Origin of and a Solution for Uneven Efficiency by Cinchona Alkaloid-Derived, Pseudoenantiomeric Catalysts for Asymmetric Reactions

Article abstract of DOI:10.1021/jacs.8b09010

Cinchona alkaloid-derived chiral catalysts represent one of the most widely applied classes of organocatalysts, which have been successfully utilized in the promotion of a wide variety of asymmetric reactions. Cinchona alkaloids exist in nature as pseudoe

Full text of DOI:10.1021/jacs.8b09010

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Article
On the Origin of and a Solution for Uneven Efficiency by Cinchona
Alkaloid-Derived, Pseudoenantiomeric Catalysts for Asymmetric Reactions
Bin Hu, Mark W. Bezpalko, Chao Fei, Diane A Dickie, Bruce M Foxman, and Li Deng
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 25 Sep 2018
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On the Origin of and a Solution for Uneven Efficiency by Cinchona Al-
kaloid-Derived, Pseudoenantiomeric Catalysts for Asymmetric Reac-
tions
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Bin Hu, Mark W. Bezpalko, Chao Fei, Diane A. Dickie, Bruce M. Foxman and Li Deng*
Department of Chemistry, Brandeis University, Waltham, Massachusetts 02454-9110, United States
ABSTRACT: Cinchona alkaloid-derived chiral catalysts represent one of the most widely applied class of organocatalysts,
which have been successfully utilized in the promotion of a wide variety of asymmetric reactions. Cinchona alkaloids exist
in nature as pseudoenantiomers, which allow cinchona alkaloid-catalyzed reactions to provide high enantioselectivities and
yields toward both enantiomers of interest in many reactions. On the other hand, the subtle structural difference between
pseudoenantiomeric cinchona alkaloids could also lead to uneven efficiency that severely limits the applicability of some
cinchona alkaloid-catalyzed reactions. We describe here the elucidation of the origin of and the consequent development of
novel modified cinchona alkaloids to address such a problem in asymmetric imine umpolung reactions by cinchonium salts.
1. INTRODUCTION
Natural and modified cinchona alkaloids constitute one of
the most widely applied class of organocatalysts in asym-
metric synthesis.1,2 The existence of pseudoenantiomeric
cinchona alkaloids, as exemplified by the structural pairs
of cinchonine/cinchonidine and quinidine/quinine (Figure
1), is unique among natural products and allows cinchona
alkaloid-derived chiral organic catalysts to provide ready
access to both enantiomers of desired chiral products in
numerous reactions.3 Nevertheless, there are many exam-
ples of significant discrepancy in enantioselectivity, and
usually in reactivity, for asymmetric reactions mediated by
a pair of pseudoenantiomeric cinchona alkaloid-derived
catalysts; namely one afforded highly enantioselective re-
actions producing enantioenriched products with good to
high yields while the corresponding pseudoenantiomer
Scheme 1. Examples of discrepancy in enantioselectivity
failed to furnish the antipode of the chiral products with
and reactivity mediated by a pair of pseudoenantiomeric
similar levels of enantioselectivities and yields.4,5 In most
cinchona catalysts
cases, the origin of such undesirable deterioration in the
catalytic efficiency, caused by a seemingly subtle structural
difference of one pseudoenantiomer vs the other, re-
mained mysterious and the solution for this pseudoenanti-
omer problem proved elusive.6
We recently demonstrated that cinchonium salts such as
cinchonine-derived catalysts C-2 or quinidine-derived cat-
alyst QD-1 could activate trifluoromethyl ketimines and
simple aldimines 1 as nucleophiles for highly chemo-, re-
gio-, diastereo- and enantioselective reactions with a varie-
ty of electrophiles.7 These reactions provide a new ap-
proach to the enantioselective generation of chiral amines
(Scheme 1). While catalysts C-2 and QD-1 consistently af-
forded exceedingly high reactivity and selectivity, the cor-
responding pseudoenantiomeric catalysts derived from
cinchonidine CD-2 or quinine Q-1 are in general less effi-
cient and selective. For reactions with relatively active
electrophiles such as enals 7, even the less efficient cata-
lysts CD-2 could still provide synthetically useful access to
the chiral amine products ent-8 with 61-89% ee values and
32-86% yield (see scheme 1a).
Figure 1. Representative nature-originated cinchona alkaloids
2. RESULTS AND DISCUSSION
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Figure 2. Crystal structures of catalyst QD-1, Q-1 and epiQ-1. The structure of vdQ-1 was a model based on the crystal structure of
Q-1. The protons and solvent molecules have been omitted for clarity (C: grey, O: red, N: blue, Br: orange, Cl: green).
