, CDCl3) δ 15.61 (CH3), 55.98 (CH), 69.97 (CH2), 75.65 (CH), 114.71
(CH), 125.41 (CH), 127.32 (CH), 127.45 (CH), 128.04 (CH), 128.60 (CH), 130.63 (CH), 132.15 (C),
132.89 (CH), 133.36 (CH), 134.80 (C), 136.75 (C), 147.61 (C), 158.47 (C); HRMS (FAB)
C22H22N2O6SNa (M+Na)+ 465.1096, found 465.1091.
(4S,5R)-5-(4-Benzyloxyphenyl)-4-methyl-3-(2-nitrophenylsulfonyl)-1,3-oxazolidin-2-one
(9).
Triphosgene (42.1 mg, 0.14 mmol) was added at 0 °C to a solution of 8 (62.8 mg, 0.14 mmol, 91% ee)
and Et3N (71.8 mg, 0.71 mmol) in CH2Cl2 (3 mL). After stirring at 0 °C for 0.5 h, the reaction was
quenched with crushed ice. The mixture was partitioned between EtOAc (20 mL) and water (3 mL). The
organic layer was washed with brine (2 × 3 mL) and dried over anhydrous Na2SO4. Filtration and
evaporation in vacuo furnished the crude product, which was purified by column chromatography (silica
gel, 2:1 hexane/EtOAc) to provide 9 (60.5 mg, 92%) as colorless needles; Rf = 0.34 (2:1 hexane/EtOAc);
23
mp 107.0–108.5 °C; [α]D +235.1° (c 1.14, CHCl3); IR (KBr) ν: 2924, 1779, 1543, 1516, 1373, 1348,
1253, 1178, 969 cm-1; 1H NMR (500 MHz, CDCl3) δ 1.16 (d, J = 6.9 Hz, 3H, C4-CH3), 4.82 (dq, J = 6.9,
7.4 Hz, 1H, C4-H), 5.08 (s, 2H, PhCH2O), 5.82 (d, J = 7.4 Hz, 1H, C5-H), 7.03 (d, J = 8.6 Hz, 2H, Ar),
13
7.25 (d, J = 8.6 Hz, 2H, Ar), 7.33–7.44 (m, 5H, Ar), 7.80–7.86 (m, 3H, Ar), 8.48 (m, 1H, Ar); C NMR
(125 MHz, CDCl3) δ 17.36 (CH3), 58.77 (CH), 70.08 (CH2), 80.39 (CH), 115.10 (CH), 124.59 (CH),
124.66 (C), 127.28 (CH), 127.49 (CH), 128.12 (CH), 128.63 (CH), 130.67 (CH), 132.25 (CH), 134.80 (C),
135.40 (C), 136.49 (C), 147.94 (C), 151.18 (C), 159.33 (C=O); HRMS (EI) C23H20N2O7S (M+) 468.0991,
found 468.1002.
(1R,2S)-1-(4-Benzyloxyphenyl)-2-[(2-nitrophenylsulfonyl)amino]-1-propyl acetate (10). Acetic
anhydride (195 mg, 1.91 mmol) was added to a solution of 8 (564.5 mg, 1.28 mmol) and
4-(N,N-dimethylamino)pyridine (15.9 mg, 0.13 mmol) in pyridine (2 mL) at 0 °C. After stirring at rt for

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HETEROCYCLES, Vol. 76, No. 2, 2008
0.5 h, the reaction was quenched with crushed ice. The mixture was partitioned between EtOAc (25 mL)
and H2O (5 mL). The organic layer was washed with 1 N HCl (2 × 5 mL) and brine (2 × 5 mL), and dried
over anhydrous Na2SO4. Filtration and concentration in vacuo furnished the crude product, which was
purified by column chromatography (silica gel, 3:1 hexane/EtOAc) to give 10 (576.7 mg, 93%) as a white
23
solid; Rf = 0.38 (3:2 hexane/EtOAc); mp 51.0–55.0 °C; [α]D –35.9° (c 1.06, CHCl3) for 91% ee; IR
