Asymmetric synthesis of a selective endothelin A receptor antagonist

Article abstract of DOI:10.1016/S0040-4020(02)00280-6

An asymmetric synthesis of a selective endothelin A receptor antagonist 1b is described. A highly substituted pyridine intermediate 11a was efficiently prepared via a mono-amination of inexpensive 2,6-dichloropyridine followed by a Vilsmeier formylation.

Full text of DOI:10.1016/S0040-4020(02)00280-6

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 3409±3415
Asymmetric synthesis of a selective endothelin A
receptor antagonist
Yoshiaki Kato,a,p Kenji Niiyama,b Takayuki Nemoto,a Hideki Jona,b Atsushi Akao,a
Shigemitsu Okada,a Zhiguo J. Song,c Matthew Zhao,c Yoshimi Tsuchiya,b Koji Tomimotoa
and Toshiaki Masea
aProcess R&D, Laboratories for Technology Development, Process Research, Banyu Pharmaceutical Co. Ltd, Kamimutsuna 3-chome-9-1,
Okazaki, Aichi 444-0858, Japan
bBanyu Tsukuba Research Institute, Okubo-3, Tsukuba 300-2611, Ibaraki, Japan
cDepartment of Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA
Received 11 December 2001; accepted 4 March 2002
AbstractÐAn asymmetric synthesis of a selective endothelin A receptor antagonist 1b is described. A highly substituted pyridine inter-
mediate 11a was ef®ciently prepared via a mono-amination of inexpensive 2,6-dichloropyridine followed by a Vilsmeier formylation.
Asymmetric conjugate addition of aryl lithium 14 to the chiral oxazoline 13 followed by hydrolysis afforded 15 in 90% ee. Pd(OAc)2/
dppf catalyzed carbonylation followed by chemoselective addition of aryl lithium 18 gave ketone 19. Diastereoselective reduction of the
ketone with LS-Selectridew followed by concomitant activation of the resulting alcohol and cyclization gave the late intermediate 21.
Deprotection and puri®cation by crystallization furnished the enantiomerically pure target molecule 1b in 10% overall yield from 11a.
q 2002 Elsevier Science Ltd. All rights reserved.
Endothelin receptor antagonists are currently being
evaluated as potential therapeutic agents for the treatment
of hypertension, congestive heart failure and renal diseases.1
Medicinal chemistry efforts led to the discovery of the
earlier drug candidate 1a, which is a relatively non-selective
antagonist for the receptor subtypes.2 Recently, a more
selective endothelin A receptor antagonist 1b was identi®ed
and is being developed as a potentially more effective drug.3
the highly substituted pyridine 8 to access the Michael
acceptor 7, an asymmetric conjugate addition of the top
aryl metal to the Michael acceptor 7 or its equivalents,
construction of the chiral alcohol 5 followed by the stereo-
speci®c cyclization to form the fused ®ve-member ring with
three consecutive chiral centers.
The highly substituted pyridine intermediate 11a was
ef®ciently prepared from inexpensive 2,6-dichloropyridine
(9a).6 Amination of 9a with i-Pr(Bn)NH in the presence of
catalytic Pd(DPPF)Cl2, DPPF and sodium tert-pentoxide in
THF at re¯uxing temperature gave 10a in only 23±45%
yield. Surprisingly, the reaction with i-PrNH2 under the
same conditions proceeded smoothly to afford 2-chloro-6-
isopropylaminopyridine in 96% yield. Subsequent benzyl-
ation with BnBr and NaH in THF±DMF at 508C gave the
desired product 10a in 90%-quant. yield. This two step
sequence was replaced by a more ef®cient process by direct
treatment of 9a with 1.3 equiv. of i-Pr(Bn)NLi in toluene to
give mono-amination product 10a in 99% yield. Regio-
selective Vilsmeier formylation of 10a by treatment with
slight excess of POCl3 in DMF at 708C gave aldehyde 11a
(Scheme 2). Similar sequence of amination and formylation
starting from 2,6-dibromopyridine 9b gave comparable
results.5,7
Synthetically, these are quite challenging target molecules.
The main common structural feature is the fused ®ve-
member ring with three contiguous chiral centers. Two
general approaches can be envisioned as outlined in Scheme
1. Both of them require chiral conjugate addition and stereo-
speci®c cyclization as the key steps. Earlier work on the
synthesis of 1a showed that both are viable approaches.4
We have recently disclosed a practical asymmetric synthesis
of 1b utilizing the `bottom to top' approach A5 (Scheme 1).
In this paper, we wish to report an alternative synthesis of 1b
adopting the `top to bottom' approach B. In this approach,
the major challenge is to carry out a series of asymmetric
reactions to build the fused cyclopentane ring with three
chiral centers. The key steps will include preparation of
Keywords: endothelin antagonist; substituted pyridine; amination; asym-
metric conjugate addition; oxazoline; thiomicamine; phosphate mediated
cyclization.
Corresponding author. Tel.: 181-564-51-5668; fax: 181-564-51-7086;
e-mail: katoys@banyu.co.jp
A number of methods have been reported for the stereo-
selective conjugate additions of chiral a,b-unsaturated
esters or their equivalents8 including Meyers' oxazoline,9
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00280-6

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Y. Kato et al. / Tetrahedron 58 (2002) 3409±3415
Scheme 1.
