Asymmetric Hydroesterification of Diarylmethyl Carbinols

Article abstract of DOI:10.1002/anie.202015450

An efficient asymmetric hydroesterfication of diarylmethyl carbinols is developed for the first time with a Pd-WingPhos catalyst, resulting in a series of chiral 4-aryl-3,4-dihydrocoumarins in excellent enantioselectivities and good yields. The method features mild reaction conditions, a broad substrate scope, use of easily accessible starting materials, and low palladium loadings. A plausible stereochemical model is also proposed with the Pd-WingPhos catalyst. This method has enabled a 4-step asymmetric synthesis of (R)-tolterodine from readily available starting materials.

Full text of DOI:10.1002/anie.202015450

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Accepted Article
Title: Asymmetric Hydroesterification of Diarylmethyl Carbinols
Authors: Wenjun Tang, Duanshuai Tian, Ronghua Xu, Jinbin Zhu,
Jianxun Huang, Wei Dong, and Jerome Claverie
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10.1002/anie.202015450
Angewandte Chemie International Edition
DOI: 10.1002/anie.200((will be filled in by the editorial staff))
Asymmetric Carbonylation
Asymmetric Hydroesterification of Diarylmethyl Carbinols
Duanshuai Tiana; Ronghua Xua; Jinbin Zhua; Jianxun Huanga; Wei Donga; Jerome Claverie,* Wenjun
Tanga*
Abstract: An efficient asymmetric hydroesterfication of diarylmethyl
carbinols is developed for the first time with a Pd-WingPhos
catalyst, resulting in a series of chiral 4-aryl-3,4-dihydrocoumarins
in excellent enantioselectivities and good yields. The method
features mild reaction conditions, a broad substrate scope, use of
easily accessible starting materials, and low palladium loadings. A
plausible stereochemical model is also proposed with the Pd-
WingPhos catalyst. This method has enabled a 4-step asymmetric
carboxylic acid derivatives have received considerable attention,
with the development of
few efficient examples.[4][5][6][7]
a
Nevertheless, asymmetric hydroesterification is an underdeveloped
area with limited effective chiral catalysts and substrates.
Development of an effective asymmetric hydroesterification with
high enantioselectivities, yields, regioselectivities, and low catalyst
loadings remains an important goal. Asymmetric hydroesterification
of tertiary alcohols, utilizing more convenient starting materials than
synthesis of (R)-tolterodine from readily available starting materials. disubstituted olefins, would provide an even more facile method for
chiral carboxylic acid derivatives and such approach has not been
The hydroesterification of alkenes (Reppe carbonylation) using
carbon monoxide as the C1 feedstock is a powerful and essential
transformation for producing carboxylic acid derivatives in both
academia and industry.[1][2] Recent development on this
transformation have extended to various functionalized substrates
including alcohols, halides, pseudo halides, and et al.[3] Accordingly,
asymmetric hydroesterification of alkenes to produce nonracemic
studied to our knowledge (Scheme 1). Herein we report the first
asymmetric hydroesterification of diarylmethyl carbinols that have
provided a wide array of chiral 4-aryl-3,4-dihydrocoumarins in good
yields and excellent enantioselectivities. The method enjoyed mild
reaction conditions with the palladium loading as low as 0.1 mol %.
Coumarin derivatives are important structural units in
numerous biologically active natural products.[8] The chiral 4-aryl-
3,4-dihydrocoumarins are also important building blocks for the
synthesis of chiral diarylpropanoic acid derivatives, which exist in
the structures of numerous bioactive compounds or therapeutic
agents including RORγ inhibitor I[9], GPR40 agonist II[10], and
[11]
muscarinic antagonist (R)-tolterodine (III)
(Figure 1).
Asymmetric synthesis of chiral 4-aryl-3,4-dihydrocoumarins has
become an important research subject. Although a few asymmetric
synthetic methods toward 4-aryl-3,4-dihydrocoumarins are
available,[12-17] the asymmetric hydroesterification of diarylmethyl
carbinols, which are readily prepared from nucleophilic addition of
2’-hydroxyacetophenone with aryl Grignard reagent, would offer a
convenient and facile synthetic method of such structures. Herein
we report a convenient synthesis of (R)-tolterodine by asymmetric
hydroesterification.
