N-triflylthiophosphoramide catalyzed enantioselective mukaiyama aldol reaction of aldehydes with silyl enol ethers of ketones

Article abstract of DOI:10.1021/ol100233t

The first Bronsted acid catalyzed asymmetric Mukaiyama aldol reaction of aldehydes using silyl enol ethers of ketones as nucleophiles has been reported. A variety of aldehydes and silyl enol ethers of ketones afforded the aldol products in excellent yield

Full text of DOI:10.1021/ol100233t

ORGANIC
LETTERS
2010
Vol. 12, No. 11
2476-2479
N-Triflylthiophosphoramide Catalyzed
Enantioselective Mukaiyama Aldol
Reaction of Aldehydes with Silyl Enol
Ethers of Ketones
Cheol Hong Cheon and Hisashi Yamamoto*
Department of Chemistry, The UniVersity of Chicago, 5735 South Ellis AVenue,
Chicago, Illinois 60615
yamamoto@uchicago.edu
Received March 4, 2010
ABSTRACT
The first Brønsted acid catalyzed asymmetric Mukaiyama aldol reaction of aldehydes using silyl enol ethers of ketones as nucleophiles has
been reported. A variety of aldehydes and silyl enol ethers of ketones afforded the aldol products in excellent yields and good to excellent
enantioselectivities. Mechanistic studies revealed that the actual catalyst may be changed from the silylated Brønsted acid to the Brønsted
acid itself depending on the reaction temperature.
The addition of silyl enol ethers to carbonyl compounds,
known as the Mukaiyama aldol reaction, has been the subject
of extensive investigation due to the usefulness of products
containing one new carbon-carbon bond and up to two new
stereogenic centers.1,2 Although many successful examples
employing either Lewis acid3 or Lewis base4 catalysts have
been developed for enantioselective Mukaiyama aldol reac-
tions, only a few examples of chiral Brønsted acid catalyzed
enantioselective Mukaiyama aldol reactions have been
reported. Rawal reported a TADDOL catalyzed Mukaiyama
aldol reaction of aldehydes and acylphosphonates with silyl
enol ethers of amides.5 Jørgensen described a chiral bis-
sulfonamide Brønsted acid catalyst in a Mukaiyama aldol
reaction with silyl ketene acetal.6 However, these Brønsted
acid catalyzed asymmetric Mukaiyama aldol reactions gener-
ally required highly activated substrates for both nucleophiles
and electrophiles presumably because of their lower acidities.
Most recently List and co-workers have developed a
disulfonimide derived from BINOL as a new chiral Brønsted
acid catalyst and applied it to an asymmetric Mukaiyama
aldol reaction.7 Although this new catalyst showed potential
to solve the previous problems of the asymmetric Mukaiyama
aldol reaction with weak Brønsted acids, such as limited
substrate scope, this catalyst system still needs to use reactive
silyl ketene acetals as nucleophiles. In addition, the active
(1) For a seminal reference of Mukaiyama aldol reaction, see: Mu-
kaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973, 1011
(2) For reviews, see: Ishihara, K.; Yamamoto, H. In Modern Aldol
Reactions; Mahrwald, R., Ed.; Wiley-VCH, Weinheim, Germany, 2004;
.
(5) (a) McGilvra, J. D.; Unni, A. K.; Modi, K.; Rawal, V. H. Angew.
Chem., Int. Ed. 2006, 45, 6130. (b) Gondi, V. B.; Hagihara, K.; Rawal,
V. H. Angew. Chem., Int. Ed. 2009, 48, 776.
Vol. 2, Chapter 2, p 25
.
(3) Carreira, E. M.; Kvaerno, L. Classics in StereoselectiVe Synthesis;
(6) Zhuang, W.; Poulsen, T. B.; Jørgensen, K. A. Org. Biomol. Chem.
2005, 3, 3284.
Wiley-VCH: Weinheim, Germany, 2009.
(4) Denmark, S. E.; Fujimori, S. In Modern Aldol Reactions; Mahrwald,
R., Ed.; Wiley-VCH: Weinheim, Germany, 2004; Vol. 2, Chapter 7, p 229.
