1,4-Addition of arylboronic acids to β-aryl-α,β-unsaturated ketones and esters catalyzed by a rhodium(I)-chiraphos complex for catalytic and enantioselective synthesis of selective endothelin A receptor antagonists

Article abstract of DOI:10.1016/j.tet.2006.07.075

An enantioselective synthesis of acyclic β-diaryl ketones and esters via 1,4-addition of arylboronic acids to β-aryl-α,β-unsaturated ketones or esters is described. The complex in situ prepared from [Rh(nbd)₂]BF₄ and chiraphos was fo

Full text of DOI:10.1016/j.tet.2006.07.075

Tetrahedron 62 (2006) 9610–9621
1,4-Addition of arylboronic acids to b-aryl-a,b-unsaturated
ketones and esters catalyzed by a rhodium(I)–chiraphos complex
for catalytic and enantioselective synthesis of selective endothelin
A receptor antagonists
a
b
c
c
Takahiro Itoh,a, Toshiaki Mase, Takashi Nishikata, Tetsuji Iyama, Hiroto Tachikawa,
*
Yuri Kobayashi,d Yasunori Yamamotod and Norio Miyaurad,
*
aProcess R&D, Banyu Pharmaceutical Co. Ltd, Okazaki, Aichi 4440858, Japan
bInnovation Plaza Hokkaido, Japan Science and Technology Agency, Sapporo 060-0819, Japan
cDivision of Materials Chemistry, Graduate School of Engineering, Hokkaido University, Sapporo 060-8628, Japan
dDivision of Chemical Process Engineering, Graduate School of Engineering, Hokkaido University, Sapporo 060-8628, Japan
Received 19 June 2006; revised 19 July 2006; accepted 26 July 2006
Abstract—An enantioselective synthesis of acyclic b-diaryl ketones and esters via 1,4-addition of arylboronic acids to b-aryl-a,b-unsaturated
ketones or esters is described. The complex in situ prepared from [Rh(nbd)2]BF4 and chiraphos was found to be an excellent catalyst to achieve
high enantioselectivities in a range of 83–89% ee for the ketone derivatives and 78–94% ee for tert-butyl b-arylacrylate derivatives. The
protocol provided a catalytic method for the enantioselective synthesis of selective endothelin A receptor antagonists (7, 8) reported by
SmithKline Beecham and Merck–Banyu. The enantioselection mechanism and efficiency of the chiraphos ligand for b-aryl-a,b-unsaturated
ketones and esters are discussed on the basis of results of DFT computational studies on the modes of coordination of the enone substrates
to the phenylrhodium(I)–(S,S)-chiraphos complex.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
monophosphine ligands of phosphoramidites.17 For the
corresponding palladium-catalyzed reactions of organo-
boron,18–20 silicon,20–22 and bismuth20,22 compounds, bis-
phosphines bridged by two carbons, such as chiraphos and
dipamp, resulted in high yields and high enantioselectivities.
Among these extensive studies on 1,4-addition of organo-
boronic acids, the synthesis of b-diaryl carbonyl ketones
or esters (4) has attracted much attention in recent years
(Scheme 1). Since compounds incorporating a diarylmethine
stereogenic centers are an important class of compounds due
to the frequent occurrence of these fragments in natural
products,23 there are excellent precedents achieved by
Friedel–Crafts alkylation of arenes24 and 1,4-addition of
electron-rich arenes to enals.25 Another reliable and flexible
approach for introducing two different aryl fragments is
1,4-addition of aryl metal reagents to a,b-unsaturated car-
bonyl compounds, which was recently accomplished by
usingrhodiumcomplexesofchiraldienes(5)16 oradicationic
palladium(II)–chiraphos complex.19,20,22 In this paper, we
show the efficiency of a rhodium(I)–chiraphos complex (3)
for enantioselective preparation of b-diaryl carbonyl com-
pounds (4) via the 1,4-addition of arylboronic acids (2) to
b-aryl-a,b-unsaturated ketones or esters (1). The protocol
1,4-Additions of electrophiles to a,b-unsaturated carbonyl
compounds are a versatile methodology for forming car-
bon–carbon bonds.1 Among these extensive studies in conju-
gate additions, we have disclosed the rhodium-catalyzed
reaction of aryl- and 1-alkenylboronic acids.2 Since the reac-
tion yields a stereogenic center at the b-carbon, considerable
efforts have been devoted to the development of asymmetric
syntheses via metal-catalyzed 1,4-addition of organoboron,3
silicon,4 magnesium,5 zinc,6 tin,7 bismuth,8 titanium,9 and
indium10 compounds to cyclic and acyclic a,b-unsaturated
ketones,3 esters,3 amides,11 phosphonates,12 and nitro13
compounds. A rhodium(I)–binap catalyst was the first cata-
lyst to be successfully used in enantioselective 1,4-addition
of aryl- and 1-alkenylboronic acids to cyclic and acyclic
enones.3a Other ligands effective for rhodium(I) catalysts
are bisphosphine ligands of chiraphos14 and diphospho-
nites,3e P–N ligands of amidomonophosphines,15 bis(alkene)
ligands based on
a
norbornadiene skeleton,16 and
* Corresponding authors. Tel./fax: +81 11 706 6561; e-mail: miyaura@
org-mc.eng.hokudai.ac.jp
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.07.075

T. Itoh et al. / Tetrahedron 62 (2006) 9610–9621
9611
provides the first catalytic method for enantioselective syn-
thesis of endothelin receptor antagonists.
Reaction at room temperature resulted in 84% ee (entry 4)
and selectivity was increased to 89% ee by lowering the re-
action temperature to 0 ꢀC (entry 5). The bulkiness of ester
groups of cinnamates greatly affected on both the reaction
rates and enantioselectivities (entries 6–9). The reaction
was slow at room temperature, but the best enantioselectivity
(92%, 93% ee) was obtained by using the most hindered tert-
butyl cinnamate at 50 ꢀC in the presence of KOH (1 equiv)
(entry 8) rather than methyl and isopropyl esters (entries 6
and 7). Carbonates, fluorides, and triethylamine were less ef-
fective (entries 9–13). These results are in contrast to the low
efficiency of previous rhodium(I)–binap catalysts for b-aryl-
a,b-unsaturated carbonyl compounds. A Rh(acac)(C2H4)2–
binap catalyst resulted in 28% yield and 78% ee for isopropyl
cinnamate3d and 4-tolylboronic acid at 100 ꢀC, and [Rh-
(binap)(nbd)]BF4 resulted in 84% yield and 76% ee in
addition of 3-methoxyphenylboronic acid to 4-phenyl-
3-buten-2-one at 50 ꢀC in the presence of Et3N.20
Ar' B(OH)2
2
Ar
Ar'
Ar
O
O
Rh(I) catalyst (3)
R
R
R= alkyl, aryl, OR'
4
1
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
P
P
P
P
B(OH)2
+ [Rh(nbd)2]BF4
+ [Rh(nbd)2]BF4
Ph
FG
Ph
Ph
3b
2
3a
[Rh(R,R-chiraphos)]BF4
[Rh(S,S-chiraphos)]BF4
R2
R3
R1
R4
5a: R1,R2,R3=H, R4,R5=CH2Ph
5b: R1=Me, R2=OMe, R3=Me, R4=t-Bu, R5=CH2Ph
R5
Scheme 1. Rhodium(I)-catalyzed 1,4-addition of arylboronic acids to
b-aryl-a,b-unsaturated ketones and esters.
1,4-Additions of representative arylboronic acids to b-aryl-
a,b-unsaturated ketones and tert-butyl esters with a
rhodium(I)/(S,S)-chiraphos catalyst are shown in Table 2.
All additions to ketones were completed within 5 h at room
temperature with enantioselectivities in a range of 83–89%
ee (entries 1–5). Additions to tert-butyl esters were carried
out at 50 or 80 ꢀC, but these reactions resulted in 5–10%
higher enantioselectivitiesthan thoseof ketone series (entries
6–16). Substituents on arylboronic acids (FG in 2) and b-sub-
stituents of carbonyl compounds (Ar in 1) affected the
enantioselectivities, suggesting their participation in enan-
tioselection as is discussed in the mechanistic section.
Substituents of arylboronic acids increased the selectivities
in the order of 3,4-methylenedioxy (entries 2 and 9)>4-
methoxy (entries 1 and 6)>3-methoxy (entry 7)>3,4-di-
methoxy(entry8)[4-dimethylamino(entry10).Inadditions
of 3-methoxyphenylboronic acid to a series of b-arylacryl-
ates, the selectivities of 4-methoxyphenyl, 4-methylphenyl,
and 2-methoxyphenyl derivatives were comparable to that
of the phenyl group (entries 7 and 11–13), but 4-trifluoro-
methylphenyl and 2-naphthyl derivatives resulted in signifi-
cantly lower enantioselectivities presumably due to steric
reason (entries 14 and 15). Although the pyridine nitrogen
often retards metal-catalyzed reactions due to its strong abil-
ity to coordinate to most metal catalysts, it was interesting
that arylboronic acids underwent very smooth addition to
tert-butyl 3-pyridylacrylate under standard conditions (entry
16). The absolute configurations of most products were not
known, but the formation of S-product from (S,S)-chiraphos
complex was established by the specific rotation reported for
(S)-3-(3-methoxyphenyl)-1,3-diphenylpropan-1-one ([a]D +7.1
(c 0.71, CHCl3))20 (entry 4).
