Design and development of highly effective Lewis acid catalysts for enantioselective Diels-Alder reactions

Article abstract of DOI:10.1021/ja026088t

This report describes the design and development of chiral Co(III)-salen catalysts for enantioselective Diels-Alder reactions. A crystal structure of a Co-salen catalyst with two equivalents of benzaldehyde provided insight on the factors that may be impo

Full text of DOI:10.1021/ja026088t

Published on Web 05/07/2002
Design and Development of Highly Effective Lewis Acid Catalysts for
Enantioselective Diels-Alder Reactions
Yong Huang, Tetsuo Iwama, and Viresh H. Rawal*
Department of Chemistry, The UniVersity of Chicago, 5735 South Ellis AVenue, Chicago, Illinois, 60637
Received March 4, 2002
The development of effective methods for the synthesis of chiral
compounds in high enantiomeric purity is of pressing current
importance.1 In the pharmaceutical area, for example, single
enantiomer drugs constitute an important and growing segment of
the total market.2 Ideally, asymmetric synthesis methods must be
effective and practical. They must afford the desired products in
high yields and high enantiomeric purities, and be atom-economics
hence catalyticsand environmentally benign.3,4 Among the trans-
formations that are reliably used for the synthesis of complex
molecules, the Diels-Alder (DA) reaction is perhaps the most
powerful, allowing the stereocontrolled construction of six-
membered ring compounds, with up to four embedded chiral
centers.5 Given its prominent position, there has been an intense
search for catalysts that would selectively produce only one of the
DA adduct enantiomers.6 Of the many catalysts identified to date,
the vast majority are used at the 5-20 mol % level, with respect
to the amount of the reactants.7 We report here the design and
development of catalysts that are not only exceptionally effective
(catalyst loadings down to 0.05 mol %) but are also used at room
temperature, under an air atmosphere, using a minimum amount
Figure 1. X-ray crystal structure of (1R,2R)-salen-Co(III)-SbF6‚2PhCHO
complex 3. For clarity, SbF6 is not shown. (a) Side view. (b) Edge view
(H’s not shown). (c) Space-filling representation of top-view of 3. (d)
Representation generated by replacing the two bay-region tert-butyl groups
of the structure of 3 with SiMe3 groups.
of solvent.
We recently reported the use of Jacobsen’s chiral Cr(III)-salen
catalyst8 for promoting the DA reaction between R-substituted
acroleins and 1-carbamate-3-siloxybutadienes9 to give cycload-
ducts in excellent yield (>90%) and up to 97% ee.10 To uncover
catalysts capable of even faster turnover, the salen complexes of
other metals were prepared and their activity examined. This search
revealed that Co(III)-salen, 1, was remarkably effective for
catalyzing the reaction between carbamate-substituted diene 2 and
methacrolein. This reaction was complete after 2 h at room
temperature with 5 mol % of catalyst 1 and afforded the product
in high ee (95%).11
that crystallized from an ethanol-water solution of 1 and 2.0 equiv
of benzaldehyde (Figure 1). The crystal structure showed two
benzaldehyde molecules coordinated in the axial positions of the
C2-symmetric octahedral complex.12 The edge view of the complex
(Figure 1b) not only illustrates the remarkably flat topography of
the salen scaffold, save for a small zigzag step,13 but also reveals
the nonperpendicular coordination of the two carbonyl groups.
Given their structural similarities, the activation of methacrolein
by 1 is likely to parallel the coordination observed for benzaldehyde.
The enantioselection obtained from the cycloaddition can be
explained by considering preferential approach of the diene from
the “open” quadrants of the dienophile-catalyst complex, those
that form an obtuse angle rather than an acute angle (i.e., from the
top right or bottom left in Figure 1b).14
The space-filling model of 3 (Figure 1c) shows the two bay-
region t-Bu groups in close proximity. The steric congestion from
larger groups at these positions, we hypothesized, might force the
two aromatic rings out of near-parallel arrangement, and thereby
accentuate the subtle helical chirality in the scaffold. With that
objective in mind, we prepared the corresponding o-silyl substituted
salen complexes, 4a,b (eq 2). The longer C-Si bonds would
position the two bay-region substituents to well within van der
Waals radii of one other (Figure 1d).
