Asymmetric Latent Carbocation Catalysis with Chiral Trityl Phosphate

Article abstract of DOI:10.1021/jacs.5b11085

Stable carbocations such as tritylium ions have been widely explored as organic Lewis acid catalysts and reagents in organic synthesis. However, achieving asymmetric carbocation catalysis remains elusive ever since they were first identified over one century ago. The challenges mainly come from their limited compatibility, scarcity of chiral carbocations, as well as the extremely low barrier to racemization of chiral carbenium ions. We reported here a latent concept for asymmetric carbocation catalysis. In this strategy, chiral trityl phosphate is employed as the carbocation precursor, which undergoes facile ionic dissociation upon mild external stimulation (e.g., acid, H-bonding, polar substrates) to form a catalytically active chiral ion pair for substrate activation and chiral induction. The latent strategy provides a solution for the long sought-after asymmetric carbocation catalysis as illustrated in three different enantioselective transformations.

Full text of DOI:10.1021/jacs.5b11085

Subscriber access provided by Penn State | University Libraries
Article
Asymmetric Latent Carbocation Catalysis with Chiral Trityl Phosphate
Jian Lv, Qichao Zhang, Xingren Zhong, and Sanzhong Luo
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b11085 • Publication Date (Web): 23 Nov 2015
Downloaded from http://pubs.acs.org on November 23, 2015
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 24
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
Asymmetric Latent Carbocation Catalysis with Chiral
Trityl Phosphate
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Jian Lv1,2,‡, Qichao Zhang1,‡, Xingren Zhong1and Sanzhong Luo1,2,*
1Beijing National Laboratory for Molecular Sciences (BNLMS), Key Laboratory of
Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences,
2
Beijing 100190, China.
Collaborative Innovation Center of Chemical Science and
Engineering (Tianjin), Tianjin 300071, China.
Abstract: Stable carbocations such as tritylium ions have been widely explored as organic
Lewis acid catalysts and reagents in organic synthesis. However, to achieve asymmetric
carbocation catalysis remains elusive ever since their first identification over one century ago.
The challenges mainly come from their limited compatibility, scarcity of chiral carbocation as
well as the extremely low barrier to racemization of chiral carbenium ions. We reported here
in a latent concept for asymmetric carbocation catalysis. In this strategy, chiral trityl
phosphate is employed as the carbocation precursor, which undergoes facile ionic
dissociation upon mild external stimulation (e.g. acid, Hꢀbonding, polar substrates) to form a
catalytically active chiral ionꢀpair for substrate activation and chiral induction. The latent
strategy provides an enabling solution to the long soughtꢀafter asymmetric carbocation
catalysis as illustrated in three different enantioselective transformations.
1
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 24
1
2
3
4
5
6
7
8
9
The development of new catalytic motif remains a frontline in the evolution of asymmetric
catalysis.1 Ever since the discovery of the first trityl cation in 1901,2 stable carbocations have
been actively pursued as conceptually attractive organic Lewis acid catalysts.3ꢀ5 However,
progresses along this line have been rather slow and to achieve asymmetric carbocation
catalysis remains elusive despite of the prevalence of organocatalytic concepts and
strategies.6 The primary reason is the limited compatibility of carbocations with many
nucleophilic reactants.7 Though as bench stable and easily accessible salts, carbocations such
as tritylium ions can still react with most nucleophiles, resulting in the interception of the
active centers. Consequently, there have been always concerns regarding the precise nature of
carbocation catalysis. For examples, hidden proton/silyl catalysis has been noted due to the
reaction of carbocations with nucleophilic reactants or even moisture.8 Last but not the least,
regulation of chiral inductions by a sp2ꢀhybridized carbocation is a notoriously challenging
task, due to the scarcity of chiral carbocations9 as well as the extremely low barrier to
racemization of chiral carbenium ions.10 The install of remote chiral centers to trityl cations
has been attempted with unfortunately poor enantioselectivity.6d Clearly, new concept and
strategy is required in order to achieve asymmetric carbocation catalysis.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Capitalizing on the known chiral counteranion effect and chiral ion pair catalysis,11 we
proposed here a latent carbocation concept for asymmetric carbocation catalysis. Accordingly,
chiral trityl phosphates were employed as latent carbocationic species by either inꢀsitu mixing
chiral phosphate salt and trityl derivatives or separately prepared. The chiral phosphate anion
plays a key role in stabilizing tritylcation as a neutral species to suppress uncontrolled
catalyst interception. Provided with the labile nature of phosphate CꢀO bonds as known in
2
ACS Paragon Plus Environment

Page 3 of 24
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
many chemical12 and enzymatic13 processes, the resulted trityl phosphate may undergo facile
ionic dissociation upon mild external stimulation (e.g. acid, Hꢀbonding, polar substrates) to
form a chiral ionꢀpair,14ꢀ16 which simultaneously participates in catalysis to activate substrate
and to induce stereoselectivity via the known counter anion effect (Figure 1).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Challenges with asymmetric carbocation catalysis
LA
Tr
O
O
LUMO activation
Challenges:
- scarce of chiral carbocations
- hidden proton catalysis
- Interception of carbocations
Trityl cation
(1901)
This work: Asymmetric Latent Carbocation Catalysis
Simultaneous Trityl cation generation and activation:
S
*
O
O
S
*
O
S
Tr+
*
P
P
P
O Tr
O
Tr
O
Chiral ion pair
Trityl Phosphate
Activation &
chiral induction
Latent carbocation
Substrate stimulation
Figure 1.Asymmetric carbocation catalysis.
Results and Discussion
Characterizations of chiral trityl phosphate. We started by first examining the properties
of chiral trityl phosphate (TP-1). Upon in situ mixing sodium phosphate 1a and Ph3CBF4 (eq.
13
1), typical orange color of tritylium ion solution became colorless. The methine carbon C
signal was completely shifted from 210.8 ppm, characteristic of a deshielded carbenium ion,
to 81.9 ppm corresponding to the formation of phosphate CꢀO bond (Figure 2A). Identical
methine carbon signal was also observed when Ph3CꢀBr with a CꢀBr covalent bond (δ = 79.2
cmꢀ1) was treated with 1a. In UVꢀvis spectra, free tritylium ion such as Ph3CBF4 showed a
3
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 24
1
2
3
4
5
6
7
8
9
characteristic twin absorption band at λmax = 432 and 411 nm. When a solution of free
tritylium ion Ph3CBF4was titrated with sodium phosphate 1a, the twin absorption was
gradually decayed and completely disappeared with one equivalent of 1a (Figure2B, Figure
S1 for UV titration spectra). The in situ formed species can be fully characterized as trityl
phosphate (e.g. TP-1) by 1H NMR, 13C NMR, 31P NMR and DOSY spectrums (Figure 2, and
SI). Latent trityl carbocation TP-1 could also be obtained when Ph3CꢀOH was treated with
free acid 1b or Ph3CꢀBr treated with silver phosphate1c. In addition, trityl phosphates with
variations on phosphate moiety such as TP-2 and TP-3 can be prepared inꢀsitu following the
same procedure, and the obtained latent carbocations demonstrated similar spectroscopic
properties (Figure 2B).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CH2Cl2, RT
[Ph3C]+[BF4]-
1
(1)
TP
+
Ar1
1a: Ar1 = Ar2 = 4-PhC6H4, X = Na
1b: Ar1 = Ar2 = 4-PhC6H4, X = H
1c: Ar1 = Ar2 = 4-PhC6H4, X = Ag
TP-1: Ar1 = Ar2 = 4-PhC6H4,
O
O
P
O
OX
X =C
TP-2: Ar1 = Ar2 = 2,4,6-(CH3)3C6H2,
TP-3: Ar1 = 2,4,6-(CH3)3C6H2, Ar2 = H,
3
Ar2
Figure 2. Characterizations of chiral trityl phosphate. (A) 13C NMR (CD2Cl2) spectra of compounds
Ph3CBF4, 1a and TP-1, the label of red, blue and green dots represents the responding carbon signal in the
structure of TP-1. (B) UVꢀVis absorption spectra of Ph3CBF4 (0.1 mM) and TP-1, 2 and 3 (0.05 mM),
respectively, in CH2Cl2 at room temperature.
4
ACS Paragon Plus Environment