(7) Grac´ıa-Grac´ıa, P.; Lay, F.; Grac´ıa-Grac´ıa, P.; Babalakos, C.; List,
B. Angew. Chem., Int. Ed. 2009, 48, 4363.
10.1021/ol100233t  2010 American Chemical Society
Published on Web 05/13/2010

catalyst in this system was shown to be the silylated Brønsted
acid acting as Lewis acid rather than Brønsed acid itself. To
the best of our knowledge, there have been no reports of
Brønsted acid catalyzed enantioselective Mukaiyama aldol
reaction using less reactive silyl enol ethers of ketones as
nucleophiles.8 Herein, we report the first Brønsted acid
catalyzed asymmetric Mukaiyama aldol reaction of silyl enol
ethers of ketones with simple aldehydes. Moreover, mecha-
nistic studies revealed that the actual catalyst in this system
is the Brønsted acid itself rather than the silylated Brønsted
acid.
Table 1. Optimization of Reaction Conditions
Since Akiyama and Terada’s seminal reports in 2004,9,10
chiral phosphoric acid catalysis to activate π-electrophiles
toward nucleophilic attacks has been one of the growing
fields in asymmetric catalysis.11 Many enantioselective
addition reactions to imines have been achieved with these
chiral Brønsted acids;12 however, successful application of
these acids to reactions through carbonyl group activation
has remained challenging because of their lower reactivi-
ties.13 In order to increase the reactivities of chiral phosphoric
acid catalysts and thus broaden their applicabilities, we have
recently developed chiral N-triflyl oxo-, thio, and seleno-
phosphoramides 1-3 as strong Brønsted acids and success-
fully applied them to organic reactions.14,15 To further extend
the utilities of these acids, we have employed these acids in
the Mukaiyama aldol reaction of a variety of aldehydes with
silyl enol ethers of ketones.
entry
catalyst
temp (°C)
time (h)
yield (%)a
erb
1
2
3
4
5
6
7
8
1
2b
3
rt
rt
rt
rt
rt
rt
rt
-78
-86
-86
-86
48
1
1
1
1
1
1
6
8
NR
96
93
95
96
94
96
95
94
96
95
ND
57:43
55:45
54:46
57:43
65:35
67:33
87:13
89:11
92:8
2a
2c
2d
2e
2e
2e
2e
2e
9
10c
12
16
11c d
92:8
,
a Yield of isolated product. b er was determined by HPLC on OD-H
column. c Toluene/hexanes (1:1) mixture was used as a solvent. d 1 mol %
catalyst was used.
First, we began our investigation with a comparison of
reactivities of these Brønsted acids 1-3 for a Mukaiyama
aldol reaction of benzaldehyde 5a with silyl enol ether of
acetophenone 4a (Table 1). Although these Brønsted acids
showed similar reactivities in the asymmetric protonation
reaction,15 Brønsted acids 1-3 exhibited a dramatic differ-
ence in reactivities toward Mukaiyama aldol reaction (entries
1-3). Brønsted acids 2b and 3 provided the aldol product
6aa in excellent yields in 1 h, whereas Brønsted acid 1 did
not afford any product even after 2 days. Since thiophos-
phoramide 2b gave enantioselectivity slightly better than that
of selenophosphoramide 3, we chose the thiophosphoramide
as a catalyst for further investigation. Next, we optimized
the catalyst structure by examining the effect of the aryl
substituent at 3,3′-position of the binaphthyl scaffold on
enantioselectivity (entries 2, 4-7). Introduction of bulky
aromatic substituents at the para-position of aryl substituents
at the 3,3′-position of the binaphthyl scaffold had a beneficial
effect on enantioselectivity.16 Brønsted acid 2e bearing bulky
9-anthryl at the para-position of the aryl group17 provided
the aldol product in 67:33 enantiomeric ratio (er) (entry 7).
With catalyst 2e, we further examined the effect of size of
the silyl group. Among the silyl groups tested, the TMS
group gave the best enantioselectivity.18 Then, we further
optimized the reaction conditions, such as temperature and
solvents (entries 8-11).19 Interestingly, the enantioselectivity
showed strong dependence on reaction temperature (entries
7-9). The enantioselectivity significantly increased when the
reaction was carried out at -86 °C (entry 9). The enanti-
oselectivity could be improved further by using a mixture
of toluene and hexanes as a solvent (entry 10). To our delight,
the catalyst loading could be decreased to 1 mol % without
any loss of enantioselectivity (entry 11).