(KBr) ν: 3290, 2979, 1719, 1540, 1365, 1336, 1251, 1163, 1032 cm-1; 1H NMR (500 MHz, CDCl3) δ 1.10
(d, J = 6.9 Hz, 3H, CH3CHN), 2.02 (s, 3H, CH3CO), 3.97 (ddq, J = 4.6, 8.6, 6.9 Hz, 1H, CH3CHN), 5.01
(s, 2H, PhCH2O), 5.40 (d, J = 8.6 Hz, 1H, NH), 5.54 (d, J = 4.6 Hz, 1H, CHOAc), 6.87 (d, J = 8.6 Hz, 2H,
Ar), 7.13 (d, J = 8.6 Hz, 2H, Ar), 7.32–7.42 (m, 5H, Ar), 7.70 (m, 2H, Ar), 7.82 (dd, J = 1.1, 7.4 Hz, 1H,
13
Ar), 8.10 (dd, J = 1.1, 7.4 Hz, 1H, Ar); C NMR (125 MHz, CDCl3) δ 17.22 (CH3), 20.87 (CH3), 53.86
(CH), 69.89 (CH2), 76.43 (CH), 114.73 (CH), 125.43 (CH), 127.40 (CH), 127.89 (CH), 127.95 (C),
128.02 (CH), 128.57 (CH), 130.37 (CH), 132.99 (CH), 133.40 (CH), 134.76 (C), 136.61 (C), 147.48 (C),
158.72 (C), 169.82 (C=O); HRMS (EI) C24H24N2O7S (M+) 484.1304, found 484.1299; Anal. Calcd for
C24H24N2O7S: C, 59.49; H, 4.99; N, 5.78; S, 6.62. Found: C, 59.31; H, 4.95; N, 5.72; S, 6.60.
10 (419.0 mg, 91% ee) was dissolved in 4.5 mL of boiling MeOH and stored at rt overnight. Colorless
needles of 10 (47.0 mg, 11%, 3% ee){mp 130.5–131.5 °C, [α]D23 –1.46° (c 1.12, CHCl3)} were removed
by filtration, and the filtrate was concentrated in vacuo to afford 10 (350 mg, 84%, >99% ee) as colorless
needles; mp 50.0–51.0 °C; [α]D23 –41.2° (c 1.05, CHCl3).
The homochirality of 10 was established by comparison of retention time in HPLC (Chiralpak, AD-H, 1:1
hexane/i-PrOH, 1.0 mL/min) with a racemic sample: tR (minor) = 8.45 min for ent-10, tR (major) = 10.53
min for 10.
(1R,2S)-1-(4-Benzyloxyphenyl)-2-[N-[2-(4-benzyloxyphenyl)ethyl]-N-(2-nitrophenylsulfonyl)amino]-
1-propyl acetate (11). Diethyl azodicarboxylate (2.2 M in toluene, 0.75 mL, 1.65 mmol) was added to a
solution of 10 (400 mg, 0.826 mmol, >99% ee), 2-(4-benzyloxyphenyl)ethan-1-ol32 (377.1 mg, 1.65
mmol), and triphenylphosphine (433.3 mg, 1.65 mmol) in THF (4 mL) at rt, and the mixture was stirred
for 3 h. The mixture was concentrated in vacuo and the residue was purified by column chromatography
(silica gel, 9:1 toluene/Et2O) to afford 11 (468.4 mg, 82%) as a colorless viscous oil; Rf = 0.36 (2:1
hexane/EtOAc); [α]D23 –30.4° (c 1.07, CHCl3); IR (CHCl3) ν: 3031, 2942, 1744, 1544, 1372, 1349, 1233,
1175, 1024 cm-1; 1H NMR (500 MHz, CDCl3) δ 1.35 (d, J = 6.9 Hz, 3H, CH3CHN), 2.07 (s, 3H, CH3CO),
2.79 (dt, J = 5.4, 11.5 Hz, 1H, ArCH2CH2N), 2.91 (dt, J = 5.4, 11.8 Hz, 1H, ArCH2CH2N), 3.44 (ddd, J =
5.4, 11.5, 15.1 Hz, 1H, ArCH2CH2N), 3.50 (ddd, J = 5.4, 11.8, 15.1 Hz, 1H, ArCH2CH2N), 4.33 (dq, J =
5.7, 6.9 Hz, 1 H, CH3CHN), 5.01 (s, 2H, PhCH2O), 5.05 (s, 2H, PhCH2O), 5.83 (d, J = 5.7 Hz, 1H,
ArCHOAc), 6.80-6.83 (m, 2H, Ar), 6.91-6.94 (m, 2H, Ar), 7.08-7.11 (m, 2H, Ar), 7.13-7.16 (m, 2H, Ar),