Page 5 of 24
Journal of the American Chemical Society
1
2
3
4
CD2Cl2
RT
(2)
LA•OPPh3
+
LA
OPPh3
5
6
7
8
31P NMR (ppm)
ꢀδ vs. OPPh3
OPPh3
TP-1•OPPh3
0
5.0
17.5
18.3
27.8
32.8
45.3
46.1
Ph3CBF4•OPPh3
(C6F5)3B•OPPh3
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 3.Analytical Lewis acidity of latent carbocation
The Lewis acidity of latent carbocation was examined by using the GutmannꢀBeckett
method.17 The binding of triphenylphosphine oxide (1.0 equiv) to TP-1 (1.0 equiv) was
evaluated on the basis of the change in the 31P NMR chemical shift of OPPh3 upon
31
complexation in CD2Cl2 at room temperature (eq. 2). A change of +5.0 ppm in the P NMR
chemical shift of OPPh3 was observed. This chemical shift is much smaller than the change
observed upon binding to B(C6F5)3 (ꢁδ = +18.3 ppm) and Ph3CBF4 (ꢁδ = +17.5 ppm)
(Figure 3, S2), suggesting that TP-1, as a neutral species, still behaves like a Lewis acid
though in a much lower apparent acidity.
C
( )
O
2
Tr
F3C
CO2Et
O
OP*
OP*
Tr
2n
Tr OP*
F3C
CO2Et
Trityl Phosphate
UV active
@ 405 and 424 nm
Activated chiral ion pair
Figure 4.UVꢀVis titrations of carbocarion with ethyl trifluoropyruvate 2. (A) The UVꢀvis absorption
spectra of TP-1 (2.5mM in 2.0 mL CH2Cl2) upon the addition of 2 (0ꢀ84.7 mM) at room temperature,
respectively. The insets show a plot of ꢁA @ 405 nm against [2]/[TP-1]. (B) The UVꢀVis absorption
spectra of Ph3CBF4 (0.25 mM in 1.0 mL CH2Cl2) upon the addition of 2 (0, 0.25, 0.50, 1.00, 1.50, 2.50,
5
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 24
1
2
3
4
5
3.50, 5.0 mM) at room temperature, respectively. (C) Illustration of simultaneous trityl cation generation
and substrate activation.
6
7
8
9
The interaction of TP with a typical carbonyl compound in Lewis acid catalysis such as
ethyl trifluoropyruvate 2 was next examined. Upon in situ mixing TP-1 and ethyl
trifluoropyruvate 2, the colorless solution became yellow (Figure 4A, inside) and the
characteristic twin absorption of trityl cation at λmax= 425 and 405 nm was clearly observed
by UVꢀvisible spectra (Figure 4A). The twin absorption signal was gradually enhanced with
the addition of trifluoropyruvate, an indication of the increasing formation of trityl cation
(Figure 4A). There seems also a threshold concentration of trifluoropyruvate required for
effective generation of trityl cation (Figure 4A, inside figure). These results suggested that
trifluoropyruvate could stimulate the dissociation of trityl phosphate to generate the trityl
cation, likely via the known polarization effect as frequently encountered in SNꢀ1 type
reactions. The inꢀsitu generated trityl cation may simultaneously engage in substrate
activation if the stimulator itself is a reaction partner, thus setting the stage for effective
catalysis (Figure 4C). UV titration of TrBF4 by trifluoropyruvate 2 confirmed the interception
of free tritylium ion with pyruvate and this interaction (Figure 4B) could be further verified
by19FꢀNMR (SI, Figure S3).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Asymmetric catalysis bytrityl phosphate
Friedel-Crafts reactions of α
-ketoesters and indoles.18ꢀ20 We next investigated whether
the latent carbocation could facilitate asymmetric catalytic reaction via in situ formed chiral
carbocationic ion pair (Figure 1). To implement this strategy, different trityl cations, chiral
phosphoric acids or salts 1,21,22 and their combinations were then examined in the model
reactions of indole 3a and
αꢀketoester 4a. In experiments, trityl derivatives were first treated
6
ACS Paragon Plus Environment