With the optimized conditions in hand, we examined the
generality of aldehyde scope (Table 2). A variety of
Table 2. Aldehyde Scope
entry
1
R
time (h)
yield (%)a
erb
Ph
12
24
18
24
18
18
12
18
18
12
12
18
95
94
96
91
92
93
96
94
95
97
87
92
92:8
96:4
94:6
95:5
91:9
90:10
92:8
90:10
81:19
84:16
86:14
85:15
2c d
4-NO2-Ph
3-NO2-Ph
2-NO2-Ph
4-Br-Ph
,
3
4c d
,
5
6c
7
4-Cl-Ph
4-MeO-Ph
2-naphthyl
1-naphthyl
2-Me-Ph
(E)-CHdCH-Ph
2-thienyl
8
9
10
11
12c
a Yield of isolated product. b Determined by HPLC on chiral column.
c Reaction was carried out in toluene. d 3 mol % catalyst was used. e Absolute
configuration was assigned by comparison of optical rotation (see Supporting
Information). Remaining products assigned by analogy.
aldehydes 5a-l afforded the aldol products 6aa-al in
excellent yields and good to excellent enantioselectivities.
Org. Lett., Vol. 12, No. 11, 2010
2477

Although the nitro group had a beneficial effect on enanti-
oselectivity (entries 2-4), the electronic properties of alde-
hydes showed little influence on enantioselectivities (entries
5-7). Aldehydes bearing either electron-donating or electron-
withdrawing groups at the 4-position of the phenyl group
gave the aldol products with almost the same level of
enantioselectivity. However, the electronic properties of
aldehydes significantly affected the reaction rate. The
electron-withdrawing group at 2- and 4- position of the aryl
group decreased reactivities toward aldol reaction due to
diminished basicity of aldehydes (entries 2, 4-6). Steric
properties of aryl substituents also played a role in enanti-
oselectivity. Bulky substituents at the 2-position of aldehydes
had a deleterious effect on the enantioselectivity (entries 9
and 10). It is noteworthy that the application of this catalyst
is not limited to benzaldehyde derivatives. R,ꢀ-Unsaturated
aldehyde as well as heterocyclic aldehyde gave the aldol
products in excellent yields and good to high enantioselec-
tivity (entries 11 and 12).
(entries 1-4). It is noteworthy that electronic and steric
properties of aryl group had little to no effect on enantiose-
lectivities. (Table 2 entry 1, Table 3 entries 1-4). We further
investigated the applicability of this catalyst system to the
diastereoselective Mukaiyama aldol reaction (entries 5 and
6). Silyl enol ether derived from cyclopentanone gave the
product in high yield and excellent enantioselectivity with
5:1 dr (entry 5). This method was further extended to the
other cyclic silyl enol ethers bearing an aromatic rings,
although enantioselectivities were moderate (entry 6).
To gain more information about the reaction mechanism
and strong temperature dependence of the enantioselectivity
of the aldol product,20 we hypothesized that a different
reaction pathway might be operating depending on the
reaction temperature. There are two plausible reaction
pathways: Brønsted acid itself directly protonates the car-
bonyl compound (Brønsted acid pathway), or Brønsted acid
may first be silylated with silyl enol ether and the silylated
Brønsted acid then activates the carbonyl compound (Lewis
acid pathway).21,22
We further investigated the scope of silyl enol ethers of
various ketones 4b-g with benzaldehyde 5a (Table 3). Silyl
(8) According to Mayr’s π-nucleophilicity scale, TMS silyl enol ether
of acetophenone 4a is 103 times less reactive than TMS silyl ketene acetal
of methyl isobutylate; see: Mayr, H.; Kempe, B.; Ofial, A. R. Acc. Chem.
Rec. 2003, 36, 66.
Table 3. Scope of Silyl Enol Ethers
(9) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem., Int.
Ed. 2004, 43, 1566.
(10) Uraguchi, D.; Tereda, M. J. Am. Chem. Soc. 2004, 126, 5356.
(11) For reviews of chiral phosphoric acid catalysis, see: (a) Akiyama,
T. Chem. ReV. 2007, 107, 5744. (b) Tereda, M. Chem. Commun. 2008,
4097.
(12) Recent examples of activation of imines by chiral phosphoric acids,
see: (a) Li, G.; Antilla, J. C. Org. Lett. 2009, 11, 1075. (b) Liu, H.;
Dagousset, G.; Masson, G.; Retailleau, P.; Zhu, J. J. Am. Chem. Soc. 2009,
131, 4598. (c) Li, C.; Villa-Marcos, B.; Xiao, J. J. Am. Chem. Soc. 2009,
131, 6967. (d) Zeng, X.; Zeng, X.; Xu, Z.; Lu, M.; Zhong, G. Org. Lett.
