Palladium-catalyzed diastereoselective synthesis of β,β-diarylpropionic acid derivatives and its application to the total synthesis of (R)-tolterodine and the enantiomer of a key intermediate for MK-8718

Article abstract of DOI:10.1016/j.tetlet.2017.12.082

Palladium-catalyzed diastereoselective synthesis of optically active β,β-diarylpropionic acid derivatives employing 4-(tert-butyl)oxazolidin-2-one as the chiral auxiliary under an air atmosphere in excellent yields with high diastereoselectivity is reported. The catalytic system is applied to the total synthesis of (R)-tolterodine and the enantiomer of a key intermediate for MK-8718.

Full text of DOI:10.1016/j.tetlet.2017.12.082

Accepted Manuscript
Palladium-Catalyzed Diastereoselective Synthesis of β, β-Diarylpropionic Acid
Derivatives and Its Application to the Total Synthesis of (R)-Tolterodine and
the Enantiomer of a key Intermediate for MK-8718
Wubin Zhi, Jingya Li, Dapeng Zou, Yangjie Wu, Yusheng Wu
PII:
S0040-4039(17)31626-X
https://doi.org/10.1016/j.tetlet.2017.12.082
TETL 49584
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
26 November 2017
22 December 2017
29 December 2017
Please cite this article as: Zhi, W., Li, J., Zou, D., Wu, Y., Wu, Y., Palladium-Catalyzed Diastereoselective Synthesis
of β, β-Diarylpropionic Acid Derivatives and Its Application to the Total Synthesis of (R)-Tolterodine and the
Enantiomer of a key Intermediate for MK-8718, Tetrahedron Letters (2017), doi: https://doi.org/10.1016/j.tetlet.
2
017.12.082
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Palladium-Catalyzed Diastereoselective Synthesis
of β, β-Diarylpropionic Acid Derivatives and Its
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Application to the Total Synthesis of (R) -Tolterodine
and the Enantiomer of a key Intermediate for MK-8718
Wubin Zhi, Jingya Li, Dapeng Zou,* Yusheng Wu,* Yangjie Wu*

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Palladium-Catalyzed Diastereoselective Synthesis of β, β-Diarylpropionic Acid
Derivatives and Its Application to the Total Synthesis of (R)-Tolterodine and the
Enantiomer of a key Intermediate for MK-8718
a
b,c
a,b
a
b,d
Wubin Zhi , Jingya Li , Dapeng Zou , Yangjie Wu 1, Yusheng Wu 
a
The College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, 450052, PR China.
Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, PR China.
Tetranov Biopharm, LLC., No.75 Daxue Road, Zhengzhou, 450052, PR China.
Tetranov International, Inc., 100 Jersey Avenue, Suite A340, New Brunswick, NJ 08901, USA.
b
c
d
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Palladium-catalyzed diastereoselective synthesis of optically active β, β-diarylpropionic acid
derivatives employing 4-(tert-butyl)oxazolidin-2-one as the chiral auxiliary under an air
atmosphere in excellent yields with high diastereoselectivity is reported. The catalytic system is
applied to the total synthesis of (R)-tolterodine and the enantiomer of a key intermediate for
MK-8718.
Available online
2
017 Elsevier Ltd. All rights reserved.
Keywords:
Palladium-catalyzed
diastereoselective synthesis
β, β-diarylpropionic acid derivatives
(R)-tolterodine
MK-8718
Introduction
for palladium-catalyzed diastereoselective synthesis of
optically active β, β-diarylpropionic acids and its application
Chiral β, β-diaryl-substitued compounds are important
1, 12
to the total synthesis of (R)-tolterodine
and the
structural moieties that are found in many pharmaceuticals
3
enantiomer of a key intermediate for MK-8718. (R)-
tolterodine, an important urological drug used in the
treatment of urinary incontinence. MK-8718, a novel HIV
protease inhibitor with a favorable pharmacokinetic profile
with potential for further development, is discovered by
Merck research laboratory.
1
2
(
e.g., tolterodine, sertraline ), bioactive compounds (e.g.,
3
4
MK-8718 ) and natural products (e.g., podophyllotoxin,
5
cherylline ). Due to their diverse biological properties such
as antioxidant activity, bacteriostatic, growth modulation,
disease prevention and antitumor properties, the
enantioselective construction of stereogenic carbon centers
substituted with two aryl groups has become an attractive
subject.
Thus far, many methods for accessing chiral β, β-
6
diarylpropionic acids have been reported, such as cuprum -,
7
8
cobalt -, or rhodium - catalyzed asymmetric 1,4-reduction of
β, β-diaryl-substitued unsaturated acrylates or nitriles using
hydrosilane or borohydride as the reductants, and direct
enantioselective hydrogenation of β,β-diaryl-substitued9
unsaturated acrylic acids or acrylates with molecular H2.
Among these, asymmetric 1, 4-addition of nucleophilic
reagents to α, β-unsaturated carbonyl compounds catalyzed
by Pd, Rh, or Cu complexes is a more popular and practical
1
0
method.
Recently, we have explored the palladium-catalyzed
diastereoselective conjugate addition of arylboronic acids to
chiral imides as a convenient method to obtain optically
Figure 1. Chiral β, β-diaryl-substituted pharmaceuticals,
bioactive compounds, and natural products
1
1
active 3-arylbutanoic acids. Herein, we report the method

