Organocatalytic enantioselective direct additions of aldehydes to 4-vinylpyridines and electron-deficient vinylarenes and their synthetic applications

Article abstract of DOI:10.1021/ja511143b

We describe a synergistic catalysis strategy for the asymmetric direct addition of simple aldehydes to 4-vinylpyridines. By means of independent activation of weakly electrophilic 4-vinylpyridines by the Bronsted acid CF₃SO₃H (TfOH) and aldehydes by chiral diphenylprolinol tert-butyldimethylsilyl (TBDMS) ether-catalyzed formation of nucleophilic enamines in a cooperative manner, the previously unattainable highly enantioselective addition process has been realized for the first time. Notably, the power of the addition process is fueled by its high efficiency in the production of synthetically valued chiral pyridines. ¹H NMR studies of the process suggested that the nucleophilic enamine formed in situ from the chiral amine catalyst and the aldehyde is directly added to the trimeric 4-vinylpyridinium-derived species as a highly active electrophile generated from the 4-vinylpyridine in the presence of TfOH. Moreover, inspired by the similar electronic natures of pyridine and nitrobenzene, we have achieved an unprecedented chiral diphenylprolinol TBDMS ether-promoted, highly enantioselective direct addition of aldehydes to 2-nitrostyrenes without the use of TfOH as a cocatalyst. In this approach, introducing a strong electron-withdrawing group such as NO₂, CF₃, SO₂Me, etc. on the 2-nitrostyrene creates a highly electrophilic vinyl moiety, which enables the direct addition of the in situ-formed enamine derived from the chiral amine promoter and the aldehyde. This method significantly expands the scope of the enantioselective addition process. While the electron-withdrawing nitro group is essential for activation of the vinyl group, we have demonstrated that it can be readily transformed to diverse functionalities. Furthermore, as shown, a chiral pyridine adduct serves as a key building block in the synthesis of the potent fibrinogen receptor antagonist L-734,217.

Full text of DOI:10.1021/ja511143b

Article
pubs.acs.org/JACS
Organocatalytic Enantioselective Direct Additions of Aldehydes to
4‑Vinylpyridines and Electron-Deficient Vinylarenes and Their
Synthetic Applications
Sinan Wang,† Xiangmin Li,†,‡ Hongwei Liu,† Li Xu,† Jinchen Zhuang,† Jian Li,† Hao Li,*,†
and Wei Wang*,†,‡
†Shanghai Key Laboratory of New Drug Design, School of Pharmacy, and State Key Laboratory of Bioengineering Reactor, East
China University of Science and Technology, 130 Mei-long Road, Shanghai 200237, China
‡Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, New Mexico 87131-0001, United States
S
* Supporting Information
ABSTRACT: We describe a synergistic catalysis strategy for the
asymmetric direct addition of simple aldehydes to 4-vinylpyridines.
By means of independent activation of weakly electrophilic 4-
vinylpyridines by the Brønsted acid CF3SO3H (TfOH) and
aldehydes by chiral diphenylprolinol tert-butyldimethylsilyl
(TBDMS) ether-catalyzed formation of nucleophilic enamines in
a cooperative manner, the previously unattainable highly
enantioselective addition process has been realized for the first
time. Notably, the power of the addition process is fueled by its
high efficiency in the production of synthetically valued chiral
pyridines. 1H NMR studies of the process suggested that the nucleophilic enamine formed in situ from the chiral amine catalyst
and the aldehyde is directly added to the trimeric 4-vinylpyridinium-derived species as a highly active electrophile generated from
the 4-vinylpyridine in the presence of TfOH. Moreover, inspired by the similar electronic natures of pyridine and nitrobenzene,
we have achieved an unprecedented chiral diphenylprolinol TBDMS ether-promoted, highly enantioselective direct addition of
aldehydes to 2-nitrostyrenes without the use of TfOH as a cocatalyst. In this approach, introducing a strong electron-withdrawing
group such as NO2, CF3, SO2Me, etc. on the 2-nitrostyrene creates a highly electrophilic vinyl moiety, which enables the direct
addition of the in situ-formed enamine derived from the chiral amine promoter and the aldehyde. This method significantly
expands the scope of the enantioselective addition process. While the electron-withdrawing nitro group is essential for activation
of the vinyl group, we have demonstrated that it can be readily transformed to diverse functionalities. Furthermore, as shown, a
chiral pyridine adduct serves as a key building block in the synthesis of the potent fibrinogen receptor antagonist L-734,217.
philes such as indoles,6 malonates and their derivatives,7
INTRODUCTION
■
amines,8 and thiols9 are generally used. Moreover, these
Twelve therapeutics containing a pyridine moiety in the top
processes are often performed under basic or acidic conditions
or with the assistance of transition metals and/or at high
temperature for effective transformations.