HETEROCYCLES, Vol. 76, No. 2, 2008
1641
7.32–7.36 (m, 2H, Ar), 7.38-7.44 (m, 8H, Ar), 7.54 (dd, J = 1.1, 7.4 Hz, 1H, Ar), 7.56 (dd, J = 1.1, 7.4 Hz,
13
1H, Ar), 7.62 (dt, J = 1.1, 7.4 Hz, 1H, Ar), 7.85 (dd, J = 1.1, 7.4 Hz, 1H, Ar); C NMR (125 MHz,
CDCl3) δ 14.53 (CH3), 21.20 (CH3), 36.82 (CH2), 46.78 (CH2), 57.68 (CH), 69.88 (CH2), 69.96 (CH2),
77.64 (CH), 114.59 (CH), 115.00 (CH), 124.23 (CH), 127.41 (CH), 127.43 (CH), 127.81 (CH), 127.92
(CH), 128.03 (CH), 128.54 (C), 128.58 (CH), 128.59 (CH), 129.95 (C), 130.66 (C), 130.86 (CH), 131.58
(CH), 133.46 (CH), 133.58 (C), 136.73 (C), 136.94 (C), 147.95 (C), 157.53 (C), 169.56 (C=O); HRMS
(FAB) C24H24N2O7S (M+Na)+ 717.2247, found 717.2245.
(1R,2S)-1-(4-Benzyloxyphenyl)-2-[2-(4-benzyloxyphenyl)ethyl]amino-1-propanol
(12).
Cs2CO3
(628.0 mg, 1.93 mmol) was added to a solution of sulfonamide 11 (447.1 mg, 0.643 mmol) and PhSH
(132 µL, 1.29 mmol) in DMF (0.3 mL) at rt. After stirring for 1 h, the mixture was poured into 10%
aqueous NaOH (3 mL) and the whole was extracted with EtOAc (2 × 15 mL). The combined organic
layers were washed with H2O (2 × 4 mL) and brine (2 × 4 mL) and dried over anhydrous Na2SO4.
Filtration and evaporation in vacuo furnished the crude product, which was dissolved in MeOH (0.5 mL).
K2CO3 (444.3 mg, 3.22 mmol) was added to the mixture at rt. After stirring for 2 h, the mixture was
partitioned between EtOAc (5 mL) and H2O (5 mL). The whole was extracted with EtOAc (2 × 15 mL)
and the organic layer was washed with brine (2 × 7 mL) and dried over anhydrous Na2SO4. Filtration and
evaporation in vacuo furnished the crude product, which was purified by column chromatography (silica
gel, 19:1 CHCl3/MeOH) to afford 12 (249.6 mg, 83% for 2 steps) as a colorless solid; Rf = 0.32 (9:1
23
CHCl3/MeOH); mp 52.0–53.0 °C; [α]D –8.1° (c 1.16, MeOH); IR (KBr) ν: 3401, 3304, 3104, 1611,
1
1511, 1455, 1382, 1241, 1170, 1014 cm–1; H NMR (400 MHz, CDCl3) δ 0.82 (d, J = 6.3 Hz, 3H,
CH3CHN), 2.34 (br-s, 1H, OH), 2.68–2,81 (m, 2H), 2.85–2.99 (m, 3H), 4.68 (d, J = 3.6 Hz, 1 H,
ArCHOH), 5.04 (s, 2H, PhCH2O), 5.05 (s, 2H, PhCH2O), 6.91 (d, J = 8.6 Hz, 2H, Ar), 6.93 (d, J = 8.6 Hz,
13
2H, Ar), 7.11 (d, J = 8.6 Hz, 2H, Ar), 7.21 (d, J = 8.6 Hz, 2H, Ar), 7.30–7.44 (m, 10H, Ar); C NMR
(100 MHz, CD3OD) δ 16.37 (CH3), 35.98 (CH2), 49.74 (CH2), 50.65 (CH2), 60.59 (CH), 71.73 (CH2),
77.85 (CH), 116.61 (CH), 116.79 (CH), 129.36 (CH), 129.40 (CH), 129.58 (C), 129.60 (C), 130.25 (CH),
130.27 (CH), 131.31 (CH), 131.34 (CH), 133.29 (CH), 136.34 (C), 139.38 (C), 139.49 (C), 159.50 (C),
160.53 (C); HRMS (FAB) C31H34NO3 (M+H)+ 468.2539, found 468.2530.