Critical insight on the activation of the carbonyl group by the
catalyst was obtained from the X-ray structure of a complex (3)
* To whom correspondence should be addressed. E-mail: vrawal@uchicago.edu.
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J. AM. CHEM. SOC. 2002, 124, 5950-5951
10.1021/ja026088t CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 1. DA Reactions between Diene 2 and Methacrolein
Catalyzed by Silylsalen-Co(III) Complexes 4a,b
of 2 and acrolein using 0.1 mol % of 4a at 0 °C afforded the
cycloadduct in quantitative yield, with excellent endo selectivity
(>50/1) and good enantioselectivity. Furthermore, the enantiose-
lectivity improved considerably, to 97%, when the reaction was
performed at -78 °C (entry 6).
In summary, we have developed highly effective Co(III)-salen
complexes for the enantioselective catalysis of Diels-Alder reac-
tions. A rational framework for understanding the observed
enantioselectivities for the DA reactions was provided by the X-ray
crystal structure of a complex between catalyst 1 and benzaldehyde.
This structural information provided the basis for the design of silyl-
substituted catalysts, which proved exceptionally effective for DA
reactions. Importantly, the reactions are conveniently carried out
at room temperature, under an air atmosphere, and with minimal
solvent, conditions that are desirable for industrial applications. The
high turnovers observed with these Co(III) complexes may have
implications for other Lewis acid-catalyzed processes.
c
entry
catalyst
loading
time (h)
yieldb (%)
ee (%)
1a
2a
3
4a
4a
4a
4a
4a
4b
4
4
1
0.1
0.05
0.1
1
2
3
18
3 d
20
98
100
96
98
93
98
97
98
98
98
98
4
5
6a
100
a 4 Å molecular sieves used (see ref 16). b Isolated yields. c ee’s
determined by Mosher ester NMR analysis of the corresponding alcohols.
See Supporting Information for details.
Table 2. Reactions between 2 and Various Acroleins Catalyzed
by 4a
Acknowledgment. This work was supported by the National
Institutes of Health. Financial support from Abbott Laboratories
(Graduate Fellowship to Y.H.) and Merck Research Laboratories
are gratefully acknowledged. We thank Dr. Ian M. Steele for the
X-ray structure determination.
4a
loading
c
entry
R )
R′ )
time (h)
yield (%)
eed (%)
1
2
3
Me
Et
H
H
H
0.1
0.1
0.5
2.0
0.1
2
16
30
18
3 d
18
40
98
93
100
78
100
90
98
>97
>97
>95
85
TBSO(CH2)2
Supporting Information Available: General experimental proce-
dures and spectroscopic data of new cycloadducts (PDF). X-ray
crystallographic file (CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
4
-(CH2)4-
5a
6b
H
H
H
H
>97
a Reaction performed at 0 °C. b Reaction performed at -78 °C. c Isolated
yields. d ee’s determined through Mosher esters. See Supporting Information.
References
(1) Noyori, R. AdV. Synth. Catal. 2001, 343, 1.
(2) Sales from such drugs topped $130 billion in 2000srepresenting 40% of
the total marketsand are expected to surpass $200 billion in 2008. See:
Chem. Eng. News 2001, 79, 79.
(3) Trost, B. M. Science 1991, 254, 1471.
(4) Keith, J. M.; Larrow, J. F.; Jacobsen, E. N. AdV. Synth. Catal. 2001, 343,
5.
(5) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388.
(6) Evans, D. A.; Johnson, J. S. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds; Springer: New York,
1999; Vol. III, p 1177.
(7) The lowest catalyst loading previously reported for the Diels-Alder
reaction was 0.5 mol % (substrate/catalyst ) 200): Bao, J.; Wulff, W.
D.; Rheingold, A. L. J. Am. Chem. Soc. 1993, 115, 3814. See also ref 6.