Page 7 of 24
Journal of the American Chemical Society
1
2
3
4
5
Table 1. Optimization studies for asymmetric catalyzed FriedelꢀCrafts reaction by
carbocationsa
6
7
8
9
NH
CPh3
O
TrX (10 mol%)
1 (10 mol%)
O
O
Ph
+
O
N
N
Ph
O
CH2Cl2, -70 °C
4 h
H
H
O
4a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3a
5a
5a'
Entry
TrX
1
Yield (%)b/5a
ee (%)c
‒
1
TrBF4
TrBF4
TrClO4
TrBr
TrBr
TrBr
‒
‒
<10
62
2
83
90
93
92
‒
1a
1a
1a
1a
‒
3
65
4
72
5d
82
6
trace
trace
75
7
‒
1a
1b
1c
1a
8
TrOH
TrBr
TrBr
88
91
96
9
75
10d,e
81
a General conditions: 3a (0.1 mmol), 4a (0.12 mmol), TrX (10 mol%) and 1 (10 mol%) in CH2Cl2 (0.5 mL)
at ꢀ70 °C for 4 h. b Yields of isolated products. c Determined by HPLC analysis on a chiral stationary phase.
d 1a(5 mol%) and TrBr (5 mol%). e Toluene (0.5 mL) as reaction solvent.
with chiral phosphate salt, e.g. 1a, to ensure their complete conversion to trityl phosphate
before they were subject to a catalytic test. We were gratified to find that the joint use of 1a
and trityl cation Ph3CBF4 (10 mol%), led to the desired adduct 5a with 62% yield and in 83%
ee at ꢀ70 °C for 4 h (Table 1, entry 2). In sharp contrast, the use of Ph3CBF4 only led to minor
desired product (Table 1, entry 1), with the trityl cation completely intercepted and isolated as
the side adduct 5a’. Trityl phosphates derived from other trityl derivatives and chiral
phosphates have also been examined, giving consistently high enantioselectivity (Table 1,
entries 3, 8 and 9). Finally, the combination of Ph3CBr and sodium phosphate 1a was
identified to give the best results (Table 1, entry 4, 72% yield and 93%ee), to note neither
7
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 24
1
2
3
4
5
6
7
8
9
Ph3CBr nor 1a alone was active for the reaction (Table 1, entries 6 and 7). This is a strong
indication that the formation of trityl phosphate (TP-1) is critical for effective catalysis. The
catalysis of TP-1 derived from Ph3CBr/1a could be further improved when conducting in
toluene, and under this condition, 5 mol % loading of catalyst was suffice to give 81% yield
and 96% ee (Table 1, entry 10).23
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2. Enantioselective FriedelꢀCrafts reactions of α
ꢀketoesters and indolesa
Entry
1
R
H
R1
Ph
R2
Yield (%)b
81
ee (%)c
CH3,5a
96
95
90
99
93
93
96
92
26
2
3
4
5
6
7
8
9
H
4ꢀClꢀPh
CH3,5b
CH3, 5c
CH3, 5d
CH3, 5e
75
80
80
88
79
75
75
71
H
4ꢀBrꢀPh
H
3,4ꢀCl2ꢀPh
4ꢀCH3ꢀPh
H
H
4ꢀCH3OꢀPh CH3, 5f
2ꢀThiophen CH3, 5g
H
6ꢀF
H
Ph
CH3, 5h
C2H5, 5i
CH3
a General conditions: 3 (0.1 mmol), 4 (0.12 mmol), TrBr (5 mol%) and 1a (5 mol%) at ꢀ70 °C in PhCH3
(0.5 mL) for 4 h. b Yields of isolated products. c Determined by HPLC analysis on a chiral stationary phase.
8
ACS Paragon Plus Environment

Page 9 of 24
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The catalysis of TP-1 (5 mol%) could be applied to other αꢀketoesters and indoles to give
the desired 1,4ꢀaddition products 5a-o in good yields and high enantioselectivities (Table 2,
entries 1ꢀ8). Aliphatic β,γꢀunsaturated αꢀketo esters 4i were examined in the current catalysis
and gave poor enantioselectivity but good reactivity (Table 2, entry 9). The reaction could
also be successfully applied in similar FriedelꢀCrafts reaction of simple phenol 6. In previous
studies, it was found that the free phosphoric acid 1b itself didn’t catalyze the reaction in the
absence of Lewis acid.20c To our delight, the latent carbocation TP-1 turned out to be much
more effective Lewis acid catalyst for the reaction than the corresponding Brønsted acid itself,
giving the 1,4ꢀadduct 7 with 59% yield and in 84% ee (eq. 3).
Asymmetric inverse-electron-demanding hetero-Diels-Alder reaction.24,25 It was found
that the latent carbocation could also catalyze asymmetric inverseꢀelectronꢀdemanding
heteroꢀDielsꢀAlder reactions (HDA) of
αꢀketoester 4a and cyclopentadiene 8 (Scheme 1).
The latent carbocation TP-2 (5 mol%) derived from Ph3COH/1d in the presence of 4 Å
molecular sieve could smoothly catalyze the reaction to afford cycloadduct 9a (HDA/DA =
70:30) in 99% yield and 90% ee. Importantly, the free phosphoric acid 1d itself only gave
trace racemic adduct 9a, indicating that the latent carbocation as a Lewis acid plays a pivotal
role in the reaction. Moreover, αꢀketoesters bearing either electronꢀwithdrawing or
electronꢀdonating group can be applied in the reactions with cyclopentadiene to give the
desired HDA products HDA-9 and DA products DA-9 in good yields (HDA/DA up to 75:25)
9
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 24
1
2
3
4
and excellent enantioselectivity for HDA-9 (up to 91% ee).
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1.Asymmetric HDA reaction
Asymmetric carbonyl-ene reaction.26 Furthermore, we found that the asymmetric
carbonylꢀene reaction between trifluoropyruvate and αꢀmethyl styrene derivatives 10 could
also be achieved with the latent carbocation (Scheme 2). Trityl phosphate TP-3 (5 mol%),
derived from 3ꢀsubstituted unsymmetric BINOLs, was identified to give 61% yield and 84%
ee, while the corresponding Brønsted acid (52% yield and 69% ee for 11a) and sodium
phosphate (28% yield and 27% ee) were much less effective in terms of both activity and
stereoselectivity. The electronꢀwithdrawing and electronꢀdonating αꢀmethyl styrene (10b and
10c) were tolerated to give 78% and 84% ee, respectively.
Scheme 2. Asymmetric carbonylꢀene reaction
Mechanistic studies of latent cation catalysis.
Exclusion of free acid catalysis. One of the most important issues in carbocation catalysis
is to rule out that trace acids, either present as impurities or formed during the reaction, are
10
ACS Paragon Plus Environment