Despite the significant value and broad application of chiral
200 pharmaceutical products by U.S. retail sales in 2012,
including the top one, Nexium, manifest the “privileged” status
of the heteroaromatic structure in synthesis and medicinal
chemistry.1 Among the heteroarenes, pyridine perhaps is the
pyridine building blocks in organic synthesis and medicinal
most studied system because of its broad utility. In addition to
chemistry, the development of catalytic enantioselective 1,4-
their ubiquitous distribution in biologically active natural
products, pharmaceuticals, and agrochemicals,2 pyridines are
conjugate addition processes with 2- and 4-vinylpyridines has
been difficult. To date, to the best of our knowledge, only four
also widely employed as ligands in catalysis and molecular
recognition.3 Therefore, the capacity to functionalize the
catalytic processes to effect enantioselective conjugate addition
processes have been investigated. In 1993, Houpis and co-
privileged structure would leverage new broad-ranging
applications.4
workers reported the first asymmetric addition reaction of
Grignard and organozinc reagents to 4-alkenylpyridines
Direct addition of nucleophiles to electrophilic alkenylpyr-
catalyzed by a nickel catalyst, but the products were obtained
idines is a viable strategy for the facile synthesis of pyridine
with less than 15% ee.10 The breakthrough in this field came 16
years later, when Lam and colleagues uncovered the Cu(II)−
derivatives.5 In this context, readily available 2- and 4-
vinylpyridines have been subjected to intensive studies in a
nonasymmetric fashion. It is noteworthy that as a result of their
lower reactivity compared with classic α,β-unsaturated systems
as Michael acceptors in conjugate additions, strong nucleo-
Received: October 29, 2014
© XXXX American Chemical Society
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DOI: 10.1021/ja511143b
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Article
Josiphos complex-catalyzed highly enantioselective reduction of
electron-deficient β,β′-disubstituted 2-alkenylpyridines and
other heteroarenes with PhSiH3 (Scheme 1, eq 1).11 More
catalysis approach.15 Through independent activation of
separate electrophilic and nucleophilic substrates by two
distinct catalysts, this synergistic catalytic strategy may enable
a new, previously unattainable addition process. Specifically, a
Brønsted acid activates the 4-vinylpyridines through acid−base
interactions16 while a chiral amine promotes the formation of
highly active nucleophilic enamines from their precursor
aldehydes17 (Scheme 1, eq 2). The two resultant active species
may allow for an unprecedented enantioselective addition
reaction of 4-vinylpyridines with aldehydes.
Scheme 1. Catalytic Enantioselective Addition Reactions
with Alkenylpyridines
b. Exploration and Optimization of the Reaction
Conditions. To demonstrate the feasibility of the novel
process, we embarked on the model reaction of 4-vinylpyridine
(1a) (1.0 mmol) and n-octanal (2a) (3.0 mmol) in the
presence of diphenylprolinol trimethylsilyl (TMS) ether (I) (30
mol %) and CF3SO3H (0.5 equiv) as cocatalysts in 1 mL of
N,N-dimethylformamide (DMF) at room temperature (rt) for
48 h (Table 1, entry 1). Under the reaction conditions, fast
Table 1. Optimization of Reaction Conditions for the
a
Addition of Aldehydes to 4-Vinylpyridines
recently, the same group reported an elegant arylation reaction
of alkenylpyridines and -heteroarenes catalyzed by a chiral Rh
complex with high enantioselectivity (up to 98% ee).12 Similar
chemistry has been nicely carried out by Lautens and co-
workers13 in a Rh/Pd-cocatalyzed cascade process for the one-
pot synthesis of chiral aza-dihydrodibenzoxepines. Unfortu-
nately, these chiral transition-metal-catalyzed processes display
poor efficiency on 4-alkenylpyridines because of the difficulty of
complexation with the Lewis acid for activation of these
substrates.
Herein we report an alternative catalytic strategy using a
Brønsted acid and chiral amine as cocatalysts in promoting the
enantioselective direct addition of aldehydes to 4-vinylpyridines
for the first time (Scheme 1, eq 2).14 The Brønsted acid (e.g.,
CF3SO3H (TfOH)) activates the 4-vinylpyridine to generate a
highly active electrophilic trimeric 4-vinylpyridinium ion, while
the amine promotes the formation of a nucleophilic enamine
from the corresponding aldehyde. Notably, the cooperative
catalysis achieves high enantioselectivities (up to 97% ee) and
good yields (up to 83%). Furthermore, trigged by the similar
electronic natures of pyridine and nitrobenzene, we have
successfully designed electron-deficient-substituted 2-nitrostyr-
enes as effective acceptors for the highly enantioselective
addition of aldehydes using a chiral amine as the catalyst.
Although the electron-withdrawing nitro group is essential for
activation of the vinyl group, it can be conveniently
transformed to new diverse functional groups. Furthermore,
as demonstrated experimentally, a chiral pyridine adduct serves
as a key building block in the efficient synthesis of the potent
fibrinogen receptor antagonist L-734,217.
b
c
entry
cat
acid
solvent
DMF
yield (%)
ee (%)
1
2
I
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
−
75
trace
trace
74
45
33
77
81
76
0
23
nd
nd
33
41
35
80
86
86
nd
nd
90
88
91
92
91
92
92
II
DMF
3
III
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
DMF
4
DMF
5
THF
6
toluene
7
DMF/H2O (9:1)
DMF/H2O (8:2)
DMF/H2O (7:3)
DMF/H2O (8:2)
DMF/H2O (8:2)
DMF/H2O (8:2)
DMF/H2O (8:2)
DMF/H2O (8:2)
DMF/H2O (8:2)
DMF/H2O (8:2)
DMF/H2O (8:2)
DMF/H2O (8:2)
8
9
10
11
12
13
14
AcOH
0
HCl
45
52
50
81
56
72
73
HNO3
H2SO4
d
15
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
de
,
16
17
18
df
,
g
a
Unless otherwise specified, a mixture of 1a (1.0 mmol) and 2a (3.0
mmol) in the presence of the catalyst (30 mol %) and CF3SO3H (0.5
equiv) in the indicated solvent (1.0 mL) was stirred at rt for 48 h.
Isolated yields. Determined by chiral HPLC analysis. IV (10 mol
b
c
d
e
f
%) was used. CF3SO3H (0.4 equiv) was used. CF3SO3H (0.6 equiv)
g
was used. IV (5 mol %) was used.
racemization of the aldehyde product was observed. Accord-
ingly, it was reduced to alcohol 3a by NaBH4 for character-
ization. To our delight, the desired product 3a was obtained in
good yield (75%), but the enantioselectivity was poor (23%
ee). Various amine catalysts were then screened (entries 2−4).