2. Results and discussion
2.1. Enantioselective addition to b-aryl-a,b-unsaturated
ketones and esters
The performance of a rhodium–chiraphos catalyst (3a,
3 mol %) in the 1,4-addition of 3-methoxyphenylboronic
acid (1.5 equiv) to (E)-4-phenyl-3-buten-2-one (entries 1–5)
or (E)-cinnamates (entries 6–13) was investigated (Table
1). The catalyst was prepared in situ by mixing (S,S)-chira-
phos (3.3 mol %) and [Rh(nbd)2]BF4 (3 mol %) at room tem-
perature. The addition to (E)-4-phenyl-3-buten-2-one was
very slow at room temperature (entry 1), but inorganic bases
exerted a remarkable accelerating effect (entries 2–4), as has
been demonstrated in related 1,4-addition reactions using
other phosphine–rhodium complexes.3k This effect of bases
on yields was in the order of their basic strength: KOH>
K2CO3>KHCO3. The reaction temperature effects on the
enantioselectivity is being increased at lower temperature.
Table 1. Effects of reaction temperatures, catalysts, and bases on yields and
enantioselectivitiesa
Entry 1 (Ar¼Ph) R¼ Base (equiv) Temp/time Yield/%b % eec
(ꢀC/h)
1
2
3
4
5
6
7
8
Me
Me
Me
Me
None 20/5
KHCO3 (1) 20/5
0
0
—
—
84
84
89
84
92
93
91
92
80
83
91
K2CO3 (1)
KOH (1)
KOH (1)
KOH (1)
KOH (1)
KOH (1)
K2CO3 (1)
20/5
20/5
0/18
20/21
20/19
50/6
94
99
31
94
58
92
76
83
75
77
40
Me
OMe
Oi-Pr
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
2.2. Synthesis of endothelin receptor antagonists
9
65/21
10
11
12
13
Cs2CO3 (1) 65/21
Much effort has been made by many research groups to pre-
pare selective antagonists of endothelin receptors, which are
currently being evaluated as potential therapeutic agents for
the treatment of hypertension, congestive heart failure, and
renal diseases. 1,3-Diarylindan-2-caraboxylic acid deriva-
tives are highly potent antagonists selective for endothelin
receptors among non-peptide antagonists reported by Shio-
nogi,26 Hoffmann-La Roche,27 Bristol-Myers Squibb,28
SmithKline Beecham (6, 7),29 and Merck–Banyu (8).30
KF (3)
CsF (3)
NEt3 (1)
65/21
65/21
65/21
a
A mixture of an unsaturated ketone or ester (1, Ar¼Ph) (0.5 mmol),
4-MeOC6H4B(OH)2 (0.75 mmol), and base (0.5 mmol) in dioxane–H2O
(3 mL/0.5 mL) was stirred in the presence of [Rh(nbd)2]BF4 (3 mol %)
and (S,S)-chiraphos (3.3 mol %).
Isolated yields by chromatography.
Enantiomer excess determined by a chiral stationary column.
b
c

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T. Itoh et al. / Tetrahedron 62 (2006) 9610–9621
Table 2. Asymmetric addition of arylboronic acids to b-aryl-a,b-unsaturated ketones and esters (1)a
Entry
1
2 FG¼
Base
Temp/time
(ꢀC/h)
Product
Yield/%b
% eec
Ar¼
Ph
R¼
Me
Me
Me
1
2
3
4
5
6
7
8
4-MeO
3,4-O2CH2
3-MeO
3-MeO
3-MeO
4-MeO
3-MeO
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
20/5
20/5
20/5
20/5
20/5
50/6
50/6
50/6
50/6
50/6
80/6
80/6
80/6
80/6
80/6
80/6
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
96
99
95
99
99
92
95
88
94
59
97
96
92
94
81
90
84
89
83
86 (S)
83
93
90
88
94
82
90
91
91
85
78
89
d
Ph
2-Naphthyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-MeOC6H4
2-MeOC6H4
4-MeC6H4
4-CF3C6H4
2-Naphthyl
3-Pyridyl
Ph
4-MeOC6H4
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
3,4-(MeO)2
d
9
3,4-O2CH2
4-Me2N
3-MeO
3-MeO
3-MeO
3-MeO
3-MeO
3-MeO
10
11
12
13
14
15
16
a
A mixture of 1 (1 mmol), ArB(OH)2 (1.5 mmol), and base (1 mmol) in dioxane–H2O (6/1) was stirred in the presence of [Rh(nbd)2]BF4 (3 mol %) and
(S,S)-chiraphos (3.3 mol %).
Isolated yields by chromatography.
Enantiomer excess determined by a chiral stationary column.
O2CH2 is a methylenedioxy group.
b
c
d
O
Two general and flexible methods for the synthesis of such
a fused five-membered ring with three contiguous chiral
centers have recently been accomplished by SmithKline
Beecham31 and Merck–Banyu.30 In this approach, the major
challenge of Merck–Banyu’s group was enantioselective
1,4-addition of aryl metal reagents to b-aryl-a,b-unsaturated
esters to build a five-membered ring and three chiral centers
based on the first stereogenic center. Although they achieved
excellent enantioselectivities by using a stoichiometric
chiral auxiliary for 1,4-addition of aryllithium reagents, the
catalytic protocol is preferred in large-scale preparations
of these antagonists (Fig. 1).
O
PrO
O
B(OH)2
O
PrO
[Rh(nbd)2]BF4/(S,S)-chiraphos (3a)
dioxane-H2O, 50 °C, 20 h
O
9
10
27%, 8%ee
O
Scheme 2. 1,4-Addition to indenone (9).
An alternative approach for the synthesis of 7 from aryl-
boronic acids and acyclic unsaturated esters is shown in
Scheme 3. An aryl moiety 14 desired for introduction of
the top functionality of 7 via palladium-catalyzed cross-cou-
pling was obtained from readily available 4-bromoresorcinol
(11). Chemoselective protection of the 4-hydroxy group of
11 with tosyl chloride was directly followed by treatment
with ClCH2CH2OMOM. Deprotection and methylation of
12 furnished 13 in 75% total yield. A sequential treatment
of 13 with magnesium turning and B(OMe)3 gave the de-
sired boronic acid 14 in 73% yield.
OMe
O
O
n-C3H7O
R
CO2H
OH
CO2H
N
H
N
O
OMe
O
The a,b-unsaturated ester (17) desired as a substrate for enan-
tioselective 1,4-addition was synthesized by Heck coupling
of 2-bromo-5-propoxybenzaldehyde (16), which was ob-
tained from 2-bromo-5-hydroxybenzaldehyde (15) via an
etherification, oxidation, and esterification sequence. (E)-Se-
lective Heck coupling with tert-butyl acrylate then furnished
the Michael acceptor (17) in 55% yield from 15. Addition of
3,4-methylenedioxyphenylboronic acid (1.5 equiv) to 17
smoothly occurred at 60 ꢀC under optimal conditions shown
in Table 1. The desired enantiomer (18) was obtained with
89% ee when (R,R)-chiraphos (3.3 mol %) was used for
[Rh(nbd)2]BF4 (3 mol %). Claisen cyclization of 18 with
NaHMDS gave 19 in 76% yield. The absolute configuration
of 18 ([a]2D2 ꢁ46.5 (c 0.70, CHCl3)) was established to be S by
conversion of 19 to the known compound 23 ([a]2D2 +49.7
(c 0.25, CHCl3)) via decarboxylation of the resulting keto
ester 19 (Scheme 4). The specific rotation of 23 reported in
6: R=CO2H (SB-209670)
7: R=CH2OH (SB-217242)
8
Figure 1. Endothelin receptor antagonists reported by SmithKline Beecham
and Merck–Banyu.
2.2.1. SmithKline Beecham’s antagonist (7). Most rho-
dium(I) catalysts previously reported for 1,4-addition of
arylboronic acids achieved significantly higher enantio-
selectivity for cyclic enones and esters than those for acyclic
derivatives. Thus, addition to benzo-fused 2-cyclopentenone
9 was the first choice for the synthesis of endothelin receptor
antagonists (6 and 7) reported by SmithKline Beecham
(Scheme 2). However, the substrate 9 was unfortunately
very labile as neat or even in solutions. Thus, all attempts
to use 9 as the starting compound failed. [Rh(nbd)2]BF4–
chiraphos (3a) resulted in 27% yield and 8% ee.

T. Itoh et al. / Tetrahedron 62 (2006) 9610–9621
9613
OMe
OTs
OH
Br
1. TsCl, K2CO3
1. KOH
OMOM
OMOM
12: X=Br
2. MeI, K2CO3
2. ClCH2CH2OMOM
O
O
OH
11
X
X
13: X= Br (75%)
14: X=B(OH)2 (73%)
n-C3H7O
CO2Me
CO2t-Bu
HO
CHO
1. n-PrBr, K2CO3
CH2=CHCO2t-Bu
CO2Me
n-C3H7O
2. KMnO4
Br
PdCl2(MeCN)2, P(o-tol)3
3. MeOH, H2SO4
Br
DMF/Et3N, 100 °C
17 (55% from 15)
16
15
O
OTf
n-C3H7O
n-C3H7O
CO2Me
O
n-C3H7O
CO2t-Bu
CO2t-Bu
O
B(OH)2
CO2t-Bu
3b (3 mol%), KOH
dioxane-H2O, 60 °C
NaHMDS
THF, -78 °C
NaH, Tf2O
O
O
O
O
O
O
20 (72%)
19 (76%)
18 (88%, 89%ee)
OMe
OMe
O
OMOM
n-C3H7O
O
OMOM
n-C3H7O
CO2t-Bu
2 Steps
CO2t-Bu
7
14, PdCl2(dppf)
K2CO3, toluene/H2O
H2, Pd(OH)2/C
O
21 (90%)
O
22 (90%)
O
O
Scheme 3. SmithKline Beecham’s antagonist (7).
the literature is [a]D25 +43.6 (S, 94% ee).31 The enantiomer
thus obtained was produced by the same mode of face selec-
tion as that discussed in the later section.
