Structural study-guided development of versatile phase-transfer catalysts for asymmetric conjugate additions of cyanide

Article abstract of DOI:10.1002/anie.201105536

Unprecedented phase-transfer catalysts for the first example of an organocatalytic asymmetric conjugate addition of cyanide with acetone cyanohydrin are reported (see scheme). Utilizing an accessible cupreidinium salt and a cyanation reagent suitable for industrial scale, this reaction holds significant promise for practical asymmetric synthesis. The catalysts were developed as a result of key structural insights gained by X-ray analysis. Copyright

Full text of DOI:10.1002/anie.201105536

DOI: 10.1002/anie.201105536
Asymmetric Catalysis
Structural Study-Guided Development of Versatile Phase-Transfer
Catalysts for Asymmetric Conjugate Additions of Cyanide**
Brian A. Provencher, Keith J. Bartelson, Yan Liu, Bruce M. Foxman, and Li Deng*
Significant advances have been made in the development of
catalytic 1,2-asymmetric cyanations using both chiral metal
and organic catalysts.[1] In contrast, only a few highly
enantioselective catalytic conjugate additions of cyanide
ions have been realized despite the potential of such trans-
formations in providing efficient enantioselective access to
synthetically valuable chiral building blocks.[2]
explore them for the asymmetric conjugate addition of
cyanide. Similar to other known bifunctional phase-transfer
catalysts that bear
cupreidinium salts CPD-1, could in principle mediate phase-
transfer catalysis by their association with an anionic cyan-
ation species, presumably a cyanide or cyanoalkoxide ion, by
simultaneous ion-pair and hydrogen-bonding interactions (I,
Scheme 1). Alternatively, CPD-1 could promote the conju-
gate addition by simultaneous interactions with both the
cyanation species and the enone (II, Scheme 1).
a
hydrogen-bond-donor moiety,[13–15]
The first breakthroughs were reported by Jacobsen and
co-workers, who described chiral Al-Salen[3] and bimetallic
cooperative catalyst systems[4] for the enantioselective con-
jugate additions of trimethylsilyl cyanide (TMSCN) to a,b-
unsaturated imides. Shibasaki, Kanai, and co-workers
reported two chiral bifunctional catalysts derived from
gadolinium, strontium, and different asymmetrically prepared
or carbohydrate-based chiral ligands for a highly enantiose-
lective 1,4-addition of cyanide with HCN/trialkylsilyl cya-
nides to a,b-unsaturated N-acyl pyrroles[5] and enones,[6]
respectively. Feng[7] and co-workers have reported a modular
titanium catalyst for the cyanation of alkylidine malonates.
Very recently, Ohkuma[8] and co-workers disclosed a chiral
Ru complex for the conjugate addition of TMSCN to enones.
These existing reactions, while representing remarkable
success in establishing general substrate scope and high
catalyst efficiency, require the use of various trialkylmetal
cyanides in super-stoichiometric amounts. Thus, we became
interested in the development of highly enantioselective
catalytic 1,4-additions of cyanide with readily accessible and
easy to handle cyanation reagents.
Chiral phase-transfer catalysis has been developed as an
effective strategy for the activation of practical cyanation
reagents, such as KCN[9] and acetone cyanohydrin,[10] for
asymmetric 1,2-additions of cyanides. On the other hand, this
strategy has so far been attempted only with 1,4-additions of
cyanide to nitroalkenes.[11] These attempts have so far been
met with limited success. Our recent development of cuprei-
nium salts 1, as highly enantioselective phase-transfer cata-
lysts for an asymmetric Darzens reaction,[12] prompted us to
Scheme 1. Proposed modes of activation by the bifunctional chiral
catalysts.
