Palladium(II)-catalyzed 1,4-addition of arylboronic acids to β-arylenals for enantioselective syntheses of 3,3-diarylalkanals: a short synthesis of (+)-(R)-CDP 840

Article abstract of DOI:10.1016/j.tetlet.2007.04.038

1,4-Addition of arylboronic acid to trans-β-arylenals proceeded smoothly in acetone-water (10/1) at 10-25 °C in the presence of [Pd(S,S-chiraphos)(PhCN)₂](SbF₆)₂ (0.5 mol %), AgX (X = BF₄, SbF₆, 10 mo

Full text of DOI:10.1016/j.tetlet.2007.04.038

Tetrahedron Letters 48 (2007) 4007–4010
Palladium(II)-catalyzed 1,4-addition of arylboronic acids
to b-arylenals for enantioselective syntheses of
3,3-diarylalkanals: a short synthesis of (+)-(R)-CDP 840
Takashi Nishikata,a Yasunori Yamamotob and Norio Miyaurab,*
aInnovation Plaza Hokkaido, Japan Science and Technology Agency, Sapporo 060-0819, Japan
bDivision of Chemical Process Engineering, Graduate School of Engineering, Hokkaido University, Sapporo 060-8628, Japan
Received 20 March 2007; revised 4 April 2007; accepted 6 April 2007
Available online 14 April 2007
Abstract—1,4-Addition of arylboronic acid to trans-b-arylenals proceeded smoothly in acetone–water (10/1) at 10–25 °C in the
presence of [Pd(S,S-chiraphos)(PhCN)2](SbF6)2 (0.5 mol %), AgX (X = BF4, SbF6, 10 mol %) and aqueous 42% HBF4 to afford
optically active 3,3-diarylalkanals with high enantioselectivities in a range of 86–97% ee. The protocol provided a method for
short-step synthesis of optically active (+)-(R)-CDP 840.
Ó 2007 Published by Elsevier Ltd.
Chiral diaryl-fragments, particularly b-diarylaldehydes,
are valuable intermediates for the syntheses of natural
and pharmaceutical compounds1 since they are easily
convertible into alcohol, ester, amide or alkene deriva-
tives. A promising method for the synthesis of these
optically active compounds is metal-catalyzed 1,4-addi-
tion of arylmetal reagents to b-arylenals,2 which has
been demonstrated by rhodium-catalyzed asymmetric
1,4-addition of arylboronic acids to a,b-unsaturated car-
bonyl compounds.3–10 Enantioselectivities exceeding
90% ee were achieved by Hayashi and Carreira by using
chiral diene ligands as auxiliaries of rhodium(I) cata-
lysts.11,12 On the other hand, traditional chiraphos was
found to be an excellent ligand for palladium(II) cata-
lysts that achieved higher enantioselectivity than the
corresponding Rh(I) complex for the 1,4-addition of
arylmetal reagents to b-aryl-a,b-unsaturated ketones to
give chiral b-diarylketones up to 99% ee.13 The reaction
can be used for 1,4-addition of ArB(OH)2,14 Ar-
Si(OMe)3,15 Ar3Bi,16 ArSiF317 and [ArBF3]K.17,18 Here-
in, we report the enantioselective preparation of
b-diarylaldehydes (4) from arylboronic acids (2) and
b-arylenals (1) with dicationic palladium(II) catalysts
(0.5 mol %) in aqueous acetone (3). The presence of
either HBF4 or AgSbF6 (10 mol %) or both of the addi-
tives was found to be effective for achieving high yields.
The protocol was applied to the first catalytic synthesis
of (+)-(R)-CDP 840. For convenience of analyses, all
enantioselectivities were determined by alcohol deriva-
tives (5) obtained by treatment of 4 with NaBH4, since
diarylaldehydes (4) were not easily separable by chiral
stationary columns (Scheme 1).
The reaction between p-tolylboronic acid and trans-cin-
namaldehyde was carried out at room temperature for
20 h in the presence of [Pd(S,S-chiraphos)(PhCN)2]-
(SbF6)2 (3a, 0.5 mol %) in acetone/water (10/1) to
Ar' B(OH) (2)
2
O
Ar' O
Ar
H
Ar
H
Pd(2+) catalyst (3)
o
acetone-H O, 10-25 C
2
1
4
AgX and/or aq. HBF (if used)
4
Ar'
NaBH
4
Ar
OH
5
Ph
Ph
Ph
P
Ph
Me
Me
(SbF )
Me
Me
(SbF )
6 2
P
NCPh
NCPh
6 2
NCPh
NCPh
Pd
Pd
P
P
Ph
Ph
Ph Ph
Keywords: Conjugate addition; Asymmetric synthesis; Asymmetric
catalyst; Arylboronic acid; Chiral aldehydes.
3b
3a
*
Corresponding author. Tel./fax: +81 11 706 6561; e-mail: miyaura@
eng.hokudai.ac.jp
Scheme 1.
0040-4039/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.04.038