Table 1a. Development of novel cinchona catalysts for generation of opposite enantiomers with high optical
purities.a
Entry
cat. (x mol%)
QD-1 (5.0)
Q-1 (5.0)
conv. (%)b
4Ja/5Jab
>95:5
90:10
>95:5
>95:5
>95:5
4Ja/6Jb
>95:5
63:37
87:13
>95:5
>95:5
ee of 4Ja (%)c
91 (R)
1
2
3
4
5
95
83
67 (S)
vdQ-1 (5.0)
epiQ-1 (5.0)
epiQ-1 (3.0)
95
83 (S)
100
99
95 (S)
95 (S)
aUnless noted, reactions were performed with trifluoromethyl imine 1J (0.025 mmol), α,β-unsaturated N-acyl pyrrole 3a (0.05
mmol), aqueous KOH solution (0.25 μL, 50 wt%, 10 mol%), mesitol (6.8 mg, 2.0 equiv.), and catalyst (x mol%) in PhMe (0.25 mL)
b
c
at -40 °C for 1 h. Reaction conversion and product ratios were determined by 19F NMR analysis. The ee value of product 4Ja was
determined by HPLC analysis.
However, for reactions with less reactive electrophiles
such as α,β-unsaturated N-acyl pyrroles 3, the
pseudoenantiomeric catalyst Q-1 proceeded with drasti-
cally lower enantioselectivities and yields (32-69% ee, 22-
78% yield, see Scheme 1b). As illustrated by a comparison
of results obtained respectively from QD-1 and Q-1 cata-
lyzed additions of trifluoromethyl imine 1J to α,β-
unsaturated N-acyl pyrrole 3a (entry 1 vs 2, Table 1a), Q-1
not only afforded significantly lower enantioselectivity of
desired product 4Ja (67% ee vs 91% ee), but also poorer
chemoselectivity (63:37 vs >95:5) and regioselectivity
(90:10 vs >95:5) with obviously decreased reaction con-
version (83% conv. vs 95% conv.).
catalysts such as QD-1 critically depends on how the qua-
ternary nitrogen-centered tetrahedron, with C2, C6, C8,
and Ca as vertices, interacts with the anionic nucleophiles.9
Highly enantioselective phase transfer catalysis requires
that the anionic nucleophiles to be associated with great
preference with only one of the four faces of this tetrahe-
dron in cinchonium salts, where efficient chiral recognition
of the reacting substrates are attained. Reaction pathways
involving other faces of the cinchonium salts most likely
result in low enantioselectivity of the desired products. In
the X-ray structure of catalyst QD-1 (see Figure 2a), one
face of the quaternary ammonium salt was blocked by the
quinuclidine backbone (C2-C6-C8). The bulky N-(9-
anthrylmethyl) group provided an effective screening for
the C2-C6-Ca face, while the 5-phenyl ring of the PYR (4-
chloro-2,5-diphenylpyrimidine) group efficiently shielded
the face of C2-C8-Ca. The C6-C8-Ca face where the bromide
resided was the only open pocket. We therefore inferred
To gain insight into such disparity on both enantioselec-
tivity and catalytic reactivity mediated by this pair of
pseudoenantiomeric cinchona catalysts, we carried out
structural analysis of both cinchona catalysts QD-1 and Q-
1 (Figure 2).8 The catalytic efficiency of the cinchonium
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Table 1b. Substrate scope studies of trifluoromethyl imines with α, β-unsaturated N-acyl pyrroles.a
4
5
6
7
8
9
Entry
1
R1; 1
Me; 1A
Et; 1B
3
cat. (x mol%)
Mesitol (%) T (°C) conv. (%)b
4/5; 4/6b
Yield (%)c ee (%)d
95 | 78 (4Aa) 94 | 58
96 | 75 (4Ba) 94 | 59
91 | 73 (4Ca) 93 | 46
94 | 76 (4Da) 93 | 63
93 | 60 (4Ea) 95 | 66
91 | 61 (4Fa) 94 | 69
94 | 65 (4Ga) 92 | 58
93 | 22 (4Ha) 96 | 32
85 | 35 (4Ia) 95 | 59
85 | 33 (4Ja) 95 | 67
80 | 31 (4Ka) 94 | 60
83 | 33 (4La) 95 | 63
78 | 30 (4Ma) 94 | 60
80 | 28 (4Na) 95 | 56
82 | 35 (4Ob) 90 | 56
71 | 42 (4Ab) 93 | 54
65 | 32 (4Bb) 91 | 54
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11
12
13
14
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17
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22
23
24
25
26
27
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29
30
31
32
33
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35
36
37
38
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41
42
43
44
45
46
47
48
49
50
51
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53
54
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56
57
58
59
60
3a
3a
3a
epiQ-1 | Q-1 (0.5)
epiQ-1 | Q-1 (1.5)
epiQ-1 | Q-1 (1.5)
epiQ-1 | Q-1 (1.5)
epiQ-1 | Q-1 (3.0)
epiQ-1 | Q-1 (3.0)
epiQ-1 | Q-1 (1.5)
epiQ-1 | Q-1 (1.5)
epiQ-1 | Q-1 (2.0)
epiQ-1 | Q-1 (3.0)
epiQ-1 | Q-1 (3.0)
epiQ-1 | Q-1 (3.0)
epiQ-1 | Q-1 (2.0)
epiQ-1 | Q-1 (3.0)
epiQ-1 | Q-1 (3.0)
epiQ-1 | Q-1 (3.0)
epiQ-1 | Q-1 (3.0)
10
10
-20
-20
-20
-20
-20
-20
-20
-50
-20
-40
-40
-20
-20
-30
-20
-20
-20
100 | 85
100 | 86
100 | 83
100 | 85
100 | 82
97 | 82
>95:5; >95:5 | >95:5; >95:5
>95:5; >95:5 | >95:5; >95:5