L-Proline (II) and (S)-pyrrolidine sulfonamide III failed to
promote this process (entries 2 and 3). The more hindered
RESULTS AND DISCUSSION
■
1. Conjugate Addition to 4-Vinylpyridines. a. Design
Plan. In light of the poor reactivity of 4-vinylpyridines in
nucleophilic addition reactions, we proposed a synergistic
B
DOI: 10.1021/ja511143b
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catalyst diphenylprolinol tert-butyldimethylsilyl (TBDMS)
ether (IV) afforded better enantioselectivity without loss of
yield (33% ee, 74% yield; entry 4). Although a slight
improvement in the enantioselectivity was observed in less
polar solvents (tetrahydrofuran (THF) and toluene), lower
yields were obtained as a result of the poor solubility of the
formed pyridinium salt, which was precipitated out during the
course of the reaction (entries 5 and 6). Further optimization of
the reaction conditions revealed H2O to be critical for the
enantioselectivity (entries 7−9). A mixture of DMF and H2O
(9:1 v/v) as the solvent led to a dramatic increase in the
enantioselectivity (80% ee; entry 7). Further fine-tuning of the
ratio showed 8:2 to be the optimal choice (entries 8 and 9).
The acid catalyst had a significant impact on the reaction. No
reaction took place without acid or with a weaker acid (AcOH)
(entries 10 and 11). This suggests that activation of the 4-
vinylpyridine is essential in this synergistic catalysis, proving our
working hypothesis. Strong acids such as HCl, HNO3, and
H2SO4 afforded the alkylation products with excellent
enantioselectivities in moderate yields (entries 12−14). When
the loading of the amine catalyst was decreased to 10 mol %,
the reaction gave rise to a significantly improved yield while
maintaining excellent enantioselectivity (entry 15). Further
decreasing the catalyst loading to 5 mol % led to a lower
reaction yield despite similarly high enantioselectivity (entry
18). In contrast, using a smaller (0.4 equiv) or larger amount
(0.6 equiv) of CF3SO3H deteriorated the yield (entries 16 and
17).
The length and size of the aldehyde have a limited effect on the
enantioselectivity (entries 1−6), and it appears that sterically
demanding branched aldehydes are beneficial to the enantio-
selectivity (entries 5 and 6). Furthermore, aldehydes bearing a
diverse array of functional groups, including aromatic ring,
ester, and amine, reacted smoothly under the optimal
conditions to give the desired products (entries 7−10). It is
recognized that 4-vinylpyridines with electron-donating sub-
stituents on the pyridine ring delivered excellent results in
terms of yield and enantioselectivity (entries 11−13). However,
electron-withdrawing moieties decreased the reactivity of the 4-
vinylpyridine, presumably because of a reduction in the basicity
of the pyridine for activation by CF3SO3H. A low yield but still
a high level of enantioselectivity were achieved (entry 14). The
absolute configurations of the products were determined on the
basis of single-crystal X-ray diffraction analysis of compound 4
derived from aldehyde 5i by two-step conversion (Figure 1;
also see the Supporting Information).18
c. Reaction Scope. With the optimal conditions in hand, we
then probed the scope of the new addition process (Table 2).
Table 2. Scope of the Asymmetric Addition of Aldehydes to
a
4-Vinylpyridines
Figure 1. X-ray crystal structure of compound 4.
We then turned our attention to 2-vinylpyridine (1b) as the
reactant in the IV-promoted enantioselective addition process
(Scheme 2). It was found that under the same reaction
ee
(%)
b
c
entry
X
R
yield (%)
1
2
H
H
H
H
H
H
H
H
H
H
n-hexyl
Et
81 (3a)
70 (3b)
74 (3c)
82 (3d)
62 (3e)
62 (3f)
83 (3g)
73 (3h)
71 (3i)
76 (3j)
83 (3k)
76 (3l)
92
93
93
93
97
96
90
92
94
95
97
97
92
93
Scheme 2. IV-Catalyzed Addition of n-Hexanal (2c) to 2-
Vinylpyridine
3
n-butyl
n-octyl
isopropyl
cyclohexyl
Bn
4
5
6
7
8
(CH2)3CO2Me
(CH2)4NHBoc
(CH2)3NH(Cbz)CH2CO2Et
n-hexyl
9
10
11
12
13
14
2-Me
conditions, the process proceeded with good enantioselectivity
(85% ee) but low yield (24%). This outcome is consistent with
that observed by Gray and co-workers in their studies of the
acid-catalyzed morpholine−isobutyraldehyde-derived enamine,
where only a 13% yield was obtained.14b It is believed that the
poor reactivity of 2-vinylpyridine is attributable to its much
lower basicity (pKa = 4.92) compared with 4-vinylpyridine (pKa
= 5.62).19 Its poor protonation efficiency makes it difficult to
form the more active pyridinium ion. This is also in agreement
with what was observed in our mechanistic investigations (see
below). In the presence of CF3SO3H, it is difficult for 2-
vinylpyridine to form the corresponding pyridinium trimer, the
actual active species for the catalytic addition process.
2-HOCH2
3-NHAc
3-CO2Me
n-hexyl
n-hexyl
73 (3m)
43 (3n)
n-hexyl
a
See the Supporting Information for the experimental protocol.
Isolated yields. Determined by chiral HPLC analysis.
b
c
The results showed that the catalytic addition reaction serves as
a general approach to structurally diverse products 3. A wide
range of aldehydes and various 4-vinylpyridines could engage in
the process, affording the corresponding products with
excellent enantioselectivities in overall good to high yields.
