Barriers to enantiocontrol in Lewis acid catalyzed hetero-Diels-Alder reactions

Article abstract of DOI:10.1039/b913019e

Lewis bases, including reactant aldehydes, inhibit the rate of conversion for cycloaddition and those, like aldehydes or nitriles, cause a decrease in enantiocontrol due to the Lewis acidity of the activated complex.

Full text of DOI:10.1039/b913019e

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Barriers to enantiocontrol in Lewis acid catalyzed hetero-Diels–Alder
reactionswz
Xiaochen Wang, Zhuoyan Li and Michael P. Doyle*
Received (in Cambridge, UK) 1st July 2009, Accepted 14th August 2009
First published as an Advance Article on the web 26th August 2009
DOI: 10.1039/b913019e
Lewis bases, including reactant aldehydes, inhibit the rate of
conversion for cycloaddition and those, like aldehydes or nitriles,
cause a decrease in enantiocontrol due to the Lewis acidity of the
activated complex.
of Rh(II)Rh(III),8 Cu(II),9 and Cr(III)10 in the same hetero-
Diels–Alder reaction, and representative examples of these
applications are reported in Table 1. Reactions were
performed under the same conditions, and catalyst amounts
are as reported. As can be seen from these data, the change in
enantiomeric excess as a function of excess aldehyde is
relatively small, but the numbers are real. The variation in
% ee over multiple runs (at least three per catalyst under
each condition) performed under the same conditions show
variations that are no more than ꢀ0.5% in the reported
values. In addition, % ee values from reactions performed
between the two extremes of aldehyde use were between
the two reported values of % ee in Table 1. When equal
amounts of both p-nitrobenzaldehyde and p-anisaldehyde
Hetero-Diels–Alder reactions between carbonyl compounds
or imines and a reactive diene have constituted an important
synthetic methodology, and the use of chiral catalysts in these
reactions is a common platform for evaluation of catalyst
effectiveness for enantiocontrol.1,2 Lewis acids are employed
as catalysts to activate the hetero-dienophile for cycloaddition,
and with few exceptions, catalyst loading is between five and
ten mole percent.3 Optimized conditions are commonly
reported, and they almost universally involve using the diene
component in excess over the dienophile. In the course of our
recent studies of the hetero-Diels–Alder reactions between
aldehydes and the Danishefsky diene using chiral dirhodium
carboxamidate catalysts,4,5 knowing that the rate of reaction
has first-order dependence on the concentration of aldehyde,6
we increased the concentration of aldehyde in order to increase
the rate for product formation. In these investigations we
observed a decrease in enantioselectivity as the concentration
of aldehyde was increased (Scheme 1).7 We now report the
extent and cause of this aldehyde-dependent selectivity and its
potential generality.
[Keq(p-MeOC6H4CHO)/Keq(p-NO2C6H4CHO)
=
12 for
coordination with Rh2(4S-MPPIM)4]6 were used, only
p-nitrobenzaldehyde reacted with the Danishefsky diene, but
the rate of reaction was 2.6 times slower than that without
p-anisaldehyde and the % ee for 2 was 86% ee (compare with
Scheme 1). Although we could not find a reference to a study
reporting lower enantioselection with increased ratio of
aldehyde to diene,2,3 that understanding appears to exist
because these investigations uniformly report the use of only
one equivalent of aldehyde even when the first-order depen-
dence on aldehyde is known and the rate of reaction is low.6
If excess aldehyde can cause a decrease in enantioselectivity,
then so should dipolar aprotic solvents. A clear indication of
this is seen in the comprehensive report by Evans and
co-workers on the effect of solvents on Diels–Alder reactions
catalyzed by chiral bis(oxazoline)copper(II) complexes;11 they
found that acetonitrile, in particular, lowered the % ee by half
the values found for reactions performed in dichloromethane.