2.2.2. Merck–Banyu’s antagonists. For the synthesis of
Merck–Banyu’s antagonist 8, an unsaturated ester (27) was
chosen as a substrate for the enantioselective addition of
arylboronic acids to introduce the chiral stereogenic center,
which was previously achieved by 1,4-addition of aryl-
lithiums to unsaturated esters possessing a chiral auxiliary
(Scheme 5). Ester 27 was obtained in a high yield by the re-
ported procedures starting from 2,6-dichloropyridine (24).32
With the substrate 27 in hand, the key asymmetric step was
then investigated. The optimal conditions shown in Table 1
worked well for variously functionalized arylboronic acids
with selectivities in a range of 90–95% ee, thus allowing
the parallel synthesis of chiral b-aryl ester derivatives
(28a–e). It was interesting that neither the substituents on
the pyridyl ring nor the two nitrogens of 27 significantly af-
fected the yields or enantioselectivities. They were compara-
ble or even higher than those of unsaturated esters shown in
Table 2. The absolute configurations of 28e thus obtained by
the (R,R)-chiraphos complex was established to be S by the
specific rotation reported for (S)-28e (Fig. 2).33 Thus, the
product was produced by the same mode of face selection
same as that discussed in the later section (Fig. 3). In five
steps, 28e completes a formal synthesis of one of Merck–
Banyu’s antagonists (8).32
O
n-C3H7O
19
THF, conc.HCl
O
O
23 (60%, 89%ee)
Scheme 4. Absolute configuration of 23.
The chiral diester 19 thus obtained was led to the target an-
tagonist 7 by a method similar to that previously reported by
SmithKline Beecham. Thus, the enolate resulting from 19
with NaH was sulfonylated with trifluoromethanesulfonic
anhydride to yield the triflate 20 in 72% yield (89% ee).
Cross-coupling of 20 with 14 in the presence of PdCl2(dppf)
and K2CO3 to give 21 in 90% yield was followed by olefin
reduction with H2 and a palladium catalyst to give 22 in
90% yield. Finally, epimerization of the tert-butyl ester
group in 22 was followed by deprotection of tert-butyl ester
and MOM group to furnish 7.31
2.3. DFT computational study on enantioselection
The strategy thus achieved by asymmetric 1,4-addition and
cross-coupling reaction of arylboronic acids has a structural
flexibility for both top and bottom aryl groups for parallel
synthesis of candidates.
The catalytic cycle of rhodium(I)-catalyzed 1,4-addition of
arylboronic acids to a,b-unsaturated carbonyl compounds
in aqueous media involves (i) transmetalation of an aryl-
boronic acid to a HO–[Rh] complex (29) giving an Ar0–[Rh]

9614
T. Itoh et al. / Tetrahedron 62 (2006) 9610–9621
CHO
1) i-Pr(Bn)NH
CO2t-Bu
Ph3PCHCO2t-Bu
BuLi
N
Bn
N
Cl
2) POCl3
DMF
Cl
N
Cl
N
Bn
N
Cl
25 (>90%)
26 (85%)
24
FG
FG
CO2t-Bu
CO2n-Bu
27 (87%)
B(OH)2
CO (1 atm), n-BuOH
CO2t-Bu
CO2n-Bu
N
Bn
N
Pd(OAc)2-dppf, toluene
[Rh(nbd)2]BF4 (3 mol%)
(R,R)-chiraphos (3.3 mol%)
KOH (1 eq), dioxane-H2O, 45-50 °C
N
Bn
N
28
28a:
90%, 90%ee
89%, 92%ee
82%, 95%ee
91%, 90%ee
B(OH)2
B(OH)2
28b:
28c:
28d:
28e:
MeO
F
Br
O
B(OH)2
O
O
O
B(OH)2
B(OH)2
CO2H
N
H
N
5 steps
OH
80%, 90%ee
8
OMe
Scheme 5. Merck–Banyu’s endothelin A receptor antagonists (8).
Ar'B(OH)2
mode of a coordination of (E)-4-phenyl-3-buten-2-one to the
[Rh(Ph)(S,S-chiraphos)] intermediate was calculated, i.e.,
the reaction stage directly preceding the stereodetermin-
ing insertion step by DFT computations at the B3LYP/
LANL2DZ level of theory. The four modes of coordination
of the enone substrate to the current phenylrhodium(I) inter-
mediate are shown in Scheme 5. Two stable adducts between
[Pd(Ph)(S,S-chiraphos)] and (E)-4-phenyl-3-buten-2-one
located computationally are shown in 33 and 35, which are
skewed 28.9ꢀ and 127ꢀ, respectively, from the orientation re-
quired for insertion of an enone (34 and 36). Although both
si- and re-coordination of the substrate is preferred thermo-
dynamically without significant steric interaction, only the
precursor of the experimentally observed enantiomer giving
an S product has a low energy barrier (34, 20.8 kcal/mol) for
parallel coordination of the C–C double bond to the Pd–P
bond. In mode 34, the two phenyl groups on rhodium and
phosphine atoms constitute a planar free space for coordina-
tion of an enone to the metal center and the upper-right area is
being blocked by one of the equatorial phenyl groups of the
(S,S)-chiraphos ligand. The efficiency of chiraphos for planer
a,b-unsaturated carbonyl compounds, the participation of
Rh-bound aryls in enantioselectivity, and the substituent
effect of arylboronic acids can be interpreted by this model
(34). On the other hand, the coordination of an enone from
its opposite re face is also probable with an analogous low
energy level (35, 1.6 kcal/mol), but the subsequent insertion
process can be strongly retarded, because of a high energy
barrier for parallel orientation of the C–C double bond and
the Ph–Rh bond (36, 231.8 kcal/mol).
P
P
P
P
Rh OH
Ar'
Rh
B(OH)3
29
30
4
enone (1)
H2O
Ar
P
Ar'
Ar
P
Rh
Rh
Ar'
P
P
R
O
R
O
31
32
Figure 2. A catalytic cycle.
species (30), (ii) insertion of alkene into the Ar0–Rh bond
(31) to yield a rhodium enolate (32) and finally (iii) forma-
tion of an addition product (4) and regeneration of 29 via
hydrolysis of the rhodium enolate intermediate with water.3j
Thus, absolute configuration and enantioselectivity can be
determined at the insertion step of alkenes into an arylrho-
dium(I)–phosphine intermediate (31). There is a precedent
for the X-ray structure of a rhodium(I)–chiraphos complex;
however, the solid-state structure of such a conformationally
flexible complex, in general, is not reliable for the mecha-
nism of enantioselection since the intermediate conformation
differs from the structure of the catalyst precursor. Thus, the

T. Itoh et al. / Tetrahedron 62 (2006) 9610–9621
9615
33 (si, 28.9°, 0 kcal/mol)
34 (si, 0°, 20.8 kcal/mol)
35 (re, 127°, 1.6 kcal/mol)
36 (re, 0°, 231.8 kcal/mol)
Figure 3. Transition states for coordination of (E)-PhCH]CHCOCH3 to a [Rh(Ph)(S,S-chiraphos)] intermediate.
3. Conclusion
commercially available from Lancaster. Other boronic acids
were synthesized from the corresponding Grignard or lith-
ium reagents and trimethyl borate or isopropyl borate.34
[Rh(nbd)2]BF4,35 PdCl2(MeCN)2,36 and PdCl2(dppf)37
were synthesized by reported procedures. (S,S)-Chiraphos
and (R,R)-chiraphos were purchased.
We have documented the successful use of a traditional chir-
aphos ligand for rhodium(I)-catalyzed 1,4-additions of aryl-
boronic acids to b-aryl unsaturated ketones and esters for
enantioselective synthesis of b-diaryl carbonyl compounds.
The high flexibility of this ligand widely applicable even
for sterically hindered carbonyl compounds or substrates
possessing a donating pyridine nitrogen was demonstrated
in two syntheses of selective endothelin antagonists. The
DFT calculation revealed that the catalyst has a planar free
space for coordination of an enone to the metal center and
that one of quadrants is being blocked by an equatorial phenyl
group of the chiraphos ligand, thus suggesting high per-
formance in recognition of planar alkene substrates such
as b-aryl ketones and esters. This model would present an
alkene recognition mechanism with square planar metal–
chiraphos complexes.
4.2. Asymmetric addition to a,b-unsaturated ketones
and esters (Table 2)—A general procedure
A solution of[Rh(nbd)2]BF4 (3.0 mol %)and (S,S)-chiraphos
(3.3 mol %) in 1,4-dioxane (3.0 mL) and water (0.1 mL) was
stirred for 15 min at room temperature under N2 atmosphere.
Alkene (0.5 mmol), aqueous KOH (0.4 mL, 1.25 M), and
arylboronic acid (1.5 mmol) were then added. The mixture
was stirred at the temperature shown in Table 1. The product
was purified by column chromatography on silica gel.
Following products were synthesized by the above general
method. The spectral data of compounds 4a,38 4c,20 4d,20
and 4f39 were previously reported.
4. Experimental
4.1. General
4.2.1. Compound (4b). Colorless oil; [a]2D3 +1.8 (c 0.41,
1
CHCl3); IR (neat): 1486, 1230, 1036, 699, 533 cmꢁ1; H
All experiments were carried out under an argon or nitrogen
atmosphere. HPLC analysis was directly performed with
chiral stationary phase column, Chiralcel OD-H, AD, AD-
H, OJ-H, and OB-H purchased from Dicel Co., Ltd. Phenyl-
boronic acid and (4-methylphenyl)boronic acid were
NMR (400 MHz, CDCl3): d 2.10 (s, 3H), 3.14 (d, J¼
7.3 Hz, 2H), 4.52 (t, J¼7.6 Hz, 1H), 5.91 (s, 2H), 6.70–
6.74 (m, 3H), 7.17–7.31 (m, 5H); 13C NMR (100 MHz,
CDCl3): d 30.6, 45.7, 49.7, 100.9, 108.2, 108.2, 120.5,
126.5, 127.5, 128.6, 137.8, 143.9, 146.0, 147.7, 206.7; MS

9616
T. Itoh et al. / Tetrahedron 62 (2006) 9610–9621
(m/z) 77 (4.8), 152 (22), 211 (100), 225 (3.2), 268 (44, M+);
exact mass calcd for C17H16O3: 268.1099; found: 268.1101.
