Cooperative dual catalysis: Application to the highly enantioselective conjugate cyanation of unsaturated imides

Article abstract of DOI:10.1021/ja046653n

Cooperative heterobimetallic catalysis was used as a design principle to achieve a highly reactive system for the enantioselective conjugate addition of cyanide to α,β-unsaturated imides. A dual-catalyst pathway involving chiral (salen)Al complex 1b and chiral (pybox)Er complex 4b provides measurable improvements in rates and enantioselectivities relative to single-catalyst systems. Mechanistic studies point to a cooperative bimetallic mechanism involving activation of the imide by the Al complex and activation of cyanide by the Er complex. Copyright

Full text of DOI:10.1021/ja046653n

Published on Web 07/24/2004
Cooperative Dual Catalysis: Application to the Highly Enantioselective
Conjugate Cyanation of Unsaturated Imides
Glenn M. Sammis, Hiroshi Danjo, and Eric N. Jacobsen*
Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138
Received June 7, 2004; E-mail: jacobsen@chemistry.harvard.edu
Catalysts for asymmetric additions of nucleophiles to electro-
philes have traditionally been designed around the principle of
Lewis acid activation of the electrophilic reacting partner (Figure
1
1
, type 1). By comparison, cooperative activation of both reacting
partners can lead to enhanced reactivity and more specific control
of the transition structure with respect to the catalyst’s asymmetric
environment, and this may serve to explain why two-metal ion
2
catalysis is a common feature in enzyme-catalyzed reactions. Dual
activation with bimetallic systems has been established only recently
in small-molecule-catalyzed asymmetric reactions, with the iden-
tification of two important classes of cooperative catalysts. Com-
plexes of a single chiral ligand bearing two different metal ions
have been developed and exploited extensively by Shibasaki and
co-workers.3 In these catalysts, one ion (usually a lanthanide or
main group metal) serves as a Lewis acid activator of the
electrophile, and the other (often an alkali metal) acts as a counterion
to the nucleophile (type 2). Alternatively, several catalyst systems
have been identified that promote addition reactions through dual
activation of both substrates in nucleophile-electrophile additions
,4
Figure 1. Different approaches to the catalysis of nucleophile (Nu)-
electrophile (E) reactions. Geometric shapes (ovals, triangle) symbolize
discrete chiral ligands.
5
by the same metal-ligand framework (type 3). While catalyst
6
oligomerization strategies have provided a means to achieve type
3
systems with heightened reactivity, homobimetallic catalysis is
intrinsically limited to systems in which the same metal-ligand
complex is capable of activating both the electrophile and the
nucleophile. We have been interested in developing a potentially
more general design principle for cooperative catalysis, by engaging
two different chiral catalysts tailored for their specific roles in
Figure 2. (Salen)Al complexes.
7
substrate activation (type 4). We describe here the successful
illustration of this approach, wherein two distinct chiral metal
complexes operate cooperatively in the highly enantioselective
conjugate addition of cyanide to unsaturated imides.
Figure 3. (Pybox)lanthanide complexes.
the possibility of promoting a type 4 system by incorporating a
second chiral catalyst capable of activating cyanide more effectively.
3
Chiral lanthanide complexes such as (pybox)YbCl (4a) have
been shown to promote the enantioselective addition of cyanide to
meso epoxides with a second-order kinetic dependence on cata-
lyst.1 A cooperative (type 3) mechanism was proposed wherein
one role of the catalyst is that of a cyanide activator. Similar
lanthanide complexes displayed poor reactivity in the conjugate
addition of cyanide to 2 (Table 1, entry 2), presumably as a result
of inefficient activation of the imide. In contrast to the (salen)AlCl
complex 1a, the analogous µ-oxo dimer 1b proved to be completely
unreactive in the model reaction (entry 1), consistent with a
complete absence of activation of the cyanide component. Remark-
ably, the combination of the two catalysts led to a highly reactive
and enantioselective system (entry 3).
Under optimized conditions,12 the dual-catalyst system afforded
distinctly superior results relative to the (salen)AlCl complex 1a
reported previously (Table 2). Reaction times were reduced from
26-48 h to 8-14 h; the amount of TMSCN needed to achieve
high conversions of imide could be lowered from 2.5 to 4.0 equiv
to 2 equiv, while total catalyst loadings were decreased from 10-
0,11
We reported recently that (salen)AlCl complex 1a catalyzes the
conjugate addition of hydrogen cyanide to unsaturated imides 2
8
(
eq 1). Highly enantioenriched cyanide adducts 3 were obtained,
but high catalyst loadings, long reaction times, and in some cases
elevated temperatures were required to induce acceptable substrate
conversions. Mechanistic studies indicated that the reaction proceeds
through a homobimetallic pathway, in which the catalyst activates
both cyanide and the imide (i.e., type 3). Given that (salen)Al
complexes have been shown to activate unsaturated imides (2)
toward a variety of other nucleophilic addition reactions,9 we
hypothesized that the low reactivity in the cyanide additions may
be due to inefficient activation of the nucleophile by the aluminum
complex. To improve the rate and scope of the reaction, we explored
9928
9
J. AM. CHEM. SOC. 2004, 126, 9928-9929
10.1021/ja046653n CCC: $27.50 © 2004 American Chemical Society