Structure variation of the aldehyde reactant could be tolerated.
C
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Finally, we probed ketones, including acetone and cyclo-
hexanone, as nucleophiles in the IV-catalyzed addition reaction
with 4-vinylpyridine. Unfortunately, the processes did not take
place. This is presumably due to the lower reactivity of ketones
compared with aldehydes that is often seen in enamine
catalysis. Other pyridine-derived heterocycles such as 2- and 4-
vinylpyrimidines and 2-vinylpyrazine also were explored in this
reaction, but no reactions were observed either. We reasoned
that similar to 2-vinylpyridine, these heterocycles cannot form
the corresponding active trimers because the basicity is
diminished by the electron-withdrawing “N” atoms.
2. Conjugate Addition to Substituted 2-Nitrostyrenes.
a. Design Plan. Having established the organocatalyzed
enantioselective direct addition of aldehydes to electron-
deficient 4-vinylpyridine CC double bonds with the
assistance of the Brønsted acid CF3SO3H for the synthesis of
useful chiral pyridine derivatives, we questioned whether this
strategy could be applied to other vinyl structures, as the
successful realization of these processes would significantly
expand the scope of the useful asymmetric addition reaction. In
the addition of aldehydes to 4-vinylpyridines, the acid cocatalyst
was necessary for activation of the pyridine. It is accepted that
the electronic nature of pyridine is similar to that of
nitrobenzene. To make the vinyl group have reactivity
comparable to that of the vinyl group in 4-vinylpyridines,
which is further activated by CF3SO3H, we surmised that
introducing into 2-nitrostyrene an additional strong electron-
withdrawing group such as NO2, CF3, or SO2Me may lead to a
highly active vinyl group for the addition reaction (Scheme 3).
Table 3. Optimization of the Reaction Conditions for the
Addition of Aldehydes to 2-Nitrostyrenes
a
b
c
entry
cat (mol %)
solvent
yield (%)
ee (%)
1
2
3
4
5
6
7
8
I (30)
CH3CN
CH3CN
CH3CN
CH3CN
DMF
82
83
85
0
83
92
94
−
70
96
95
97
98
91
89
86
V (30)
IV (30)
II (30)
IV (30)
IV (30)
IV (30)
IV (30)
IV (20)
IV (10)
IV (20)
IV (20)
34
56
73
51
85
65
87
92
THF
CH2Cl2
toluene
CH3CN
CH3CN
CH3CN
CH3CN
d
9
de
,
10
11
12
df
,
dg
,
a
Reaction conditions: unless otherwise specified, see the Experimental
b
c
Section in the Supporting Information. Isolated yields. Determined
by chiral HPLC analysis. MeCN (0.2 mL) was used. The reaction
mixture was stirred for 2 h. 2c (0.4 mmol) was used. 2c (0.3 mmol)
d
e
f
g
was used.
the reaction was performed in DMF, and a significant amount
of self-condensation product from the aldehyde was obtained
(entry 5). Other solvents such as THF, CH2Cl2, and toluene
gave high levels of enantioselectivity but lower yields (entries
6−8). Lowering the loading of catalyst IV from 30 to 20 mol %
and increasing the reaction concentration afforded both high
enantioselectivity and yield (entry 9). Further decreasing the
catalyst loading to 10 mol % led to decrease in reaction yield
and enantioselectivity (entry 10). Moreover, a drop in the ee
value was observed when the 2c:5a ratio was decreased (entries
11 and 12). Therefore, we chose the following reaction
conditions to probe the scope of the reaction: 1.0 equiv of 5a
with 3.0 equiv of 2c in the presence of 20 mol % organocatalyst
IV in CH3CN at rt.
Scheme 3. Catalytic Enantioselective Addition Reactions
with Electron-Deficient Styrenes
c. Reaction Scope. We first examined the impact of the
structural features of aldehydes 2 on the IV-catalyzed process.
As shown in Table 4, the reactions proceeded smoothly in high
yields (65−90%) with excellent levels of enantioselectivity
(93−98% ee). It appears that significant structural variation in
the aldehyde can be tolerated. Linear (entries 2−4) and
branched (entries 5 and 6) systems efficiently participate in the
process. Furthermore, a similar trend was observed with
aldehydes bearing various functional groups (entries 7−12).
For example, aromatic (entries 8 and 9), heterocyclic (entry
10), ester (entry 11), and Boc-protected amino (entry 12)
moieties were included in these studies. Therefore, structurally
diverse chiral arylethyl aldehydes 6 are produced.
Next, we probed the reaction scope with respect to structural
variation of the aromatic system 5 (Table 5). In addition to 2,4-
dinitrobenzene as a reliable electron acceptor (entry 1), 2-nitro-
3-trifluoromethyl and 2-nitro-4-methylsulfonyl were also
effective ones (entries 2 and 3). High enantioselectivities (96
and 94% ee, respectively) and good yields (57 and 63%) were
obtained. It should be noted that 30 mol % IV and 3.0 equiv of
2c added in three portions were required for efficient
transformation. This may be attributed to the weaker
electron-withdrawing capacity of CF3− and MeSO2− compared
Such activation may sufficiently polarize the vinyl moiety to
enable the addition reaction with aldehydes. Subsequently, a
chiral enamine formed in situ from its corresponding aldehyde
precursor as an electron donor could be added to the CC
double bond.
b. Exploration and Optimization of the Reaction
Conditions. In the exploratory study, we conducted a model
reaction between 2,4-dinitro-1-vinylbenzene (5a) (0.2 mmol)
and n-hexanal (2c) (0.6 mmol) in the presence of 30 mol %
organocatalyst I in CH3CN at rt (Table 3). To our delight, the
process was complete in 30 min and gave the desired alkylation
product 6a in high yield with good enantioselectivity (entry 1).