We first investigated the asymmetric conjugate addition of
acetone cyanohydrin to enone 5a. As the equilibrium
between cyanohydrin and the enone is known to favor the
latter under basic conditions,[16] we reasoned that chiral
phase-transfer catalysis might provide an attractive strategy
to address the 1,2- vs. 1,4-chemoselectivity issue in the
conjugate addition of cyanide to enones. Accordingly, enone
5a was treated with acetone cyanohydrin in the presence of
cupreidinium salt CPD-1a and Cs2CO3 in toluene/CHCl3 at
room temperature. We were pleased to find that the reaction
proceeded cleanly to give the 1,4-adduct 6a as the only
detectable product. Although CPD-1a exhibited very low
enantioselectivity (entry 1, Table 1), the easily modifiable 9-
and N-substituents in CPD-1 should provide valuable handles
for catalyst tuning (see Scheme 2).
[*] B. A. Provencher, K. J. Bartelson, Dr. Y. Liu, Prof. B. M. Foxman,
Prof. L. Deng
We obtained a single crystal X-ray structure of CPD-1a
(Figure 1a), which revealed the possible cause of the poor
asymmetric induction demonstrated by CPD-1a.[17] The
catalytic efficiency of the cupreidinium salts critically depends
on how the quaternary nitrogen-centered tetrahedron, with
C2, C6, C8, and CBn (Bn = benzyl; quinine numbering) as
vertices, interacts with the anionic nucleophile.[18] In order to
achieve optimal efficiency, the catalyst should minimize other
possible transition states by allowing the anion to preferen-
tially associate with one face of the tetrahedron. In CPD-1a,
one face is completely blocked by the quinuclidine backbone
(C2-C6-C8), while the N1-benzyl and the O-benzyl groups
Department of Chemistry, Brandeis University
Waltham, MA 02454-9110 (USA)
E-mail: deng@brandeis.edu
Dr. Y. Liu
State Key Laboratory of Catalysis, Dalian Institute of Chemical
Physics
Dalian 116023 (China)
[**] We are grateful for the generous financial support of the National
Institutes of Health (GM-61591).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201105536.
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Communications
Table 1: Conjugate addition of cyanide to 5a.[a]
Entry
PTC
t [h]
Conv.[b]
ee[c]
1
2
3
4
5
6
CPD-1a
CPD-1b
CPD-1c
CPD-1d
CPD-1e
CPD-1 f
CPD-1 f
CPD-1g
CPD-2
CPD-2
CPN-2
CPN-1c
CPN-1 f
CPN-3
25
45
65
65
65
65
24
24
24
24
24
24
24
24
96
24
72
65
72
80
72
8
40
60
73
82
90
90
25
95
91
7[d]
8[d]
9[d]
10[d,e]
11[d]
12[d]
13[d]
14[d]
15[d,e]
16[d]
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
95
À71
À16
À64
À90
À90
À21
CPN-3
CPN-4
[a] Unless otherwise noted, reactions were performed with 5a
(0.05 mmol), acetone cyanohydrin (0.05 mmol) and Cs2CO3
(0.06 mmol) in 0.5 mL of toluene/CHCl3 (7:3 v/v) with 10 mol% of
catalyst. [b] % Conversion determined by GC. [c] ee was determined by
HPLC on a chiral stationary phase, see the Supporting Information for
details. [d] Acetone cyanohydrins (0.1 mmol). [e] 5.0 mol% cat.
PTC=phase-transfer catalyst.
Scheme 2. Structure of the phase-transfer catalysts.
Figure 1. Single-crystal X-ray structures of cupreidinium and cuprei-
nium salts 1. The tetrahedral face on which the bromide ion resides is
highlighted. Except for the stereogenic centers, the protons and
solvent molecules have been removed for clarity. The Br···H distances
are: a) CPD-1a: 2.41 ꢀ, b) CPD-1c: 2.40 ꢀ, c) CPN-1c: 2.54 ꢀ; see the
Supporting Information for full details. (C: gray, H: white, O: red, N:
blue, Br: orange, Cl: green).
shield the C2-C6-CBn and the C2-C8-CBn faces, respectively.
The C6-C8-CBn face appeared to be least hindered and the
bromide ion residing on this face was also able to engage in a
hydrogen-bonding interaction with the 6’-OH. Assuming the
anionic nucleophile replaces the bromide in the transition
state, the hydrogen-bonding interaction between the 6’-OH
and the nucleophile contributes to the preferential interaction
of the nucleophile with the C6-C8-CBn face. Consequently,
reducing the rotational flexibility of the C9-C4’ bond could
improve the catalytic enantioselectivity of the cupreidinium
salt CPD-1a.