C O MMU N I C A T I O N S
Table 1. Cyanide Conjugate Addition with Individual Catalysts vs
the Dual-Catalyst System
complex 4c was combined with (S,S)-1b (entry 3), the conjugate
addition proceeded with an intermediate level of enantioselectivity.
Significantly, the combination of achiral (salen)Al complex 1c and
(
pybox)erbium complex (S,S)-4b led to substantially higher enan-
tioselectivity than that obtained with (S,S)-4b alone (entry 4 vs entry
). Taken together, these results point to a mechanism of catalysis
5
where both complexes not only are engaged in the rate-determining
step but also function cooperatively in the asymmetric induction.
To our knowledge, this represents the first example of a system
in which two distinct chiral metal complexes operate cooperatively
to catalyze a highly enantioselective reaction. The dual-catalyst
protocol also represents a significant practical improvement over
the homobimetallic system for the conjugate addition of hydrogen
cyanide to R,â-unsaturated imides, affording substantially increased
rates and similar or better enantioselectivites. We are currently
exploring the general applicability of the dual-chiral catalyst design
concept.
entry
Al complex
Er complex
conversion (%)a
ee (%)b
1
2
3
(S,S)-1b
<3
<3
99
(S,S)-4b
(S,S)-4b
c
(S,S)-1b
96
a
Determined by 1H NMR. b Determined by HPLC using a Pirkle
L-Leucine column. c (S,S)-1b (2 mol %), (S,S)-4b (3 mol %).
Table 2. Conjugate Addition of TMSCN to R,â-Unsaturated Imides
Promoted by the Dual-Catalyst System 1b/4b
Acknowledgment. This work was supported by the NIH (GM-
43214) and by a predoctoral fellowship from the National Science
Foundation to G.M.S.
Supporting Information Available: Experimental procedures for
the preparation of the catalysts and for the conjugated addition reactions
(
PDF). This material is available free of charge via the Internet at
http://pubs.acs.org.
References
(
1) Lewis Acids in Organic Synthesis; Yamamoto, H., Ed.; Wiley-VCH: New
York, 2000.
a
(2) Strater, N.; Lipscomb, W. N.; Klabunde, T.; Krebs, B. Angew. Chem.,
Determined by HPLC using a Pirkle L-Leucine column.
Int. Ed. Engl. 1996, 35, 2024-2055.
(
3) For reviews, see: (a) Shibasaki, M.; Yoshikawa, N. Chem. ReV. 2002,
Table 3. Effect of Ligand Stereochemistry on the Asymmetric
Conjugate Addition of TMSCN/ PrOH to 2c
102, 2187-2209. (b) Sasai, H.; Arai, T.; Watababe, S.; Shibasaki, M.
i
a
Catal. Today 2000, 62, 12-22. (c) Shibasaki, M.; Sasai, H.; Arai, T.
Angew. Chem., Int. Ed. 1997, 36, 1236-1256.
entry
Al complex
Er complex
conversion (%)b
ee (%)
(
4) For selected examples of conceptually related catalysts proposed or shown
to function via bifunctional mechanisms, see: (a) Josephsohn, N. S.; Kuntz,
K. W.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123,
1
2
3
4
5
(S,S)-1b
(S,S)-1b
(S,S)-1b
(S,S)-4b
(R,R)-4b
4c
(S,S)-4b
(S,S)-4b
99 (87)
99 (20)
45
<3
98
96
72
84
1
1594-1159. (b) Mermerian, A. H.; Fu, G. C. J. Am. Chem. Soc. 2003,
1
25, 4050-4051. (c) Ooi, T.; Ohara, D.; Tamura, M.; Maruoka, K. J.
c
16
Am. Chem. Soc. 2004, 118, 6844-6845.
1c
78
(5) (a) Hansen, K. B.; Leighton, J. L.; Jacobsen, E. N. J. Am. Chem. Soc.
996, 118, 10924-10925. (b) Nielsen, L. P. C.; Stevenson, C. P.;
1
a
Blackmond, D. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 118, 1360-
Reactions were carried out for 24 h at room temperature under the