In preliminary studies of the hetero-Diels–Alder reaction
Although there are several explanations for this phenomenon,
the one that we chose to explore involved the possible
utilization of the activated aldehyde as a Lewis acid catalyst
in addition to the chiral ligated transition metal catalyst
(Scheme 2). In such a case, with the activated aldehyde (3)
able to coordinate with a second aldehyde, an intermediate
diastereomeric complex (4) is produced that would be expected
to diminish the enantiomeric excess of the final product.
Previous studies showed that the Rh2(4S-MPPIM)4-catalyzed
reaction was at least 100-fold faster than the background
reaction which conflicted with an explanation of diminution
of % ee due to the background reaction,6 and this large rate
differential was confirmed in this investigation.
To ascertain if this was a general phenomenon among Lewis
acids from chiral transition metal catalysts we surveyed those
Department of Chemistry and Biochemistry, University of Maryland,
College Park, MD 20742, USA. E-mail: mdoyle3@umd.edu;
Fax: +1 301-314-2779; Tel: +1 301-405-1788
w This article is part of a ChemComm ‘Catalysis in Organic Synthesis’
web-theme issue showcasing high quality research in organic
chemistry. Please see our website (http://www.rsc.org/chemcomm/
organicwebtheme2009) to access the other papers in this issue.
z Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/b913019e
Scheme 1 Initial observation of a decrease in enantioselectivity as the
aldehyde equivalent was increased.
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Table 1 Influence of the relative amount of aldehyde on enantio-
selectivity in the hetero-Diels–Alder reactions of p-nitrobenzaldehyde
(ArCHO) with the Danishefsky dienea
Scheme 2 Proposed mechanistic pathway causing the decrease of
enantioselectivity.
between p-nitrobenzaldehyde and the Danishefsky diene the
use of acetone or nitromethane was found to drastically
lower % ee, whereas the use of THF did not.12 To further
understand this phenomenon, we performed this hetero-
Diels–Alder reaction in dichloromethane, catalyzed by
Rh2(4S-MPPIM)4, in the presence of varying amounts of
either acetonitrile or THF. The results of % conversion and
% ee are reported in Fig. 1.
Both acetonitrile and tetrahydrofuran inhibit the reaction,
and both are known to coordinate with the dirhodium(II)
catalyst at the axial positions,13 which are themselves the
catalytically active Lewis acidic sites. In this coordination
acetonitrile and THF block the catalyst’s Lewis acid site and
inhibit activation of the aldehyde (Scheme 3). However,
consistent with what is observed with excess aldehyde
(Scheme 1 and Table 1), the role of acetonitrile is also to act
as a surrogate site for Lewis acid activity towards the hetero-
Diels–Alder reaction. Even when the amount of acetonitrile is
only 75% that of p-nitrobenzaldehyde, conversion decreased
to 37% (24 h) and enantiomeric excess was only 72%. Both
THF and acetonitrile can inhibit the background reaction as
well as the catalyzed reaction: without catalyst over the same
time reactions gave 6% conversion in DCM, 2% in THF, and
3% in acetonitrile demonstrating that the background
reaction is too slow to account for the decrease of ee.
a
Reactions were performed at room temperature with the
b
specified amount of catalyst in dichloromethane for 24 h. With
0.25 M Danishefsky diene in 1.0 mL dichloromethane. c With 0.125 M
d
Danishefsky diene in 2.0 mL dichloromethane.
With 0.25 M
Danishefsky diene and molecular sieves 4 A (100 mg per 2 mL) in
2.0 mL dichloromethane.
8
Similar results were obtained with chiral Rh2(5S-MEPY)4BF4
(Fig. 2) as the catalyst with the same set of concentrations of
acetonitrile or tetrahydrofuran as co-solvent as are described
in Fig. 1. In this case, however, enantiomeric excess for
reactions in acetonitrile decreased to 46% (in acetonitrile as
the sole reaction solvent) in what appears to be a more
complex pathway, and when the amount of acetonitrile was
only 35% that of p-nitrobenzaldehyde, % ee decreased to 90%
(as compared to an estimated 83% with Rh2(4S-MPPIM)4,
Fig. 1).