>95:5; >95:5 | 92:8; >95:5
>95:5; >95:5 | 95:5; >95:5
>95:5 >95:5 | 91:9; >95:5
>95:5; >95:5 | 87:13; >95:5
>95:5; >95:5 | >95: 5; >95:5
>95:5; >95:5 | 77:23; 36:64
>95:5; >95:5 | 89:11; 73:27
>95:5; >95:5 | 90:10; 63:37
>95:5; >95:5 | 93:7; 56:44
>95:5; >95:5 | 70:30; 82:18
>95:5; >95:5 | 70:30; 79:21
>95:5; >95:5 | 75:25; 70:30
>95:5; >95:5 | 90:10; 65:35
90:10; >95:5 | 65:35; >95:5
81:19; >95:5 | 62:38; >95:5
2
3
n-Bu; 1C
10
4
CH2=CH(CH2)3; 1D 3a
10
5
Cy; 1E
CyCH2; 1F
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
10
6
10
7
PhCH2CH2; 1G
PhCH=CH; 1H
Ph; 1I
10
99 | 90
8
200
100
200
200
100
100
200
20
100 | 95
99 | 80
9
10
11
12
13
14
15e
16e
17e,f
4-ClC6H4; 1J
4-CF3C6H4; 1K
4-MeOC6H4; 1L
3-MeC6H4; 1M
2-Naphthyl; 1N
H; 1O
99 | 83
100 | 93
99 | 90
97 | 77
98 | 73
100 | 100
100 | 83
98 | 80
Me; 1A
20
Et; 1B
20
aUnless noted, reactions were performed with trifluoromethyl imines 1 (0.2 mmol), α,β-unsaturated N-acyl pyrroles 3 (0.4
mmol), mesitol (y mol%) and aqueous KOH solution (2.2 μL, 50 wt%, 10 mol%), and catalyst (x mol%) in PhMe (2.0 mL) at indi-
cated temperature (-20~-50 °C) for 1 h, see supporting information for details. For entries 1-7, PhMe/CHCl3 (4:1, 2.0 mL in total)
was used as the solvent. bReaction conversion and product ratios were determined by 19F NMR analysis. cYield of isolated products.
dThe ee value of products 4 was determined by HPLC analysis. Anhydrous NaOH solid powder (1.0 equiv.) was used as the base,
reaction time was 0.5 h and the diastereoselectivity of the products 4 were >95:5. The absolute configuration of compound 4Bb
was further determined to be R, R by X-ray crystallographic analysis.8
e
f
that this face was where the 2-azaallyl anions such as 2J
associate with the cinchonium catalyst and then selectively
reacted with the electrophile in a highly enantioselective
manner. By a similar analysis of the X-ray structure Q-1,
we concluded that the C6-C8-Ca face was still the most
open and was where the enantioselective reaction of oppo-
site sense of asymmetric induction occurred. However, the
respective location of the vinyl group was shown to not
only render the two respective C6-C8-Ca faces in QD-1 and
Q-1 pseudoenantiomeric but also to intrude into the C6-
C8-Ca face in Q-1 (see Figure 2b). By making the C6-C8-Ca
face more congested, the presence of the vinyl group could
negatively impact the catalyst efficiency of Q-1 either by
slowing down the rate of the enantioselective reaction or
diminishing its ability to exercise chiral recognition.
the other hand, it was interesting to observe that vdQ-1
was still not as effective as QD-1 for the efficient steric con-
trol (83% ee vs 91% ee) and chemoselectivity (87/13 vs
>95/5, entry 3 vs 1). A plausible explanation of the dis-
crepancy in catalytic efficiency between vdQ-1 and QD-1
was that the presence of the vinyl group in the latter by
working together with the PYR group provided effective
shielding of the C2-C8-Ca face, thereby contributing to the
catalyst efficiency of QD-1 by minimizing non-selective
reaction pathways that could occur in the C2-C8-Ca pocket.
In principle, creating the exact enantiomer of QD-1
would provide a catalyst of equal efficiency with the com-
plementary sense of asymmetric induction. Unfortunately,
we were not able to design a synthetic route to accomplish
this task without compromising the practical accessibility
of this catalyst.11 Nevertheless, the unexpected effect of the
vinyl group confirmed the importance of effectively shield-
ing the faces of the quaternary nitrogen-centered tetrahe-
dron other than the face in which the desirable asymmetric
reaction occurred. We therefore designed epiQ-1 as a new
pseudoenantiomer of QD-1 for the development of an effi-
cient catalyst of complementary sense with the asymmet-
ric induction. Our design was based on the considerations
We envisaged that, by removing the vinyl group from Q-
1, a new quinine-derived catalyst with a more accessible
C6-C8-Ca pocket might afford improved enantioselectivity
and catalytic efficiency. Following these considerations, we
prepared the “vinyl deleted” catalyst vdQ-1 (see Figure
2c).10 To our delight, we found that vdQ-1 indeed per-
formed significantly better than Q-1 in terms of chemo-,
regio- and enantioselectivity (entry 3 vs 2, Table 1a). On
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that the vinyl group in epiQ-1 would not intrude into the
C6-C8-Ca face but also serve as an extra steric barrier to
the C2-C6-Ca face.