The more bulky catalysts V and IV significantly improved the
enantioselectivity from 83% to 92% and 94%, respectively
(entries 2 and 3), while II failed to promote this process (entry
4). Probing the solvent effects with catalyst IV revealed that a
lower reaction yield and enantioselectivity were obtained when
D
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Journal of the American Chemical Society
Article
Table 4. Scope of the IV-Catalyzed Enantioselective
a
Alkylation of Vinylarenes
b
c
entry
1
R, 6
n-C4H9, 6a
yield (%)
ee (%)
85
68
90
92
65
82
84
83
84
86
90
76
98
94
95
97
96
97
94
95
93
93
95
95
d
2
C2H5, 6b
e
3
n-C6H13, 6c
e
4
df
,
n-C8H17, 6d
5
6
i-Pr, 6e
e
cyclohexyl, 6f
Bn, 6g
7
8
4-MeOC6H4CH2, 6h
4-ClC6H4CH2, 6i
2-furanyl, 6j
Figure 2. X-ray crystal structure of compound 7.
9
10
11
12
e
synthetic building blocks in organic synthesis. To probe the
utility of the chiral pyridine adducts produced from this
addition process, we developed a synthetic approach to the
important chiral intermediate 9, which serves as a key
component of the synthesis of L-734,217, a potent fibrinogen
receptor antagonist (Scheme 4).21 The reported synthetic
MeO2C(CH2)3, 6k
BocNH(CH2)4, 6l
d
a
Reaction conditions: unless otherwise specified, see footnote a of
Table 3 and the Experimental Section in the Supporting Information.
b
c
d
Isolated yields. Determined by chiral HPLC analysis. Catalyst (30
e
f
mol %) was used. The reaction finished in 20 min. 5a (0.4 mmol)
and aldehyde (1.2 mmol) were used.
Scheme 4. Synthesis of Chiral Intermediate 9 Leading to L-
734,217
Table 5. Scope of IV-Catalyzed Enantioselective α-
Arylethylation of n-Hexanal with Different Styrenes
a
method relies on resolution, and the highest yield for the
synthesis of this chiral intermediate was very low (ca. 26%).
The strategy we developed is much more efficient, involving
one single purification operation. The required chiral aldehyde
ent-3j was rapidly accessed from simple 4-vinylpyridine 1a and
the N-Cbz-protected aldehyde precursor in the presence of
CF3SO3H (0.5 equiv) and ent-IV (10 mol %). The resulting
crude product was directly used for the subsequent oxidation
without purification. Treatment of the aldehyde with the
oxidant NaClO2 and NaH2PO4 furnished the corresponding
acid. After Pd-catalyzed hydrogenation to remove the Cbz
group, intramolecular cyclization of the amine and the
carboxylic acid using 1-ethyl-3-(3-dimethylaminopropyl)-
carbodiimide (EDCI) as a coupling reagent afforded chiral
lactam 9 in 68% yield for the total four-step transformation
without isolation of these intermediates. It is noted that no ee
erosion was observed in these conversions. By means of the
reported procedures, the lactam can be readily converted to the
target L-734,217 in three steps.21
a
Reaction conditions: unless otherwise specified, see the Experimental
b
c
Section in the Supporting Information. Isolated yields. Determined
by chiral HPLC analysis. Catalyst (30 mol %) was used. Three 1.0
equiv portions of aldehyde were added at 30 min intervals; the total
reaction time was 90 min. The product 6 was directly reduced to the
d
e
f
g
alcohol 6′ by BH3 for chiral HPLC analysis. Three 1.0 equiv portions
of aldehyde were added at 10 min intervals.
with −NO2. Finally, heterocyclic 5-nitro-2-vinylpyridine was an
effective acceptor, providing a high yield with high
enantioselectivity under the optimized reaction conditions
(entry 4). The absolute configurations of the products were
determined on the basis of single-crystal X-ray diffraction
analysis of compound 7 derived from aldehyde 6i by two-step
conversion (Figure 2; alos see the Supporting Information).20
3. Synthetic Applications. a. Synthesis of Key Inter-
mediate 9 of Fibrinogen Receptor Antagonist L-734,217
from Chiral Pyridine Adducts. Chiral pyridines are versatile
E
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b. Synthetic Elaboration of Chiral Adducts 6. The strong
electron-withdrawing nitro group(s) on the aromatic ring is
essential for creating highly active electronic acceptors in the
IV-promoted α-arylethylation of aldehydes. Nevertheless, from
the synthetic utility point of view, the nitro moiety should be
conveniently transformed into new functionalities. Therefore,
we carried out studies using products 6a and 6m as examples
(Schemes 5 and 6).
The BH3-mediated reduction of aldehyde 6a gave the
corresponding alcohol, which was then converted to esters 10
and 12 in high yields by treatment with AcCl and TsCl,
respectively (Scheme 5). Pd-catalyzed reduction of both nitro
By means of similar strategies, the aldehyde was converted to
ester 14 in two steps by reaction with BH3 and then AcCl.
Hydrogenation of the nitro moiety catalyzed by Pd/C offered
an amine. Diazotization of the amine in the presence of NaNO2
under acidic conditions with reflux led to denitronation to
afford compound 15 in 73% yields in two steps. The nitro
group could also be transferred to iodide using a similar
protocol in the presence of KI, affording 16 in 76% yield. In
these transformations, only slight racemization was observed.