Fig. 1 Influence of co-solvent (either tetrahydrofuran or acetonitrile)
on Rh2(4S-MPPIM)4 catalyzed hetero-Diels–Alder reactions of
p-nitrobenzaldehyde with Danishefsky diene. Reaction conditions:
aldehyde (0.25 mmol), diene (0.30 mmol), catalyst (0.0025 mmol),
solvent (1.00 mL), rt, 24 h.
A similar study was carried out with (salen)Cr(III)BF4,10
but enantioselectivity decreased with addition of either aceto-
nitrile or THF. Subsequent experiments showed that the 4 A
molecular sieves, used to remove the pre-coordinated water
molecule from (salen)Cr(III)BF4, accelerated the background
reaction as the rate of the hetero-Diels–Alder reaction was
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Notes and references
1 (a) S. J. Danishefsky and T. Kitahara, J. Am. Chem. Soc., 1974, 96,
7807; (b) S. J. Danishefsky, H. G. Selnick, R. E. Zelle and
M. P. DeNinno, J. Am. Chem. Soc., 1988, 110, 4368.
2 For reviews, see: (a) S. J. Danishefsky and M. P. DeNinno, Angew.
Chem., Int. Ed. Engl., 1987, 26, 15; (b) E. J. Corey and A. Guzman-
Perez, Angew. Chem., Int. Ed., 1998, 37, 388; (c) D. Carmona,
M. P. Lamata and L. A. Oro, Coord. Chem. Rev., 2000, 200–202,
717; (d) K. A. Jørgensen, Angew. Chem., Int. Ed., 2000, 39, 3558;
(e) J. S. Johnson and D. A. Evans, Acc. Chem. Res., 2000, 33, 325;
(f) H. M. I. Osborn and D. Coisson, Mini–Rev. Org. Chem., 2004,
1, 41.
3 Publications of hDA reactions on or after 2000:
(a) K. B. Simonsen, N. Svenstrup, M. Roberson and
K. A. Jørgensen, Chem.–Eur. J., 2000, 6, 123; (b) D. A. Evans,
J. S. Johnson and E. J. Olhava, J. Am. Chem. Soc., 2000, 122, 1635;
(c) P. I. Dalko, L. Moisan and J. Cossy, Angew. Chem., Int. Ed.,
2002, 41, 625; (d) B. Wang, X.-M. Feng, Y.-Z. Huang, H. Liu,
X. Cui and Y.-Z. Jiang, J. Org. Chem., 2002, 67, 2175; (e) J. Long,
J.-Y. Hu, X. Shen, B. Ji and K.-L. Ding, J. Am. Chem. Soc., 2002,
124, 10; (f) H.-F. Du, J. Long, J.-Y. Hu, X. Li and K.-L. Ding,
Org. Lett., 2002, 4, 4349; (g) Y. Yamashita, S. Saito, H. Ishitani
and S. Kobayashi, Org. Lett., 2002, 4, 1221; (h) D. R. Williams and
R. W. Heidebrecht, J. Am. Chem. Soc., 2003, 125, 1843;
(i) Y. Yamashita, S. Saito, H. Ishitani and S. Kobayashi, J. Am.