Page 11 of 24
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
the “hidden” catalytic active species. In our case, control experiment with free phosphoric
acid 1b (10 mol%) could give 61% yield and 82% ee (Table 3, entry 1). Generally, two
processes, depending on the reacting nucleophile, can be invoked to account for the
consumption of tritylium ions to generate free phosphoric acid(eq. 4 and 5):
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
First, we examined the reactivity of carbocation with a typical nucleophileindole3a, by
using in situ IR (Figure 5A). TP-1 could still react with indole 3a to form tetraarylated adduct
5a’ at room temperature (eq. 6), but with an initial rate 15 times slower than Ph3CBF4, and
o
this reactivity can be largely suppressed at lower temperature (ꢀ70 C) (Figure 5A),
highlighting the critical role of phosphate anion in stabilizing carbocation. To our delight, in
the presence of αꢀketoester4a, no tetrarylated adduct 5a was obtained even at room
temperature. Thus, we excluded the generation of free phosphoric acid via electrophilic
substitution of TP-1 with indole 3a. Moreover, we found even a trace chiral phosphoric acid
1b existed in carbocation catalysis could give lower results. In a control experiment, TP-1
(10 mol%) was first treated with indole 3a (1.0 equiv) at room temperature to afford chiral
phosphoric acid 1b, the resulted mixture was then treated with ketoester at ꢀ70 ºC to give 52%
yield and 81% ee (eq. 7). This result indicates that free phosphoric acid, if present, would
lead to reduction of both yield and enantioselectivity.
11
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 12 of 24
1
2
3
4
5
6
7
8
9
The other pathway may involve the reaction of the carbocation with traces of water to form
free phosphoric acid 1b (eq. 5). However, it is known that trityl ester is quite stable and only
undergoes hydrolysis under high concentration of water.7b In fact, the reaction worked equally
well even in the presence of 5.0 equiv. of water (Table 3, entry 6),27 suggesting that the
existence of trace water may only have a neglectable effect on the reaction.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Next, the use of nonꢀnucleophilic base to exclude acid catalysis has been explored (Table 3,
entries 3 and 4). Organic base such as 2,6ꢀbis(tertꢀbutyl)pyridine reacted with carbocation
leading to its decomposition, thus the depletion of activity. Similar observation has also been
reported in carbocation catalysis.5a In fact, it has even been shown the use of organic base
may induce acid catalysis, rather than inhibit it. Nevertheless, the model reaction, conducted
in the presence of inorganic Na2CO3 (1.0 equiv) at ꢀ70 °C in CH2Cl2,28 proceeded smoothly to
give the desired adduct 5a in 66% yield and with 92% ee (Table 3, entry 5). In contrast, the
catalysis with free acid 1b was largely suppressed by the addition of Na2CO3 (1.0 equiv) in
CH2Cl2 (Table 3, entry 3).
Figure 5. (A) Kinetic profiles of the reaction of indole 3a and TP-1relative to Ph3CBF4 to give adduct 5a’,
monitored by inꢀsitu IR at 1105 cmꢀ1. (B) The conversion of asymmetric FriedelꢀCrafts reaction of
αꢀketoesters 5a and indole 2a catalyzed by 1b (2.5ꢀ5 mol%) or TPꢀ1 (5 mol%), monitored by in-situ IR at
12
ACS Paragon Plus Environment

Page 13 of 24
Journal of the American Chemical Society
1
2
3
1737 cmꢀ1 (C=O, ester).
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
We further compared the kinetic profiles of carbocation catalysis and free acid catalysis. As
shown in Figure 5B, kinetic profile of 1b (2.5ꢀ5.0 mol%) catalyzed reaction was found to be
significantly different from that of TP-1 (5.0 mol%) process with the latter being much faster,
showing they are different in catalytic nature. 29
Taken together, the above observations exclude the possibility of free acid catalysis in
TP-1 catalyzed reactions.
Table 3. Comparison experiments a
NH
O
O
O
Cat. (10 mol%)
Ph
+
O
N
Ph
O
CH2Cl2, -70 °C
4 h
H
O
4a
3a
5a
Entry
Cat.
1b
Additive
Yield (%)b
ee (%)c
1
2
3
4
5
6
‒
61
82
‒
1b
DBPy (10 mol%)
trace
<10
45
Na2CO3 (1.0 equiv)
DBPyd (10 mol%)
Na2CO3 (1.0 equiv)
H2O (5.0 equiv)
‒
1b
72
92
91
TP-1
TP-1
TP-1
66
83
a General conditions: 3a (0.1 mmol), 4a (0.12 mmol), Cat. (10 mol%) in CH2Cl2 (0.5 mL) at ꢀ70 °C for 4 h.
b
c
Yields of isolated products. Determined by HPLC analysis on a chiral stationary phase. d DBPy =
2,6ꢀdiꢀtertꢀbutylpyridine.
Verification of the carbocation catalysis. In experiments, we have noticed that different
TPs e.g. TP-1-3, showed dramatically different performance in terms of both activity and
13
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 14 of 24
1
2
3
4
5
6
7
8
9
stereoselectivity (eq. 8, Figure S6). Given the common trityl cation involved in TP-1-3, these
results showed that the chiral phosphate moiety could tune both the reactivity and
stereoꢀinductions. To probe the nature of the cationic catalysis with trityl phosphate, we have
determined the kinetics as well as its dependence on inꢀsitu generated active trityl cations
(Figure S6) and the ene reaction between αꢀmethyl styrene 10a and ethyl trifluoropyruvate 2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
was chosen for the model studies as this reaction was readily monitored
O
F3C
TP, CH2Cl2, RT
OH
CO2Et
+
(8)
Ph
F3C
CO2Et
Ph
10a
2
11
TP-1
: 5.0 mol%, -9% ee;
TP-1
: 2.5 mol%, <-5% ee;
TP-2: 5.0 mol%, 15% ee; TP-2: 2.5 mol%, 8% ee;
TP-3: 1.0 mol%, 32% ee; TP-3: 5.0 mol%, 48% ee
Figure 6. Asymmetric carbonylꢀene reaction catalyzed by TP. (A) Kinetics of TP catalyzed carbonylꢀene
reaction of αꢀmethyl styrene 10a (0.6 M) and 2(0.2 M) monitored by inꢀsitu IR at 1778 cmꢀ1 (C=O, ester)
at room temperature. (B) UVꢀVis absorption spectra of TP in the presence of ethyl trifluoropyruvate 2
(0.025 M). (C) Correlation between the initial rate and the determined apparent UVꢀVis absorbance of trityl
cations, initial rates of the reaction were determined in the interval between 0ꢀ20% conversions of the
reaction. (D) The color change of the reaction mixture, before adding alkene 10a (top) and after the
14
ACS Paragon Plus Environment