Evans' oxazolidone,10 and Oppolzer's sultam.11 For our
substrate, only (R)-4-phenyl-2-oxazolidinone gave satisfac-
tory stereoselectivity and chemical yield among chiral
oxazolidinones and sultams evaluated. However, the oxazo-
line derived from inexpensive (1S,2S)-(1)-thiomicamine
was much more economical and thus preferred. Therefore,
aldehyde 11a was coupled with the Horner±Emmons
reagent, generated in situ from the oxazoline 12 and
(EtO)2P(O)Cl in the presence of 2 equiv. of LDA, to give
the conjugate addition precursor 13 with E-stereochemistry.
The ef®cient synthesis of the top aryl bromide 14, 6-bromo-
2,3-dihydrobenzofuran, has been reported.5 The conjugate
addition was carried out by ®rst reacting n-butyl lithium
with the aryl bromide 14 at 2788C in THF followed by
addition of the Michael acceptor 13. The addition product
was then hydrolyzed by treatment with sulfuric acid in
dioxane/H2O to give the carboxylic acid 15 in 72% isolated
yield. The carboxyl group was then protected by esteri®ca-
tion with tert-BuOH to give 16. The enantiomeric excess
was determined to be 90% ee at this stage by chiral HPLC.
temperature in the presence of catalytic Pd(OAc)2 and DPPF
produced the n-butyl ester 17 in 87% yield (Scheme 3).
From the readily accessible 4-bromo-3-hydroxymethyl-
anisole,4 the bottom aryl bromide 18 was prepared by intro-
duction of PMB protecting group to the hydroxymethyl
group under standard conditions. Chemoselective addition
of ArLi from 18 to the n-butyl ester of 17 at low temperature
afforded ketone 19 in 75% yield (Scheme 4). In order to set
up the alkylative cyclization, the ketone needs to be stereo-
selectively reduced and the resulting alcohol activated. A
variety of reducing agents were screened and the results are
summarized in Table 1. L-Selectride gave a 3/1 mixture of
product in 63% combined yield. Lithium 9-BBN hydride
and BH3/THF complex gave essentially the same selectivity
(2/1) and yield (80%). As expected, NaBH4 offered no
selectivity at all (1/1) but gave a very clean reaction (96%
yield). Interestingly, Dibal-H selectively reduced the tert-
butyl ester over the ketone! The best result was obtained
with LS-Selectridew. The stereoselectivity was satisfactory
(5/1) and yield was very good (84%) (Table 1). Puri®cation
of the crude product by crystallization gave alcohol 20 in
66% yield with enhanced diastereomeric purity (.99.5%
de). The chiral alcohol stereochemistry was assigned
based on subsequent chemistry (see later).
Efforts were then directed to carbonylation of the chloro-
pyridine 16.12 Methoxycarbonylation of 16 with various
palladium catalysts, ligands, bases etc. afforded only
10±30% of the product. Obviously, the chloropyridine 16
was much less reactive than the corresponding bromo-
substrate13 since the latter gave 90% yield of the product
under similar conditions. After many attempts, we found
that the reaction of 16 with n-BuOH at a higher reaction
With the alcohol 20 in hand, the key cyclization step was
then investigated. Based on the experience with earlier
drug candidate 1a, we opted for using a phosphate for the
Scheme 2.

Y. Kato et al. / Tetrahedron 58 (2002) 3409±3415
3411
Scheme 3.
Scheme 4.
activation of the alcohol. Mesylate and tosylate are probably
too active and will likely decompose or scramble the stereo-
chemistry of the carbinol. Indeed, the activation of the
alcohol and the cyclization was accomplished in one step
by sequential treatment of 20 with (EtO)2POCl and
NaHMDS to give the late intermediate 21 in 78% yield.
The reaction presumably involves deprotonation of the
alcohol, formation of the phosphate intermediate, enoliza-
tion of the ester and alkylation of the enolate by the phos-
phate. The stereospeci®city (SN2 inversion) of this type of
cyclization was demonstrated in the synthesis of the 1a.4a
This was also the basis for the stereochemical assignment
for the chiral alcohol center in 20. The success of this phos-
phate mediated cyclization is in sharp contrast to the failure
of phosphate to mediate similar cyclization of intermediate
22 used in the alternate route, probably due to much less
stability (thus decomposition) of the desired phosphate
intermediate.14 The fact that the isopropylbenzylamino
group is at the para position to the alcohol in 22 but at
the meta position in 20 must be the main reason.
Table 1. Reduction of ketone 19
Reducing agent
Selectivity
Yield (%)
L-Selectride
Li 9-BBNH
BH3/THF
NaBH4
3/1
2/1
2/1
1/1
63
81
79
96
9-BBN
Dibal-H
No reaction
Reduction of tert-butyl ester
5/1
LS-Selectridew
84

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Y. Kato et al. / Tetrahedron 58 (2002) 3409±3415
Scheme 5.