Chem. Soc., 2003, 125, 3793; (j) Q. Fan, L. Lin, Y. Huang, X. Feng
and G. Zhang, Org. Lett., 2004, 6, 2185; (k) A. K. Unni,
N. Takenaka, H. Yamamoto and V. H. Rawal, J. Am. Chem.
Soc., 2005, 127, 1336; (l) B. Gao, Z.-Y. Fu, Z.-P. Yu, L. Yu,
Y. Huang and X.-M. Feng, Tetrahedron, 2005, 61, 5822;
(m) W.-Q. Yang, D.-J. Shang, Y.-L. Liu, Y. Du and
X.-M. Feng, J. Org. Chem., 2005, 70, 8533; (n) X. Zhang,
H.-F. Du, Z. Wang, Y.-D. Wu and K.-L. Ding, J. Org. Chem.,
2006, 71, 2862; (o) H. Liu, L.-F. Cun, A.-Q. Mi, Y.-Z. Jiang and
L.-Z. Gong, Org. Lett., 2006, 8, 6023; (p) A. Landa, B. Richter,
R. L. Johansen, A. Minkkila and K. A. Jørgensen, J. Org. Chem.,
2007, 72, 240; (q) Z.-P. Yu, X.-H. Liu, Z.-H. Dong, M.-S. Xie and
X.-M. Feng, Angew. Chem., Int. Ed., 2008, 47, 1308;
(r) X.-B. Yang, J. Feng, J. Zhang, N. Wang, L. Wang, J.-L. Liu
and X.-Q. Yu, Org. Lett., 2008, 10, 1299.
4 M. P. Doyle, I. M. Phillips and W. Hu, J. Am. Chem. Soc., 2001,
123, 5366.
5 M. Valenzuela, M. P. Doyle, C. Hedberg, W. Hu and
A. Holmstrom, Synlett, 2004, 2425.
6 M. P. Doyle, M. Valenzuela and P. Huang, Proc. Natl. Acad. Sci.
U. S. A., 2004, 101, 5391.
7 Aldehyde concentration was increased from 0.25 M to 1.25 M
while keeping the initial diene concentration at 0.25 M. All
reactions reached 100% completion.
8 Y. Wang, J. Wolf, P. Zavalij and M. P. Doyle, Angew. Chem., Int.
Ed., 2008, 47, 1439.
9 A. K. Ghosh, P. Mathivanan, J. Cappiello and K. Krishnan,
Tetrahedron: Asymmetry, 1996, 7, 2165.
10 S. E. Schaus, J. Branalt and E. N. Jacobsen, J. Org. Chem., 1998,
63, 403.
11 D. A. Evans, S. J. Miller, T. Lectka and P. von Matt, J. Am. Chem.
Soc., 1999, 121, 7559.
Scheme 3 Roles played by tetrahydrofuran and acetonitrile in Lewis
acid catalyzed hetero-Diels–Alder reactions.
Fig. 2 Influence of co-solvent (either tetrahydrofuran or acetonitrile)
on Rh2(5S-MEPY)4BF4 catalyzed hetero-Diels–Alder reactions
of p-nitrobenzaldehyde with Danishefsky diene. Reaction conditions:
aldehyde (0.53 mmol), diene (0.63 mmol), catalyst (0.0053 mmol),
solvent (1.00 mL), rt, 24 h.
inhibited by both THF and acetonitrile. As mentioned earlier,
the Evans group had reported that with chiral bis(oxazoline)-
copper(II) complexes11 acetonitrile lowered the % ee by half
the values found for reactions performed in dichloromethane.
The results presented here provide a clear explanation for
the loss of enantiocontrol when Lewis acid catalyzed reactions
are performed in the presence of certain dipolar aprotic
solvents, including nitriles, aldehydes, and ketones. As
anticipated, these solvents cause a decrease in rate because
they compete with the substrate for the catalytically active site.
Furthermore, for those transformations involving activation
of an aldehyde or ketone, the activated substrate may itself
serve as the Lewis acid, causing less than optimum reactivity
and selectivity. The implications of this outcome extend well
beyond hetero-Diels–Alder reactions.
12 M. V. Valenzuela, PhD dissertation, University of Maryland,
College Park, 2004.
13 M. P. Doyle and T. Ren, in Progress in Inorganic Chemistry,
ed. K. Karlin, John Wiley & Sons, Inc., New York, 2001,
vol. 49, pp. 113–168.
We are grateful to the National Institutes of Health
(GM 465030) for their support of this research. We wish to
thank M. Valenzuela for preliminary results that led to this
investigation.
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This journal is The Royal Society of Chemistry 2009
5614 | Chem. Commun., 2009, 5612–5614