Scheme 1. Asymmetric hydroesterfication of diarylmethyl carbinols
[] Prof. Dr. W. Tang, D. Tian, State Key Laboratory of Bio-Organic
and Natural Products Chemistry
Figure 1. Bioactive compounds or therapeutic agents containing
chiral diarylpropanoic acid substructures
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Ling Ling Rd, Shanghai 200032
E-mail: tangwenjun@sioc.ac.cn
To realize an efficient asymmetric hydroesterification of
diarylmethyl carbinols, we set out a program to develop an effective
asymmetric hydroesterification of 1,1-diaryl olefins. The Pd-
catalyzed hydroesterification of 2-(1-phenylvinyl)phenol (1a) was
thus studied with various chiral phosphorus ligands (Table 1). The
reactions were carried out at 90 oC under syngas atmosphere (CO/H2
5:1, 600 psi) with Pd(OAc)2 (2.5 mol %) as the catalyst precursor, a
chiral bisphosphorus ligand (5 mol %), p-toluenesulfonic acid (10
mol %) as the additive, and dichloromethane as the solvent (Table 1).
Previous work by Shi reported a low yield (30%) and a moderate ee
(56%) with DTBM-SEGPHOS as the ligand.[7a] Under the current
reaction conditions, a low ee (9%) and a moderate yield (52%) were
obtained with DTBM-SEGPHOS (Entry 2). A poor ee was also
observed with (S)-DM-SEGPHOS, (-)-DIOP or (S)-BINAP as the
ligand (Entries 1, 3-4). When a BIBOP-type ligand such as
(R,R,R,R)-iPrO-BIBOP(L1) or (R,R,R,R)-BnO-BIBOP (L2) was
employed, the enantioselectivity remained low (Entries 5-6). To our
Prof. Dr. W. Tang
School of Chemistry and Materials Science, Hangzhou Institute
for Advanced Study, University of Chinese Academy of
Sciences, 1 Sub-lane Xiangshan, Hangzhou 310024, China
Prof. Dr. Jerome Claverie
Department of Chemistry, University of Sherbrooke, 2500 Blvd
de l'Université, Sherbrooke, Qc, J1K2R1, Canada
Email: Jerome.Claverie@USherbrooke.ca
[] We are grateful to the Strategic Priority Research Program of the
Chinese Academy of Sciences XDB20000000, CAS (QYZDY-
SSW-SLH029), NSFC (21725205, 21432007, 21572246)，and
K.C. Wong Education Foundation.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
1
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10.1002/anie.202015450
Angewandte Chemie International Edition
delight, the enantioselectivity increased to 61% with (R,R,R,R)-
BIBIDIME (L3) as the ligand, (Entry 7). When (R,R,R,R)-
WingPhos(L4)[18] was applied as the ligand, the desired lactone 2a
was obtained in 67% ee and 88% yield (Entry 8). We then
investigated the temperature effect of the asymmetric
hydroesterification. When the reaction temperature dropped from
90°C to 50°C with L4 as the ligand, the enantioselectivity increased
to 87%, while the yield did not drop (Entry 9). When the reaction
temperature was further reduced to 45oC, product 2a was afforded in
89% yield and 90% ee with a prolonged reaction time (48 h, Entry
10). Further screening of various palladium precursors such as
Pd(O2CCF3)2 and Pd(dba)2 provided similarly high yields and ee
values (Entries 11-12). However, no reaction was observed when
Pd(PPh3)2Cl2 was employed as the palladium precursor (Entry 13).
Finally, the effect of p-toluenesulfonic acid as the additive was
studied. When the reaction was performed in the absence of p-
toluenesulfonic acid, no formation of product 2a was observed,
indicating the importance of the acidic environment for the
transformation (Entry 14).
Interestingly, the hydroesterification was compatible with heteroaryl
group such as thiophene (2x). Substituents with strong coordinating
ability such as methylthio and cyano groups were all compatible and
products 2o and 2u were afforded in excellent enantioselectivities
and good yields. It was particularly noteworthy that this
transformation was tolerant with substrates with halogen
substituents (2s, 2t, 2zd). Even the bromo-substituted lactone 2t was
isolated in 91% ee and 64% yield without noticeable formation of
dehalogenation and other related side-products. Delightfully,
asymmetric
hydroesterification
of
4-methyl-2-(1-
phenylvinyl)phenol (1za, 2.1 g) was carried out at a gram scale in
the presence of Pd(OAc)2 (0.1 mol %) and (R,R,R,R)-WingPhos (L4,
0.12 mol %), and the desired chiral lactone 2za (1.6 g) was afforded
in 70% yield and 90% ee, demonstrating the high practicality of this
asymmetric transformation.