With the intermediate 21 in hand, all that remained to be
done was to remove three protecting groups. Hydrogenoly-
sis removed both the PMB and the N-benzyl groups. Subse-
quent treatment of the crude product with TFA gave the
®nal product 1b. It was puri®ed by crystallization from
MeOH to afford the target molecule 1b in 53% yield from
21 with .99% purity as a single enantiomer (Scheme 5).
distillation with toluene (2£2 L) to give the crude product
(1.88 kg). HPLC assay indicated 1.23 kg (99% yield) of the
title compound in the crude mixture, which was used for the
next reaction without further puri®cation. A pure sample of
10a was isolated as an oil after silica gel column chromato-
graphy. IR(KBr) 3433, 2975, 1593, 1546, 1474, 1415,
1365, 1135, 770 cm21 1H NMR(300 MHz, CDCl 3) d
.
7.1±7.4 (m, 6H), 6.51 (d, Jˆ7.6 Hz, 1H), 6.12 (d,
Jˆ8.3 Hz, 1H), 5.09 (m, 1H), 4.50 (s, 2H), 1.19 (d,
Jˆ6.6 Hz, 6H). 13C NMR(125 MHz, CDCl 3) d 20.56,
46.58, 46.86, 105.45, 111.26, 126.60, 127.14, 128.78,
139.48, 139.75, 149.55, 158.86. LC-HRMS (APCI) calcd
for C15H18ClN2 (M11) 261.1159, found 261.1184.
In conclusion, a new asymmetric synthesis of 1b was
accomplished in 10% overall yield from the pyridine inter-
mediate 11a in a highly stereo- and regio-controlled
manner. Highly functionalized pyridine 11a was also
ef®ciently synthesized from inexpensive 2,6-dichloro-
pyridine via mono-amination with the lithium amide and
Vilsmeier formylation.
1.1.2. 2-(N-Benzylisopropylamino)-6-chloro-5-formyl-
pyridine (11a). POCl3 (477 mL, 5.12 mol) was added to
DMF (1584 mL) below 88C under N2 atmosphere, and the
mixture was allowed to warm to 208C. After stirring at 208C
for 30 min, a solution of 10a (1213 g assay, 4.65 mol) in
toluene (1.5 L) was added at ambient temperature. The
mixture was stirred at 708C for 8 h, cooled to 208C, and
poured into chilled water (13.5 L) keeping the temperature
below 158C. Toluene (1.5 L) was added to the mixture, and
the organic layer was separated and washed with sat.
NaHCO3 (2 L) and water (3 L). The organic layer was
concentrated and subjected to the azeotropic distillation
with toluene (3£1 L) to give the crude product (1.59 kg).
HPLC assay indicated 1.33 kg (99% yield) of the title
compound in the crude mixture, which was used for the
next reaction without further puri®cation. A pure sample
of 11a was isolated as an oil after silica gel column chro-
matography (C-300, hexane/EtOAcˆ95/5). IR(KBr) 1666,
1.Experimental
1.1. General
1.1.1. 2-(N-Benzylisopropylamino)-6-chloropyridine (10a).
To
a solution of N-benzylisopropylamine (989 mL,
5.91 mol) in toluene (989 mL) was added 1.58 M solution
of n-BuLi in hexane (3.60 L, 5.68 mol) keeping the
temperature below 2648C under N2 atmosphere. The
temperature was allowed to warm to 08C after the addition
of n-BuLi. The pink suspension was added dropwise to a
solution of 2,6-dichloropyridine (700 g, 4.73 mol) in
toluene (3.5 L) below 48C and then was allowed to warm
to ambient temperature. The reaction was quenched with
water (2 L), and the organic layer was washed with 10%
citric acid twice (2.5 and 2.9 L) and water (2 L). The organic
layer was concentrated and subjected to the azeotropic
1
1583, 1483, 1392, 1350, 1198, 1140, 1041, 500 cm21. H
NMR(300 MHz, CDCl 3) d 10.15 (s, 1H), 7.85 (d,

Y. Kato et al. / Tetrahedron 58 (2002) 3409±3415
3413
Jˆ8.9 Hz, 1H), 7.10±7.40 (m, 5H), 6.27 (d, Jˆ8.6 Hz, 1H),
5.00±5.30 (br, 1H), 4.64 (s, 2H), 1.24 (d, Jˆ6.6 Hz, 6H).
13C NMR(125 MHz, CDCl 3) d 20.20, 46.62, 47.55, 106.02,
118.36, 126.08, 127.21, 128.78, 137.42, 138.37, 154.33,
160.15, 188.06. LC-HRMS (APCI) calcd for C16H18ClN2O
(M11) 289.1108, found 289.1120.
tate. The organic layer was separated, washed with water
and brine, dried over MgSO4, and concentrated to dryness to
give the title compound (9.58 g, 72% yield) as a solid. The
enantiomeric excess was determined to be 90% by chiral
HPLC after the esteri®cation with tert-BuOH. Recrystalli-
zation (ethyl acetate/hexane) of the crude acid product gave
optically pure white crystalline solid (99% ee) in 60% crys-
20
1.1.3. 2-(N-Benzylisopropylamino)-6-chloro-5-{(E)-[2-
(4S,5S)-4-methoxymethyl-5-(4-methylthiophenyl)-4,5-
dihydro-1,3-oxazol-2-yl]vinyl}pyridine (13). To a solution
of diisopropylamine (18.5 mL, 133 mmol) in THF
(81.6 mL), was added n-BuLi (1.63 M in hexane,
81.6 mL, 133 mmol) at 2788C. A solution of (4S,5S)-4-
methoxymethyl-2-methyl-5-(4-methylthiophenyl)-4,5-di-
hydro-1,3-oxazole (12) (16.3 g, 64.8 mmol) in THF
(36 mL) was added dropwise to the LDA solution at the
same temperature and the mixture was stirred at 2788C
for 30 min. ClPO(OEt)2 (9.19 mL, 63.6 mmol) was added
to the mixture, then the reaction mixture was warmed to 08C
and stirred for 30 min. A solution of 11a (16.7 g,
57.8 mmol) in THF (34 mL) was added dropwise to the
reaction mixture and the mixture was stirred at 08C for
30 min. The reaction was quenched with 10% NH4Cl and
extracted with ethyl acetate. The organic layer was sepa-
rated, washed with water and brine, dried over MgSO4, and
concentrated to dryness. HPLC assay indicated 30.2 g
(quant.) of the title compound 13 in the crude product. It
was used for the next reaction without further puri®cation. A
pure sample of 13 was isolated as an oil after silica gel
column chromatography (C-300, hexane/acetoneˆ8/2).