2009, 11, 3036. (e) Jiang, J.; Qing, J.; Gong, L.-Z. Chem.sEur. J. 2009,
15, 7031. (f) Zhu, C.; Akiyama, T. Org. Lett. 2009, 11, 4180. (g) Yue, T.;
Wang, M.-X.; Wang, D.-X.; Masson, G.; Zhu, J. Angew. Chem., Int. Ed.
2009, 48, 6717. (h) Dagousset, G.; Drouet, F.; Masson, G.; Zhu, J. Org.
Lett. 2009, 11, 5546. (i) Chen, X.-H.; Wei, Q.; Luo, S.-W.; Xiao, H.; Gong,
L.-Z. J. Am. Chem. Soc. 2009, 131, 13819. (j) Li, N.; Chen, X.-H.; Song,
J.; Luo, S.-W.; Fan, W.; Gong, L.-Z. J. Am. Chem. Soc. 2009, 131, 15301.
(13) For examples of activation of functionalized carbonyl groups by
chiral phosphoric acids, see: (a) Terada, M.; Soga, K.; Momiyama, N.
Angew. Chem., Int. Ed. 2008, 47, 4122. (b) Momiyama, N.; Tabuse, H.;
Terada, M. J. Am. Chem. Soc. 2009, 131, 12882.
(14) (a) Nakashima, D.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128,
9626. (b) Jiao, P.; Nakashima, D.; Yamamoto, H. Angew. Chem., Int. Ed.
2008, 47, 2411.
(15) Cheon, C. H.; Yamamoto, H. J. Am. Chem. Soc. 2008, 130, 9246.
(16) For the beneficial effect of bulky para-substituent at the aryl
substituent on enantioselectivity in chiral phosphoric acid catalysis, see:
(a) Cheng, X.; Goddard, R.; Buth, G.; List, B. Angew. Chem., Int. Ed. 2008,
47, 5079. (b) Cheng, X.; Vellalath, S.; Goddard, R.; List, B. J. Am. Chem.
Soc. 2008, 130, 15786. (c) Reference 14b. (d) Reference 15.
(17) For the synthesis of BINOL derivative bearing bulky 9-anthryl
substituent at the para-position at the aryl substituent, see ref.16a
(18) TBS, pentamethyldisilyl (PMDS), and TIPS enol ethers provided
the aldol products in 56:14, 64:36, and 59:41 er, respectively.
(19) For more detailed information, see Supporting Information.
(20) For examples of strong temperature dependence of enantioselectivity
in Brønsted acid catalysis, see: (a) Gondi, V. B.; Gravel, M.; Rawal, V. H.
Org. Lett. 2005, 7, 5657. (b) Reference 6.
a Yield of isolated product. b Determined by 1H NMR analysis.
c Determined by HPLC on chiral column. d Absolute configuration was
assigned by comparison of optical rotation (see Supporting Information).
Remaining products assigned by analogy.
(21) For an example of Lewis acid catalysis via in situ generation of
the silylated Lewis acids from strong Brønsted acids, see: Mathieu, B.;
Ghosez, L. Tetrahedron 2002, 58, 8219
.
(22) For recent examples of asymmetric Lewis acid catalysis via in situ
generation of the silylated Brønsted acids from Brønsted acids, see: (a)
Zamfir, A.; Tsogoeva, S. B. Org. Lett. 2010, 12, 188. (b) Reference 7. (c)
Rowland, E. B.; Rowland, G. B.; Rivera-Otero, E.; Antilla, J. C. J. Am.
enol ethers derived from aryl methyl ketones gave the aldol
adducts in excellent yields and high enantioselectivities
Chem. Soc. 2007, 129, 12084
.
2478
Org. Lett., Vol. 12, No. 11, 2010

To differentiate between these two pathways, we carried
out Mukaiyama aldol reactions in the presence of 2,6-di(tert-
butyl)pyridine (DTBP), which is known to inhibit any
potential Brønsted acid catalysis (Scheme 1).23 At room
that two different reaction pathways are operative depending
on reaction temperature. At room temperature the Lewis acid
catalyzed pathway would be operative, whereas at low
temperature Brønsted acid be the actual catalyst.