catalyst than QD-1, as demonstrated by the employment of
lower catalyst loadings and the generation of the desired
chiral products with better optical purities.7c
1
2
3
4
5
6
7
8
9
There was only one literature report of the preparation
of epi-vinyl quinine or quinidine (epiQ or epiQD) through a
complicated synthetic route.12 To establish efficient access
to epiQ-1, we developed an oxidation-epimerization-Wittig
olefination sequence through the epimerizable aldehyde
intermediate 17 for the preparation of epiQ-1 in 20%
overall yield from quinine (Scheme 2). We next applied
catalyst epiQ-1 to promote the model reaction of imine 1J
with α,β-unsaturated N-acyl pyrrole 3a. To our delight,
epiQ-1 mediated a highly regio-, chemo- and enantio-
selective reaction, even superior to those catalyzed by QD-
1 (entry 4 vs 1, Table 1a), to furnish product 4Ja as nearly
an exclusive product. Further lowering the loading of epiQ-
1 to 3.0 mol% did not lead to any deterioration in reaction
outcomes (entry 5, Table 1a).
An X-ray structure of epiQ-1 was also successfully ob-
tained (see Figure 2d).8 Gratifyingly, the considerations
behind the design of epiQ-1 were validated, namely, by
switching the orientation of the vinyl group from pointing
at C6-C8-Ca pocket to the C2-C6-Ca pocket, the barrier to
the active site for the desired asymmetric reaction was
removed while a barrier was erected to the site for unde-
sirable reaction pathways leading to low enantioselectivi-
ty.
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11
12
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Table 2a. Catalysts comparison for asymmetric
reaction of trifluoromethyl imine 1B with acrolein.a
Scheme 2. Efficient preparation of epi-vinyl cinchona alka-
loid phase transfer catalyst epiQ-1.
Entry
cat (x mol%)
C-2a (0.2)
conv. (%)b
Yield (%)c
82 (10Ba)
81 (10Ba)
88 (10Ba)
91 (10Ba)
91 (10Ba)
ee (%)d
91 (S)
78 (R)
91 (R)
93 (R)
93 (R)
1
2
3
4
5
99
97
CD-2a (0.2)
epiCD-2a (0.2)
epiQ-2a (0.2)
epiQ-2a (0.1)
99
Reagents and conditions; (a) Ac2O, r.t., 1 h; (b) OsO4 (4% aq.
solution, 0.02 equiv.), K2CO3 (3.0 equiv.), K3[Fe(CN)6] (3.0
100
99
t
equiv.), BuOH/H2O (1:1 ratio), r.t., 6 h; (c) NaIO4 (1.1 equiv.),
Silica gel, CH3CN, r.t., 12 h, 85% yield over three-steps; (d)
Ph3PMeBr (1.2 equiv.), KOtBu (1.2 equiv.), THF, CH2Cl2, -78 to
0 °C, 0.5 h, 38% yield; (e) 4,6-dichloro-2,5-diphenylpyrimidine
(PYR-Cl, 1.2 equiv.), ground KOH (15.0 equiv.), PhMe, reflux,
0.5 h, 75% yield; (f) CH3CN, r.t, 5 h, 83% yield.
aReactions were performed with trifluoromethyl imine 1B
(0.2 mmol), acrolein 7a (0.4 mmol), aqueous KOH solution
(2.2 μL, 50 wt%, 10 mol%), and catalyst (x mol%) in PhMe
b
(2.0 mL) at -10 °C for 3 h. Reaction conversion was deter-
mined by 19F NMR analysis after 3 h. cYield of isolated product.
dThe ee value of product 10Ba was determined by HPLC anal-
ysis.
We next investigated whether this remarkably efficient
catalysis by epiQ-1 could be extended from the model reac-
tion to additions of other imines 1 to 3. As summarized in
Table 1b, the trifluoromethyl imines 1A-G bearing simple
and functionalized linear, α, β, or γ-branched aliphatic
groups reacted efficiently with 3a in not only consistently
high enantioselectivity but also virtually perfect chemo-
and regioselectivity, generating the corresponding chiral
products 4Aa-Ga in 92-95% ee and 91-96% yields (entries
1-7, Table 1b). Catalyst epiQ-1 also afforded highly efficient
catalysis for reactions involving various alkenyl and aryl-
substituted trifluoromethyl imines 1H-N (entries 8-14,
Table 1b). Even for the additions to the less reactive β-
methyl α,β-unsaturated N-acyl pyrrole 3b, the reaction
furnished the desired adducts with exceedingly high dia-
stereoselectivity and excellent enantioselectivity (dr >
95/5 and 90-93% ee, entries 15-17, Table 1b). In compari-
son, the reactions in the presence of the quinine-derived
catalyst Q-1 only afforded moderate enantioselectivity and
poor chemo- and regioselectivity, leading to low reaction
yield in most cases (Table 1b). Interestingly, epiQ-1 was
found to be an even more reactive and enantioselective
Following these encouraging results, we became inter-
ested in exploring whether epi-vinyl cinchona catalysts
were applicable to other type of reactions. We then inves-
tigated the asymmetric imine umpolung reactions with
enals.7a As shown in Table 2a, we reported earlier that cat-
alyst C-2a mediated a highly chemo-, regio-, diastereo- and
enantio-selective reaction of trifluoromethyl imines 1 with
various enals 7 to deliver desired enantiomerically en-
riched amino alcohol products such as 10Ba with high
yield and excellent enantioselectivity (entry 1, Table 2a).