[a]
Table 2. Asymmetric hydroesterification of alkenes compound 1
[a][g]
Table 1. Asymmetric hydroesterification reaction of 1a
Yield
(%)[b]
Ee
Entries
Pd precursor
L
T/oC
(%)[c]
1
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(O2CCF3)2
Pd(dba)2
(S)-DM-SEGPHOS
90
90
90
90
90
90
90
84
52
88
85
86
85
86
88
88
89
87
82
0
22
9
(S)-DTBM-SEGPHOS
3
(-)-DIOP
7
4
(S)-BINAP
23
15
25
61
67
87
90
88
90
ND
ND
5
L1
L2
L3
L4
L4
L4
L4
L4
L4
L4
6
7[d]
8
90
50
45
45
45
45
45
9
10[d][f]
11[d]
12[d]
13[d]
14[d][e]
Pd(PPh3)2Cl2
Pd(OAc)2
0
[a] Unless otherwise specified, all reactions were performed in
dichloromethane (1.5 mL) for 24 h with 1a (0.2 mmol), Pd precursor (2.5
mol %), L (5 mol %), TsOH.H2O (10 mol %) and syngas (CO/H2 5:1, 600
psi). The absolute configuration of 2a was determined by comparing the
sign of the optical rotation with reported data[13b]. [b] Isolated yields. [c]
Determined by chiral HPLC on a chiralcel OD-H column. [d] t: 48 h. [e]
Without TsOH.H2O. [f] Pure CO instead of syngas was also employed with
[a] Unless otherwise specified, all reactions were performed in
dichloromethane (1.5 mL) and 45 oC for 48 h with 1 (0.2 mmol), Pd(OAc)2
(2.5 mol %), L (5 mol %), TsOH.H2O (10 mol %) and syngas (CO/H2 5:1,
600 psi). [b] T: 35 oC. [c] (S,S,S,S)-L3 (5 mol %) was employed as the
ligand. [d] Pd(OAc)2 (0.1 mol %).
least influence. [g] TsOH: p-toluenesulfonic acid; DCM ：
dichloromethane.
The successful development on asymmetric hydroesterification
of 1,1-diaryl olefins prompted us to further investigate the
asymmetric hydroesterification of diarylmethyl carbinols, which
were more advantageous from a point view of process chemistry: 1)
the diarylmethyl carbinols can be readily prepared from methyl aryl
ketones by nucleophilic addition with aryl Grignard reagent, thus
eliminating the additional step for preparation of the corresponding
olefins; 2) in contrast to often oily nature of 1,1-diaryl olefins, most
diarylmethyl carbinols were solids easy for purity control and
storage. Despite with no precedence, we envisioned that the
diarylmethyl carbinol will be readily converted to 1,1-diaryl olefin
by elimination of water under the reaction conditions. If water can
We then looked into the asymmetric hydroesterification of 1,1-
diaryl olefins. As depicted in Table 2, a series of chiral 4-aryl-3,4-
dihydrocoumarins were obtained in excellent ee‘s and moderate to
good yields with Pd-WingPhos as the catalyst. Substrates containing
either electron-donating substituents such as alkyl, alkoxy, and
trimethylsilyl groups (2a-o 2za-zf), or electron-withdrawing
substituents such as phenyl, fluoro, chloro, bromo, and
trifluoromethyl groups (2p-2v) were all applicable, providing 79-
96% ee’s. When the substituent on the aryl group was at ortho or
meta position, the enantioselectivity dropped slightly (2k, 2l, 2r).
2
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10.1002/anie.202015450
Angewandte Chemie International Edition
be tolerated during the course of carbonylation, asymmetric
hydroesterification of diarylmethyl carbinols could be accomplished.
Indeed, when a series of diarylmethyl carbinols 3 were subjected to
hydroesterification with Pd-WingPhos catalyst under similar
reaction conditions mentioned above, an array of enantiomerically
enriched 4-aryl-3,4-dihydrocoumarin products were successfully
obtained
without
significant
deterioration
of
both
enantioselectivities and yields (Table 3). The in situ formed water
was well tolerated with the Pd-WingPhos catalyst system. Thus, we
have developed for the first time an efficient asymmetric
hydroesterification of tertiary alcohols.