4. Mechanistic Studies. Singerman and Danishefsky
proposed a cycloaddition pathway involving pyridylcyclobutane
intermediates for the conjugate addition reactions of enamines
with 2- and 4-vinylpyridines.14a The intermediates were then
observed by Gray and co-workers only with enamines of α,α-
diasubstituted aldehydes and only under conditions of acid
catalysis.14b Preformed enamines were used in their cases, while
we employed a catalytic process for in situ formation of the
enamines. We questioned whether the catalytic process
involved a similar cycloaddition process with the pyridylcyclo-
butane intermediate. Therefore, 1H NMR studies were
performed using the reaction of n-hexanal 2c and 4-vinyl-
pyridine 1a as an example under the standard reaction
conditions we identified, except for the use of DMSO-d6
instead of DMF-d7 as the reaction medium (Figure 3).
Scheme 5. Synthetic Elaboration of Compound 6a
groups in 10 with H2 gave rise to amine 11 in 91% yield. The
amine formed by reduction of 12 underwent a cyclization in the
presence of K2CO3 to afford benzazepine 13, one member of a
class of biologically important “privileged” molecules.22 It is
noteworthy that in these transformations, no or minimal
racemization was observed.
Furthermore, the nitro group can be removed or transformed
to H or I, as demonstrated using compound 6m (Scheme 6).
Figure 3. 1H NMR studies of the reaction of 4-vinylpyridine (1a) with
n-hexanal (2c) cocatalyzed by IV and TfOH. (a) Spectrum of a
mixture of 1a (0.5 mmol) and TfOH (0.25 mmol) in DMSO-d6 (0.5
mL) after 1 h. (b−d) A mixture of 1a (0.5 mmol), TfOH (0.25
mmol), and DMSO (0.17 mmol) in DMSO-d6 (0.5 mL) was shaken
for 10 min, and then catalyst IV (0.05 mmol) and 2c (0.5 mmol) were
added; the reaction was monitored by 1H NMR spectroscopy after (b)
15 min, (c) 4 h, and (d) 26 h.
Scheme 6. Synthetic Elaboration of Compound 6m
However, we did not observe the pyridylcyclobutane
intermediate. Instead the pyridinium trimer species B (as a
mixture of protonated and unprotonated forms) was formed on
the basis of 1H NMR analysis. The unexpected outcome
prompted us to carry out a deeper investigation. First, to verify
the formation of the intermediate from TfOH-catalyzed
trimerization of 4-vinylpyridine, we performed the experiment
by simply mixing 1a (0.5 mmol) with TfOH (0.25 mmol) in
1
DMSO-d6 (0.5 mL) and then shaking the mixture for 1 h. H
NMR monitoring (Figure 3a). It was found that the trimer of 4-
vinylpyridinium ion, B, was quickly formed as the dominant
species with the copresence of the protonated form of 4-
F
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vinylpyridine, A, which was first observed by Fife and
colleagues.23 The trimer structure B was determined by 3:8
ratio of the vinyl protons to the alkyl protons. Without TfOH,
no B was produced, indicating that the acid plays a key role in
the formation of B through A. To confirm that B was the actual
active electrophile for the direct addition reaction with the in
situ-formed chiral enamine without the involvement of a
pyridylcyclobutane, we added catalyst IV and aldehyde 2c into
CONCLUSION
■
We have developed a synergistic catalysis strategy to realize for
the first time a catalytic asymmetric direct addition of simple
aldehydes to 4-vinylpyridines. Activation of weakly electrophilic
4-vinylpyridines by the Brønsted acid CF3SO3H and aldehydes
by the chiral diphenylprolinol TBDMS ether-catalyzed
formation of nucleophilic enamines in a cooperative manner
enables the new, previously unattainable highly enantioselective
addition process. The power of the addition process is
underscored by its mild reaction conditions and high efficiency
in the production of synthetically valued chiral pyridines with a
broad substrate scope. 1H NMR studies of the reaction process
revealed a trimeric 4-vinylpyridinium species as the actual
highly active electrophile for the direct addition of the chiral-
amine-promoted nucleophilic enamine. Moreover, inspired by
the similar electronic natures of pyridine and nitrobenzene, we
have successfully expanded the reaction scope beyond 4-
vinylpyridines, realizing the novel chiral diphenylprolinol
TBDMS ether-promoted, highly enantioselective direct addi-
tion of aldehydes to substituted 2-nitrostyrenes without the use
of CF3SO3H as a cocatalyst. In this approach, introducing a
strong electron-withdrawing group such as NO2, CF3, SO2Me,
etc. on 2-nitrostyrene creates a highly electrophilic vinyl moiety,
which displays reactivity comparable to that of protonated 4-
vinylpyridines in the chiral-amine-catalyzed addition of
aldehydes. The processes exhibit a broad substrate scope for
both electron donors and acceptors. While the electron-
withdrawing nitro group is essential for activation of the vinyl
group, we have demonstrated that it can be readily transformed
to diverse functionalities. Furthermore, a chiral pyridine
adducts serves as a key building block in the synthesis of the
fibrinogen receptor antagonist L-734,217. Further exploration
of the strategy and the application of this methodology in the
synthesis of biologically relevant molecules are under
investigation in our laboratory.
1
the mixture and monitored the reaction process by H NMR
spectroscopy (Figure 3b). The cyclobutane intermediate was
1
not observed by H NMR analysis. Trimer B disappeared
rapidly and was transformed to the dimeric adduct E. After 4 h,
both A and B were consumed, and the new protonated product
3′ was generated. The ratio of E to 3′ was about 1:1 (Figure
3c). This suggests that 3′ was produced from E. Furthermore,
the transformation of E to 3′ seems to be the rate-determining
step (Figure 3d). Even after 48 h of reaction, there was still
about 10% E left (see the Supporting Information).