tallization yield. Mp 1618C; [a]D ˆ215.68 (cˆ1.0,
CHCl3). IR(KBr) 2976, 1741, 1603, 1539, 1483, 1255,
1063, 945, 868, 797, 725 cm21 1H NMR(300 MHz,
.
CDCl3) d 7.18±7.35 (m, 5H), 7.13 (d, Jˆ8.6 Hz, 1H),
7.07 (d, Jˆ7.6 Hz, 1H), 6.73 (dd, Jˆ7.6 and 1.5 Hz, 1H),
6.63 (d, Jˆ1.5 Hz, 1H), 6.10 (d, Jˆ8.6 Hz, 1H), 5.02 (qq,
Jˆ6.8 and 6.8 Hz, 1H), 4.78 (t, Jˆ7.7 Hz, 1H), 4.52 (t,
Jˆ8.6 Hz, 2H), 4.45 (s, 2H), 3.13 (t, Jˆ8.6 Hz, 2H), 2.93
(d, Jˆ7.7 Hz, 2H), 1.17 (d, Jˆ6.8 Hz, 3H), 1.15 (d,
Jˆ6.8 Hz, 3H). 13C NMR(125 MHz, CDCl 3) d 20.56,
29.85, 39.96, 42.28, 46.66, 46.97, 71.76, 106.18, 109.04,
120.30, 123.61, 125.20, 125.82, 126.63, 127.13, 128.95,
138.29, 139.61, 142.79, 148.53, 157.24, 160.78, 177.55.
HRMS (FAB) calcd for C26H28ClN2O3 (M11) 451.1788,
found 451.1784. Anal. Calcd for C26H27ClN2O3: C, 69.25;
H, 6.03; N, 6.21. Found: C, 69.24; H, 6.03; N, 6.18.
1.1.5. tert-Butyl (3S)-3-[6-(N-benzyl-N-isopropylamino)-
2-chloro-3-pyridinyl]-3-(2,3-dihydro-1-benzofuran-6-
yl)propanoate (16). To a solution of compound 15 (87.7 g,
194 mmol) in THF (500 mL) and tert-BuOH (500 mL), was
added EDCl (44.6 g, 233 mmol) and 4-dimethylamino-
pyridine (28.5 g, 233 mmol), and the mixture was stirred
at room temperature for 12 h. The mixture was diluted
with ethyl acetate and hexane, and the organic solution
was washed with 0.5N HCl, sat. NaHCO3, and brine. The
organic solution was dried over MgSO4, and concentrated to
dryness to give the title compound 16 (73.8 g assay, 90% ee,
75% yield) as an oil. A pure sample of 16 was isolated
through silica gel column chromatography (C-300, hexane/
ethyl acetateˆ9/1) as a yellow oil. HPLC: column, DAICEL
CHIRALPAK AD: eluent, hexane/2-propanol (95/5): ¯ow
rate, 1.0 mL min21; tR for ester 16, 12.5 min; tR for enantio-
20
[a]D ˆ11158 (cˆ1.000, CHCl3). IR(KBr) 3329, 1635,
1
1589, 1475, 1388, 1353, 1198, 1138, 627, 496 cm21. H
NMR(300 MHz, CDCl ) d 7.70 (d, Jˆ16.2 Hz, 1H), 7.57
3
(d, Jˆ8.7 Hz, 1H), 7.10±7.35 (m, 9H), 6.40 (d, Jˆ16.2 Hz,
1H), 6.23 (d, Jˆ8.7 Hz, 1H), 5.34 (d, Jˆ6.9 Hz, 1H), 5.00±
5.20 (m, 1H), 4.56 (s, 2H), 4.20 (ddd, Jˆ6.9, 6.4 and 4.5 Hz,
1H), 3.65 (dd, Jˆ9.6 and 4.5 Hz, 1H), 3.55 (dd, Jˆ9.6 and
6.4 Hz, 1H), 3.42 (s, 3H), 2.48 (s, 3H), 1.21 (d, Jˆ6.8 Hz,
6H). 13C NMR(125 MHz, CDCl ) d 15.66, 20.03, 46.29,
3
46.64, 59.16, 74.17, 74.48, 82.87, 106.14, 112.36, 116.51,
125.98, 126.08, 126.67, 126.80, 128.49, 135.55, 136.03, 137.55,
138.22, 138.40, 149.53, 157.86, 164.01. HRMS (FAB) calcd
for C29H33ClN3O2S (M11) 522.1982, found 522.1986.