7.04–7.09 (m, 3H); 13C NMR (100 MHz, CDCl3): d 27.7,
42.1, 46.5, 54.9, 55.0, 80.3, 111.3, 113.6, 113.7, 119.9,
128.5, 129.3, 135.5, 145.5, 158.0, 159.5, 171.0; MS (m/z):
57 (6.0), 227 (100), 269 (6.4), 285 (54), 342 (8.0, M+); exact
mass calcd for C21H26O4: 342.1831; found: 342.1826; Anal.
Calcd for C21H26O4: C, 73.66%; H, 7.65%. Found: C,
73.81%; H, 7.69%.
4.2.2. Compound (4e). Colorless oil; [a]2D1 +11 (c 0.63,
1
CHCl3); IR (neat): 1252, 1597, 1167, 832, 698 cmꢁ1; H
NMR (400 MHz, CDCl3): d 3.67 (d, J¼7.3 Hz, 2H), 3.85
(s, 3H), 4.77 (s, 3H), 4.79 (t, J¼7.3 Hz, 1H), 6.69–6.72
(m, 1H), 6.80–6.92 (m, 4H), 7.15–7.27 (m, 6H), 7.90–7.94
(m, 2H); 13C NMR (100 MHz, CDCl3): d 44.3, 46.0, 55.1,
55.4, 111.2, 113.7, 114.0, 120.2, 126.3, 127.8, 128.5,
129.5, 130.3, 144.1, 145.9, 159.6, 163.4, 196.4; MS (m/z)
77 (12), 107 (5.8), 197 (22), 211 (36), 346 (51, M+); exact
mass calcd for C23H22O3: 346.1569; found: 346.1565.
4.2.8. Compound (4l). Colorless oil; [a]2D3 +21 (c 0.47,
1
CHCl3); IR (neat): 1490, 1242, 1142, 752, 696 cmꢁ1; H
NMR (400 MHz, CDCl3): d 1.26 (s, 9H), 2.89 (dd, J¼8.7,
15 Hz, 1H), 2.96 (dd, J¼7.8, 15 Hz, 1H), 3.71 (s, 3H), 3.74
(s, 3H), 4.87 (t, J¼8.3 Hz, 1H), 6.66–6.69 (m, 1H), 6.78–
6.88 (m, 4H), 7.11–7.19 (m, 3H); 13C NMR (100 MHz,
CDCl3): d 27.7, 40.4, 40.8, 54.9, 55.2, 80.0, 110.5, 111.1,
113.9, 120.2, 120.3, 127.4, 127.7, 128.9, 131.7, 144.9,
156.7, 159.3, 171.2; MS (m/z) 57 (21), 227 (29), 241 (9.8),
269 (22), 342 (5.0, M+); exact mass calcd for C21H26O4:
342.1831; found: 342.1843.
4.2.3. Compound (4g). Colorless oil; [a]2D3 +2.2 (c 0.52,
1
CHCl3); IR (neat): 1725, 1255, 1141, 769, 698 cmꢁ1; H
NMR (400 MHz, CDCl3): d 1.18 (s, 9H), 2.85 (d,
J¼8.3 Hz, 2H), 3.61 (s, 3H), 4.35 (t, J¼8.3 Hz, 1H), 6.59–
6.62 (m, 1H), 6.69–6.75 (m, 2H), 7.03–7.17 (m, 6H); 13C
NMR (100 MHz, CDCl3): d 27.9, 41.9, 47.3, 54.9, 80.3,
111.4, 113.7, 120.0, 126.3, 127.6, 128.3, 129.3, 143.3,
145.1, 159.5, 170.9; MS (m/z) 197 (100), 210 (30.2), 211
(7.8), 239 (12.7), 312 (6.0, M+); exact mass calcd for
C20H24O3: 312.1725; found: 312.1719.
4.2.9. Compound (4m). Colorless oil; [a]2D1 ꢁ1.0 (c 0.53,
1
CHCl3); IR (neat): 1726, 1255, 1142, 779, 697 cmꢁ1; H
NMR (400 MHz, CDCl3): d 1.19 (s, 9H), 2.18 (s, 3H),
2.83 (d, J¼7.8 Hz, 2H), 3.63 (s, 3H), 4.36 (t, J¼8.1 Hz,
1H), 6.59–6.62 (m, 1H), 6.69–6.74 (m, 2H), 6.96–7.11 (m,
5H); 13C NMR (100 MHz, CDCl3): d 20.9, 27.8, 42.0,
46.9, 55.0, 80.3, 111.4, 113.7, 120.0, 127.5, 129.0, 129.3,
135.8, 140.4, 145.4, 159.5, 171.0; MS (m/z) 57 (21), 211
(100), 225 (3.9), 253 (7.9), 269 (16), 326 (4.9, M+); exact
mass calcd for C21H26O3: 326.1882; found: 326.1887.
4.2.4. Compound (4h). Colorless oil; [a]2D3 +0.71 (c 0.21,
1
CHCl3); IR (neat): 1253, 1138, 1028, 700, 511 cmꢁ1; H
NMR (400 MHz, CDCl3): d 1.28 (s, 9H), 2.93 (d,
J¼8.3 Hz, 2H), 3.80 (s, 6H), 4.43 (t, J¼8.1 Hz, 1H), 6.75–
6.80 (m, 3H), 7.13–7.27 (m, 5H); 13C NMR (100 MHz,
CDCl3): d 27.8, 42.1, 46.8, 55.5, 80.2, 110.9, 111.1, 119.3,
126.2, 127.4, 128.2, 136.0, 143.6, 147.4, 148.6, 170.8; MS
(m/z) 57 (10.1), 227 (100), 269 (5.9), 285 (78.1), 342
(34.6, M+); exact mass calcd for C21H26O4: 342.1831;
found: 342.1827.
4.2.10. Compound (4n). Colorless oil; [a]2D2 +2.5 (c 0.55,
1
CHCl3); IR (neat): 1323, 1257, 1113, 1068, 842 cmꢁ1; H
NMR (400 MHz, CDCl3): d 1.29 (s, 9H), 2.96 (t,
J¼8.3 Hz, 2H), 3.74 (s, 3H), 4.52 (t, J¼8.1 Hz, 1H), 6.73–
6.82 (m, 3H), 7.18–7.23 (m, 1H), 7.36 (d, J¼8.3 Hz, 2H),
7.52 (d, J¼8.3 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d 27.7, 41.5, 47.1, 55.0, 80.7, 111.7, 113.8, 119.9, 122.8,
125.3, 125.3, 128.0, 129.6, 144.2, 147.5, 159.7, 170.5; MS
(m/z) 57 (24), 265 (64), 279 (9.9), 307 (18), 323 (7.2), 380
(6.0, M+); exact mass calcd for C21H23F3O3: 380.1599;
found: 380.1608.
4.2.5. Compound (4i). Colorless oil; [a]2D2 +0.35 (c 0.43,
1
CHCl3); IR (neat): 1243, 1141, 1037, 699, 515 cmꢁ1; H
NMR (400 MHz, CDCl3): d 1.31 (s, 9H), 2.91–2.93 (m,
2H), 4.41 (t, J¼8.1 Hz, 1H), 5.87 (s, 2H), 6.70–6.75 (m,
3H), 7.17–7.30 (m, 5H); 13C NMR (100 MHz, CDCl3):
d 27.8, 42.1, 47.0, 80.4, 100.8, 108.0, 108.2, 120.5, 126.4,
127.5, 128.4, 137.5, 143.6, 146.0, 147.6, 170.9; MS (m/z)
57 (6.8), 211 (100), 253 (9.7), 269 (43.9), 326 (15.4, M+); ex-
act mass calcd for C20H22O4: 326.1518; found: 326.1519.
4.2.11. Compound (4o). White solids; mp 72 ꢀC; [a]D23 ꢁ18
(c 0.51, CHCl3); IR (neat): 1719, 1244, 1140, 758,
1
712 cmꢁ1; H NMR (400 MHz, CDCl3): d 1.16 (s, 9H),
4.2.6. Compound (4j). White solids; mp 76–77 ꢀC; [a]D23
+3.8 (c 0.18, CHCl3); IR (neat): 1716, 1149, 812, 696,
2.89–2.99 (m, 2H), 3.60 (s, 3H), 4.53 (t, J¼8.1 Hz, 1H),
6.59–6.61 (m, 1H), 6.73–6.77 (m, 2H), 7.07 (t, J¼7.8 Hz,
1H), 7.21–7.33 (m, 3H), 7.59–7.68 (m, 4H); 13C NMR
(100 MHz, CDCl3): d 27.8, 41.8, 47.3, 55.0, 80.4, 111.5,
113.9, 120.2, 125.4, 125.6, 125.9, 126.5, 127.5, 127.7,
128.1, 129.4, 132.2, 133.3, 140.8, 145.0, 159.6, 171.0; MS
(m/z) 57 (9.0), 247 (100), 261 (3.2), 289 (8.3), 305 (32),
362 (12, M+); exact mass calcd for C24H26O3: 362.1882;
found: 362.1879; Anal. Calcd for C24H26O3: C, 79.53%;
H, 7.23%. Found: C, 79.62%; H, 7.37%.
1
533 cmꢁ1; H NMR (400 MHz, CDCl3): d 1.27 (s, 9H),
2.88 (s, 6H), 2.92 (d, J¼8.8 Hz, 2H), 4.38 (t, J¼8.3 Hz,
1H), 6.63–6.67 (m, 2H), 7.05–7.27 (m, 7H); 13C NMR
(100 MHz, CDCl3): d 27.8, 40.6, 42.3, 46.5, 80.2, 112.7,
126.1, 127.7, 128.2, 128.3, 131.7, 144.3, 149.2, 171.3; MS
(m/z) 57 (6.6), 210 (100), 224 (3.9), 268 (56.0), 325 (29.0,
M+); exact mass calcd for C21H27NO2: 325.2042; found:
325.2044; Anal. Calcd for C21H27NO2: C, 77.50%; H,
8.36%. Found: C, 77.55%; H, 8.35%.
