Highly enantioselective intermolecular alkylation of aldehydes with alcohols by cooperative catalysis of diarylprolinol silyl ether with Bronsted acid

Article abstract of DOI:10.1002/asia.201100692

Two cooperative systems: I/2,3,4-trihydroxybenzoic acid and I/TfOH effect highly enantioselective intermolecular α-alkylation of aldehydes. These systems afford functionalized aldehydes in high yields, and with excellent ee and de values with broad substrate scope (see scheme; R¹=alkyl, R²,R³=aryl, or R²=ferrocenyl, R ³=phenyl, or R²=indolyl, R³=phenyl).

Full text of DOI:10.1002/asia.201100692

COMMUNICATION
DOI: 10.1002/asia.201100692
Highly Enantioselective Intermolecular Alkylation of Aldehydes with
Alcohols by Cooperative Catalysis of Diarylprolinol Silyl Ether with
Brønsted Acid
[
a, b]
[a]
[a]
Jian Xiao,
Kai Zhao, and Teck-Peng Loh*
[10]
The catalytic enantioselective intermolecular a-alkylation
design, we envisioned that highly enantioselective alkyla-
tion of aldehydes could be realized through reaction of alde-
hydes with stabilized carbocations, generated in situ from an
activated alcohol under Lewis acidic or Brønsted acidic con-
ditions in the presence of a chiral secondary amine catalyst.
The obvious advantage of this strategy is the generation of
water as the single byproduct, thereby making it an efficient,
economical, and environmentally valuable process
(Scheme 1).
However, designing such a catalytic system is further com-
plicated by the susceptibility of a Lewis basic amine catalyst
towards an unproductive alkylation reaction and self-
quenching reaction with the acid, deactivation of the acid
through the reaction with the water byproduct, as well as
of aldehydes is one of the long-standing problems in asym-
[1]
metric catalysis. The conventional organometallic methods
are plagued by the need of preformed metal enolates, stoi-
chiometric amounts of chiral auxiliaries, as well as difficulty
in controlling the reaction with many undesirable side reac-
[2]
tions. This elusive reaction was soon deemed as “the Holy
[1b]
Grail” reaction for asymmetric aminocatalysis. Although
List and Vignola have reported a highly enantioselective or-
ganocatalytic intramolecular version of this reaction using
an alkyl halide as the alkylating agent, the corresponding in-
[3]
termolecular version has been proven difficult. On the
[4]
other hand, in situ-generated stable carbocations have
been employed as alternative alkylating agents to accom-
plish this challenging goal as pioneered by the groups of
potentially severe racemization of the product. Despite the
[5]
[11]
Petrini, Melchiorre, and Cozzi. It was not until recently
that some breakthroughs were achieved, in which high enan-
tioselectivities were observed by using Jacobsenꢀs hydrogen-
report that diarylprolinol silyl ether
this type of reaction,
was inefficient for
[5,8a]
we envisaged the use of cooperative
catalysis by combining Lewis or Brønsted acid catalysis with
[6]
[12]
bond catalysis through anion binding and MacMillanꢀs
SOMO catalysis or photoredox catalysis combination strat-
organocatalysis to solve the reactivity problem.
Herein,
we report the efficient cooperative catalytic systems, involv-
ing diarylprolinol silyl ether I with Brønsted acids to effect
the highly enantioselective a-alkylation of aldehydes.
Initially, the model reaction between butyraldehyde and
xanthydrol was carried out in the presence of different
metal catalysts (20–50 mol%) to screen for a suitable cata-
lytic system. Expectantly, the control reaction in dichloro-
methane using I without any acid did not give the desirable
[
7]
egy. Despite these significant advances, the highly enantio-
selective a-alkylation of aldehydes is rare and development
of new systems, which work with a wide variety of substrates
[8]
still remains a great challenge. With our earlier successes
in employing carbocationic intermediates to perform various
[9]
organic transformations as well as new organocatalyst
[
a] Dr. J. Xiao, K. Zhao, Prof. T.-P. Loh
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University
Singapore, 637371
Fax :
ACHTUNGTRENNUNG( +65)6791-1961
E-mail: teckpeng@ntu.edu.sg
[
b] Dr. J. Xiao
Dalian Institute of Chemical Physics
The Chinese Academy of Sciences
Dalian 116023 (P. R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201100692.
Scheme 1. Asymmetric alkylation of aldehydes with alcohols by coopera-
tive catalysis.
2890
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 2890 – 2894