(8) (a) Jacobsen, E. N. Acc. Chem. Res. 2000, 33, 421. (b) Tokunaga, M. J.;
Larrow, F.; Kakiuchi, F.; Jacobsen, E. N. Science 1997, 277, 936. (c) For
application of Cr(III)-salen catalysts in enantioselective hetero-Diels-
Alder reactions: Schaus, S.; Brånalt, J.; Jacobsen, E. N. J. Org. Chem.
1998, 63, 3, 403.
(9) (a) Kozmin, S. A.; Janey, J. M.; Rawal, V. H. J. Org. Chem. 1999, 64,
3039. (b) Kozmin, S. A.; Rawal, V. H. J. Am. Chem. Soc. 1999, 121,
9562. (c) Kozmin, S. A.; He, S.; Rawal, V. H. Org. Synth. 2000, 78, 152
and 160.
(10) (a) Huang, Y.; Iwama, T.; Rawal, V. H. J. Am. Chem. Soc. 2000, 122,
7843. (b) Huang, Y.; Iwama, T.; Rawal V. H. Org. Lett. 2002, 4, 1163.
(c) Kozmin, S. A.; Iwama, T.; Huang, Y.; Rawal, V. H. J. Am. Chem.
Soc. 2002, 124, 4628.
(11) The absolute stereochemistry of the ethacrolein cycloadduct (Table 2, entry
2) was determined from the X-ray structure of the Mosher ester of the
corresponding alcohol. The stereochemistry of 5 is assigned by analogy.
(12) For X-ray structures of other salen complexes see: (a) Pospisil, P. J.;
Carsten, D. H.; Jacobsen, E. N. Chem. Eur. J. 1996, 2. 974. (b) Leung,
W.; Chan, E. Y. Y.; Chow, E. K. F.; Williams, I. D.; Peng, S. J. Chem.
Soc., Dalton Trans. 1996, 1229. (c) Bernardo, K.; Leppard, S.; Robert,
A.; Commenges, G.; Dahan, F.; Meunier, B. Inorg. Chem. 1996, 35, 387.
(d) Hashihayata, T.; Punniyamuthy, T.; Irie, R.; Katsuki, T.; Akita, M.;
Moro-oka, Y. Tetrahedron 1999, 55, 14599.
The o-silyl substituted complexes (4) were readily prepared from
the corresponding salicylaldehydes and 1,2-diaminocyclohexane,
as shown.15 These silyl-substituted Co(III) complexes are the most
effective catalysts reported to date for an enantioselective DA
reaction (Table 1). With 4 mol % of catalyst 4a, the cycloaddition
of 1-carbamate butadiene (2a) and methacrolein was complete in
less than an hour and afforded the product in excellent yield and
ee (Table 1, entry 1). Comparable yields and ee’s were obtained
using lower catalyst loadings. The result in entry 4 is from a reaction
carried out on a 5.0 mmol scale (1.08 g) using 4.3 mg of catalyst
4a. The reaction went to completion overnight, and removal of the
volatiles gave the expected product, which was pure by NMR.
Significantly, the reaction is effectively catalyzed with just 0.05
mol % of catalyst 4a (entry 5), which represents the lowest catalyst/
substrate ratio for a DA reaction.7 Simple concentration of the
reaction mixture followed by trituration to remove the remaining
reactants afforded pure cycloadduct in high yield and excellent ee.
The catalyst possessing the sterically more demanding tert-
butyldimethyl group (4b) was comparable in effectiveness to the
TMS catalyst (4a) (entry 6).
(13) A Cu-salen also shows similar structural features. See ref 12c.
(14) Assuming Cr-salen complexes coordinate similarly to complex 1, this
model explains the observed enantioselectivities in our Diels-Alder work
(ref 10) and in the hetero Diels-Alder work of Jacobsen (ref 8c).
(15) Please see Supporting Information.
Silyl catalyst 4a efficiently catalyzes the DA reactions of other
acroleins (Table 2). It is noteworthy that even the DA reaction of
acrolein is effectively catalyzed by 4a (entries 5 and 6). The reaction
(16) Molecular sieves do not significantly accelerate the reactions.
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