Page 15 of 24
Journal of the American Chemical Society
1
2
3
4
5
reaction complete (bottom). (E) Track of the formation of free trityl cation by UVꢀVis at 403 nm in TP-2 (5
mol%) catalyzed reaction of αꢀmethyl styrene 10a (0.075 M) and 2(0.025 M) at room temperature.
6
7
8
9
by both IR and UV spectroscopy. The stimulated trityl cation generation was probed by UV
under otherwise identical (with catalytic reaction) but dilute conditions in the presence of 2
(Figure 6A). As shown, TPs bearing different phosphate moiety showed varied tendency to
dissociate into free trityl ion pair, with TP-2 as the most active (Figure 6A, S6). A quick
analysis revealed that the initial reaction rates correlated linearly with the determined trityl
cation concentration, proving unequivocally the involvement of free cation as the catalytic
active species (Figure 6B). An estimation based on UV absorption showed that ca. 6% of
TP-2 was dissociated into trityl cation at the onset of the reaction and the solutions exhibited
a bright yellow color (Figure S8). As the reaction proceeded, it was found that the
concentration of free trityl cation gradually decreased and the reaction became colorless once
the reaction was complete at room temperature (Figure 6C & D). Independent tests indicated
that neither alkene nor the eneꢀproduct 11a was able to induce or intercept tritylium ion.
Taken together, these results highlight the latent nature of the catalysis with the active
tritylium ion returning back to its latent form as trityl phosphate once the stimulating
substrate was consumed.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Conclusion
We have developed a latent strategy for the long soughtꢀafter enantioselective carbocation
catalysis. Chiral trityl phosphate was found to undergo facile dissociation to form a catalytic
active chiral trityl ion pair under the stimulus by the reacting substrate. The latent strategy
bypasses the typical pitfalls associated with active carbocations and provides an enabling
15
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 16 of 24
1
2
3
4
5
6
7
8
9
solution to organic Lewis acid catalyzed transformations as illustrated in FriedelꢀCrafts
alkylation reaction, heteroꢀDielsꢀAlder and carbonylꢀene reaction. We believed the latent
carbocation catalysis would provide a complementary strategy to the typical chiral
Brønsted/Lewis acid catalysis, and enormous potentials along this line are anticipated
provided with the structural flexibility and versatility of stabilized carbocations, e.g. tritylium
ion. Further investigations to develop the scope of this latent carbocation system and to
explore chiral carboncation catalysis are currently in progress in our laboratory.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ASSOCIATED CONTENT
Supporting Information.
Experimental details and characterization of new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* luosz@iccas.ac.cn
Author contributions
‡These authors contributed equally
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
We thank the Natural Science Foundation of China (21390400, 21202170 and 21472193) and
the National Basic Research Program of China (2012CB821600) for financial support. S.L. is
16
ACS Paragon Plus Environment

Page 17 of 24
Journal of the American Chemical Society
1
2
3
4
5
6
supported by the National Program of Topꢀnotch Young Professionals, CAS Oneꢀhundred
Talents Program and CAS Youth Innovation Promotion Association.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Reference
1. (a) Naredla, R. R.; Klumpp, D. A. Chem. Rev. 2013, 113, 6905ꢀ6948. (b) Stang, P. J. In
Carbocation Chemistry; Olah, G. A. & Prakash, G. K. S., EDs.; Wiley: Hoboken, NJ, 2004,
pp 1ꢀ6.
2. (a) Norris, J. F. Am. Chem. J. 1901, 25, 117ꢀ122. (b) Kehrman, F.; Wentzel, F. Chem. Ber.
1901, 34, 3815ꢀ3819.
3. (a) Mukaiyama, T.; Kobayashi, S.; Shoda, S.ꢀi. Chem. Lett. 1984, 13, 907ꢀ910. (b)
Mukaiyama, T.; Kobayashi, S.; Shoda, S.ꢀi. Chem. Lett.1984, 13, 1529ꢀ1530. (c) Mukaiyama,
T.; Kobayashi, S.; Murakami, M. Chem. Lett.1984, 13, 1759ꢀ1762. (d) Mukaiyama, T.;
Kobayashi, S.; Murakami, M. Chem. Lett.1985, 14, 447ꢀ450. (e) Kobayashi, S.; Murakami,
M.; Mukaiyama, T. Chem. Lett.1985, 14, 953ꢀ956. (f) Mukaiyama, T.; Nagaoka, H.;
Murakami, M.; Ohshima, M. Chem. Lett.1985, 14, 977ꢀ980. (g) Kobayashi, S.; Murakami,
M.; Mukaiyama, T. Chem. Lett. 1985, 14, 1535ꢀ1538. (h) Ohshima, M.; Murakami, M.;
Mukaiyama, T. Chem. Lett.1985, 14, 1871ꢀ1874. (i) Kobayashi, S.; Matsui, S.; Mukaiyama, T.
Chem. Lett. 1988, 17, 1491ꢀ1494. (j)Yanagisawa, M.; Mukaiyama, T. Chem. Lett.2001, 30,
224ꢀ225.
4. Roy, S. R.; Nijamudheen, A.; Pariyar, A.; Ghosh A.; Vardhanapu, P. K.; Mandal, P. K.;
Datta, A.; Mandal, S. K. ACS. Catal. 2014, 4, 4307ꢀ4319.
5. (a) Bah, J.; Franzén, J. Chem. Eur. J. 2014, 20, 1066ꢀ1072. (b) Bah, J.; Naidu, V. R.; Teske,
J.; Franzén, J. Adv. Synth. Catal. 2015, 357, 148ꢀ158. (c) Naidu. V. R.; Bah, J.; Franzén, J.
17
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 18 of 24
1
2
3
4
5
6
Eur. J. Org. Chem. 2015, 1834ꢀ1839. (d) Naidu, V. R.; Ni, S.; Franzén, J. ChemCatChem
2015, 7, 1896ꢀ1905.
7
8
9
6. (a) Riant, O.; Samuel, O.; Kagan, H. B. J. Am. Chem. Soc. 1993, 115, 5835ꢀ5836.
(b)Taudien, S.; Riant, O.;Kagan, H. Tetrahedron Lett. 1995, 36, 3513ꢀ3516. (c) Sammakia, T.;
Latham, H. A. Tetrahedron Lett.1995, 36, 6867ꢀ6870. (d) Chen, C.ꢀT.; Chao, S.ꢀD.; Yen,
K.ꢀC.; Chen, C.ꢀH.; Chou, I.ꢀC.; Hon, S.ꢀW. J. Am. Chem. Soc. 1997, 119, 11341ꢀ11342. (e)
Magdziak, D.; Pettus, L.H.; Pettus, T. R. R. Org. Lett. 2001, 3, 557ꢀ559. (f) Bjurling, E.; Berg,
U.; Andersson, C.ꢀM. Organometallics, 2002, 21, 1583ꢀ1590.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7. (a) Mayr, H.; Bug, T.; Gotta, M. F.; Hering, N.; Irrgang, B.; Janker, B.; Kempf, B.; Loos, R.;
Ofial, A. R. J. Am. Chem. Soc.2001; 123, 9500ꢀ9512. (b) Horn, M.; Mayr, H. Chem. Eur. J.
2010, 16, 7478ꢀ7487. (c) Mayr, H.; Ammer, J.; Baidya, M.; Maji, B.; Nigst, T. A.; Ofial, A. R.;
Singer, T. J. Am. Chem. Soc.2015,137, 2580ꢀ2599.
8. Denmark, S. E.; Chen, C.ꢀT. TetradedronLett., 1994, 35, 4327ꢀ4330.
9.Blaser, H.ꢀU. Chem. Rev. 1992, 92, 935ꢀ952.
10. (a) Wallis, E. S. J. Am. Chem. Soc.1931, 53, 2253ꢀ2260. (b) Gomberg, M.; Gordon, W. E.
J. Am. Chem. Soc. 1935, 57, 119ꢀ124.
11. For reviews on chiral counteranion effect and chiral ion pair catalysis, see: (a) Phipps, R.
J.; Hamilton, G. L.; Toste, F. D. Nature Chem. 2012, 4, 603ꢀ614. (b) Mahlau, M.; List, B.
Angew. Chem. Int. Ed. 2013, 52, 518ꢀ533. (c) Brak, K.; Jacobsen, E. N. Angew. Chem. Int. Ed.
2013, 52, 534ꢀ561. (d) Lacour, J.; Moraleda, D. Chem. Commum. 2009, 7073ꢀ7089. For some
selected recent examples, see (e) Merten, C.; Pollok, C. H.; Liao, S.; List, B. Angew. Chem.
Int. Ed. 2015, 54, 8841ꢀ8845. (f) Jindal, G.; Sunoj, R. B. J. Org. Chem. 2014, 79, 7600ꢀ7606.
18
ACS Paragon Plus Environment