(1R,2S)-1-(4-Hydroxyphenyl)-2-[N-[2-(4-hydroxyphenyl)ethyl]amino]-1-propanol
[(–)-ritodrine]
(1g). A solution of benzyl ether 12 (111.0 mg, 0.238 mmol) in EtOH (2 mL) was vigorously stirred with
10% Pd/C (20 mg) under 1 atm of hydrogen at rt for 3 h. The catalyst was removed by filtration through a
Celite® pad, and the filtrate was evaporated in vacuo. The residue was purified by column
chromatography (silica gel, 3:1 CHCl3/MeOH) to afford 1g (65.7 mg, 96%) as a colorless viscous oil; Rf

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HETEROCYCLES, Vol. 76, No. 2, 2008
21
= 0.28 (3:1 CHCl3/MeOH); [α]D –5.33° (c 1.43, EtOH); IR (neat) ν: 3282, 3022, 2927, 1614, 1596,
1516, 1451, 1238 cm–1; 1H NMR (500 MHz, DMSO-d6) δ 0.85 (d, J = 6.3 Hz, 3H, CH3CHN), 2.64-2.67
(m, 2H), 2.79–2.90 (m, 3H), 4.65 (d, J = 2.9 Hz, 1 H, CHOHAr), 6.68 (d, J = 8.6 Hz, 2H, Ar), 6.71 (d, J =
8.6 Hz, 2H, Ar), 6.98 (d, J = 8.6 Hz, 2H, Ar), 7.10 (d, J = 8.6 Hz, 2H, Ar); 13C NMR (125 MHz,
DMSO-d6) δ 12.91 (CH3), 33.82 (CH2), 47.78 (CH2), 58.39 (CH), 72.27 (CH), 114.67 (CH), 115.16 (CH),
127.20 (CH), 129.32 (C), 129.44 (CH), 132.98 (C), 155.71 (C), 156.21 (C); HRMS (FAB) C31H34NO3
(M+H)+ 288.1600, found 288.1610.
(–)-Ritdorine·hydrochloride (1g·HCl).13,14 Saturated HCl in EtOH (0.5 mL) was added to a solution of
1g (50.7 mg) in EtOH (0.5 mL). The solvent was evaporated under reduced pressure to afford (–)-1g·HCl
(48.8 mg, 89%) as a colorless gum; [α]D23–13.6° (c 0.30, EtOH) {lit.,13 [α]D20 –13.2° (c 0.24, EtOH)}; IR
(neat) ν: 3250, 3019, 2977, 1614, 1596, 1516, 1446, 1223 cm–1; 1H NMR (400 MHz, DMSO-d6) δ 0.94 (d,
J = 6.9 Hz, 3H, CH3CHN), 2.82-2.96 (m, 2H), 3.13 (brs, 2H), 3.34 (1H, m), 5.03 (s, 1 H, ArOH), 5.96 (d,
J = 4.0 Hz, 1H, CHOHAr), 6.73 (d, J = 8.6 Hz, 2H, Ar), 6.75 (d, J = 8.6 Hz, 2H, Ar), 7.06 (d, J = 8.6 Hz,
13
2H, Ar), 7.16 (d, J = 8.6 Hz, 2H, Ar); C NMR (125 MHz, DMSO-d6) δ 9.37 (CH3), 30.85 (CH2), 46.13
(CH2), 58.43 (CH), 69.29 (CH), 114.89 (CH), 115.39 (CH), 126.91 (CH), 127.57 (C), 129.60 (CH),
131.19 (C), 156.21 (C), 156.58 (C).
ACKNOWLEDGEMENTS
This research was supported in part by a Grant-in-Aid for Scientific Research on Priority Areas
"Advanced Molecular Transformations of Carbon Resources" from the Ministry of Education, Culture,
Sports, Science and Technology, Japan and by Grant-in-Aid from Innovation Plaza Hokkaido in Japan
Science and Technology Agency. We thank S. Oka, M. Kiuchi and T. Hirose of the Center for
Instrumental Analysis at Hokkaido University, for technical assistance in MS and elemental analysis.
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