Table 3. Asymmetric hydroesterification reaction of tertiary
[a]
alcohols 3
Figure 2. Proposed mechanism
The asymmetric hydroesterification of diarylmethyl carbinols
were further applied to the synthesis of biologically intersting
compounds or therapeutic agents. Chiral β,β-diaryl carboxylic acid
II is a potent GPR40 agonist, a potential drug for the treatment of
diabetes.[9] Using tertiary alcohol 1zg as the starting material, we
successfully obtained chiral 2zg in 79% yield and 76% ee with Pd-
(S,S,S,S)-BIBIDIME
as
the
catalyst
by
asymmetric
hydroesterification. Hydrolysis of 2zg with LiOH as the base formed
II in 87% yield (Scheme 2a). (R)-Tolterodine[10] is a therapeutic
agent for the treatment of urinary incontinence, frequent urination,
and urgency. Its synthesis started with nucleophilic addition of
ketone 4 with phenyl Grignard reagent, forming tertiary alcohol 3za
in 94% yield. Asymmetric hydroesterification of 3za in
dichloromethane with Pd(OAc)2 (2.5 mol %) and (S,S,S,S)-
o
WingPhos (3 mol %) as the catalyst system at 40 C for 48 h led to
the formation of 2za in 91% ee and 69% isolated yield. This was
followed by DIBAL-H reduction and reductive amination with
diisopropylamine under conditions of Pd/C and H2, forming (R)-
tolterodine in four overall steps from ketone 4. Thus, a convenient
synthesis of (R)-tolterodine by asymmetric hydroesterification was
successfully developed (Scheme 2d).
[a] Unless otherwise specified, all reactions were performed in
dichloromethane (1.5 mL) and 45 oC for 48 h with 3 (0.2 mmol), Pd(OAc)2
(2.5 mol %), L4 (5 mol %), TsOH.H2O (10 mol %) and syngas (CO/H2 5:1,
600 psi), isolated yields, ee’s were determined by chiral HPLC. [b] T = 40
oC
A plausible mechanism was proposed in Figure 2.Oxidative
addition of the Pd(0)-WingPhos species (A) with TsOH forms the
cationic Pd(ΙΙ)-WingPhos hydride species B. This is followed by
coordination with olefin 1a, which is formed by elimination of 3a
under acidic conditions, and an ensuring insertion to provide the
alkyl Pd(II) species C. Next, CO insertion of C forms the acyl Pd(II)
species D, which undergoes reductive elimination to form the
lactone product 2a and regenerate the Pd(0)-WingPhos catalyst.
Apparently, the olefin coordination and insertion process from B to
C determines the stereoselectivity of this transformation. Based on
the X-ray structure of the Pd-(R,R,R,R)-WingPhos complex in our
previous report[18], the upper left and lower right parts of the C2-
symmetric Pd hydride species are blocked by two anthracenyl
groups. When olefin 1a approaches the cationic Pd species through
a chelating fashion with olefin coordination in the same plane as the
phosphorus centers and the hydroxy group in apical position, the
phenol moiety would locate preferentially at lower left position of
the Pd species as shown in Figure 2c and the resulting migratory
insertion and further transformations proceed to provide lactone 2a
with the observed S configuration.
Scheme 2. Synthetic applications
In conclusion, we have developed for the first time an efficient
asymmetric hydroesterification of diarylmethyl carbinols powered
by a Pd-WingPhos catalyst, resulting in a series of chiral 4-aryl-3,4-
dihydrocoumarins in excellent enantioselectivities and good yields.
The method features mild reaction conditions, a broad substrate
scope, use of easily accessible starting materials, and low palladium
3
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10.1002/anie.202015450
Angewandte Chemie International Edition
loadings. A plausible stereochemical model of the asymmetric
hydroesterification is proposed with the Pd-WingPhos catalyst. This
method has also enabled a 4-step asymmetric synthesis of (R)-
tolterodine from readily available starting materials.
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Received: ((will be filled in by the editorial staff))
Published online on ((will be filled in by the editorial staff))
Keywords:
hydroesterification,
diarylmethyl
carbinols,
enantioselectivity, carbon monoxide, tolterodine
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Asymmetric Catalysis
Duanshuai Tian; Ronghua Xu; Jinbin
Zhu; Jianxun Huang; Wei Dong; Jerome
Claverie;* Wenjun Tang*
Page
Asymmetric
Hydroesterification
of
Diarylmethyl Carbinols
An efficient asymmetric hydroesterfication of diarylmethyl carbinols is
developed for the first time with a Pd-WingPhos catalyst, resulting in a
series of chiral 4-aryl-3,4-dihydrocoumarins in excellent enantioselectivities
and good yields. The method features mild reaction conditions, a broad
substrate scope, use of easily accessible starting materials, and low
palladium loadings. A plausible stereochemical model is proposed with the
Pd-WingPhos catalyst. This method has also enabled a 4-step asymmetric
synthesis of (R)-tolterodine from readily available starting materials.
6
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