Based on the structure of CPD-1a, we reasoned that
increasing the steric bulk of the 9-substiuent could in turn
provide a more effective barrier to lock the quinoline ring in
place and thus produce a catalyst that provides better
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enantioselectivity. Following this consideration we investi-
gated cupreidinium salts CPD-1b and CPD-1c, which
afforded significantly higher enantioselectivities of 40% and
60%, respectively (entries 2 and 3, Table 1). Fortunately, we
were able to obtain an X-ray structure of CPD-1c (b,
Figure 1), which showed that the 9-OPYR (PYR = 6-chloro-
2,5-diphenylpyrimidin-4-yl) was clearly a more effective
barrier than 9-OBn (B vs. A). The structure of CPD-1c also
suggested an additional means for catalyst tuning. Specifi-
cally, increasing the bulk of the aryl group on the tetrahedral
nitrogen atom could further hinder the interaction of the
nucleophile with the C2-C6-CBn face, thereby enhancing the
preference for the nucleophile to associate with the C6-C8-
CBn face. Subsequent investigations identified several 9-
OPYR cupreidinium salts (CPD-1d–f) that bear various
bulky N-substituents that afforded improved enantioselectiv-
ity (entries 3-6, Table 1). Among these cupreidinium salts,
CPD-1 f was found to be the most selective (entry 6, Table 1),
although an increased reaction time was required to reach
over 90% conversion. By increasing the amount of the
cyanohydrin from 1.0 to 2.0 equivalents, the reaction time
could be shortened to 24 h without compromising the
enantioselectivity (entries 7, Table 1). To confirm the bifunc-
tional nature of catalyst CPD-1 f, CPD-1g, the corresponding
quinidinium catalyst, was prepared and was found to furnish
6a in only 25% ee, thus demonstrating the importance of the
6’OH.
A surprising observation with the structure of cupreidi-
nium-derived CPD-1c is the proximity of the vinyl group to
the 9-OPYR. This observation led us to examine the impact of
altering the vinyl group on the catalytic enantioselectivity. To
our delight, cupreidinium salt CPD-2, the dihydro analogue of
CPD-1 f, was found to be noticeably more enantioselective,
affording 95% ee for the transformation of 5a into 6a (entry 9
vs. 7, Table 1). Furthermore, the loading of CPD-2 could be
reduced to 5 mol% without any negative impact on the
reaction (entry 10 vs. 9, Table 1).
To establish facile access to both enantiomers of 6a, we
turned our attention to the cupreinium-derived catalyst CPN-
2. Unfortunately, the pseudoenantiomeric nature of the
cinchona alkaloid had a significantly negative impact as
CPN-2 afforded drastically lower enantioselectivity than that
offered by CPD-2 (entry 11 vs. 10, Table 1). Similarly,
compared to CPD-1c, CPN-1c furnished lower enantioselec-
tivity (entry 12 vs. 3). To gain insight into this disparity in
enantioselectivity between the cupreidinium and cupreinium
salts, we attempted to obtain X-ray structures of CPN-2 and
CPN-1c. With our best efforts, only the structure of CPN-1c
could be obtained (Figure 1c), which showed that the bromide
ion resides on the C2-C8-CBn face while forming a hydrogen
bond with the 6’-OH. Without the vinyl group, the two
bromide-ion-binding pockets in CPD-1c and CPN-1c are
enantiomeric with respect to each other. However, as
represented by the structure of CPN-1c, the presence of the
vinyl group in proximity to the anionic-binding pocket could
function as a barrier to impede the incoming electrophile,
thereby negatively impacting the catalytic efficiency of
cupreinium salts CPN-1c and CPN-2.