4.2.12. Compound (4p). Colorless oil; [a]2D2 +9.7 (c 0.52,
1
4.2.7. Compound (4k). White solids; mp 54–55 ꢀC; [a]D22
+1.3 (c 0.41, CHCl3); IR (neat): 1247, 1511, 1176, 1142,
CHCl3); IR (neat): 1723, 1257, 1143, 715, 699 cmꢁ1; H
NMR (400 MHz, CDCl3): d 1.21 (s, 9H), 2.84–2.94 (m,
2H), 3.68 (s, 3H), 4.39 (t, J¼8.3 Hz, 1H), 6.66–6.75
(m, 3H), 7.10–7.21 (m, 2H), 7.45–7.47 (m, 1H), 8.36–8.37
(m, 1H), 8.48–8.51 (m, 1H); 13C NMR (100 MHz, CDCl3):
1
1036 cmꢁ1; H NMR (400 MHz, CDCl3): d 1.19 (s, 9H),
2.82 (d, J¼8.3 Hz, 2H), 3.62–3.63 (m, 6H), 4.31 (t,
J¼8.3 Hz, 1H), 6.59–6.62 (m, 1H), 6.67–6.73 (m, 4H),

T. Itoh et al. / Tetrahedron 62 (2006) 9610–9621
9617
d 27.8, 41.5, 44.9, 55.1, 80.9, 111.8, 113.7, 119.9, 123.3,
129.6, 135.0, 138.8, 143.9, 147.9, 149.3, 159.7, 170.4; MS
(m/z) 57 (35), 198 (44), 212 (100), 240 (12), 313 (7.0, M+);
exact mass calcd for C19H23NO3: 313.1678; found:
313.1674.
96.5, 67.5, 65.7, 55.4, 55.3; Anal. Calcd for C11H17BO6: C,
51.60%; H, 6.69%. Found: C, 51.45%; H, 6.62%.
4.3.4. 2-(2-tert-Butoxycarbonylvinyl)-5-propoxybenzoic
acid methyl ester (17). A solution of 2-bromo-5-hydroxy-
benzaldehyde (15)40b (6 g, 30.0 mmol), 1-bromopropane
(4.5 mL, 50.0 mmol), and K2CO3 (6.6 g, 48.0 mmol) in
EtOH (60 mL) and water (20 mL) was heated under reflux
for 17 h. The solvent was then evaporated and the residue
was filtrated through silica gel pad with hexane/EtOAc
(1/1). The combined filtrate was concentrated to dryness.
4.3. SmithKline Beecham’s antagonist (Scheme 3)
4.3.1. Toluene-4-sulfonic acid 4-bromo-3-(2-methoxy-
methoxyethoxy)phenyl ester (12).40a A mixture of 4-
bromoresorcinol (11) (5.5 g, 29.1 mmol), K2CO3 (14 g,
101 mmol), and p-TsCl (6 g, 35.7 mmol) in acetone
(100 mL) was refluxed for 21 h. The solvent was removed
in vacuo and 1-chloro-2-methoxymethoxyethane (5.5 g,
44.4 mmol), K2CO3 (5.5 g, 39.9 mmol), NaI (2.9 g,
19.3 mmol), and DMF (100 mL) were then added. The re-
sulting mixture was stirred for 24 h at 90 ꢀC. The product
(12) was isolated by chromatography on silica gel (hexane/
EtOAc¼10/1 to 5/1) (11.3 g, 90%). Colorless viscous oil;
1H NMR (CDCl3, 400 MHz): d 7.70 (d, J¼8.3 Hz, 2H),
7.39 (d, J¼8.7 Hz, 1H), 7.32 (d, J¼8.3 Hz, 2H), 6.63 (d,
J¼2.4 Hz, 1H), 6.40 (dd, J¼8.3, 2.4 Hz, 1H), 4.72 (s, 2H),
4.06–4.08 (m, 2H), 3.89–3.91 (m, 2H), 3.40 (s, 3H), 2.45
(s, 3H); 13C NMR (CDCl3, 100 MHz): d 155.7, 149.4,
145.6, 133.3, 131.9, 129.8, 128.5, 115.4, 110.4, 108.1,
96.5, 68.8, 65.3, 55.3, 21.7; IR (neat): 2938, 2885, 1594,
1477, 1372, 1273, 1191, 1179, 1143, 1117, 1036, 983, 810,
784, 724, 661, 549 cmꢁ1; MS (m/z): 45 (87), 91 (100), 155
(67), 430 (M+, 18), 432 (M++2, 19); exact mass calcd for
C17H19BrO6S: 430.0085; found: 430.0087.
The crude product was dissolved in acetone (56 mL) and
water (18 mL), and slowly treated with KMnO4 (9.5 g,
60.0 mmol) with stirring on a water bath. After being stirred
for 30 min, it was heated for 1 h at 70 ꢀC. The reaction mix-
ture was passed through Celite 545, rinsed with acetone, and
then concentrated to a small volume. The reaction mixture
was extracted with AcOEt and the organic layer was washed
with dil HCl. The organic layer was dried over MgSO4 and,
finally, concentrated to dryness.
The crude product was dissolved in MeOH (100 mL) and
H2SO4 (2 mL), and heated under reflux for 6 h using
Dean–Stark apparatus. The solution was concentrated to
a small volume and extracted with Et2O. The organic layer
was washed successively with brine and water. The organic
layer was dried over MgSO4 and concentrated to dryness to
give crude 16 (6.3 g).
A solution of the crude 16, PdCl2(MeCN)2 (204 mg,
0.79 mmol), P(o-tol)3 (458 mg, 1.50 mmol), and tert-butyl
acrylate (3.6 mL, 24.9 mmol) in DMF (23 mL) and Et3N
(7.6 mL) was stirred at 100 ꢀC for 10 h. The product (17)
was isolated by recrystallization from pentane (four steps
from 15, 5.3 g, 55%). White solids; mp 67–68 ꢀC; 1H NMR
(CDCl3, 400 MHz): d 8.26 (d, J¼15.8 Hz, 1H), 7.56 (d,
J¼8.3 Hz, 1H), 7.40 (d, J¼2.4 Hz, 1H), 7.03 (dd, J¼2.4,
8.3 Hz, 1H), 6.18 (d, J¼8.3 Hz, 1H), 3.97 (t, J¼6.8,
7.3 Hz, 2H), 3.93 (s, 3H), 1.83 (sext, J¼6.8, 7.3 Hz, 2H),
1.53 (s, 9H), 1.04 (t, J¼7.3 Hz, 3H); 13C NMR (CDCl3,
100 MHz): d 167.3, 166.2, 159.8, 141.8, 131.4, 129.0,
128.2, 120.8, 118.8, 115.7, 80.3, 69.8, 52.4, 28.2, 22.4,
10.4; IR (neat): 2975, 1719, 1707, 1601, 1499, 1296, 1238,
1142, 1065, 982, 866, 831, 784, 593, 566 cmꢁ1; MS (m/z):
177 (39), 219 (100), 320 (M+, 13); exact mass calcd for
C18H24O5: 320.1624; found: 320.1626; Anal. Calcd for
C18H24O5: C, 67.48%; H, 7.55%. Found: C, 66.43%; H,
7.38%.
4.3.2. 1-Bromo-4-methoxy-2-(2-methoxymethoxyethoxy)-
benzene (13). A solution of 12 (8.3 g, 19.2 mmol) and
KOH (5.9 g, 105 mmol) in EtOH (250 mL) and water
(30 mL) was heated under reflux for 2 h. The solvent was
evaporated to reduce the volume. HCl (4 M) was added at
room temperature until pH 4. The product (13) extracted
with Et2O was isolated by chromatography on silica gel
(hexane/EtOAc¼25/1 to 5/1) (4.1 g, 74%). Colorless oil;
1H NMR (CDCl3, 400 MHz): d 7.39 (d, J¼8.7 Hz, 1H),
6.49 (d, J¼2.4 Hz, 1H), 6.41 (dd, J¼8.7, 2.4 Hz, 1H), 4.74
(s, 2H), 4.15–4.17 (m, 2H), 3.92–3.95 (m, 2H), 3.78 (s, 3H),
3.41 (s, 3H); 13C NMR (CDCl3, 100 MHz): d 160.0, 155.8,
133.1, 106.3, 103.0, 101.1, 96.6, 68.5, 65.5, 55.5, 55.3; IR
(neat, cmꢁ1): 2937, 2885, 1582, 1485, 1442, 1304, 1281,
1203, 1168, 1116, 1060, 1022, 917, 823, 608; MS (m/z): 45
(100), 89 (47), 202 (7), 290 (M+, 16), 292 (M++2, 16); exact
mass calcd for C11H15BrO4: 290.0153; found: 290.0155.