However, this model reaction in the presence of
pseudoenantiomeric catalyst CD-2a afforded the opposite
enantiomeric product 10Ba with only 78% ee (entry 2).
We next examined the epi-vinyl catalyst epiCD-2a13 and
found that the reaction efficiently proceeded to the desired
product with excellent yield and high optical purity (88%
yield and 91% ee, entry 3). Moreover, we found that cata-
lyst epiQ-2a,13 the quinidium analogue of epiCD-2a, per-
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formed as a slightly better catalyst to mediate the highly
efficient fashion (8/9 = 93/7, dr >95/5, 91% ee, entry 13),
thereby delivering the desired product 10Ae in useful
yield (73% yield)
1
2
3
4
efficient formation of product 10Ba with even higher en-
antioselectivity (93% ee, entry 4). Further lowering cata-
lyst loading of epiQ-2a to 0.1 mol%, the reaction still pro-
ceeded without any deterioration in both reaction selectiv-
ity and yield (entry 5).
5
6
7
8
9
Table 3. Catalysts comparison and substrate scope
studies for reaction of aldimines with acrolein.a
Table 2b. Substrate scope studies for the reaction of
trifluoromethyl imines with various enals catalyzed by
epiQ-2a.a
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11
12
13
14
15
16
17
18
19
20
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Entry
1d
2d
R1; 1
Me; 1A
R2; 7
H; 7a
t (h)
3
8/9 Yield (%)b ee (%)c
>95/5 88 (10Aa) 95
Catalyst comparison
n-Bu; 1C
PhCH=CH; 1H
Ph; 1I
H; 7a
3
>95/5 83 (10Ca)
>95/5 92 (11Ha) 97
94/6 73 (11Ia) 99
92/8 77 (11Ka) 98
93/7 68 (11La) 97
93
Entry
R1; 1
Cat (x mol%) t (h) Yield (%)b ee (%)c
3
H; 7a
1
1
2
3
4
Ph; 1P
Ph; 1P
Ph; 1P
Ph; 1P
C-2b (2.5)
CD-2b (2.5)
8
8
3
8
55 (12Pa) 93 (S)
52 (12Pa) 89 (R)
61 (12Pa) 93 (R)
60 (12Pa) 93 (R)
4
H; 7a
3
5
4-CF3C6H4; 1K
4-MeOC6H4; 1L
Me; 1A
H; 7a
3
epiCD-2b (2.5)
epiCD-2b (0.5)
6
7e
8e
9e
10e
11e
12e
13e,f
H; 7a
3
Me; 7b
Me; 7b
Me; 7b
Me; 7b
Et; 7c
5
>95/5 82 (10Ab) 94
>95/5 84 (10Bb) 93
Substrate scope studies
Et; 1B
5
5
6
7
8
4-MeOC6H4; 1Q
4-MeO2CC6H4; 1R epiCD-2b (0.5)
PhCH=CH; 1S epiCD-2b (0.5) 12 60 (12Sa) 90 (R)
4-BrC6H4CH=CH; 1T epiCD-2b (0.5) 12 55 (12Ta) 90 (R)
epiCD-2b (1.0) 12 56 (12Qa) 94 (R)
n-Bu; 1C
CyCH2; 1F
Me; 1A
5
>95/5 80 (10Cb)
>95/5 53 (10Fb)
84/16 64 (10Ac)
93
94
94
5
62 (12Ra) 91 (R)
5
5
Me; 1A
n-Hex; 7d 12 87/13 55 (10Ad) 97
Ph; 7e 93/7 73 (10Ae) 91
aUnless noted, reactions were performed with aldimines 1
(0.2 mmol), acrolein (7a, 0.4 mmol), aqueous KOH solution
(2.2 μL, 50 wt%, 10 mol%), and catalyst (x mol%) in PhMe
(2.0 mL) at 0 °C for indicated time. Yield of isolated product.
cThe ee value of product 12 was determined by HPLC analysis.
Me; 1A
8
aUnless noted, reactions were performed with trifluorome-
thyl imines 1 (0.2 mmol), enals 7 (0.4 mmol), aqueous KOH
(2.2 μL, 50 wt%, 10 mol%), and epiQ-2a (0.1 mol%) in PhMe
b
b
(2.0 mL) at -20 °C for indicated time. Yield of isolated prod-
We then explored the addition of aryl-substituted al-
dimines such as 1P to acrolein (7a) with the newly-
developed epi-vinyl catalyst epiCD-2b,13 which turned out
to be a considerably more powerful catalyst than either C-
2b or CD-2b (entries 3 vs 1-2, Table 3).7a Even at a drasti-
cally decreased loading of epiCD-2b (from 2.5 mol% to 0.5
mol%), a highly regio- and enantioselective reaction was
still realized to deliver the desired product 12Pa with good
yield and excellent enantioselectivity (entry 4). The subse-
quent substrate scope studies revealed that epiCD-2b in
0.5-1.0 mol% catalyst loadings continued to perform bet-
ter than CD-2b in 2.5-5.0 mol% loadings for reactions with
the more challenging aryl and alkenyl-substituted al-
dimines 1Q-T, furnishing the desired products 12Q-T with
improved yields (55-62% yield) and, for the first time,
greater than 90% ee (entries 5-8, Table 3).
c
uct. The ee value of product 10 or 11 was determined by
d
HPLC analysis. Reactions were performed at -10 °C through
slow addition, see supporting information for details. e0.2
mol% catalyst loading was used, the dr values of product 10
(entries 7-13) were >95/5. fThe regioselectivity of 8/9 = 93/7,
see supporting information for details.