Table 1. Screening of the acids.
successful example of a pyrrolidine-based catalyst,
capable of effecting the highly enantioselective
asymmetric alkylation of aldehydes and overcomes
the fallacy of the failure of pyrrolidine-based cata-
[5,8a]
lysts in this elusive reaction.
With the optimized conditions in hand, we pro-
ceeded to examine the substrate scope using I/2,3,4-
trihydroxybenzoic acid (2–5 mol%) as the catalytic
system in the reaction of xanthydrol with different
aldehydes (Table 2, entries 1–9). Gratifyingly, in all
cases, the desired products were obtained in good
to high yields with excellent enantioselectivities
[
a]
[b]
[c]
Entry
Acids
–
x [mol%]
t [h]
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
9
0
12
12
12
12
12
12
12
12
12
6
48
6
6
24
12
8
0
0
0
0
0
0
0
–
–
–
–
–
–
–
33
86
–
(
91–98% ee), thus making this methodology highly
InCl
FeCl
LaCl
In(OTf)
Zn(OTf)
La(OTf)
CAN
3
50
50
50
50
50
50
50
50
10
10
10
10
10
10
10
10
10
5
valuable in view of the biochemical and pharma-
3
[13]
3
ceutical importance of xanthene derivatives. With
propionaldehyde, bis(4-(dimethylamino)phenyl)me-
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
3
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
2
[14]
thanol 2b
gave the desired product 3j in 87%
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
3
yield and 91% ee (Table 2, entry 10). Given the
24
59
trace
trace
56
48
72
67
80
64
92
91
83
CuCl
CSA
2
vital importance of ferrocene-based chiral ligands
10
11
12
13
14
15
16
17
18
19
20
[15]
and catalysts in asymmetric catalysis and the key
C
6
H
5
CO
2
H
–
role of the indole skeleton in natural products and
TFA
p-TSA
79
94
93
95
90
94
95
95
96
[16]
pharmaceutical chemisty, we proceeded to inves-
tigate the reactions of ferrocene- and indole-based
substrates. The results are summarized in Table 3.
To our surprise, the catalytic system I/2,3,4-trihy-
droxybenzoic acid did not work for ferrocene- and
indole-based substrates. Fortunately, it was found
that I/TfOH (TfOH=trifluouromethanesulfonic
acid), on the other hand, was an effective catalytic
2-NO
3-NO
4-NO
2
2
2
-C
6
H
H
H
4
4
4
CO
CO
CO
2
2
2
H
H
H
-C
-C
6
6
4-CF
3
-C
6
H
4
CO
2
H
6
6
12
15
[
[
[
d]
e]
f]
(HO)
(HO)
(HO)
3
3
3
C
C
C
6
6
6
H
H
H
2
2
2
CO
CO
CO
2
H
2
H
2
H
2
[
a] Reactions were conducted with butyraldehyde (0.4 mmol), xanthydrol (0.1 mmol),
catalyst I (0.01 mmol), and acid in CH Cl
isolated product. [c] ee was determined by chiral HPLC on a chiral stationary phase.
d] 2,3,4-Trihydroxybenzoic acid. [e] catalyst I (5 mol%) was used. [f] Catalyst
2 mol%) was used. CAN=ceric ammonium nitrate.
2
2
(0.5 mL) at room temperature. [b] Yield of system for these two important substrates. For fer-
rocene-based substrates, high yields and ee were ob-
served (3k and 3l). In sharp comparison, for
Cozziꢀs system, 90 mol% of MacMillan’s catalyst
was necessary to drive the reaction to completion
and the product was obtained in low yield and mod-
[
(
I
[5b]
product (Table 1, entry 1). Subsequently, a wide variety of
commonly used Lewis acids were added in addition to I. It
was found that the commonly used Lewis acids such as
indium salts, lanthanide complexes, and zinc complexes are
all ineffective for this transformation (Table 1, entries 2–8).
erate ee. To our delight, for indole-based substrates, the I/
TfOH system can also catalyze reaction of substrate 2d
(without 2-substitution) with aldehydes to provide 3m and
3n in good yields (70% yield and 69% yield, respectively),
excellent enantioselectivities (97–99% ee), and excellent
diastereoselectivities (anti/syn=93:7 for 3m, anti/syn=92:8
for 3n). In strong contrast with Melchiorreꢀs report on the
asymmetric a-alkylation of aldehydes through vinylogous
iminium ion intermediates generated by indole deriva-
It is interesting to note that CuCl catalyzed the reaction to
2
afford the desired product in good enantioselectivity, albeit
in moderate yield (Table 1, entry 9). Next, we turned our at-
tention to examine if Brønsted acids can work well with or-
ganocatalyst I. During our screening of a different combina-
tion of Brønsted acids with I, it was found that good yields
and high enantioselectivities (90%–95% ee) could be ob-
tained for most of the electron-deficient benzoic acids
[17]
tives, substrate 2d gave the product in only 11% ee and
(
Table 1, entries 14–17). However, no reaction was observed
with camphorsulfonic acid (CSA) and benzoic acid (Table 1,
entries 10–11). Trifluoroacetic acid (TFA) and p-TSA can
also afford satisfactory results (Table 1, entries 12–13).
Among them, 2,3,4-trihydroxybenzoic acid was found to
give the best results and the catalyst loading of organocata-
lyst I and acid could be decreased to as low as 2 mol% with-
out compromising the reactivity and enantioselectivity
(
Table 1, entries 18–20). Therefore, our method provides the
Scheme 2. Transition-state model for asymmetric alkylation of aldehydes.
Chem. Asian J. 2011, 6, 2890 – 2894
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
2891