4.3.3. 4-Methoxy-2-(2-methoxymethoxyethoxy)phenyl-
boronic acid (14). A solution of 13 (4.4 g, 15 mmol) in
THF (5 mL) was dropwise added to Mg turnings (368 mg,
16 mmol) to prepare Grignard solution. To this solution
was then added (MeO)3B (2 mL, 18 mmol in 10 mL of
THF) at ꢁ78 ꢀC. The resulting mixture was allowed to stir
overnight, treated with dil HCl, extracted with Et2O, and
finally washed with brine. A pure boronic acid (14) was iso-
lated by recrystallization (2.8 g, 11 mmol, 73% yield). White
solids; mp 67–68 ꢀC; 1H NMR (CDCl3, 400 MHz): d 7.76 (d,
J¼8.3 Hz, 1H), 6.57 (dd, J¼2.4, 8.3 Hz, 1H), 6.45 (d, J¼
2.4 Hz, 1H), 5.87 (s, 2H), 4.73 (s, 2H), 4.20–4.22 (m, 2H),
3.91–3.93 (m, 2H), 3.86 (s, 3H), 3.44 (s, 3H); 13C NMR
(CDCl3, 100 MHz): d 165.0, 163.4, 138.0, 105.8, 99.1,
4.3.5. (L)-(S)-2-(1-Benzo[1,3]dioxol-5-yl-2-tert-butoxy-
carbonylethyl)-5-propoxy-benzoic acid methyl ester
(18). To the round-bottom flask charged with [Rh(nbd)2]BF4
(39.2 mg, 3.0 mol %), (R,R)-chiraphos (49.2 mg, 3.3 mol %),
and 17 (1.2 g, 3.5 mmol) were added 1,4-dioxane (10.5 mL)
and water (0.7 mL). After being stirred for 15 min at
ambient temperature, a KOH solution (1.25 M in H2O,
4.2 mL) and 3,4-(methylenedioxy)phenylboronic acid
(970 mg, 5.3 mmol) were added. The mixture was stirred
at 60 ꢀC for 20 h. The mixture was filtered through a silica
and MgSO4 pad, and the pad was then rinsed with hexane/
EtOAc (1/1). The product (18, 1.36 g, 88%) was isolated
by chromatography on silica gel with hexane/EtOAc

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T. Itoh et al. / Tetrahedron 62 (2006) 9610–9621
(20/1). Ee (89%) (Chiralcel AD-H, n-hexane/2-propanol¼
4.3.8. 1-Benzo[1,3]dioxol-5-yl-3-[4-methoxy-2-(2-meth-
oxymethoxyethoxy)phenyl]-5-propoxy-1H-indene-2-
carboxylic acid tert-butyl ester (21). A solution of 20
(155 mg, 0.29 mmol), boronic acid 14 (80.5 mg,
0.31 mmol), and K2CO3 (59 mg, 0.43 mmol) in toluene
(1.1 mL) and water (0.19 mL) was stirred for 4 h at 70 ꢀC.
The mixture was filtered through a silica gel and MgSO4
pad, and the pad was then rinsed with hexane/EtOAc (1/1).
The coupling product (21) was isolated by chromatography
on silica gel (hexane/EtOAc¼5/1 to 3/1) (155 mg, 90%
yield). Pale yellow oil; 1H NMR (CDCl3, 400 MHz): d 7.32
(d, J¼8.3 Hz, 0.44H), 7.13 (d, J¼8.3 Hz, 0.56H), 7.07 (d,
J¼8.3 Hz, 1H), 5.88–6.82 (m, 7H), 5.87 (m, 2H), 4.79 (s,
0.44H), 4.78 (s, 0.56H), 4.46–4.48 (m, 2H), 4.05–4.15 (m,
2H), 3.86 (s, 3H), 3.70–3.83 (m, 4H), 3.19 (s, 1.3H), 3.13
(s, 1.7H), 1.73–1.75 (m, 2H), 1.17–1.19 (m, 9H), 0.96–1.00
(m, 3H); 13C NMR (CDCl3, 100 MHz): d 163.6, 160.74,
160.70, 158.7, 156.9, 149.2, 147.5, 147.4, 146.1, 146.0,
145.0, 141.0, 140.8, 139.6, 139.2, 133.8, 133.5, 130.9,
130.8, 124.3, 124.2, 121.28, 121.25, 117.0, 116.4, 114.6,
114.4, 108.4, 108.2, 108.1, 108.0, 107.7, 107.4, 104.6,
100.7, 100.6, 99.8, 99.7, 96.49, 96.46, 79.8, 79.7, 69.6,
67.8, 67.6, 65.9, 65.7, 55.37, 55.33, 55.2, 54.9, 27.9, 27.8,
22.5, 10.5; IR (neat): 2932, 1694, 1595, 1578, 1502, 1484,
1440, 1352, 1242, 1220, 1151, 1111, 1035, 919, 799,
782 cmꢁ1; MS (m/z): 441 (35), 472 (86), 503 (96), 530
(100), 604 (M+, 42); exact mass calcd for C35H40O9:
604.2672; found: 604.2674.
1
9/1). Colorless oil; [a]2D2 ꢁ46.5 (c 0.70, CHCl3); H NMR
(CDCl3, 400 MHz): d 7.30 (d, J¼2.9 Hz, 1H), 7.22 (d,
J¼8.8 Hz, 1H), 6.97 (dd, J¼8.8, 2.9 Hz, 1H), 6.74–6.86
(m, 3H), 5.87 (s, 2H), 5.31 (t, J¼8.3 Hz, 1H), 3.90 (t,
J¼6.3, 6.8 Hz, 2H), 3.87 (s, 3H), 2.87 (dd, J¼3.4, 8.3 Hz,
2H), 1.76 (sext, J¼6.8, 7.3 Hz, 2H), 1.01 (t, J¼7.3 Hz,
3H); 13C NMR (CDCl3, 100 MHz): d 170.8, 168.0, 157.0,
147.5, 145.7, 137.8, 136.2, 131.0, 129.4, 120.6, 118.3,
115.7, 108.6, 107.8, 100.7, 80.3, 69.6, 52.0, 42.6, 41.3,
27.8, 22.4, 10.4; IR (neat): 2971, 1720, 1487, 1436, 1285,
1216, 1143, 1073, 1038, 933, 803 cmꢁ1; MS (m/z): 57
(12), 253 (20), 267 (18), 295 (65), 309 (41), 327 (40), 340
(54), 354 (100), 367 (27), 386 (68), 442 (M+, 11); exact
mass calcd for C25H30O7: 442.1992; found: 442.1995.
4.3.6. 1-Benzo[1,3]dioxol-5-yl-3-oxo-5-propoxyindan-2-
carboxylic acid tert-butyl ester (19). A solution of
NaHMDS (1 M, 3.6 mL) in THF was slowly added to a solu-
tion of 18 (797 mg, 1.8 mmol) in THF (18 mL) at ꢁ78 ꢀC.
The mixture was stirred for 30 min at ꢁ78 ꢀC and for 3 h at
ꢁ15 ꢀC. The reaction was quenched with satd aqueous
NH4Cl. Isolation by chromatography on neutral silica gel
with hexane/EtOAc (30/1 to 20/1) gave 19 (560 mg, 76%
yield). Pale yellow oil; 1H NMR (CDCl3, 400 MHz):
d 7.15–7.21 (m, 3H), 6.75 (d, J¼7.8 Hz, 1H), 6.65 (dd,
J¼1.4, 7.8 Hz, 1H), 6.53 (s, 1H), 5.93 (s, 1H), 4.77
(d, J¼4.4 Hz, 1H), 3.96 (t, J¼6.3, 6.8 Hz, 1H), 3.50 (d,
J¼4.4 Hz, 2H), 1.82 (sext, 6.8, 7.3 Hz, 2H), 1.49 (s, 9H),
1.04 (t, J¼7.3 Hz, 3H); 13C NMR (CDCl3, 100 MHz):
d 167.5, 159.4, 148.8, 148.1, 146.7, 136.4, 136.2, 127.3,
125.3, 121.1, 108.4, 107.8, 105.6, 101.1, 82.1, 69.9, 65.3,
47.7, 28.2, 22.3, 10.4; IR (neat): 2971, 1708, 1486, 1440,
1273, 1228, 1145, 1037, 931, 842, 823, 801, 766 cmꢁ1; MS
(m/z): 59 (81), 149 (24), 266 (39), 308 (98), 336 (100), 354
(81), 410 (M+, 33); exact mass calcd for C24H26O6:
410.1729; found: 410.1733.
4.3.9. 1-Benzo[1,3]dioxol-5-yl-3-[4-methoxy-2-(2-meth-
oxymethoxyethoxy)phenyl]-5-propoxyindan-2-car-
boxylic acid tert-butyl ester (22). The coupling product (21,
155 mg, 0.26 mmol) was dissolved in EtOH (1.3 mL) and
treated with 20 wt % Pd(OH)2/C (8.9 mg) for 5 h at 60 ꢀC
under hydrogen atmosphere (0.3 MPa). The mixture was fil-
tered through Celite 545 and the pad was rinsed with EtOH.