The subsequent substrate scope studies revealed that
the reactions of a variety of alkyl, alkenyl and aryl substi-
tuted trifluoromethyl imines 1 with acrolein (7a) consist-
ently proceeded in good yields and high enantioselectivi-
ties (68-92% yield and 93-99% ee) with only 0.1 mol%
catalyst loadings (entries 1-6, Table 2b). For a series of β-
substituted enals such as 7b-d, epiQ-2a mediated similarly
highly stereoselective reactions with various trifluorome-
thyl imines bearing either linear or branched alkyl substit-
uents (entries 7-12). The sterically hindered cinnamalde-
hyde (7e) was previously shown to be a considerably chal-
lenging substrate due to moderate regioselectivity (8/9 =
78/22) and obviously decreased enantioselectivity (61%
ee).7a Notably, epiQ-2a catalyst promoted a highly chemo-,
regio-, diastereo- and enantio-selective reaction in a highly
The positive impact of the epi-vinyl group was also ob-
served with cinchonium catalysts developed for the um-
polung additions of imines 1 to different enones 13 (Table
4).7b In the model reaction of aryl-substituted aldimine 1P
and methyl vinyl ketone 13a, epiCD-2c13 catalyst showed
better reactivity and enantioselectivity than either CD-2c
or C-2c. The most dramatic improvement was on regiose-
ACS Paragon Plus Environment

Journal of the American Chemical Society
lectivity as reflected by the 14/15 ratio, which resulted in
significantly improved yield (entry 3 vs 1-2, Table 4). Once
again, decreasing the loading of epiCD-2c did not negative-
ly impact the reaction outcomes (entry 4 vs 3, Table 4).
The subsequent substrate scope studies demonstrated that
the superiority of epiCD-2c could be extended to reactions
between different imines (1U-V, 1A, 1I) and enones (13a-
b) (entries 5-8, Table 4).
Page 6 of 8
was found to be a considerably superior catalyst, allowing
the highly enantioselective isomerization of 1K to proceed
in 91% ee (entry 3). Even at a loading of 0.05 mol%, the
reaction still proceeded to full conversion without any de-
terioration on the yield and enantioselectivity (entry 4).
Meanwhile, catalyst Q-3 at a loading of 0.05 mol% mediat-
ed the isomerization of 1K to 6K with significantly de-
creased enantioselectivity (61% ee, entry 5). In parallel to
previous observations, the superiority of the epi-vinyl cata-
lyst epiQ-3 was not substrate-dependent. Excellent enanti-
oselectivities and quantitative yields were routinely ob-
tained for a series of alkyl, alkenyl and aryl substituted
substrates with only 0.05 mol% of epiQ-3 in all cases (93-
96% ee and 96-98% yield, Table 5, entries 6-10).
1
2
3
4
5
6
7
8
Table 4. Catalysts comparison and substrate scope
studies for the reaction of imines with enones.a
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
Table 5. Catalysts comparison and substrate scope
studies for catalytic asymmetric isomerization of
trifluoromethyl imines.a
Catalyst comparison
Entry
1
13 Cat (x mol%) t (h) 14/15b Yield (%)c ee (%)d
1
2
3
4
1P 13a
C-2c (2.5)
12 71:29 50 (16Pa) 82 (S)
12 66:34 45 (16Pa) 80 (R)
1P 13a CD-2c (2.5)
1P 13a epiCD-2c (2.5)
6
83:17 71 (16Pa) 86 (R)
1P 13a epiCD-2c (1.0) 12 82:18 70 (16Pa) 86 (R)
Catalyst comparison
Substrate scope studies
Entry
R1; 1
Cat (x mol%)
QD-3 (0.2)
Q-3 (0.4)
t (h) Yield (%)b ee (%)c
5
6
7e
8e
1U 13a epiCD-2c (1.0)
1V 13b epiCD-2c (1.0) 12 83:17 71 (16Vb) 86 (R)
1A 13b epiCD-2c (0.2) >95:5 91 (14Ab) 85 (R)
1I 13a epiCD-2c (0.2) 24 >95:5 93 (14Ia) 90 (S)
8
82:18 68 (16Ua) 86 (R)
1
2
3
4
5
4-CF3C6H4; 1K
4-CF3C6H4; 1K
4-CF3C6H4; 1K
24
24
12
24
24
96 (6K) 83 (R)
98 (6K) 76 (S)
97 (6K) 91 (S)
98 (6K) 91 (S)
96 (6K) 61 (S)
5
epiQ-3 (0.2)
4-CF3C6H4; 1K epiQ-3 (0.05)
aUnless noted, reactions were performed with imines 1 (0.2
mmol), enones 13 (0.4 mmol), aqueous KOH solution (2.2 μL,
50 wt%, 10 mol%), and catalyst (x mol%) in PhMe (2.0 mL) at
0 °C for indicated time. bProduct ratios were determined by 1H
NMR or 19F NMR analysis. Yield of isolated product. The ee
value of products 16 or 14 was determined by HPLC analysis.
eReactions were performed at -50 °C.