4008
T. Nishikata et al. / Tetrahedron Letters 48 (2007) 4007–4010
Table 1. Reaction conditionsa
Me
(HO) B
Me
2
O
4a (85% ee)
O
Ph
H
3a (0.5 mol %), rt, 20h
Ph
H
Run
AgX (mol %)
None
AgSbF6 (10)
None
AgSbF6 (10)
AgBF4 (10)
Solvent and acid
Yield (%)
Method
1
2
3
4
5
Acetone/H2O (10/1)
Acetone/H2O (10/1)
Acetone/H2O/HBF4 (20/2/1)
Acetone/H2O/HBF4 (20/2/1)
Acetone/H2O/HBF4 (20/10/1)
54
75
81
70
64
A
B
C
a A mixture of PhCH@CHCHO (0.5 mmol), 4-MePhB(OH)2 (1 mmol), Pd(S,S-chiraphos)(PhCN)2](SbF6)2 (3a, 0.5 mol %), AgX (10 mol %, if used)
and 42 wt % HBF4 (0.1 mL, if used) in acetone (2 mL) and water (0.2 or 1 mL) was stirred for 20 h at room temperature.
optimize the reaction conditions (Table 1). The reaction
resulted in 54% yield under the standard conditions used
for previous reaction for b-arylenones (run 1), though
there was no side reaction that yielded a Heck coupling
product or Grignard-type addition product to the car-
bonyl group of aldehyde. On the other hand, the addi-
tion of AgSbF6 (10 mol %) (run 2) and the addition of
HBF4 (10 mol %) (run 3, method A) had remarkable
accelerating effects, giving b-diarylenal (4a) in 75% and
81% yield with 85% ee, respectively. Although the yields
were not improved when both silver salt and HBF4 were
used in aqueous acetone (runs 4 and 5, methods B and
C), the presence of both additives resulted in higher
yields in other combinations of arylboronic acids and
enals as shown in Table 2. Both rhodium- and palla-
dium-catalyzed 1,4-additions of organoboronic acids
to enals in aqueous solvents have suffered from slow
reaction due to the formation of a stable hydrate (7).
The acid catalyst may accelerate this equilibrium via a
protonated intermediate (6), which would be much more
activated for 1,4-addition than the parent aldehyde (1)
(Scheme 2).
GC yields of the product were plotted against time dur-
ing the reaction of p-tolylboronic acid with cinnamalde-
hyde at 20 °C under four conditions (runs 1–4) shown in
Table 1 (Fig. 1). The presence of either HBF4 (d) or
AgSbF6 (n) significantly accelerated the reaction,
though the effect of the former additive was slightly
greater than that of the latter additive. It was interesting
to note that the presence of both HBF4 and AgSbF6
(10 mol %) (s) had the effect of further increasing the
initial rate to complete the reaction within 2 h. The
results suggest different roles of the proton and silver
ion, though no mechanistic information is currently
available.
Asymmetric 1,4-additions of representative arylboronic
acids to b-arylenals with a palladium(II)/(S,S)-chira-
phos catalyst (3a) in acidic aqueous acetone are shown
Table 2. Asymmetric 1,4-addition of arylboronic acids to b-arylenals
Run
1 (Ar=)
2 (Ar0=)
Methoda
Temp (°C)
Yieldb (%)
Product no.
% eec
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3-MeOPh
3-MeOPh
2-MeOPh
4-MeOPh
3-(n-C4H9O)Ph
3-(PhCH2O)Ph
3,4-(MeO)2Ph
3-Me-4-MeOPh
3-(c-C5H9O)-4-MeOPhd
3,5-Me2-4-MeOPh
4-PhPh
3-MeOPh
3-MeOPh
3-MeOPh
3-(c-C5H9O)-4-MeOPhd
3-MeOPh
A
C
B
10
10
rt
rt
rt
10
10
10
10
10
10
10
rt
29
78
Trace
59
76
76
66
61
72 (70)
80
79
78
72
86 (89)
80 (80)
78
76 (70)
80 (75)
4b
4b
4c
4d
4e
4f
92
92
—
86
91
90
92
90
94 (S)
88
97
91
91
90
94
91
90
93
B
C
C
A
A
A
A
A
Be
B
4g
4h
4i
9
Ph
Ph
Ph
10
11
12
13
14
15
16
17
18
4j
4k
4l
4-MeOPh
2-MeOPh
2-Naphthyl
2-Naphthyl
4-MePh
4-PhPh
4-PhPh
4m
4n
4o
4p
4q
4r
B
rt
rt
10
rt
rt
C
C
B
3-MeOPh
3-(c-C5H9O)-4-MeOPhd
C
a See Table 1. Method A: acetone/H2O/aq 42 wt % HBF4 (20/2/1); method B: acetone/H2O/aq 42 wt % HBF4 (20/2/1) and AgSbF6 (10 mol %);
method C: acetone/H2O/aq 42 wt % HBF4 (20/10/1) and AgBF4 (10 mol %).
b NMR yields and isolated yields are in parentheses.
c Enantiomeric excess of the corresponding alcohol derivatives (5) obtained by reduction of 4 with NaBH4.
d 3-Cyclopentyloxy-4-methoxyphenyl group.
e In acetone/aq 42 wt % HBF4 (20/1) and AgSbF6 (10 mol %).