Corresponding author. Tel.: +1 732 253 7326; fax: +1 732 253 7327; e-mail: yusheng.wu@tetranovglobal.com, wyj@zzu.edu.cn,
zdp@zzu.edu.cn

2
Tetrahedron
Results and Discussion
important role in this diastereoselective conjugate addition of
arylboronic acid to cinnamamide with chiral auxiliaries.
1
3
Evans-oxazolidinones have been used as chiral auxiliaries in
PdCl showed a similar activity compared to Pd(OAc) in
many stereoselective transformations and applied to synthesis of
varies of nature products and bioactive compounds. At first, three
Evans-oxazolidinones were used as the chiral auxiliaries (entries
2
2
the mixture solvent of methanol and water (entry 8-9). When
the loading of 2,2'-bipyridine was reduced to 0.1 equiv, the
conversion decreased to 70% even if the reaction proceeded
for 24 h (entry 12).
1
-3), (S)-4-tert-butyloxazolidin-2-one, (S)-4-benzyloxazolidin-2-
one (a), and (S)-4-phenyloxazolidin-2-one, were installed on
cinnamoyl chloride to give the corresponding cinnamamides
Table 2. Palladium-catalyzed conjugate addition of
arylboronic acids to chiral Imide
(1a−c). As shown in Table 1, (S)-4-tert-butyloxazolidin-2-one
a
was found to be a more efficient chiral auxiliary for the
diastereoselective conjugate addition of o-tolylboronic acid to
imide, using Pd(OAc) as the catalyst and 2,2'-bipyridine as the
2
ligand in mixed solvent of MeOH/H O (1:3) at 80 °C. And 3a
2
with S-configuration could be easily isolated by column
chromatography on silica gel using petroleum ether/ethyl acetate
as the eluent. And the higher conversion was due to 1a’s better
solubility in the mixed solvent.
b
c
d
entry
Ar
Conv.(%)
>99
>99
>99
0
dr
Yield(%)
3a 89
3b 92
3c 93
-
1
2
3
4
o-MeC
6
H
4
93:7(NMR)
99:1
99:1
-
a
Table 1. Optimization of the Reaction Conditions
6
m-MeC H4
p-MeC
o-CF
m-CF
p-CF
o-ClC
m-ClC
6 4
H
3 6 4
C H
e
5
3
C
6
H
4
95
99:1
96:4
90:10
99:1
99:1
92:8
96:4
98:2
93:7
96:4
99:1
95:5
95:5
94:6
93:7
99:1
98:2
99:1
-
3d 91
3e 89
3f -62
3g 94
3h 92
3i 85
3j 87
3k 92
3l 86
3m 88
3n 93
3o 86
3p 85
3q 82
3r 84
3s 95
3t 95
3u 80
-
e
c
6
3
C
6
H
4
93
entry
1
catalyst
solvent
Conv
dr (3/3')
e
b
7
6
H
4
85
(%)
8
6
H
4
>99
>99
95
1
2
3
4
5
6
7
8
9
1a
1b
1c
1a
1a
1a
1a
1a
1a
1a
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
2
2
2
MeOH/H
2
2
2
O(1:3)
>99
62
15:1
6:1
9
6 4
p-ClC H
MeOH/H
MeOH/H
O(1:3)
O(1:3)
e
1
1
0
1
6 4
m-CNC H
81
3:1
e
p-CNC
o-MeOC
m-MeOC
p-NH COC
p-OHCH
p-CHOC
m-MeCOC
p-HOC
3,4-difuoro C
3,4-MeO C
6
H
4
98
MeOH
>99
>99
75
6:1
1
2
6
H
4
>99
>99
98
MeOH/H
2
O(1:1)
O(1:5)
11:1
10:1
6:1
1
3
6 4
H
MeOH/H
2
e
1
4
2
6
6
H
4
4
2
H O
65
1
5
2
C
H
98
PdCl
PdCl
2
MeOH/H
2
O(1:1)
O(1:3)
>99
>99
NR
11:1
15:1
e
1
6
6
H
4
98
2
MeOH/H
2
1
7
6
H
4
>99
>99
96
1
0
Pd(OAc)
2
HOAc/THF/
O(1:2:0.6)
H
2
18
19
20
21
6 4
H
1
1
d
1a
1a
Pd(OAc)
2
2