We then hypothesized that this negative impact could be
mitigated by converting the vinyl group into a hydrogen-
bond-donor moiety as an attractive hydrogen-bonding inter-
action between the electrophile and this moiety could
improve the catalytic efficiency of the cupreinium salts. To
test this hypothesis, we prepared CPN-3 by converting the
vinyl group in CPN-1 f into a 2-hydroxyethyl moiety. To our
delight, catalyst CPN-3 provided significantly improved
enantioselectivity over that provided by either CPN-2 or
CPN-1 f (entries 14 vs. 11 and 13, Table 1). Lowering the
loading of CPN-3 from 10 mol% to 5 mol% did not
compromise enantioselectivity, although a longer reaction
time was necessary to reach completion (entry 15, Table 1).
To verify whether the 6’-OH in CPN-3 is still necessary for its
catalytic efficiency we also examined CPN-4, which produced
6a in only 21% ee (entry 16, Table 1). The considerably
inferior enantioselectivity afforded by CPN-1 f, CPN-2, and
CPN-4 illustrates that both the 6’-OH and the aliphatic
alcohol are required to achieve high efficiency with CPN-3.
With the development of highly enantioselective phase-
transfer catalysts from both cupreidinium (CPD-2) and
cupreinium (CPN-3) salts, we began to investigate the scope
of these phase-transfer catalysts for the asymmetric 1,4-
addition of acetone cyanohydrin. With respect to the 1,4-
additon to enones, mediated by CPD-2 and CPN-3, the high
enantioselectivity observed with enone 5a was found to be
sustainable over a considerable range of acyclic enones that
bear various linear and branched alkyl groups as the
b substituent (Table 2). Notably, the length of the linear
Table 2: Conjugate addition of cyanide to 5.[a]
Entry
5
R1
R2
PTC
t [h] Yield[b] ee[c]
1
2
3
4
5
6
5a Ph
5a Ph
5b Ph
5b Ph
5c Ph
5c Ph
5d Ph
5d Ph
5e Ph
5e Ph
5 f Ph
5 f Ph
5g 4-Me-C6H4
5g 4-Me-C6H4
5h 4-OMe-C6H4 Me
5h 4-OMe-C6H4 Me
5i 4-Cl-C6H4
5i 4-Cl-C6H4
Et
Et
Me
Me
n-C5H11
n-C5H11
iPr
iPr
CH2iPr
CH2iPr
CPD-2 24
CPN-3 24
CPD-2 24
CPN-3 24
CPD-2 96
CPN-3 24
CPD-2 72
CPN-3 24
CPD-2 72
CPN-3 24
77
97
78
92
89
73
69
80
80
91
75
77
78
99
88
98
82
77
95 (S)
90 (R)
97 (S)
91 (R)
96 (S)
92 (R)
94 (S)
93 (R)
97 (S)
93 (R)
93 (S)
87 (R)
95 (S)
92 (R)
97 (S)
94 (R)
96 (S)
90 (R)
7[d]
8
9[d]
10
11[d]
12
13
14
15
16
17
18
CH2OSiEt3 CPD-2 48
CH2OSiEt3 CPN-3 24
Me
Me
CPD-2 48
CPN-3 24
CPD-2 48
CPN-3 24
Me
Me
CPD-2
CPN-3
6
4
[a] Unless otherwise noted, reactions were performed with 5 (0.1 mmol),
acetone cyanohydrin (0.2 mmol) and Cs2CO3 (0.12 mmol) in 1 mL of
toluene/CHCl3 (7:3 v/v) with 5 mol% CPD-2 (or 10 mol% CPN-3a).
[b] Yield of isolated product. [c] Determined by HPLC on a chiral
stationary phase. The absolute configuration is reported in parenthesis,
see the Supporting Information for details. [d] 10 mol% CPD-2.
PTC=phase-transfer catalyst.
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Communications
alkyl groups has little influence on the enantioselectivity
(entries 5 and 6). Moreover, the reaction proceeded in a
highly enantioselective manner with not only a d-branched
enone, but also a sterically hindered g-branched enone
(entries 7–10).[19] With respect to the ketone substituent,
aromatic rings substituted with either electron-withdrawing
or donating groups were well tolerated (entries 13–18,
Table 2). However, enones that bear an aliphatic ketone
substituent were found to be inactive for the reaction.