20
mer, 13.9 min. [a]D ˆ26.808 (cˆ1.00, CHCl3). IR(KBr)
1720, 1595, 1470, 1354, 1198, 1138, 129, 689, 617,
1
494 cm21. H NMR(300 MHz, CDCl ) d 7.15±7.35 (m,
3
6H), 7.07 (d, Jˆ7.6 Hz, 1H), 6.74 (dd, Jˆ7.6 and 1.5 Hz,
1H), 6.65 (d, Jˆ1.5 Hz, 1H), 6.13 (d, Jˆ8.6 Hz, 1H), 4.95±
5.15 (m, 1H), 4.75 (t, Jˆ8.4 Hz, 1H), 4.52 (t, Jˆ8.6 Hz,
2H), 4.46 (s, 2H), 3.13 (t, Jˆ8.6 Hz, 2H), 2.83 (d,
Jˆ8.4 Hz, 2H), 1.29 (s, 9H), 1.161 (d, Jˆ6.7 Hz, 3H),
1.1.4. (3S)-3-[6-(N-Benzyl-N-isopropylamino)-2-chloro-
3-pyridinyl]-3-(2,3-dihydro-1-benzofuran-6-yl)propanoic
acid (15). To a solution of 6-bromo-2,3-dihydro-1-benzo-
furan 14 (8.00 g, 40.2 mmol) in THF (240 mL), was added
dropwise n-BuLi (1.63 M in hexane, 24.7 mL, 40.2 mmol)
at 2788C, and the mixture was stirred for 1 h. A solution of
oxazoline 13 (15.4 g, 29.5 mmol) in THF (140 mL) was
added dropwise in 1 h. The reaction was quenched with
methanol and sat. NH4Cl. The product was extracted with
ethyl acetate and the organic layer was washed with water
and brine. The organic layer was dried over MgSO4 and
concentrated to dryness to give the crude conjugate addition
product. It was dissolved in 1,4-dioxane/water (72/24 mL),
and conc. H2SO4 was added dropwise to the mixture at 08C.
The mixture was heated to 1008C and stirred for 1.5 h, then
cooled to room temperature. The reaction mixture was
diluted with CHCl3 and the product was extracted with 2N
NaOH. The aqueous layer was separated and acidi®ed with
5N HCl, and the product 15 was extracted with ethyl ace-
1.155 (d, Jˆ6.8 Hz, 3H). 13C NMR(125 MHz, CDCl ) d
3
20.50, 28.27, 29.85, 41.93, 42.85, 46.62, 46.84, 71.72,
81.00, 106.12, 109.01, 120.31, 123.79, 125.02, 125.50,
126.61, 127.09, 128.91, 138.43, 139.66, 143.37, 148.70,
157.07, 160.71, 171.11. HRMS (FAB) calcd for
C30H36ClN2O3 (M11) 507.2414, found 507.2396. Anal.
Calcd for C30H35ClN2O3: C, 71.06; H, 6.96; N, 5.52.
Found: C, 70.96; H, 7.13; N, 5.50.
1.1.6. tert-Butyl (3S)-3-[6-(N-benzyl-N-isopropylamino)-
2-butoxycarbony-3-pyridinyl]-3-(2,3-dihydro-1-benzo-
furan-6-yl)propanoate (17). A mixture of 16 (1.00 g,
1.97 mmol), sodium acetate (194 mg, 2.37 mmol),
Pd(OAc)2 (44.2 mg, 0.197 mmol), DPPF (218 mg,
0.394 mmol) in n-butanol (4 mL) and toluene (2 mL) was

3414
Y. Kato et al. / Tetrahedron 58 (2002) 3409±3415
stirred under 1 atm of CO atmosphere (1 kg cm22) at 1208C
for 18 h. The reaction mixture was ®ltered through Celitew
and the ®ltrate was diluted with ethyl acetate. The organic
solution was washed with water and brine, dried over
MgSO4, and concentrated to dryness to give the title
compound 17 (983 mg, 87% yield) as an oil. A pure sample
of 17 was obtained through silica gel column chromato-
graphy (C-300, hexane/ethyl acetateˆ9/1). IR(KBr) 2968,
Selectridew (1.0 M in THF, 1.80 mL, 1.80 mmol) at 08C
and the mixture was stirred for 5 h. The reaction was
quenched with 30% H2O2 and 4N NaOH, and the product
was extracted with EtOAc. The organic layer was washed
with brine, dried over MgSO4, and concentrated to dryness.
The residue was crystallized from 2-propanol to give the
title compound 20 (451 mg, .99.5% de, 66% yield) as a
white crystal. Mp 124±1288C. IR(KBr) 2974, 1728, 1605,
1491, 1358, 1294, 1244, 1147, 1072, 1034, 812, 733 cm21.