Acetone/H O(1:1)
2
>99
70
9:1
6 3
H
1
2
Pd(OAc)
MeOH/H O(1:3)
2
15:1
6
H
3
>99
>99
83
a
Reaction conditions: under an air atmosphere, chiral imide (0.5 mmol), o-
3-thioenyl
2-furanyl
2-phenyl
tolylboronic acid (2) (1 mmol), catalyst (0.025 mmol), 2,2'-bipyridine (0.1
mmol), solvent (4 mL), time (12 h), in a sealed Schlenk tube at 80 °C.
e
2
2
2
3
0
b
1
Determined by H NMR analysis of the crude reaction mixture.
a
Reaction conditions: under an air atmosphere, chiral imide (1a) (0.5
mmol), arylboronic acid ( ) (1 mmol), Pd(OAc) (0.025 mmol), 2,2'-
O (3 mL), time (12 h), in a
c
1
The diastereoselective ratio (dr value) was determined according to the H
2
2
NMR peak areas of α-H in 3 and 3’ from the reaction mixture of 1 with 2a.
bipyridine (0.1 mmol), MeOH (1 mL), H
sealed Schlenk tube at 80 °C.
2
d
2
,2'-bipyridine (0.05 mmol) was used, and reacted for 24 h.
b
1
Determined by H NMR analysis of the crude reaction mixture.
Conjugate addition and oxidative Heck reaction are
c
The diastereoselective ratio (dr value) was determined according to
HPLC of the reaction mixture of 1a with 2.
competitive, the application of appropriate solvent have been
proved to be important for the palladium-catalyzed 1, 4-addition
of nucleophilic reagents to α, β-unsaturated carbonyl
d
Isolated yield.
1
4
compounds. Firstly, the effect of different rations of methanol
e
Reacted for 24 h
and water was investigated, higher diastereoselective ratio of 3/3'
As illustrated in Table 2, the present diastereoselective
conjugate additions of a broad range of arylboronic acids
were evaluated for reaction with 1a under the standard
conditions. The conjugate addition proceeded in high yields
(
dr. value up to 15:1) without oxidative Heck product was
obtained in case of the mixed solvent of MeOH/H O (1:3) was
used (entry 1). When the proportion of MeOH/H O was reduced,
the conjugate addition products were found to be major products
together with lower than 5% oxidative Heck product with lower
diastereoselective ratio of 3/3' (entries 4-7). Other solvents were
also investigated. Only trace product was found when the acidic
solvent of HOAc/THF/H O was used (entry 10), which worked
well in Lin’s work.
found in the mixture of acetone/H O (1:1) with moderate dr.
value (entry 11). The results indicated that solvents played an
2
2
(up to 95%) with excellent diastereoselectivity (dr. value up
to 99:1) for most of the substrate combinations. Arylboronic
acids substituted with diverse functional groups such as
methyl, methoxyl, trifluoromethyl, amide, halogen, ester,
ketone, aldehyde, hydroxyl and methylol at the ortho-, meta-
2
1
4a, 14e
3% Oxidative Heck product was also
,
and para-positions on the phenyl were tolerated under the
2
optimal conditions, except for (2-(trifluoromethyl)phenyl)-