Page 19 of 24
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
(g) Mahlau, M.; GarcíaꢀGarcía, P.; List, B. Chem. Eur. J. 2012, 18, 16283ꢀ16287. (h) Liao S.;
List, B. Adv. Synth. Catal.2012, 354, 2363ꢀ2367. (i) Ding Z.ꢀY.; Chen, F.; Qin, J.; He, Y.ꢀM.;
Fan, Q.ꢀH. Angew. Chem. Int. Ed. 2012, 51, 5706ꢀ5710. (j) Arthuis, M.; Beaud, R.; Gandon,
V.; Roulland, E. Angew. Chem. Int. Ed. 2012, 51, 10510ꢀ10514. (k) Rueping, M.; Uria, U.;
Lin, M.ꢀY.; Atodiresei, I. J. Am. Chem. Soc. 2011, 133, 3732ꢀ3735. (l) Jiang, G.; Halder, R.;
Fang, Y.; List, B. Angew. Chem. Int. Ed. 2011, 50, 9752ꢀ9755. (m) Jiang, G.; List, B. Chem.
Commun. 2011, 47, 10022ꢀ10024. (n) Liao, S.; List, B. Angew. Chem. Int. Ed. 2010, 49,
628ꢀ631. (o) GarcíaꢀGarcía, P.; Lay, F.; GarcíaꢀGarcía, P.; Rabalakos, C.; List, B. Angew.
Chem. Int. Ed. 2009, 48, 4363ꢀ4366. (p) Li, C.; Wang, C., VillaꢀMacros, B.; Xiao, J. J. Am.
Chem. Soc. 2008, 130, 14450ꢀ14451. (q) Hamilton, G. L.; Kanai, T.; Toste, F. D. J. Am. Chem.
Soc. 2008, 130, 14984ꢀ14986. (r) Wang, X.; List, B. Angew. Chem. Int. Ed. 2008, 47,
1119ꢀ1122. (s) Rueping, M.; Antonchick, A. P.; Brinkmann, C. Angew. Chem. Int. Ed. 2007,
46, 6903ꢀ6906. (t) Mayer, S.; List, B. Angew. Chem. Int. Ed. 2006, 45, 4193ꢀ4195.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
12. (a) Lebée, C.; Kataja, A. O.; Blanchard, F.; Masson, G. Chem. Eur. J. 2015, 21,
8399ꢀ8402. (b) Liu, C.ꢀY.; Han, F.ꢀS. Chem. Commun. 2015, 51, 11844ꢀ11847. (c) Lv, J.;
Zhong, X.; Luo, S. Chem. Eur. J. 2014, 20, 8293ꢀ8296. (d) Lv,J.; Zhang, L.; Luo, S.; Cheng,
J.ꢀP. Angew. Chem. Int. Ed. 2013, 52, 9786ꢀ9790. (e) Čorić, I.; Kim, J. ꢀH.; Vlaar, T.; Patil, M.;
Thiel, W.; List, B. Angew. Chem. Int. Ed. 2013, 52, 3490ꢀ3493. (f) Song, L.; Guo, Q.ꢀX.; Li,
X.ꢀC.; Tian, J.; Peng, Y.ꢀG. Angew. Chem. Int. Ed. 2012, 51, 1899ꢀ1902. (g) Guo, C.; Song, J.;
Huang, J.ꢀZ.; Cheng, P.ꢀH.; Luo, S.ꢀW.; Guo, L.ꢀZ. Angew. Chem. Int. Ed. 2012, 51,
1046ꢀ1050. (h) Wang, S.ꢀG.; Han, L.; Zeng, M.; Sun, F.ꢀL.; Zhang, W.; You, S.ꢀL. Org.
Biomol. Chem. 2012, 10, 3202ꢀ3209. (i) Trifonidou, M.; Kokotos, C. G. Eur. J. Org. Chem.
19
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 20 of 24
1
2
3
4
5
6
2012, 1563ꢀ1568. (j) Guo, Q.ꢀX.; Peng, Y.ꢀG.; Zhang, J.ꢀW.; Song, L.; Feng, Z.; Gong, L.ꢀZ.
Org. Lett. 2009, 11, 4620ꢀ4623.
7
8
9
13. Tantillo, D. J. Chem. Soc. Rev. 2010, 39, 2847ꢀ2854.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
14. Horn, M.; Mayr, H. Eur. J. Org. Chem. 2011, 6470ꢀ6475.
15. Mangani S.; Ferraroni, M. InSupramolecular Chemistry of Anions, Wiley, New York,
1997.
16. Fersht, A. In Structure and Mechanism in Protein Science, Freeman, New York, 1999.
17. Beckett, M. A.; Strickland, G. C.; Holland, J. R.; Varma, K. S. Polymer,1996, 37,
4629ꢀ4631.
18. For reviews on asymmetric FriedelꢀCrafts reactions, see: (a) Terrasson, V.; de Figueiredo,
R. M.;Campagne, J. M. Eur. J. Org. Chem.2010, 2635ꢀ2655. (b) Bandini, M.; Eichholzer, A.
Angew. Chem., Int.Ed. 2009, 48, 9608ꢀ9644. (c) Poulsen, T. B.; Jørgensen, K. A. Chem. Rev.
2008, 108, 2903ꢀ2915. (d) Bandini, M.; Melloni, A.; UmaniꢀRonchi, A. Angew. Chem., Int.
Ed. 2004, 43, 550ꢀ556.
19. For recent examples of asymmetric FriedelꢀCrafts reactions of α,βꢀunsaturated ketone and
indoles catalyzed by chiral Brønsted acid, see:(a) Bi, B.; Lou Q.ꢀX.; Ding Y.ꢀY.; Chen S.ꢀW.;
Zhang S.ꢀS.; Hu, WꢀH.; Zhao, J.ꢀL. Org. Lett. 2015, 17, 540ꢀ543. (b) Mori, K.; Wakazawa,
M.; Akiyama, T. Chem. Sci. 2014, 5, 1799ꢀ1803. (c) Sakamoto T.; Itoh, J.; Mori K.; Akiyama,
T. Org. Biomol. Chem. 2010, 8, 5448ꢀ5454. (d) Pei, Zꢀk; Zheng, Y.; Nie, J.; Ma, JꢀA.
Tetraheron Lett. 2010, 51, 4658ꢀ4661. (e) Tang, H.ꢀY.; Lu A.ꢀD.; Zhou, Z.ꢀH.; Zhao, G.ꢀF.;
He, L.ꢀN.; Tang, C.ꢀC. Eur. J. Org. Chem. 2008, 1406ꢀ1410. (f) Rueping, M.; Nachtsheim, B.
J.; Moreth, S. A.; Bolte, M. Angew. Chem. Int. Ed. 2008, 47, 593ꢀ596.
20
ACS Paragon Plus Environment