1726, 1601, 1485, 1354, 1248, 1151, 1072, 987, 949, 810,
731 cm21. H NMR(300 MHz, CDCl ) d 7.15±7.32 (m,
1H NMR(300 MHz, CDCl ) d 7.15±7.40 (m, 8H), 7.08 (d,
1
3
3
6H), 7.04 (d, Jˆ7.6 Hz, 1H), 6.74 (dd, Jˆ7.6 and 1.4 Hz,
1H), 6.67 (d, Jˆ1.4 Hz, 1H), 6.31 (d, Jˆ9.0 Hz, 1H), 4.95±
5.10 (m, 1H), 4.91 (t, Jˆ8.2 Hz, 1H), 4.40±4.58 (m, 4H),
4.26±4.38 (m, 2H), 3.12 (t, Jˆ8.6 Hz, 2H), 2.82 (d,
Jˆ8.2 Hz, 2H), 1.65±1.80 (m, 2H), 1.35±1.54 (m, 2H),
1.27 (s, 9H), 1.16 (d, Jˆ6.8 Hz, 6H), 0.94 (t, Jˆ7.3 Hz,
Jˆ2.4 Hz, 1H), 6.97 (d, Jˆ7.6 Hz, 1H), 6.88 (d, Jˆ8.7 Hz,
2H), 6.61±6.73 (m, 2H), 6.57 (dd, Jˆ7.6 and 1.3 Hz, 1H), 6.51
(d, Jˆ1.3 Hz, 1H), 6.35 (d, Jˆ8.9 Hz, 1H), 5.85 (s, 1H), 5.71
(br s, 1H), 4.76±4.93 (m, 1H), 4.82 (d, Jˆ12.9 Hz, 1H), 4.70
(d, Jˆ12.9 Hz, 1H), 4.46±4.60 (m, 6H), 4.09 (dd, Jˆ9.9 and
6.2 Hz, 1H), 3.81 (s, 3H), 3.77 (s, 3H), 3.11 (t, Jˆ8.6 Hz, 2H),
2.48 (dd, Jˆ15.5 and 9.9 Hz, 1H), 2.08 (dd, Jˆ15.5 and
6.2 Hz, 1H), 1.24 (d, Jˆ6.7 Hz, 3H), 1.23 (d, Jˆ6.6 Hz,
3H). 13C NMR(125 MHz, CDCl ) d 14.15, 19.58, 20.55,
3
28.25, 29.85, 31.04, 41.22, 42.39, 46.55, 47.01, 65.45,
71.65, 80.81, 109.11, 109.71, 120.36, 124.90, 125.23,
126.13, 126.73, 126.97, 128.82, 137.81, 140.17, 144.04,
146.74, 156.59, 160.67, 167.96, 171.17. HRMS (FAB)
calcd for C35H45N2O5 (M11) 573.3328, found 573.3316.
Anal. Calcd for C35H44N2O5: C, 73.40; H, 7.74; N, 4.89.
Found: C, 73.64; H, 7.87; N, 4.98.
3H), 1.17 (s, 9H). 13C NMR(125 MHz, CDCl ) d 20.61,
3
20.71, 28.17, 29.83, 40.60, 41.66, 47.18, 55.60, 55.67, 68.60,
69.45, 71.69, 72.46, 80.55, 106.25, 108.92, 113.35, 113.97,
114.16, 120.26, 123.81, 124.96, 125.45, 126.45, 127.00,
128.96, 129.51, 129.80, 131.11, 133.35, 138.10, 139.50,
140.36, 143.88, 154.57, 155.55, 159.49, 159.51, 160.75,
170.66. HRMS (FAB) calcd for C47H55N2O7 (M11)
759.4001, found 759.3994. Anal. Calcd for C47H54N2O7: C,
74.38; H, 7.17; N, 3.69. Found: C, 74.35; H, 7.27; N, 3.68.
1.1.7. tert-Butyl (3S)-3-{6-(N-benzyl-N-isopropylamino)-
2-[4-methoxy-2-(4-methoxy-benzyloxymethyl)benzoyl]-
3-pyridinyl}-3-(2,3-dihydro-1-benzofuran-6yl)propano-
ate (19). To a solution of 4-bromo-3-(4-methoxybenzyl-
oxymethyl)anisole 18 (530 mg, 1.57 mmol) in THF
(4 mL) was added dropwise n-BuLi (1.63 M in hexane,
0.96 mL, 1.57 mmol) at 2788C, and the mixture was stirred
for 30 min. To the mixture was added dropwise a solution of
compound 17 (600 mg, 1.05 mmol) in THF (8 mL) at
2788C for 2 min and the mixture was stirred for 10 min.
The reaction was quenched with sat. NH4Cl and the product
was extracted with EtOAc. The organic layer was washed
with brine, dried over MgSO4, and concentrated to dryness
to give the title compound 19 (598 mg, 75% yield) as an oil.
A pure sample of 19 was obtained through silica gel column
chromatography (C-300, hexane/ethyl acetateˆ85/15). IR
1.1.9. tert-Butyl (5S,6R,7R)-2-(N-benzyl-N-isopropyl-
amino)-5-(2,3-dihydro-1-benzo-furan-6-yl)-7-[4-methoxy-
2-(4-methoxybenzyloxymethyl)phenyl]-6,7-dihydro-5H-
cyclopenta[b]pyridine-6-carboxylate (21). To a solution
of compound 20 (152 mg, 0.200 mmol) in THF (1 mL) was
added (EtO)2POCl (37.6 mL, 0.260 mmol) under nitrogen.