On the basis of the 1H NMR experimental studies of the IV-
catalyzed conjugate addition of 2c to 1a, we propose a catalytic
cycle for this reaction (Scheme 7). TfOH catalyzes the
Scheme 7. Proposed Catalytic Cycle for IV-Catalyzed
Addition of Aldehydes to 4-Vinylpyridines
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details, spectroscopic data, and crystallographic
data for 4 and 7 (CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
formation of the more electrophilic trimeric pyridinium salt B
from protonated 4-vinylpyridinium species A. The resulting
highly active electrophile enables the addition of the
nucleophilic enamine created from the chiral amine catalyst
IV and the corresponding aldehyde to form the adduct D. Since
water is employed as the cosolvent for the reaction, D is facilely
hydrolyzed to recycle the catalyst and concurrently release the
dimer aldehyde adduct E and 1a. Finally, the aldehyde salt
product 3′ and 1a are slowly released from E. Workup of the
reaction mixture by treatment with a mixture of aqueous
Na2CO3 and EtOAc gives a relatively clean 1H NMR spectrum
of product 3. We found that under the same reaction
conditions, mixing 2-vinylpyridine with TfOH in DMSO-d6
did not lead to the expected trimer of 2-vinylpyridine. This can
help to rationalize its poor reactivity in the IV-cocatalyzed
process. Moreover, the acidity of the acid is critical for the
■
Corresponding Authors
*wwang@unm.edu
*hli77@ecust.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support of this research from the program for
Professor of Special Appointment (Eastern Scholar) at
Shanghai Institutions of Higher Learning (201226 to H. Li),
the National Natural Science Foundation of China (21372073
to W.W.), the Fundamental Research Funds for the Central
Universities and East China University of Science and
Technology (startup funds to H. Li and W.W.), the China
111 Project (Grant B07023 to H. Li and W.W.), the Chinese
Scholarship Council (X.L.) and the National Science
Foundation (CHE-1057569 to W.W.) is gratefully acknowl-
edged.
1
formation of trimeric pyridinium salt B. On the basis of H
NMR studies, strong acids such TfOH and nitric acid can
promote the formation of B, while it is difficult for the weak
acid AcOH to do so.
G
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Z.-H. Chem. Soc. Rev. 2013, 42, 1337. (l) Ceban, V.; Putaj, P.; Meazza,
M.; Pitak, M. B.; Coles, S. J.; Vesley, J.; Rios, R. Chem. Commun. 2014,
50, 7447. (m) Meazza, M.; Ceban, V.; Pitak, M. B.; Coles, S. J.; Rios,
R. Chem.Eur. J. 2014, 20, 16853.
REFERENCES
■
(1) http://www.pharmacytimes.com/publications/issue/2013/
July2013/Top-200-Drugs-of-2012 (accessed Oct 29, 2014).
(2) (a) Qiao, J. X. In Heterocyclic Chemistry in Drug Discovery; Li, J. J.,
Ed.; Wiley: Hoboken, NJ, 2013; p 398. (b) Chaubey, A.; Pandeya, S.
N. Asian J. Pharm. Clin. Res. 2011, 4, 5. (c) Kiuru, P.; Yli-Kauhaluoma,
J. In Heterocycles in Natural Product Synthesis; Majumdar, K. C.,
Chattopadhyay, S. K., Eds.; Wiley-VCH: Weinheim, Germany, 2011; p
267. (d) Henry, G. D. Tetrahedron 2004, 60, 6043. (e) Joule, J. A.;
Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell Science: Cambridge,
U.K., 2000; p 63. (f) Michael, J. P. Nat. Prod. Rep. 2005, 22, 627.
(g) Kim, J.; Movassaghi, M. Chem. Soc. Rev. 2009, 38, 3035. (h) Bagley,
M. C.; Dale, J. W.; Merritt, E. A.; Xiong, X. Chem. Rev. 2005, 105, 685.
(16) The studies by Klumpp show that acids can activate
vinylpyridines in the addition reaction with benzene. See: (a) Zhang,
Y.; Sheets, M. R.; Raja, E.; Boblak, K.; Klumpp, D. A. J. Am. Chem. Soc.
2011, 133, 8467. (b) Zhang, Y.; Briski, J.; Zhang, Y.; Rendy, R.;
Klumpp, D. A. Org. Lett. 2005, 7, 2505.
(17) For a review of enamine catalysis, see: Mukherjee, S.; Yang, J.
W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471.
(18) CCDC-1031100 contains the supplementary crystallographic
data for compound 4. These data can be obtained from the Cambridge
Crystallographic Data Centre free of charge via www.ccdc.cam.ac.uk.
(19) Pietrzyk, A.; Wiley, R.; MoDaniel, D. J. Org. Chem. 1957, 22, 83.
(20) CCDC-966469 contains the supplementary crystallographic
data for compound 7. These data can be obtained from the Cambridge
Crystallographic Data Centre free of charge via www.ccdc.cam.ac.uk.
(21) Chung, J. Y. L.; Hughes, D. L.; Zhao, D.; Song, Z.; Song, Z.;
Mathre, D. J.; Ho, G.-J.; McNamara, J. M.; Douglas, A. W.; Reamer, R.
A.; Tsay, F.-R.; Varsolona, R.; McCauley, J.; Grabowski, E. J. J.; Reider,
P. J. J. Org. Chem. 1996, 61, 215.
(i) Mishra, A.; Ma, C.-Q.; Bauerle, P. Chem. Rev. 2009, 109, 114.
(3) (a) Chelucci, G. Coord. Chem. Rev. 2013, 257, 1887. (b) Kilah, N.
L.; Beer, P. D. Top. Heterocycl. Chem. 2010, 24, 301.