This direct activation of unfunctionalized carbonyl com-
pounds through protonation is expected to have a significant
effect on a Brønsted acid catalyzed asymmetric Mukaiyama
aldol reaction. Despite the fact that strong achiral Brønsted
acids, such as TfOH and Tf2NH, have been widely used in
Mukaiyama aldol reactions with broad substrate scope,25
strong acids have rarely been used as catalysts in enantiose-
lective Mukaiyama aldol reactions. This may be because the
rapidly generated silylated Brønsted acids, considered as the
true catalysts, are associated with a non-enantioselective
pathway.26 Thus, the direct activation of carbonyl groups
via protonation with strong Brønsted acids is expected to
make a number of Mukaiyama aldol reactions accessible in
an enantioselective fashion. This will provide a complemen-
tary approach to asymmetric Mukaiyama aldol reactions
through carbonyl group activation by chiral silyl cations,
which are in situ generated from strong Brønsted acid.7
Scheme 1. Mukaiyama Aldol Reaction with DTBP
temperature, DTBP has no effect on the Mukaiyama aldol
reaction in terms of either reactivty or enantioselectivity (eq
1 and Table 1 entry 7). However, at low temperature DTBP
completely inhibited the Mukaiyama aldol reaction (eq 2 and
Table 1 entry 11). Moreover, when the reaction mixture from
eq 2 was warmed up to room temperature, the aldol reaction
proceeded again with the same yield and enantioselectivity
as that of the reaction at room temperature with DTBP (eq
1 and 3). These results suggested that the actual catalyst for
the Mukaiyama aldol reaction at room temperature is the
silylated Lewis acid (Lewis acid pathway), whereas the acutal
catalyst at low temperature is Brønsted acid itself (Brønsed
acid pathway).
In conclusion, we have demonstrated the first Brønsted
acid catalyzed asymmetric Mukaiyama aldol reaction of
aldehydes using silyl enol ethers of ketones as nucleophiles.
A variety of aldehydes were applicable to this catalyst system
and afforded the aldol products in excellent yields and good
to excellent enantioselectivities with only 1 mol % catalyst
loading. Various silyl enol ethers could be applied to this
catalyst system, including a diastereoselective Mukaiyama
aldol reaction of silyl enol ethers of cyclic ketones. Further-
more, mechanistic studies have revealed that the silylated
Brønsted acid may be an actual catalyst at room temperature
(Lewis acid pathway), whereas Brønsted acid itself may be
an actual catalyst at low temperature (Brønsted acid path-
way). Further mechanistic studies and other applications of
this Brønsted acid are currently underway in our laboratory.
To further corroborate our hypothesis, the silylated Brøn-
sted acid was pregenerated24 and subjected to the Mukaiyama
aldol reaction (Scheme 2). The silylated Brønsted acid
Acknowledgment. This work was supported by NIH
(Grant No. P50 GM086145-02S1 and 5R0 GM068433-07).
Scheme 2
.
Mukaiyama Aldol Reaction with Silylated Lewis
Acid
Supporting Information Available: Experimental pro-
cedures and spectroscopic data of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL100233T
(23) For usage of this base to differentiate the reaction pathway between
Lewis acid and Brønsted acid catalysis, see: (a) Cheon, C. H.; Yamamoto,
H. Tetrahedron Lett. 2009, 50, 3555. (b) Hara, K.; Akiyama, R.; Sawamura,
M. Org. Lett. 2005, 7, 5621. (c) References 21 and 22.
(24) 1H NMR analysis showed that the silyl enol ether 4a rapidly
silylated Brønsted acid 2e. Furthermore, a new signal from the silylated
Brønsted acid was observed in the 31P NMR. For more detailed information,
see Supporting Information.
afforded the aldol adduct with the same yield and enanti-
oselectivity at room temperature (eq 4 and Table 1 entry 7).
However, no reaction was observed at low temperature with
the silylated Brønsted acid (eq 5). This result also supported
(25) For a review of strong Brønsted acids catalyzed Mukaiyama aldol
reaction, see: Boxer, M. B.; Albert, B. J.; Yamamoto, H. Aldrichimica Acta
2009, 42, 3.
(26) Ishihara, K.; Yamamato, H. Chem. Commun. 2002, 1564.
Org. Lett., Vol. 12, No. 11, 2010
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