The mixture was cooled to 2308C, and NaHMDS (1.0 M in
THF, 1.00 mL, 1.00 mmol) was added. The reaction
mixture was stirred for 30 min and then quenched with
sat. NH4Cl. The product was extracted with EtOAc, and
the organic layer was washed with brine, dried over
MgSO4, and concentrated to dryness to give the title
compound 21 (115 mg, 78% yield) as an oil. A pure sample
of 21 was isolated through silica gel column chromato-
graphy (C-300, hexane/ethyl acetateˆ5/1). IR(KBr) 1714,
1597, 1464, 1354, 1192, 1138, 810, 741, 582, 478 cm21. 1H
(KBr) 1720, 1655, 1595, 1466, 1352, 1298, 1192, 1132,
1
955, 814, 619, 459 cm21. H NMR(300 MHz, CDCl ) d
3
7.12±7.40 (m, 10H), 6.85±6.95 (m, 3H), 6.51±6.63 (m,
3H), 6.32 (d, Jˆ9.0 Hz, 1H), 5.05 (s, 2H), 4.80 (qq, Jˆ6.8
and 6.6 Hz, 1H), 4.61 (s, 2H), 4.55 (dd, Jˆ8.9 and 7.3 Hz,
1H), 4.40±4.50 (m, 4H), 3.85 (s, 3H), 3.81 (s, 3H), 3.04 (t,
Jˆ8.6 Hz, 2H), 2.83 (dd, Jˆ15.5 and 7.3 Hz, 1H), 2.82 (dd,
Jˆ15.5 and 8.9 Hz, 1H), 1.25 (s, 9H), 1.07 (d, Jˆ6.6 Hz,
NMR(300 MHz, CDCl ) d 7.06±7.32 (m, 8H), 6.92±7.16
3
(m, 3H), 6.84 (d, Jˆ8.6 Hz, 2H), 6.72±6.80 (m, 2H), 6.69
(d, Jˆ1.2 Hz, 1H), 6.13 (d, Jˆ8.6 Hz, 1H), 4.86 (d,
Jˆ9.6 Hz, 1H), 4.50±4.78 (m, 3H), 4.56 (t, Jˆ8.6 Hz,
2H), 4.35±4.48 (m, 5H), 3.80 (s, 3H), 3.79 (s, 3H), 3.12±
3.25 (m, 3H), 1.32 (s, 9H), 1.04 (d, Jˆ6.7 Hz, 3H), 1.01 (d,
Jˆ6.7 Hz, 3H). 13C NMR(125 MHz, CDCl 3) d 19.79,
20.23, 28.06, 29.53, 46.37, 46.82, 51.48, 55.21, 55.25,
62.79, 69.68, 71.34, 71.49, 80.59, 105.22, 109.05, 113.19,
113.34, 113.68, 120.62, 124.54, 124.61, 125.40, 126.29,
126.49, 128.24, 129.46, 130.74, 134.03, 138.49, 140.54,
144.41, 157.92, 159.05, 159.16, 160.45, 162.35, 173.27.
HRMS (FAB) calcd for C47H53N2O6 (M11) 741.3904,
found 741.3892.
3H), 1.06 (d, Jˆ6.8 Hz, 3H). 13C NMR(125 MHz, CDCl )
3
d 20.04, 27.89, 29.37, 41.06, 41.86, 46.15, 46.50, 55.27,
55.36, 70.48, 71.18, 72.42, 80.31, 107.84, 108.84, 110.82,
111.71, 113.78, 120.12, 124.35, 124.70, 125.19, 126.29,
126.46, 127.34, 128.36, 129.28, 130.80, 135.94, 137.26,
139.97, 143.41, 145.02, 153.59, 155.55, 159.10, 160.10,
162.71, 170.77, 196.50. HRMS (FAB) calcd for
C47H53N2O7 (M11) 757.3835, found 757.3865.
1.1.8. tert-Butyl (3S)-3-{6-(N-benzyl-N-isopropylamino)-
2-(S)-hydroxy[4-methoxy-2-(4-methoxybenzyloxymethyl)-
phenyl]methyl-3-pyridinyl}-3-(2,3-dihydro-1-benzofuran-
6-yl)propanoate (20). To a solution of compound 19
(681 mg, 0.900 mmol) in THF (3.6 mL) was added LS-
1.1.10. (5S,6R,7R)-5-(2,3-Dihydro-1-benzofuran-6-yl)-7-
[2-(hydroxymethyl)-4-methoxy-phenyl]-2-(isopropyl-
amino)-6,7-dihydro-5H-cyclopenta[b]pyridine-6-car-
boxylic acid (1b). To a solution of compound 21 (2.22 g,

Y. Kato et al. / Tetrahedron 58 (2002) 3409±3415
3415
Society, Abstract #56, Boston, MA, August 1998. (c) Niiyama,
K.; Hayama, T.; Mase, T.; Nagase, T.; Fukami, T.; Takahashi,
H.; Hisaka, A.; Nishikibe, M.; Ihara, M.; Yano, M.; Ishikawa,
K. The 15th EFMC International Symposium on Medicinal
Chemistry, Abstract p 297, Edinburgh, Scotland, September
1998.