1362. (c) McCleland, B.; Nugent, W.; Finn, M. J. Org. Chem. 1998, 63,
656-6666. (d) Matsunaga, S.; Das, J.; Roels, J.; Vogl, E. M.; Yamamoto,
b
1
conditions shown in Table 2. Determined by H NMR. Numbers in
parentheses correspond to conversions after 3.5 h. Determined on product
obtained after 17 days of reaction time.
6
c
N.; Iida, T.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122,
2252-2253.
(6) (a) Ready, J. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 2687-
1
5 mol % to 7 mol %.13 All reactions were carried out successfully
2688. (b) Ready, J. M.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2002, 41,
1
374-1377. (c) White, D. E.; Jacobsen, E. N. Tetrahedron: Asymmetry
at room temperature, even in the case of less reactive imides. With
certain substrates such as the functionalized imide 2h, the dual-
catalyst system also afforded increased enantioselectivity relative
to catalyst 1a alone (93 vs 89% ee).
Mechanistic studies of the dual-catalyst system were undertaken
in order to glean insight into the nature of the cooperative effect
and to assess the relative role of the two chiral complexes in the
asymmetric induction. Kinetic analyses based on initial rates
revealed a first-order dependence on both (salen)aluminum dimer
2
003, 14, 3633-3638.
(7) Very recently, Lectka has exploited this principle successfully in the
context of nucleophilic catalysis: Wack, H.; France, S.; Hafez, A. M.;
Drury, W. J., III; Weatherwax, A.; Lectka, T. J. Org. Chem. 2004, 69,
531-4533.
(8) Sammis, G. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125, 4442-
443.
4
4
(
9) (a) Azide additions: Myers, J. K.; Jacobsen, E. N. J. Am. Chem. Soc.
1999, 121, 8959-8960. (b) Thiolate additions: Chen, Q.; Delmonte, A.;
Jacobsen, E. N. Unpublished results. (c) Michael reactions: Taylor, M.
S.; Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125, 11204-11205.
(10) Schaus, S. E.; Jacobsen, E. N. Org. Lett. 2000, 2, 1001-1004.
(
11) The same catalyst system has been applied successfully to the enantiose-
lective hydrocyanation of hydrazones: Keith, J. M.; Jacobsen, E. N. Org.
Lett. 2004, 6, 153-155. The role of lanthanide catalyst in this reaction
has not yet been elucidated.
1
b concentration and (pybox)erbium 4b concentration, indicating
that both complexes are engaged in the rate-determining transition
state. The relative role of the two chiral ligand environments was
assessed by comparing diastereomeric ligand combinations as well
as achiral ligand variants. Whereas one combination of catalyst
enantiomers [e.g., (S,S)-1b + (S,S)-4b] afforded high enantiose-
lectivity and rates (Table 3, entry 1), replacing the erbium complex
with its enantiomer [i.e., (S,S)-1b + (R,R)-4b] led to substantially
decreased ees and conversions (entry 2). When achiral (pybox)Er
i
(
12) Optimized conditions: 2 equiv of TMSCN, 2 equiv of PrOH, 2 mol %
[
(salen)Al]
2 3
O (1b), 3 mol % (pybox)ErCl (4b), toluene, 23 °C. Pybox:
ErCl
3
ratios of 1.2-2.0 were employed with no observable effect on ee
or yield. Full experimental details and additional substrate entries are
provided in Supporting Information.
(13) The concentration of [(salen)Al]
2
O complex 1b is expressed here in terms
of total metal concentration.
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J. AM. CHEM. SOC.
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