Page 21 of 24
Journal of the American Chemical Society
1
2
3
4
20. For recent examples of asymmetric FriedelꢀCrafts reactions of α,βꢀunsaturated ketone and
5
6
7
8
9
indoles catalyzed by chiral phosphoric acid and Lewis acid, see: (a) Lv, J.; Yan, Q.; Cheng,
J.ꢀP.; Luo, S. Acta Chim. Sinica, 2014, 72, 809ꢀ814. (b) Lv, J.; Zhang, L.; Zhou, Y.; Nie, Z.;
Luo, S.; Cheng, J.ꢀP. Angew. Chem. Int. Ed. 2011, 50, 6610ꢀ6614. (c) Lv, J.; Li, X.; Zhang, L.;
Luo, S.; Cheng, J.ꢀP. Org. Lett. 2010, 12, 1096ꢀ1099. (d) Yang, L.; Zhu, Q.; Guo, S.; Qian, B.;
Xia, C.; Huang, H. Chem. Eur. J. 2010, 16, 1638ꢀ1645.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
21. For reviews on chiral phosphoric acids, see: (a) Akiyama, T. Chem. Rev.2007, 107,
5744ꢀ5788. (b) You, S.ꢀL.; Cai, Q.; Zeng, M. Chem. Soc. Rev. 2009, 38, 2190ꢀ2201.(c) Zamfir,
A.; Schenker, S.; Freund, M; Tsogoeva, S. B. Org. Biomol. Chem. 2010, 8, 5262ꢀ5276. (d) Yu,
J.; Shi, F.; Gong, L. Z. Acc. Chem. Res. 2011, 44, 1156ꢀ1171. (e) Rueping, M.; Kuenkel, A.;
Atodiresei, I. Chem. Soc. Rev. 2011, 40, 4539ꢀ4549. (f) Wu, H.; He Y.ꢀP.; Shi, F. Synthesis
2015, 47, 1990ꢀ2016.
22. For reviews on catalysis with the combination of a chiral phosphoric acid and a metal salt,
see: (a) Rueping, M.; Koenigs, R. M.; Atodiresei, I. Chem. Eur. J. 2010, 16, 9350ꢀ9365. (b)
Chen, D.ꢀF.; Han, Z.ꢀY.; Zhou, X.ꢀL.; Gong, L.ꢀZ. Acc. Chem. Res. 2014, 47, 2365ꢀ2377. (c)
Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev. 2014, 114, 9047ꢀ9153.
23. The use of other solvents such as THF, acetone and CH3OH led to only trace amounts of
product.
24. For examples of catalysis by chiral oxazoline/Cu(II)complexes,see: (a) Evans, D. A.;
Johnson, J. S. J. Am. Chem. Soc. 1998, 120, 4895ꢀ4896. (b) Evans, D. A.; Olhava, E. J.;
Johnson, J. S.; Janey, J. M. Angew. Chem. Int. Ed. 1998, 37, 3372ꢀ3375. (c) Evans, D. A.;
Johnson, J. S.; Olhava, E. J. J. Am. Chem. Soc. 2000, 122, 1635ꢀ1649. (d) Thorhauge, J.;
21
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 22 of 24
1
2
3
4
5
6
7
8
9
Johannsen, M.;Jørgensen, K. A. Angew. Chem. Int. Ed.1998, 37, 2404ꢀ2406. (e) Audrain, H.;
Thorhauge, J.; Hazell, R. G.; Jørgensen, K. A.J. Org. Chem.2000, 65, 4487ꢀ4497.(f) Zhuang,
W.; Thorhauge, J.; Jørgensen, K. A. Chem. Commun. 2000, 459ꢀ460. (g) Audrain, H.;
Jørgensen, K. A. J. Am. Chem. Soc. 2000, 122,11543ꢀ11544. (h) Matsumura, Y.; Suzuki, T.;
Sakakura, A.; Ishihara, K. Angew. Chem. Int. Ed. 2014, 53, 6131ꢀ6134. Catalysis by chiral
Schiff base/Cr(III) complexes: (i) Gademann, K.; Chavez, D. E.; Jacobsen, E. N. Angew.
Chem. Int. Ed. 2002, 41, 3059ꢀ3061. (j) Gao, X.; Hall, D. G. J. Am. Chem. Soc.2003, 125,
9308ꢀ9309. Catalysis by chiral Lewis acid/Sc(III) complexes: (k) Desimoni,G.; Faita, G.;
Mella, M.; Piccinini, F.; Toscanini, M. Eur. J.Org. Chem. 2007, 1529ꢀ1534. (l) Desimoni, G.;
Faita, G.; Toscanini, M.; Boiocci, M. Chem. Eur. J. 2007, 13, 9478ꢀ 9485. (m) Hu, H.; Liu Y.;
Guo, J.; Lin, L.; Xu, Y.; Liu, X.; Feng, X. Chem. Commun. 2015, 51, 3835ꢀ3837. Catalysis by
chiral Lewis acid/Er(III) complexes: (n) Zhu,Y.; Xie, M.; Dong, S.; Zhao, X.; Lin, L.; Liu, X.;
Feng, X. Chem. Eur. J. 2011, 17, 8202ꢀ8208. Catalysis by chiral Lewis acid/Ni(II) complexes:
(o) Zhou, Y.; Zhu, Y.; Lin, L.; Zhang, Y.; Zheng, J.; Liu, X.; Feng, X. Chem. Eur. J. 2014, 20,
16753ꢀ16758. Catalysis by other chiral Lewis acid/Cu(II) complexes: (p) Zhou, J.; Tang, Y.
Org. Biomol. Chem. 2004, 2, 429ꢀ433.(q) Zhu, Y.; Chen, X.; Xie, M.; Dong, S.; Qiao, Z.; Lin,
L.; Liu, X.; Feng, X. Chem. Eur. J. 2010, 16, 11963ꢀ11968. Catalysis by asymmetric
binaryꢀacid: (r) Lv, J.; Zhang, L.; Hu, S.; Cheng, J.ꢀP.; Luo, S. Chem. Eur. J. 2012, 18,
799ꢀ803. (s) Lv, J.; Zhong, X.; Cheng, J.ꢀP.; Luo, S. Acta Chim. Sinica, 2012, 70, 1518ꢀ1522.
For a few examples of organocatalysis, see: (t) Albreht, Ł.; Dickmeiss, G.; Weise, C. F.;
RodríguezꢀEscrich, C.; Jørgensen, K. A. Angew. Chem. Int. Ed. 2012, 51, 13109ꢀ13113. (u)
Weise, C. F.; Lauridsen, V. H.; Rambo, R. S.; Iversen, E. H.; Olsen, M.ꢀL.; Jørgensen, K. A. J.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
22
ACS Paragon Plus Environment