3.00 mmol) in EtOAc (20 mL) and methanol (20 mL) was
added 10% Pd±C (300 mg), and the mixture was hydro-
genated at ambient temperature under H2 (1 kg cm22) for
20 h. The reaction mixture was ®ltered through Celitew and
the ®ltrate was concentrated to dryness. The residue was
treated with TFA (20 mL) at the ambient temperature for
1 h, and the mixture was neutralized with 1N NaOH. The
product was extracted with EtOAc, and the organic layer
was washed with brine, dried over MgSO4, and concentrated
to dryness. The solid residue was crystallized from
methanol to give the title compound 1b (749 mg, 100%
ee) in 53% yield as a white crystalline solid. HPLC: column,
DAICEL CHIRALPAK AD: eluent, hexane/2-propanol/
CF3COOH (700/300/1): ¯ow rate, 1.0 mL min21; tR for
1b, 8.5 min; tR for enantiomer, 13.5 min. Mp 2038C
3. Manuscript in preparation.
4. (a) Song, Z. J.; Zhao, M.; Desmond, R.; Devine, P.; Tschaen,
D. M.; Tillyer, R.; Frey, L.; Heid, R.; Xu, F.; Foster, B.; Li, J.;
Reamer, R.; Volante, R.; Grabowski, E. J.; Dolling, U-H.;
Reider, P. J.; Okada, S.; Kato, Y.; Mano, E. J. Org. Chem.
1999, 64, 9658±9667. (b) Devine, P. N.; Desmond, R.; Frey,
L. F.; Heid, R. M.; Song, Z.; Tillyer, R. D.; Tschaen, D. M.;
Zhao, M.; Kato, Y.; Mano, E.; Okada, S.; Kato, S.; Mase, T.
J. Synth. Org. Chem. Jpn 1999, 57, 1016±1025.
20
5. Song, Z. J.; Zhao, M.; Frey, L.; Li, J.; Tan, L.; Chen, C. Y.;
Tschaen, D. M.; Tillyer, R.; Grabowski, E. J. J.; Volante, R. P.;
Reider, P. J.; Kato, Y.; Okada, S.; Nemoto, T.; Sato, H.; Akao,
A.; Mase, T. Org. Lett. 2001, 3, 3357±3360.
(dec.); [a]D ˆ1638 (cˆ1.002, DMF). IR(KBr) 2966,
1670, 1618, 1500, 1394, 1250, 1171, 1034, 999, 814,
d 7.18 (d,
721 cm21
.
1H NMR(300 MHz, DMSO)
Jˆ7.6 Hz, 1H), 7.02 (d, Jˆ2.8 Hz, 1H), 6.87±6.97 (m,
2H), 6.75 (dd, Jˆ8.5 and 2.9 Hz, 1H), 6.71 (dd, Jˆ7.6
and 1.4 Hz, 1H), 6.60 (d, Jˆ1.4 Hz, 1H), 6.25 (d,
Jˆ8.3 Hz, 1H), 4.57±4.73 (m, 2H), 4.40±4.56 (m, 3H),
4.33 (d, Jˆ8.6 Hz, 1H), 3.73 (s, 3H), 3.58±3.75 (m, 1H),
3.15 (t, Jˆ8.8 Hz, 2H), 3.01 (dd, Jˆ8.8 and 8.6 Hz, 1H),
1.04 (d, Jˆ6.4 Hz, 3H), 0.98 (d, Jˆ6.4 Hz, 3H). 13C NMR
(125 MHz, DMSO) d 22.6, 22.8, 29.2, 42.2, 50.0, 51.5,
55.3, 61.1, 62.0, 71.3, 108.7, 112.5, 120.4, 124.1, 125.3,
126.2, 129.6, 132.0, 134.0, 142.6, 144.2, 158.1, 160.5,
161.9, 175.6. HRMS (FAB) calcd for C28H31N2O5 (M11)
475.2233, found 475.2247. Anal. Calcd for C28H30N2O5: C,
70.87; H, 6.37; N, 5.90. Found: C, 70.39; H, 6.43; N, 5.83.
6. (a) Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. J. Am. Chem.
Soc. 1996, 118, 7215±7216. (b) Wolfe, J. P.; Wagaw, S.;
Marcoux, J. F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31,
805±818. (c) Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc.
1996, 118, 7217±7218. (d) Hartwig, J. F. Angew. Chem., Int.
Ed. Engl. 1998, 37, 2046±2067.
7. In order to obtain good yield for the amination of 9b, premix-
ing at least 1 equiv. of i-Pr(Bn)NH with 2,6-dibromopyridine
was required and 1.5 equiv. of i-Pr(Bn)NLi was used. Addi-
tionally, chloride±bromide exchange caused formation of
small amount of chloro-compound in the formylation. So,
excess POCl3 at lower temperature was used to suppress this
side reaction.5
8. Rossiter, B. E.; Swingle, N. M. Chem. Rev. 1992, 92, 771±
806.
References
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13. Bromo-substrate corresponding to 16 was prepared from 11b
in a similar manner as 16.
2. (a) Ishikawa, K.; Nagase, T.; Mase, T.; Hayama, T.; Ihara, M.;
Nishikibe, M.; Yano, M. PCT Int. Appl. WO 9,505,374, 1995.
(b) Niiyama, K.; Hayama, T.; Mase, T.; Nagase, T.; Fukami,
T.; Hisaka, A.; Nishikibe, M.; Ihara, M.; Yano, M.; Ishikawa,
K. The 216th National Meeting of the American Chemical
14. Less reactive (Me2N)2POCl was used for cyclization of 22.5