In addition to enones, we found that both CPD-2 and
CPN-3 afforded high enantioselectivity for the addition of
acetone cyanohydrin to b-alkyl-a,b-unsaturated N-acyl pyr-
roles. This result is particularly noteworthy as it establishes a
useful method to provide ready enantioselective access to
both enantiomers of synthetically important optically active
b-cyano carboxylic acid derivatives (Table 3). For this reac-
tion, Rb2CO3 proved to be a superior base to Cs2CO3
(entries 1–2 vs. 3–4, Table 3). Once again, the high enantio-
selectivity appeared to be independent of the steric property
of the b-alkyl group affording high enantioselectivity for
linear as well as g- and d-branched a,b-unsaturated N-acyl
pyrroles.
Scheme 3. Synthesis of 6-Phenyl-4,5-dihydropyridazin-3(2H)-ones.
a) 12n HCl, 08C, 82% yield, 95% ee; b) NH2NH2, pTsOH, EtOH,
758C, 63% yield, 95% ee.
52% by a two-step sequence: 1) stirring of 6a in 12.0n HCl at
08C to form amide 9a; 2) heating the intermediate 9a in
ethanol with hydrazine in the presence of a catalytic amount
of p-toluenesulfonic acid. This route should be applicable to
the synthesis of a range of analogues of 10a. To the best of our
knowledge, only a chiral auxiliary-mediated asymmetric
synthesis of 10 has been reported so far.[23]
In summary, we have developed a new class of chiral
catalysts, CPN-3, for the asymmetric 1,4-addition of cyanide.
As only chiral metal catalysts were found to be effective prior
to this study, these chiral phase-transfer catalysts provide a
new efficient approach toward the development of these
synthetically important asymmetric transformations. Several
noteworthy features of these phase-transfer-catalyst-medi-
ated asymmetric transformations include the use of an
accessible organic catalyst as well as a practical cyanation
reagent and the ability to provide access to both enantiomers
of the 1,4-adducts derived from a,b-unsaturated ketones and
N-acyl pyrroles. Such features should render these reactions
valuable additions to synthetic methodology. It is particularly
noteworthy that the successful development of these new
chiral catalysts resulted from several key, yet non-intuitive
insights gained from structural studies of a series of catalyst
candidates of varying enantioselectivity.
Table 3: Conjugate addition of acetone cyanohydrin to 7.[a]
Entry
7
R
PTC
t [h]
Yield[b]
ee[c]
1[d]
2[d]
3
4
5
6
7
8
9
10
11
12
13
14
7a
7a
7a
7a
7b
7b
7c
7c
7d
7d
7e
7e
7 f
7 f
Et
Et
Et
Et
Me
Me
n-C5H11
n-C5H11
iPr
CPD-2
CPN-3
CPD-2
CPN-3
CPD-2
CPN-3
CPD-2
CPN-3
CPD-2
CPN-3
CPD-2
CPN-3
CPD-2
CPN-3
24
24
48
24
48
24
96
24
48
24
96
24
96
24
>95[e]
>95[e]
83
94
79
77
87
84
83
71
78
80
75
86
78
95 (S)
90 (R)
97 (S)
92 (R)
96 (S)
92 (R)
95 (S)
91 (R)
98 (S)
94 (R)
95 (S)
93 (R)
Received: August 4, 2011
Published online: September 14, 2011
Please note: Minor changes have been made to this manuscript since
its publication in Angewandte Chemie EarlyView. The Editor.
iPr
CH2iPr
CH2iPr
CH2CH2Ph
CH2CH2Ph
Keywords: asymmetric catalysis · crystal structures ·
.
70
hydrocyanation · Michael addition · phase-transfer catalysis
[a] Unless otherwise noted, reactions were performed with 7 (0.1 mmol),
acetone cyanohydrin (0.2 mmol) and Rb2CO3 (0.12 mmol) in 1 mL of
toluene/CHCl3 (7:3 v/v) with 10 mol% CPD-2 (or 10 mol% CPN-3a).
[b] Yield of isolated product. [c] Determined by HPLC on a chiral
stationary phase. The absolute configuration is reported in parenthesis,
see the Supporting Information for details. [d] Cs2CO3 (0.12 mmol) used
instead of Rb2CO3. PTC=phase-transfer catalyst.
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