4-CF3C6H4; 1K
Q-3 (0.05)
Substrate scope studies
6d
7d
8
Me; 1A
Cy; 1E
epiQ-3 (0.05)
epiQ-3 (0.05)
24
24
24
24
24
96 (6A) 96 (S)
96 (6E) 96 (S)
96 (6H) 94 (S)
98 (6I) 94 (S)
98 (6J) 93 (S)
c
d
PhCH=CH; 1H epiQ-3 (0.05)
9
Ph; 1I
epiQ-3 (0.05)
epiQ-3 (0.05)
We recently reported the discovery of cinchonium beta-
ine catalyst QD-3 for the asymmetric isomerization of tri-
fluoromethyl imines 1 to the corresponding chiral trifluo-
romethylated amines 6.14 While the quinidine-derived cat-
alyst QD-3 afforded extraordinarily high catalyst turnover
numbers, ranging from 500 to 5000 per 24 h, the quinine-
derived catalyst Q-3 was less efficient, affording the oppo-
site enantiomer of the trifluoromethyl amines 6 in lower
enantioselectivity and catalyst turnover numbers. The tri-
fluoromethyl imines bearing electron-withdrawing sub-
stituents were particularly challenging substrates. As
shown by the isomerization of imine 1K mediated by QD-3
and Q-3, the (R)- and (S)-enantiomers of the chiral amine
6K were obtained in 83% and 76% ee, respectively (en-
tries 1-2, Table 5).
10
4-ClC6H4; 1J
aUnless noted, reactions were performed with trifluorome-
thyl imines 1 (0.2 mmol), solid K2CO3 (2.8 mg, 10 mol%) and
catalyst (x mol%) in PhMe (2.0 mL) at -20 °C for indicated
time. bYield of isolated product. cThe ee value of product 6 was
determined by HPLC analysis. Reactions were performed at
room temperature.
d
3. CONCLUSION
In conclusion, we carried out structural studies of a pair
of pseudoenantiomeric cinchonium salts that demonstrat-
ed a significant discrepancy in their efficiency as catalysts
to promote asymmetric umpolung reactions of imines.
These structural studies revealed that the orientation of
the vinyl group on the quinuclidine scaffold might play an
essential role in causing the compromised efficiency of the
worse performing pseudoenantiomer catalyst. Following a
We observed that the epi-vinyl effect was in play for the-
se betaine catalysts. Specifically, epi-vinyl catalyst epiQ-313
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Journal of the American Chemical Society
(2.52 g, 45.0 mmol, 15.0 equiv.). The suspension was then re-
hypothesis-driven approach guided by these key insights
gained from our structural studies, we developed novel
epi-vinyl quinine- and epi-vinyl cinchonidine-based cata-
lysts, which afford dramatically improved reactivity and
stereoselectivity over those by the corresponding quinine-
or cinchonidine-based catalysts. Importantly, this “epi-
vinyl modification” proved consistently effective in im-
proving the poor performance of several quinine- or cin-
chonine-derived cinchonium catalysts mediating different
catalytic asymmetric imine umpolung reactions, thereby
allowing these reactions to provide efficient access to not
one but both enantiomers of the chiral amines of interest.
We expect that this “epi-vinyl approach” may be applicable
to address the “pseudoenantiomer problem” arising from
other cinchona alkaloid-mediated asymmetric reactions.
fluxed for 30 mins. The resulting mixture was cooled down to
room temperature and quenched by water (30.0 mL). The mix-
ture was separated, and the aqueous layer was extracted with
ethyl acetate (30.0 mL × 2). The combined organic extracts were
successively washed with brine (60.0 mL), dried over Na2SO4 and
concentrated under vacuum. The residue was purified through
flash chromatography on silica gel (CH2Cl2/MeOH = 100/1 to
10/1) to afford 19 as white solid (1.33 g, 75% yield).
f) To a solution of 19 (1.18 g, 2.0 mmol, 1.0 equiv.) in CH3CN
(20 mL) was added 9-(bromomethyl)anthracene (0.54 g, 2.0
mmol, 1.0 equiv.) at room temperature. The reaction mixture was
stirred at room temperature for 5 h and then concentrated under
vacuum. The resulting residue was purified through flash chroma-
tography on silica gel to afford epiQ-1 as light yellow solid (1.43 g,
83% yield).