T. Nishikata et al. / Tetrahedron Letters 48 (2007) 4007–4010
4009
(method B or C) was particularly effective for achieving
a high yield for 3-methoxyphenylboronic acid (runs 1
and 2). This system also resulted in the best yields in
most combinations of boronic acids and enals (entries
4–6 and 12–18). The reaction temperature and substitu-
ents on arylboronic acids affected the enantioselectivi-
ties. The reaction at 10 °C resulted in 1–2% higher
selectivities than that at room temperature. The use of
arylboronic acids possessing a meta substituent always
resulted in enantioselectivities higher than 90% ee (runs
2, 5–8 and 12–18), whereas 4-methyl- and 4-meth-
oxyphenylboronic acids resulted in 85% ee and 86%
ee, respectively (run 4). The absolute configurations of
most products are not known, but the formation of an
S-product from (S,S)-chiraphos complex (3a) was estab-
lished by 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-phen-
ylpropionaldehyde (4i), which was finally transformed
to CDP 840 as shown in Scheme 3 (run 9). On the other
hand, this catalyst was less effective for aliphatic unsat-
urated aldehydes. The addition of 3-methoxyphenyl-
boronic acid to trans-hexenal and trans-crotonaldehyde
resulted in 84% yield with 70% ee and 99% yield with
67% ee, respectively.
+
H
+
O
O
H O
OH
OH
H
2
Ar
H
Ar
H
Ar
1
6
7
Scheme 2.
AgSbF6 and HBF4 (run 4)
HBF4 (run 3)
75
60
45
30
15
0
AgSbF6 (run 2)
non (run 1)
Phosphodiesterase (PDE) IV is believed to be the
dominant isozyme present in inflammatory cells and in
airway smooth muscle. (+)-(R)-CDP 840 is a potential
therapeutic agent for asthma as a selective PDE IV
inhibitor that leads to an increase in the concentration
of cyclic AMP, resulting in the suppression of a broad
range of functions in inflammatory cells.19b The major
challenge for the synthesis of this clinically important
compound was enantioselective construction of a di-
arylmethylene stereogenic center by using a stoichio-
metric chiral auxiliary for the synthesis of optically
active epoxides.19 The present reaction provided the first
catalytic method for enantioselective synthesis of (+)-
(R)-CDP 840 (Scheme 3).19 1,4-Addition of arylboronic
acid possessing 3-cyclopentyloxy and 4-methoxy groups
to trans-cinnamaldehyde with a Pd/(R,R)-chiraphos
catalyst (3b) afforded (R)-8 in 70% yield and with 94%
0
15
45
75
105
135
150
time (min)
Figure 1. Effects of AgSbF6 and HBF4 on reaction rates (see, Table 1).
in Table 2. All reactions proceeded smoothly at 10–
25 °C with yields and enantioselectivities in the ranges
of 59–86% and 86–97% ee (runs 1–18), except for steri-
cally hindered 2-methoxyphenylboronic acid (run 3).
Yields were optimized by conducting each reaction by
the three methods (methods A–C) listed in Table 1.
The presence of silver salt in acidic aqueous acetone
OMe
O
OMe
OMe
O
O
ii
i
iii
iv
O
Ph
H
O
O
OMe
OTMS
97%
70%
(94% ee) Ph
H
Ph
OMe
Ph
8
9
10
OMe
OMe
OMe
O
O
O
v
O
vi
O
Ph
OMe
Ph
OMe
Ph
43%
(iii-vi, 5 steps)
N
N
N
Tf
11
12
(+)-(R)-CDP 840
Scheme 3. Synthesis of CDP 840. Reagents and conditions: (i) 3-(c-C5H9O)-4-MeOPhB(OH)2 (2 equiv), [Pd(R,R-chiraphos)(PhCN)2](SbF6)2 (3b,
0.5 mol %), acetone, aq HBF4, 10 °C, 20 h; (ii) I2 (2.5 equiv), KOH (2.5 equiv), MeOH, 0–20 °C, 20 h; (iii) LDA (1.5 equiv), TMSCl (2 equiv), THF,
ꢀ78 °C to rt, 3 h; (iv) PyTf2O (3 equiv), CH2Cl2, 0 °C, 1 h; (v) tBuONa (3 equiv), DMSO, 20 °C, 20 min; (vi) (a) EtOH–water, NaOH, reflux, 0.5 h;
(b) dioxane–water, concd HCl, reflux, 5 h.