The product (22) was isolated by chromatography on silica
gel (hexane/EtOAc¼5/1 to 2/1) (140 mg, 90% yield). Color-
less oil; 1H NMR (CDCl3, 400 MHz): d 7.37 (d, J¼8.3 Hz,
1H), 7.09 (d, J¼8.3 Hz, 1H), 6.90 (s, 1H), 6.88–6.90 (m,
2H), 6.79–6.80 (m, 2H), 6.74 (d, J¼7.8 Hz, 1H), 6.48 (m,
1H), 6.44 (dd, J¼2.4, 8.7 Hz, 1H), 5.90 (dd, J¼1.4,
11.7 Hz, 1H), 5.05 (d, J¼7.8 Hz, 1H), 4.75 (s, 2H), 4.66
(d, J¼7.8 Hz, 1H), 4.11–4.23 (m, 2H), 3.83–3.99 (m, 5H),
3.78 (s, 3H), 3.43 (s, 3H), 1.78 (sext, J¼6.8, 7.3 Hz, 2H),
1.03 (t, J¼7.3 Hz, 3H), 0.78 (s, 9H); 13C NMR (CDCl3,
100 MHz): d 170.2, 159.5, 158.4, 158.1, 147.0, 146.1,
145.7, 136.1, 133.3, 130.9, 125.2, 123.0, 119.8, 112.9,
111.2, 110.4, 107.6, 104.0, 100.7, 98.9, 96.5, 79.2, 69.7,
67.7, 66.0, 58.8, 55.3, 55.2, 52.3, 46.0, 27.4, 22.6, 10.5; IR
(neat): 2933, 1727, 1609, 1488, 1441, 1366, 1283, 1248,
4.3.7. 1-Benzo[1,3]dioxol-5-yl-5-propoxy-3-trifluoro-
methanesulfonyloxy-1H-indene-2-carboxylic acid tert-
butyl ester (20). A solution of 19 (324 mg, 0.79 mmol)
and NaH (38 mg, 1.58 mmol) in ether (7.9 mL) was stirred
for 45 min at ꢁ5 ꢀC. Tf2O (0.22 mL, 1.18 mmol) was added
and the mixturewas then stirred for 1 h at ꢁ5 ꢀC. The product
was extracted with Et2O and the organic layer was washed
successively with brine and water. Isolation by chromato-
graphy on silica gel (hexane/EtOAc¼30/1 to 15/1) gave 20
1
(390 mg, 72% yield). White solids; mp 105–106 ꢀC; H
NMR (CDCl3, 400 MHz): d 7.10 (d, J¼7.8 Hz, 1H), 6.94
(s, 1H), 6.91 (dd, J¼2.4, 8.3 Hz, 1H), 6.72 (d, J¼7.8 Hz,
1H), 6.67 (dd, J¼1.4, 7.8 Hz, 1H), 6.44 (d, J¼1.4 Hz, 1H),
5.90 (dd, J¼1.4, 7.3 Hz, 1H), 4.77 (s, 1H), 3.93 (t,
J¼6.8 Hz, 2H), 1.82 (sext, J¼6.8, 7.3 Hz, 2H), 1.40 (s,
9H), 1.04 (t, J¼7.3 Hz, 3H); 13C NMR (CDCl3, 100 MHz):
d 161.0, 159.2, 150.3, 147.7, 146.7, 138.3, 135.5, 130.7,
130.5, 125.3, 121.3, 119 (q, J¼320 Hz), 117.1, 108.3,
107.5, 105.2, 100.9, 82.5, 69.8, 52.5, 27.8, 22.4, 10.4; IR
(neat): 2966, 1702, 1490, 1423, 1337, 1249, 1202, 1124,
1040, 860, 808, 601 cmꢁ1; MS (m/z): 57 (69), 309 (100),
325 (55), 353 (45), 542 (M+, 60); exact mass calcd for
C25H25O8F3S: 542.1222; found: 542.1211; Anal. Calcd for
C25H25O8F3S: C, 55.35%; H, 4.64%. Found: C, 54.29%; H,
4.58%.
1229, 1198, 1145, 1113, 1036, 917, 815, 796, 731 cmꢁ1
;
MS (m/z): 251 (24), 321 (80), 337 (53), 473 (40), 487
(100), 505 (49), 606 (M+, 22); exact mass calcd for
C35H42O9: 606.2828; found: 606.2824.
4.4. Merck–Banyu’s antagonists (Scheme 4)
4.4.1. 3-[6-Benzyl-isopropyl-amino]-2-chloro-pyridine-
3-yl]acrylic acid tert-butyl ester (26).32 To the vessel
were added 25 (5.0 g, 17.3 mmol),32 THF (75 mL), and
tert-butyl diethylphosphonoacetate (4.6 g, 18.2 mmol), and
the mixture was then stirred for 5 h at 40 ꢀC. The completion

T. Itoh et al. / Tetrahedron 62 (2006) 9610–9621
9619
of the reaction was confirmed by HPLC. i-PrOAc (50 mL)
and aqueous NaOH (0.5 M, 20 mL) were added at ambient
temperature. The resulting aqueous layer was extracted
again with i-PrOAc (20 mL). The combined organic layers
were washed with brine and concentrated to ca. 20 mL. To
this slurry was added n-heptane (50 mL) to precipitate the
product. Compound 26 was collected by filtration and
washed with n-heptane/i-PrOAc (5/1, 20 mL). The wet solid
was dried under reduced pressure at 40 ꢀC to afford 5.7 g of
slightly yellow solids (85% yield). Mp 103–105 ꢀC; 1H
NMR (CDCl3, 500 MHz): d 7.86 (d, J¼15.9 Hz, 1H), 7.54
(d, J¼8.8 Hz, 1H), 7.18–7.35 (m, 5H), 6.20 (d, J¼8.8 Hz,
1H), 6.07 (d, J¼15.9 Hz, 1H), 5.10 (sept, J¼6.7 Hz, 1H),
4.56 (s, 2H), 1.52 (s, 9H), 1.20 (t, J¼6.7 Hz, 6H); 13C
NMR (CDCl3, 125 MHz): d 166.4, 158.3, 150.3, 138.9,
138.4, 136.6, 128.7, 127.0, 126.2, 117.6, 116.2, 106.1,
80.3, 46.9, 46.5, 28.2, 20.2; IR (KBr): 2975, 1702, 1601,
1532, 1485, 1363, 1140, 981, 935, 862, 832, 803, 719,
696, 681, 635, 609, 463 cmꢁ1; exact mass calcd for
C22H28ClN2O2 (M++H): 387.1839; found: 387.1867.
The following compounds were synthesized by the above
general procedure.
4.4.4. tert-Butyl-(3S)-3-[6-(N-benzyl-N-isopropylamino)-
2-butoxycarbonyl-3-pyridinyl]-3-phenylpropanoate
(28a). Yield, 90%; Rf¼0.61 (n-heptane/ethyl acetate¼2/1);
89.8% ee (Chiralcel OD-H, n-hexane/2-propanol¼90/10,
flow rate¼0.5 mL/min, temp¼27 ꢀC, tR for 28a: 8.3 min,
tR for enantiomer: 9.7 min); [a]2D0 ꢁ40.2 (c 3.01, CHCl3);
1H NMR (CDCl3, 500 MHz): d 7.12–7.28 (m, 11H), 6.31
(d, J¼9.0 Hz, 1H), 5.04 (sept, J¼6.7 Hz, 1H), 4.96 (t,
J¼8.2 Hz, 1H), 4.48 (s, 2H), 2.87 (d, J¼8.2 Hz, 2H),
1.68–1.76 (m, 2H), 1.40–1.48 (m, 2H), 1.25 (s, 9H), 1.16
(d, J¼6.7 Hz, 6H), 0.94 (t, J¼7.3 Hz, 3H); 13C NMR
(CDCl3, 125 MHz): d 170.8, 167.6, 156.2, 146.4, 143.1,
139.8, 137.5, 128.4, 128.3, 127.8, 127.6, 126.6, 126.3,
125.7, 109.3, 80.4, 65.1, 46.6, 46.2, 42.0, 41.0, 30.6, 27.9,
27.8, 20.2, 20.1, 19.2, 13.7; exact mass calcd for
C33H43N2O4 (M++H): 531.3223; found: 531.3319.
4.4.5. tert-Butyl-(3S)-3-[6-(N-benzyl-N-isopropylamino)-
2-butoxycarbonyl-3-pyridinyl]-3-(4-methoxyphenyl)-
propanoate (28b). Yield, 89%; Rf¼0.48 (n-heptane/ethyl
acetate¼2/1); 92.1% ee (Chiralcel OD-H, n-hexane/2-prop-
anol¼90/10, flow rate¼0.5 mL/min, temp¼27 ꢀC, tR for
28b: 9.7 min, tR for enantiomer: 13.7 min); [a]2D0 ꢁ28.4 (c
4.4.2. 6-(N-Benzyl-N-isopropylamino)-3-(2-tert-butoxy-
carbonylvinyl)pyridine-2-carboxylic acid butyl ester
(27). To the vessel were added 26 (5 g, 12.9 mmol),
AcONa$3H2O (2.6 g, 19.1 mmol), toluene (19 mL), and
n-BuOH (38 mL). The mixture was degassed three times by
vacuum/N2 cycle. Pd(OAc)2 (145 mg, 5 mol %) and DPPF
(536 mg, 7.5 mol %) were then added, and the vessel was
again degassed twice. The mixture was stirred at 120 ꢀC for
16 h. After the completion of the reaction was confirmed
by HPLC, the vessel was cooled to ambient temperature.
The insoluble material was filtered through Celite and rinsed
with EtOAc. The product was isolated by column chromato-
graphy (n-heptane/EtOAc¼20/1 to 10/1) to give 27 as oil.
The oil was dissolved in EtOAc (30 mL) and was treated
with activated carbon (Darco KB-B, 250 mg) for 2 h. Filtra-
tion through Celite and concentration to dryness under
reduced pressure gave 5.1 g (87% yield) of 27 as yellow vis-
1
2.125, CHCl3); H NMR (CDCl3, 500 MHz): d 7.15–7.28
(m, 8H), 6.78 (d, J¼8.7 Hz, 2H), 6.31 (d, J¼8.9 Hz, 1H),
5.04 (sept, J¼6.7 Hz, 1H), 4.89 (t, J¼8.3 Hz, 1H), 4.48 (s,
2H), 4.30–4.34 (m, 2H), 3.74 (s, 3H), 2.83 (d, J¼8.3 Hz,
2H), 1.72 (m, 2H), 1.38–1.50 (m, 2H), 1.26 (s, 9H), 1.16
(d, J¼6.7 Hz, 6H), 0.94 (t, J¼7.4 Hz, 3H); 13C NMR
(CDCl3, 125 MHz): d 170.8, 167.6, 158.0, 156.2, 146.4,
139.8, 137.4, 135.3, 128.7, 128.4, 126.6, 126.3, 126.0,
113.7, 109.3, 80.4, 65.0, 55.2, 46.6, 46.2, 42.1, 40.3, 30.6,
27.9, 27.8, 20.2, 20.1, 19.2, 13.7; IR (KBr): 2972, 1730,
1600, 1553, 1481, 1146, 1077, 1037, 961, 843, 731,
697 cmꢁ1; exact mass calcd for C34H45N2O5 (M++H):
561.3328; found: 561.3418.