4.2. General Procedure for reaction of trifluoromethyl
imines with α,β-unsaturated N-acyl pyrroles. At indicated
temperature, to a solution of trifluoromethyl imines 1 (0.2 mmol,
1.0 equiv.), α,β-unsaturated N-acyl pyrroles 3 (0.4 mmol, 2.0
equiv.), mesitol (y mol%) and catalyst epiQ-1 or Q-1 (x mol%) in
PhMe (2.0 mL) [For entries 1-7 in Table 1b, PhMe/CHCl3 (4/1,
totally 2.0 mL) was used as solvent] was added aqueous KOH
solution (2.2 µL, 50 wt%, 0.02 mmol). The mixture was then vig-
orously stirred and turned purple immediately. After 1 h, the
reaction was completed and passed through a small pad of deac-
tivated silica gel15 (5 cm thick), washed with Et2O (1.0 mL × 3).
The filtrates were combined, concentrated under vacuum, puri-
fied through flash chromatography with deactivated silica gel to
afford the desired products 4.
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
4. EXPERIMENTAL SECTION
4.1. Procedure for the preparation of epi-vinyl cinchona
alkaloid phase transfer catalyst epiQ-1. a) The reaction sus-
pension of cinchona alkaloids quinine (Q, 3.3 g, 10.0 mmol) in
acetic anhydride (15.0 mL) were stirred at room temperature for
1 h. After that, the reaction solution became clear and then was
poured into ice-water, basified with aqueous ammonium hydrox-
ide solution, and extracted with CH2Cl2 (100 mL × 3). The com-
bined organic phase was then successively washed with brine
solution, dried over anhydrous Na2SO4, concentrated to give acet-
ylated quinine intermediates without further purification for the
next step. b) Under nitrogen atmosphere, to a reaction mixture of
the resulting acetylated quinine, K2CO3 (4.15 g, 30 mmol, 3.0
equiv.), K3[Fe(CN)6] (9.9 g, 30 mmol, 3.0 equiv.) in tBuOH/H2O
(100 mL, 1:1 ratio) was added OsO4 (1.50 mL, 4% aq. solution,
0.02 equiv.). The reaction mixture was stirred at room tempera-
ture for 6 h, then sat. NaHSO3 solution (100 mL) was added and
stirred for 0.5 h. The resulting reaction mixture was then concen-
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
t
trated under vacuum to remove BuOH and the aqueous solution
was then extracted with CH2Cl2 (120 mL × 3). The combined or-
ganic layer was dried over anhydrous Na2SO4, concentrated under
vacuum to afford diol intermediates without further purification
for the next step. c) To a vigorously stirred suspension of diol
intermediates and silica gel (10.0 g, the formed chiral aldehyde
group could slowly epimerize into 1:1 ratio with the silica gel) in
CH3CN (100 mL) under nitrogen atmosphere was added NaIO4
(2.35 g, 11.0 mmol, 1.1 equiv.). The mixture was stirred at room
temperature until the full racemization of the chiral aldehyde
(checked with NMR). The silica gel was then filtered off and the
resulting residue was washed with CH2Cl2 (50 mL × 3). The fil-
trates were then concentrated, purified via flash chromatography
on silica gel to give desired product 17 as white foam with dr
ratio around 1:1 and 85% yield over three steps.
d) To an ice-cooled suspension of methyltriphenylphosphoni-
um bromide (0.90 g, 2.4 mmol, 1.2 equiv.) in anhydrous THF (30.0
mL) was added potassium tert-butoxide (0.27 g, 2.4 mmol, 1.2
equiv.). The reaction mixture was stirred at 0 °C for 1 h and
cooled down to -78 °C. A solution of 17 (2.0 mmol, 1.0 eq.) dis-
solved in anhydrous CH2Cl2 (15.0 mL) was then added dropwise
into the reaction mixture at -78 °C. The reaction mixture was
stirred and warmed up for 30 min before pouring into water (50
mL). The aqueous layer was extracted with CH2Cl2 (50 mL × 3).
The combined organic extracts were successively washed with
brined (100 mL), dried over Na2SO4, concentrated under vacuum.
The residue was then purified by flash chromatography on silica
gel to give desired epi-vinyl intermediate 18 with 38% yield (The
epi-vinyl version of cinchona alkaloids was slightly less polar on
TLC plate).
X-ray Crystallographic data for catalyst QD-1 (cif)
X-ray Crystallographic data for catalyst Q-1 (cif)
X-ray Crystallographic data for catalyst epiQ-1 (cif)
X-ray Crystallographic data for compound 4Bb (cif)
Experimental procedures, characterization of the product and
NMR spectra (PDF).
AUTHOR INFORMATION
Corresponding Author
*deng@brandeis.edu
Funding Sources
We are grateful for the financial support from the National
Institute of General Medical Science (GM-61591) and the Keck
Foundation.
Notes
The authors declare no competing financial interest
ACKNOWLEDGMENT
We thank Dr. Shao-Liang Zheng from Harvard University for
his help with the X-ray data collection.
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Journal of the American Chemical Society
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(14) Zhou, X.; Wu, Y.; Deng, L., J. Am. Chem. Soc. 2016, 138, 12297.
(15) The deactivated silica gel was prepared from treating nor-
mal silica gel with triethylamine. See the Supporting Information
for details.
(6) (a) Provencher, B. A.; Bartelson, K. J.; Liu, Y.; Foxman, B. M.;
Deng, L., Angew. Chem. Int. Ed. 2011, 50, 10565. (b) Wang, B.; Liu,
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