3
1
2
boronic acid (entry 4) and [1,1'-biphenyl]-2-ylboronic acid
entry 23) which was due to the bigger steric substituents in
Different approaches have been reported for the racemic and
asymmetric synthesis of tolterodine over the last decades.
(
the ortho-position. Arylboronic acids with electron-
withdrawing substituents need longer time to give high
conversion (entries 5, 6, 10, 11, 14, 16). (2-
Chlorophenyl)boronic acid also gave low conversion (entry
Scheme 2 illustrated the reaction scheme that involved. The
synthesis commenced with Wittig reaction of couple
commercially available 2-hydroxy-5-methyl-benzaldehyde 10
and ethyl 2-(triphenylphosphoranylidene)acetate, afforded the
corresponding cinnamate ester 11. A sequence of benzylation,
hydrolysis of 11 gave compound 12 with good overall efficiency.
Then compound 12 was treated with oxalyl chloride to give
corresponding cinnamoyl chloride, which reacted with (S)-4-tert-
butyloxazolidin-2-one to form the key intermediate cinnamamide
13. As a key step, the diastereoselective conjugate addition of
phenylboronic acid to cinnamamide 13 under our optimized
conditions furnished the diaryl derivative 14 in 82% yield, and
the dr value of which was determined as 14: 14’ = 90: 10 by
7
). The reaction worked well for hetero-arylboronic acids,
such as furan-2-ylboronic acid, thiophen-3-ylboronic acid
entry 21 and 22). Therefore, the present method could
(
easily afford diverse chiral β, β-diarylpropionic acid
derivatives.
In addition, a single crystal of 3j was prepared to further
confirm the absolute configuration, and its structure was
unambiguously confirmed by X-ray diffraction analysis. The
X-ray diffraction analysis indicated that the conjugate
addition intends to form the product with the S-
1
analysis of H NMR of the crude products. Reduction of
1
6
configuration.
compound 14 by treatment with LiBH in Et O at 0 °C gave 94%
4
2
yield of alcohol 15. The hydroxyl group in alcohol 15 was
successfully oxidated to corresponding aldehyde, and subsequent
reductive amination with diisopropylamine and sodium
triacetoxyborohydride gave the protected tolterodine precursor in
high yields. Deprotection of benzyl applying hydrogenolysis
gave (R)-tolterodine in high yield.
The R configuration was confirmed by comparison of the
1
5
optical rotations with that reported for (S)-tolterodine
2
0
{
[α] -23.0 (c 1.5, MeOH)}. Thus, using our new method
D
in the key step, (R)-tolterodine was synthesized through an
eight-step sequence from 2-hydroxy-5-methyl-benzaldehyde
Scheme 1. Synthesis of the enantiomer of a key intermediate
1
0
in an overall yield of 52%.
Conclusion
In summary, we have developed a convenient, efficient and
6
for MK-8718.
As shown in scheme 1, cryloyloxazolidinone 6 was a key
intermediate for synthesis of MK-8718, obtained by copper-
3
catalyzed Grignard addition at -78 °C in Bungard’s work, low
practical palladium-catalyzed method for the diastereoselective
synthesis of optically active chiral β, β-diarylpropionic acid
derivatives. The protocol relies on the use of easily available
substrates, cheap ligands and recoverable chiral auxiliary groups.
The notable advantage of this method is that it is simple and
compatible with a variety of functional groups (halide, cyano,
ester, amide, methylol, etc.). Moreover, the desired optically
active 3-arylbutanoic acid derivatives could be obtained in
excellent yields with a high diastereoselectivity. Therefore, the
present method provides a novel and valuable strategy for the
synthesis of diverse optically active 3-arylbutanoic acid
derivatives. Furthermore, this methodology is applied to the total
synthesis of (R)-tolterodine and the enantiomer of a key
intermediate for MK-8718.
temperature restricted the large scale application of this method.
Our present palladium-catalyzed diastereoselective addition was
applied to synthesis of the similar cryloyloxazolidinone 9 on a
gram scale, which was the enantiomer of a key intermediate for
MK-8718. Firstly, compound 7 reacted with oxalyl chloride to
give (E)-3-(3, 5-difluorophenyl)acryloyl chloride, then treated
with (S)-4-tert-butyloxazolidin-2-one to afford the desired
acrylooxazolidinone 8. Secondly, the diastereoselective
conjugate addition of (4-chlorophenyl)boronic acid to
acrylooxazolidinone 8 was performed under the optimized
conditions to give cryloyloxazolidinone 9 in high yields (76%
over 2 steps).
Acknowledgments
We are grateful to the National Natural Science Foundation of
China (21172200, 21702191) for financial support.
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of other products was tentatively assigned by analogy.

5
Highlights
Palladium-catalyzed diastereoselective synthesis
•
of optically active chiral β, β-diarylpropionic acid
derivatives.
•
With excellent yields and high
diastereoselectivity.
This catalytic system was applied to the total
synthesis of (R)-tolterodine.
This catalytic system was performed on gram-
scale.
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