Highly Enantioselective Intermolecular Alkylation of Aldehydes
COMMUNICATION
Table 2. Substrate scope.
pyrrolidine-based chiral secon-
dary amines did not work at
all.
[5a]
The stereoinduction could be
rationalized by the following
transition-state
model
(
Scheme 2). The bulky silyl
ether functional group efficient-
ly shielded the Re face to force
the in situ-generated carbocat-
ion attack from the Si face to
afford the desired product with
R configuration
[
a]
[b]
[c]
Entry
1
Substrates
Product
x [mol%]
t [h]
Yield [%]
50
ee [%]
91
2
36
In summary, we have devel-
oped two cooperative systems,
I/2,3,4-trihydroxybenzoic acid
and I/TfOH, to circumvent the
elusive asymmetric intermolec-
ular a-alkylation of aldehydes.
Both of these unprecedented
systems could afford the de-
sired enantioenriched function-
alized aldehydes in high yields,
2
3
4
5
2
2
2
2
15
12
12
12
83
84
85
92
96
96
97
96
excellent
enantioselectivities,
and good diastereoselectivities
with broad substrate scope. Par-
ticularly, the ferrocene deriva-
tives and indole derivatives
could be synthesized in good
yields and excellent enantiose-
lectivities by use of our catalyst
system I/TfOH; this makes
these methods extremely useful
in asymmetric synthesis and
natural product chemistry.
6
7
2
2
12
12
82
80
96
98
Experimental Section
General Procedure for the Asymmetric
a-Alkylation of Aldehydes with
Alcohols
8
9
5
24
85
98
To a solution of alcohol 2 (0.25 mmol)
in 1mL CH
2 2
Cl was added catalyst I
(
0.005 mmol) and 2,3,4-trihydroxyben-
zoic acid (0.005 mmol) prior to the ad-
dition of aldehyde (1 mmol). The re-
sulting solution was stirred at room
temperature for the indicated time.
Upon the completion of reaction, as
monitored by TLC, MeOH (1 mL)
5
5
12
12
76
87
96
91
1
0
4
was added. NaBH was then cautiously
added to the yellow solution and
stirred at room temperature for 0.5 h.
[
a] Unless otherwise noted, reactions were conducted with aldehyde 1 (1 mmol), alcohol 2 (0.25 mmol), cata-
lyst I (0.005 mmol), 2,3,4-trihydroxybenzoic acid (0.005 mmol) in CH Cl (1 mL) at room temperature.
b] Yield of isolated product. [c] ee was determined by chiral HPLC on a chiral stationary phase. The absolute
The
quenched with water (1 mL) and HCl
1m) was added. The organic phase
reaction
was
subsequently
2
2
[
(
configuration was determined by comparison of optical rotations and chiral HPLC retention times of the alde-
hyde product with those reported in the literature (Refs. [5] and [8]).
was separated and the aqueous solu-
tion was extracted with ethyl acetate
(
2 mLꢂ3). The combined organic
2892
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ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 2890 – 2894

T.-P Loh et al.
Table 3. Substrate scope.
[
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[
(
(
a] Reactions were conducted with aldehyde
1
(1 mmol), alcohol
0.25 mmol), catalyst I (0.025 mmol), and TfOH (0.025 mmol) in CH
1 mL) at room temperature. [b] Yield of isolated product. [c] Diastereomeric
2
Cl
2 2
ratio (anti:syn) was determined by chiral HPLC on a chiral stationary phase.
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[
lute configuration was determined by comparison of chiral HPLC retention
time of the aldehyde product with those reported in the literature (Ref. [5]).
TfOH=trifluouromethanesulfonic acid.
[
4
phases were washed with brine and dried over anhydrous MgSO . The
solvent was removed under reduced pressure and the resulting yellow oil
was purified by preparative chromatography or column chromatography
(
hexane/ethyl acetate=4:1) to afford the desired product 3. Both the
1
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·
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·
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Chem. Asian J. 2011, 6, 2890 – 2894
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
2893

Highly Enantioselective Intermolecular Alkylation of Aldehydes
COMMUNICATION
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[
[
[
14] For the other activated alcohols, such as diphenylmethanol, bis(4-
methoxyphenyl)methanol and triphenylmethanol do not work at all,
Received: August 16, 2011
Published online: September 26, 2011
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