̈
(4) (a) Bull, J. A.; Mousseau, J. J.; Pelletier, G.; Charette, A. B. Chem.
Rev. 2012, 112, 2642. (b) Nakao, Y. Synthesis 2011, 3209. (c) Hill, M.
D. Chem.Eur. J. 2010, 16, 12052.
(5) (a) Bergmann, E. D.; Ginsburg, D.; Pappo, R. Org. React. 1959,
10, 179. (b) Giam, C. S. In Pyridine and Its Derivatives; Abramovitch,
R. A., Ed.; Wiley: New York, 1974; Suppl. part 3, p 112. (c) Jung, M.
E. In Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon
Press: Oxford, U.K., 1991; Vol. 4, pp 10 and 77. (d) Klumpp, D. A.
Synlett 2012, 23, 1590.
(22) DeSimone, R. A.; Currie, R. A.; Mitchell, S. A.; Darrow, J. W.;
Pippin, D. A. Comb. Chem. High. Throughput Screening 2004, 7, 473.
(23) Fife, W. K.; Ranganathan, P.; Zeldin, M. J. Org. Chem. 1990, 55,
5610.
(6) Gray, A. P.; Archer, W. P. J. Am. Chem. Soc. 1957, 79, 3554.
(7) (a) Leonard, F.; Tschannen, W. J. Med. Chem. 1966, 9, 140.
(b) Gimbert, C.; Lumbierres, M.; Marchi, C.; Moreno-Manas, M.;
Sebastian, R. M.; Vallribera, A. Tetrahedron 2005, 61, 8598. (c) Siperko,
L. G.; Smith, F. X. Synth. Commun. 1979, 9, 383. (d) Yoneda, A.;
Newkome, G. R.; Theriot, K. J. J. Organomet. Chem. 1991, 401, 217.
(e) Dryanska, V.; Ivanov, C. Synthesis 1983, 143. (f) Devaux, G.;
Nuhrich, A.; Dufour, R.; Canellas, J. Bull. Soc. Pharm. Bordeaux 1975,
114, 70.
(8) (a) Han, X.; Civiello, R. L.; Mercer, S. E.; Macor, J. E.;
Dumowchik, G. E. Tetrahedron Lett. 2009, 50, 386. (b) Tucci, F. C.;
Zhu, Y.-F.; Guo, Z.; Gross, T. D.; Connors, P. J., Jr.; Struthers, R. S.;
Reinhart, G. J.; Saunders, J.; Chen, C. Bioorg. Med. Chem. Lett. 2003,
13, 3317. (c) Safak, C.; Erdogan, H.; Palaska, E.; Sunal, R.; Duru, S. J.
Med. Chem. 1992, 35, 1296. (d) Taylor, E. C.; Martin, S. F. J. Am.
Chem. Soc. 1972, 94, 6218.
(9) (a) Klemm, L. H.; McCoy, D. R.; Shabtai, J.; Kiang, W. K. T. J.
Heterocycl. Chem. 1969, 6, 813. (b) Momose, Y.; Meguro, K.; Ikeda,
H.; Hatanaka, C.; Oi, S.; Sohda, T. Chem. Pharm. Bull. 1991, 39, 1440.
(10) Houpis, I. N.; Lee, J.; Dorziotis, I.; Molina, A.; Reamer, B.;
Volante, R. P.; Reider, P. J. Tetrahedron 1998, 54, 1185.
(11) Rupnicki, L.; Saxena, A.; Lam, H. W. J. Am. Chem. Soc. 2009,
131, 10386.
(12) (a) Pattison, G.; Piraux, G.; Lam, H. W. J. Am. Chem. Soc. 2010,
132, 14373. (b) Saxena, A.; Lam, H. W. Chem. Sci. 2011, 2, 2326.
(13) Friedman, A. A.; Panteleev, J.; Tsoung, J.; Huynh, V.; Lautens,
M. Angew. Chem., Int. Ed. 2013, 52, 9755.
(14) For noncatalytic examples of reactions between enamines and
vinyl heterocycles, see: (a) Singerman, G.; Danishefsky, S. Tetrahedron
Lett. 1964, 5, 2249. (b) Heitmeier, D. E.; Hortenstine, J. T.; Gray, A. P.
J. Org. Chem. 1971, 36, 1449.
(15) The main efforts have been focused on the organocatalytic- and
transition-metal-cocatalyzed reactions. For reviews, see: (a) Shao, Z.;
Zhang, H. Chem. Soc. Rev. 2009, 38, 2745. (b) de Armas, P.; Tejedor,
D.; García-Tellado, F. Angew. Chem., Int. Ed. 2010, 49, 1013.
(c) Zhong, C.; Shi, X.-D. Eur. J. Org. Chem. 2010, 2999. (d) Rueping,
M.; Koenigs, R. M.; Atodiresei, I. Chem.Eur. J. 2010, 16, 9350.
(e) Zhou, J. Chem.Asian J. 2010, 5, 422. (f) Han, Z.-Y.; Wang, C.;
Gong, L.-Z. In Science of Synthesis: Asymmetric Organocatalysis;
Maruoka, K., Ed.; Georg Thieme Verlag: Stuttgart, Germany, 2012;
Vol. 2, p 697. (g) Loh, C. C. J.; Enders, D. Chem.Eur. J. 2012, 18,
10212. (h) Allen, A. E.; MacMillan, D. W. C. Chem. Sci. 2012, 3, 633.
(i) Patil, N. T.; Shinde, V. S.; Gajula, B. Org. Biomol. Chem. 2012, 10,
211. (j) Pellissier, H. Tetrahedron 2013, 69, 7171. (k) Du, Z.-T.; Shao,
H
DOI: 10.1021/ja511143b
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