1
cous oil. Rf¼0.65 (n-heptane/ethyl acetate¼2/1); H NMR
(CDCl3, 500 MHz): d 7.91 (d, J¼15.8 Hz, 1H), 7.61 (d,
J¼9.1 Hz, 1H), 7.21–7.31 (m, 5H), 6.40 (d, J¼9.1 Hz, 1H),
6.07 (d, J¼15.8 Hz, 1H), 5.13 (br t, J¼6.2 Hz, 1H), 4.59 (s,
2H), 4.37 (t, J¼6.6 Hz, 2H), 1.73–1.79 (m, 2H), 1.51 (s,
9H), 1.43–1.52 (m, 2H), 1.21 (d, J¼6.7 Hz, 6H), 0.96 (t, J¼
7.4 Hz, 3H); 13C NMR (CDCl3, 125 MHz): d 166.8, 166.3,
158.0, 148.3, 139.1, 138.8, 135.7, 128.6, 126.9, 126.3,
118.3, 117.8, 109.3, 80.1, 65.5, 46.7, 46.6, 30.7, 28.3, 28.2,
20.2, 19.2, 13.7; IR (neat): 2972, 1712, 1597, 1547, 1484,
1143, 1075, 982, 870, 814, 732, 609 cmꢁ1; exact mass calcd
for C27H37N2O4 (M++H): 453.2753; found: 453.2714.
4.4.6. tert-Butyl-(3S)-3-[6-(N-benzyl-N-isopropylamino)-
2-butoxycarbonyl-3-pyridinyl]-3-(4-bromo-3-fluorophe-
nyl)propanoate (28c). Yield, 82%; Rf¼0.68 (n-heptane/
ethyl acetate¼2/1); 95.4% ee (Chiralcel OD-H, n-hexane/
2-propanol¼90/10, flow rate¼0.5 mL/min, temp¼27 ꢀC, tR
for 28c: 8.4 min, tR for enantiomer: 11.8 min); [a]2D0 ꢁ32.8
(c 1.145, CHCl3); 1H NMR (CDCl3, 500 MHz): d 7.40 (dd,
J¼7.5, 8.0 Hz, 1H), 7.18–7.28 (m, 6H), 7.03 (dd, J¼1.8,
9.9 Hz, 1H), 6.94 (dd, J¼1.5, 8.3 Hz, 1H), 6.34 (d, J¼
9.0 Hz, 1H), 5.03 (sept, J¼6.7 Hz, 1H), 4.98 (t, J¼8.1 Hz,
1H), 4.50 (s, 2H), 4.29–4.35 (m, 2H), 2.83 (d, J¼8.1 Hz,
2H), 1.68–1.73 (m, 2H), 1.40–1.47 (m, 2H), 1.28 (s, 9H),
1.18 (dd, J¼1.5, 6.7 Hz, 6H), 0.94 (t, J¼7.4 Hz, 3H); 13C
NMR (CDCl3, 125 MHz): d 170.3, 167.3, 156.4, 146.3,
139.5, 137.2, 133.2, 128.5, 126.7, 126.3, 124.7, 116.1,
115.9, 109.5, 80.8, 65.2, 46.7, 46.3, 41.5, 40.3, 30.6, 27.8,
20.1, 19.2, 13.7; exact mass calcd for C33H41BrFN2O4
(M++H): 627.2234; found: 627.2415.
4.4.3. Rh-catalyzed asymmetric addition to 27. To
a round-bottom flask were added 1,4-dioxane (2.0 mL) and
water (0.5 mL), and the flask was then degassed three
times by vacuum/N2 cycle. To this solution were added
[Rh(nbd)2]BF4 (3.0 mol %) and (R,R)-chiraphos (3.3 mol %)
and the flask was again degassed twice. After the mixture
was aged for 15 min at ambient temperature, unsaturated
ester (27, 0.4 mmol) in 1,4-dioxane (1.0 mL), KOH
(0.8 mmol), and arylboronic acid (1.2 mmol) were added.
The flask was degassed twice. The mixture was heated to
50 ꢀC for 14 h with vigorous stirring. The product was puri-
fied by column chromatography on silica gel.
4.4.7. tert-Butyl-(3S)-3-[6-(N-benzyl-N-isopropylamino)-
2-butoxycarbonyl-3-pyridinyl]-3-(3,4-methylenedioxy-
phenyl)propanoate (28d). Yield, 91%; Rf¼0.52 (n-heptane/
ethyl acetate¼2/1); 89.8% ee (Chiralcel OD-H, n-hexane/

9620
T. Itoh et al. / Tetrahedron 62 (2006) 9610–9621
2-propanol¼90/10, flow rate¼0.5 mL/min, temp¼27 ꢀC, tR
for 28d: 10.0 min, tR for enantiomer: 13.0 min); [a]D20
ꢁ36.5 (c 1.76, CHCl3); 1H NMR (CDCl3, 500 MHz):
d 7.18–7.28 (m, 6H), 6.73 (s, 1H), 6.67–6.72 (m, 2H), 6.32
(d, J¼9.0 Hz, 1H), 5.87 (s, 2H), 5.04 (sept, J¼6.7 Hz, 1H),
4.88 (t, J¼8.2 Hz, 1H), 4.49 (s, 2H), 4.31–4.34 (m, 2H),
2.80 (d, J¼8.2 Hz, 2H), 1.69–1.75 (m, 2H), 1.41–1.48 (m,
2H), 1.28 (s, 9H), 1.16 (d, J¼6.7 Hz, 6H), 0.94 (t,
J¼7.4 Hz, 3H); 13C NMR (CDCl3, 125 MHz): d 170.7,
167.6, 156.2, 147.6, 146.4, 145.9, 139.7, 137.3, 137.2,
128.4, 126.6, 126.3, 125.7, 120.5, 109.3, 108.6, 107.9,
100.8, 80.5, 65.1, 46.6, 46.2, 42.1, 40.7, 30.7, 27.9, 20.2,
20.1, 19.2, 13.7; IR (KBr): 2974, 1731, 1600, 1553, 1484,
1146, 1039, 937, 813, 731, 697 cmꢁ1; exact mass calcd for
C34H43N2O6 (M++H): 575.3121; found: 575.3218.
3. (a) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura,
N. J. Am. Chem. Soc. 1998, 120, 5579; (b) Batey, R. A.; Thadani,
A. N.; Smil, D. V. Org. Lett. 1999, 1, 1683; (c) Ogasawara, M.;
Yoshida, K.; Hayashi, T. Organometallics 2000, 19, 1567; (d)
Sakuma, S.; Sakai, M.; Itooka, R.; Miyaura, N. J. Org. Chem.
2000, 65, 5951; (e) Reetz, M. T.; Moulin, D.; Gosberg, A.
Org. Lett. 2001, 3, 4083; (f) Ramnaulth, J.; Poulin, O.;
Bratovanov, S. S.; Rakhit, S.; Maddaford, S. P. Org. Lett.
2001, 3, 2571; (g) Itooka, R.; Iguchi, Y.; Miyaura, N. Chem.
^
Lett. 2001, 722; (h) Amengual, R.; Michelet, V.; Genet, J.-P.
Tetrahedron Lett. 2002, 43, 5905; (i) Pucheault, M.; Darses,
^
S.; Genet, J.-P. Tetrahedron Lett. 2002, 43, 6155; (j) Hayashi,
T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am. Chem.
Soc. 2002, 124, 5052; (k) Itooka, R.; Iguchi, Y.; Miyaura, N.
J. Org. Chem. 2003, 68, 6000; (l) Ma, Y.; Song, C.; Ma, C.;
Sun, Z.; Chai, Q.; Andrus, M. B. Angew. Chem., Int. Ed.
2003, 42, 5871; (m) Cauble, D. F.; Gipson, J. D.; Krische,
M. J. J. Am. Chem. Soc. 2003, 125, 1110; (n) Navarre, L.;
4.4.8. tert-Butyl-(3S)-3-[6-(N-benzyl-N-isopropylamino)-
2-butoxycarbonyl-3-pyridinyl]-3-(2,3-dihydro-1-benzo-
furan-6-yl)propanoate (28e). Yield, 80%; Rf¼0.55 (n-hep-
tane/ethyl acetate¼2/1); 90.3% ee (Chiralcel OD-H,
n-hexane/2-propanol¼90/10, flow rate¼0.5 mL/min, temp¼
27 ꢀC, tR for 28e: 11.2 min, tR for enantiomer: 16.9 min);
[a]2D0 ꢁ39.7 (c 1.06, CHCl3); 1H NMR (CDCl3, 500 MHz):
d 7.18–7.28 (m, 6H), 7.04 (d, J¼7.6 Hz, 1H), 6.74 (d,
J¼7.6 Hz, 1H), 6.67 (s, 1H), 6.31 (d, J¼9.0 Hz, 1H), 5.04
(sept, J¼6.6 Hz, 1H), 4.91 (t, J¼8.2 Hz, 1H), 4.50 (t,
J¼8.6 Hz, 2H), 4.49 (s, 2H), 4.30–4.35 (m, 2H), 3.11 (t,
J¼8.6 Hz, 2H), 2.82 (d, J¼8.1 Hz, 2H), 1.69–1.74 (m, 2H),
1.40–1.47 (m, 2H), 1.27 (s, 9H), 1.16 (d, J¼6.6 Hz, 6H),
0.94 (t, J¼7.4 Hz, 3H); 13C NMR (CDCl3, 125 MHz):
d 170.8, 167.5, 160.3, 156.2, 146.4, 143.7, 139.8, 137.4,
128.4, 126.6, 126.3, 125.8, 124.8, 124.5, 120.0, 109.3, 108.7,
80.4, 71.2, 65.0, 46.6, 46.2, 42.0, 40.8, 30.7, 29.5, 27.9, 20.2,
20.1, 19.2, 13.7; IR (KBr): 2975, 1730, 1599, 1481, 1147,
1078, 989, 947, 813, 759, 697 cmꢁ1; exact mass calcd for
C35H45N2O5 (M++H): 573.3328; found: 573.3412.
^
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Acknowledgements
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This work was supported by Grant-in-Aid from Innovation
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^
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