4010
T. Nishikata et al. / Tetrahedron Letters 48 (2007) 4007–4010
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ee. The oxidation of 8 with iodine and KOH in metha-
nol led to the corresponding ester (9) in 97% yield.20 Pal-
ladium- and base-catalyzed cross-coupling of 9 with 4-
bromopyridine failed to introduce a pyridine ring to
the a-carbon, presumably due to the bulkiness of two
b-substituents. Thus, 9 was converted to the ketene silyl
acetal (10) with LDA and TMSCl for nucleophilic sub-
stitution of a pyridinium salt of triflic anhydride to give
11.21 Crude 11 was treated with tBuONa in DMSO at
20 °C for 20 min for aromatization of pyridine ring.22
Finally, decarboxylation of 12 gave (+)-(R)-CDP 840
in 43% yield (5 steps from 9) and with 94% ee ([a]D
+35 (c 0.48, EtOH); lit. +37 (100% ee)23). Thus, the syn-
thesis of CDP 840 was accomplished in seven steps with
total 29% yield (84% average) starting from commer-
cially available trans-cinnamaldehyde.
General procedure for asymmetric 1,4-addition: Ar-
B(OH)2 (2.0 mmol), acetone (4 mL), AgBF4 or AgSbF6
(0.1 mmol, if necessary), enal (1 mmol) and water
(0.4 mL) were added to a flask under nitrogen.
[Pd(S,S-chiraphos)(PhCN)2](SbF6)2 (3, 0.005 mmol)
and HBF4 (0.2 mL, 42 wt % aqueous solution) were then
added at 10 °C. After being stirred for 20 h at 10 °C or
at room temperature, chromatography on silica gel gave
1,4-adduct (4). The enantiomer excess was determined
by chiral HPLC analysis of the corresponding alcohol
(5) obtained by NaBH4 reduction of 4.
15. (a) Nishikata, T.; Yamamoto, Y.; Miyaura, N. Chem.
Lett. 2003, 32, 752; (b) Gini, F.; Hessen, B.; Feringa, B. L.;
Minnaard, A. J. Chem. Commun. 2007, 710.
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