Page 23 of 24
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Org. Chem. 2014, 79, 3537ꢀ3546. (v) Pei, C.ꢀK.; Jiang, Y.; Wei, Y.; Shi, M. Angew. Chem. Int.
Ed. 2012, 51, 11328ꢀ11332. For a review on asymmetric heteroꢀDielsꢀAlder reaction: (w)
Jiang, X.; Wang, R. Chem. Rev.2013, 113, 5515ꢀ5546.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
25. For examples of inverseꢀelectronꢀdemand azaꢀDielsꢀAlder reactions, see: (a) Akiyama, T.;
Morita, H.; Fuchibe, K. J.Am. Chem. Soc.2006, 128, 13070ꢀ13071. (b) Liu, H.; Dagousset, G.;
Masson, G.; Retailleau, P.; Zhu, J. J. Am. Chem. Soc. 2009, 131, 4598ꢀ4599. (c) Xie, M.;
Chen, X.; Zhu, Y.; Gao, B.; Lin, L.; Liu, X.; Feng, X. Angew. Chem. Int. Ed. 2010, 49,
3799ꢀ3802. (d) Dagousset, G.; Zhu, J.; Masson, G. J. Am. Chem. Soc.2011, 133, 14804ꢀ14813.
(e) Shi, F.; Xing, G.ꢀJ.; Zhu, R.ꢀY.; Tan, W.; Tu, S. Org. Lett.2013, 15,128ꢀ131.
26. For reviews on asymmetric carbonylꢀene reactions, see: (a) Liu, X.; Zheng, K.; Feng, X.
Synthesis, 2014, 46, 2241ꢀ2257. (b) Clarke, M. L.; France, M. B. Tetrahedron, 2008, 64,
9003ꢀ9031. Catalysis by chiral calcium phosphate: (c) Rueping, M.; Bootwicha, T.;
Kambutong, S.; Sugiono, E. Chem. Asian J. 2012, 7, 1195ꢀ1198. Catalysis by chiral Brønsted
acid, see: (d) Rueping, M.; Theissmann, T.; Kuenkel, A.; Koenigs, R. M. Angew. Chem. Int.
Ed. 2008, 47, 6798ꢀ6801. For recent examples of asymmetric carbonylꢀene reaction, see: (e)
Luo, W.; Zhao, J.; Ji, J.; Lin, L.; Liu, X.; Mei, H.; Feng, X. Chem. Commun. 2015, 51,
10042ꢀ10045. (f) Truong, P. M.; Zavalij, P. Y.; Doyle, M. P. Angew. Chem. Int. Ed. 2014, 53,
6468ꢀ6472. (g) Xu, X.; Wang, X.; Liu, Y.; Doyle, M. P. J. Org. Chem. 2014, 79, 12185ꢀ12190.
(h) Rajapaksa, N. S.; Jacobsen, E. N. Org. Lett. 2013, 15, 4238ꢀ4241. (i) CrespoꢀPeña, A.;
Monge, D.; MartínꢀZamora, E.; Álvarez, E.; Fernández, R.; Lassaletta, J. M. J. Am. Chem.
Soc. 2012, 134, 12912-12915. (j) Zheng, K.; Yin, C.; Liu, X.; Lin, L.; Feng, X. Angew. Chem.
Int. Ed. 2011, 50, 2573ꢀ2577. (k) Zheng, K.; Yang, Y.; Zhao, J.; Yin, C.; Lin, L.; Liu, X.; Feng,
23
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 24 of 24
1
2
3
4
5
6
7
8
9
X.; Chem. Eur. J. 2010, 16, 9969ꢀ9972. (l) Zhao, J.ꢀF.; Tjan, T.ꢀB. W.; Tan, B.ꢀH.; Loh, T.ꢀP.
Org. Lett. 2009, 11, 5714ꢀ5716. (m) Zhao, J.ꢀF.; Tsui, H.ꢀY.; Wu, P.ꢀJ.; Lu, J.; Loh, T.ꢀP. J. Am.
Chem. Soc. 2008, 130, 16492ꢀ16493. (n) Zheng, K.; Shi, J.; Liu, X.; Feng, X. J. Am. Chem.
Soc. 2008, 130, 15770ꢀ15771. (o) Grachan, M. L.; Tudge, M. T.; Jacobsen, E. N. Angew.
Chem. Int. Ed. 2008, 47, 1469ꢀ1472. (p) Evans, D. A.; Wu, J. J. Am. Chem. Soc. 2005, 127,
8006ꢀ8007. (q) Yuan, Y.; Zhang, X.; Ding, K. Angew. Chem. Int. Ed. 2003, 42, 5478ꢀ5480. (r)
Evans, D. A.; Tregay, S. W.; Burgey, C. S.; Paras, N. A.; Vojkovsky, T. J. Am. Chem. Soc.
2000, 122, 7936ꢀ7943.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
27. Rueping, M.; Theissmann, T. Chem. Sci. 2010, 1, 473ꢀ476.
28. Rauniyar, V.; Lackner, A. D.; Hamilton, G. L.; Toste, F. D. Science, 2011, 334,
1681ꢀ1684.
29. The product ee value was found to correlate linearly with the catalyst ee value in the
model reaction of 3a and 4a, suggesting that a single molecular of trityl phosphate is involved
in catalysis and that a higher order of carbocation/chiral phosphate combination is unlikely to
be the catalytically active species.
Graphic abstract
24
ACS Paragon Plus Environment