Triflimide activation of a chiral oxazaborolidine leads to a more general catalytic system for enantioselective Diels-Alder addition

Article abstract of DOI:10.1021/ja035393r

The strong acid triflimide ((CF₃SO₂)₂NH) protonates chiral oxazaborolidines to form superactive, stable, chiral Lewis acids which are highly effective catalysts for a wide variety of enantioselective Diels-Alder reactions, documented herein by more than 20 examples. Copyright

Full text of DOI:10.1021/ja035393r

Published on Web 04/30/2003
Triflimide Activation of a Chiral Oxazaborolidine Leads to a More General
Catalytic System for Enantioselective Diels-Alder Addition
Do Hyun Ryu and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts, 02138
Received March 31, 2003; E-mail: corey@chemistry.harvard.edu
Table 1. Comparison of Diels-Alder Catalysts 2a and 3a
Protonation of chiral proline-derived oxazaborolidines such as
1a and 1b by triflic acid generates chiral boron Lewis acids (2a
and 2b) that are of great utility as catalysts for enantioselective
Diels-Alder reactions of a wide variety of dienes and dienophiles.1-3
These reactions were demonstrated not only to be highly enanti-
oselective for many cases but also to follow the absolute stereo-
chemistry predicted by a well-defined mechanistic model.4,5
Although the reactions were first described for R-substituted R,â-
enals and a variety of acyclic and cyclic dienes,1 subsequent studies
demonstrated a broader range with regard to the dieneophile
component, including R,â-unsaturated esters, lactones, and ketones.2
Unfortunately, the catalysts 2a and 2b decompose at an appreciable
rate at or above 0 °C, limiting the range of application. We therefore
sought a modification of these catalysts that would increase their
stability and allow effective application to a wider group of mutually
less reactive dienes and dienophiles. It was gratifying that a simple
change of the counterion from triflate (CF3SO3-) to triflimide,
(CF3SO2)2N-, as illustrated by 3a and 3b had a remarkably
beneficial effect on catalyst stability, with no loss of potency.
temp (°C),
% yield, ee
R
1
R
2
X
concn
time (h)
(endo/exo)
Me
Me
Ph
Et
Et
TfO
Tf2N
TfO
0.25
0.25
1.0
4, 72
20, 16
4, 72
46; >98 (endo) (91:9)
94; 97 (endo) (89:11)
27; 95 (endo) (85:15);
94 (exo)
79; 93 (endo) (83:17);
96 (exo)
CF3CH2
CF3CH2
CF3CH2
Ph
Tf2N
1.0
20, 16
20, 16
Pha
-
0.25
86; 0 (endo) (88:12);
0 (exo)
a EtAlCl2 (20 mol %) was used as a Lewis acid catalyst.
Table 2. Diels-Alder Reactions of Diethyl Fumarate, 20 mol % 3a
or 3b as Catalyst, and Less Reactive Dienes
Treatment of 1a with an equivalent of the strong acid6 triflimide
((CF3SO2)2NH, Aldrich Co.) results in the protonation of 1a at
nitrogen (as observed previously with triflic acid1,2) to form the
very strong chiral Lewis acid 3a. 1H NMR analysis of a 1:1 mixture
of 1a and triflimide in CD2Cl2 in the temperature range -80 to
23 °C shows the formation of three new species with several protons
shifted downfield relative to 1a. We believe these to be (a) the
trivalent boron cation 3a (largest downfield shift) and (b) two
diastereomeric tetracoordinated boron species in which the two
counterions of 3a are bonded. The ratio of 3a to the tetracoordinated
boron species was found to be ca. 1:1.2. In the 1H NMR spectrum
of 3a, the methine N-CR-H proton appears as a doublet of triplets
at δ 5.44, in contrast to a doublet of doublets at δ 4.59 for the
N-CR-H methine proton in 1a (each in CD2Cl2 at 0 °C). The
corresponding methine N-CR-H peaks in the 1H NMR spectra of
the two tetracoordinated diastereomers corresponding to 3a are
centered at δ 4.90 and 5.01.7
above, although catalyst 2a is too unstable to be used above 4 °C,
catalyst 3a functions well at 25 °C.
The experimental data summarized in Table 2 show that the
triflimide catalysts 3a and 3b produce excellent results using diethyl
fumarate as a test dienophile with a variety of less reactive dienes,
in contrast to the corresponding triflates 2a and 2b (data not shown).
The same group of dienes, including the least reactive, 1,3-
butadiene, react with the less reactive test dienophile trifluoroethyl
acrylate to give uniformly outstanding results with catalyst 3a or
The greater thermal stability and superior catalytic efficacy of
the triflimidate 3a as compared to the triflate 2a was first revealed
by the experimental results summarized in Table 1. As mentioned
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C O M M U N I C A T I O N S
Table 3. Diels-Alder Reactions of Trifluoroethyl Acrylate, 20 mol
% 3a or 3b, and Less Reactive Dienes
Table 5. Reaction of 2,5-Dimethyl-1,4-benzoquinone, 3a (20 mol
%), and Various Dienes10
Table 4. Diels-Alder Reactions of R,â-Enones with
2,3-Dimethylbutadiene in the Presence of 20 mol % 3a and 3b
Table 6. Reaction of 2,3-Dimethyl-1,4-benzoquinone, 3a (20 mol
%), and Acyclic Dienes10
data are shown in Table 6 for the reaction of 2,3-dimethyl-1,4-
benzoquinone with three acyclic dienes, for which the results were
very satisfactory.
3b, as documented by the results summarized in Table 3. In the
experiments with 3a or 3b and the reactive component cyclopen-
tadiene, the reaction proceeded rapidly at -60 °C with both
fumarate and acrylate esters, and so this lower temperature could
conveniently be used (first entry, Tables 2 and 3).
It is noteworthy that every one of the 24 examples of catalytic
enantioselective Diels-Alder reactions which are displayed in
Tables 1-6 affords with high predominance the enantiomer which
is predicted for catalysts 3a and 3b from the mechanistic model.1-5,10
The results of the quinone Diels-Alder reactions summarized
in Tables 5 and 6 prompted the further study of such reactions
between unsymmetrical dienes and dienophiles, which involve
position (or “regio-”) selectivity as well as enantioselectivity. The
use of 2,5-dimethyl-1,4-benzoquinone as the dienophile was of
special interest since the expected coordination of catalyst to this
quinone to the carbonyl lone pair anti to methyl would activate
both CdC subunits of the quinone, leading to both possible adducts,
as shown in Figure 1. In fact, as shown for two test cases in Table
7, both possible position isomers (6- and 7-) are formed, even
though the dienes have differing terminal π-nucleophilicities. These
results raised the question of whether there is any possibility of
controlling position selectivity as well as enantioselectivity in
catalytic quinone Diels-Alder reactions with two unsymmetrical
components. We were pleased to discover a simple, rational, and
highly promising solution to this general problem which utilized
3-iodo-2,5-dimethyl-1,4-benzoquinone as a synthetic equivalent of
2,5-dimethyl-1,4-benzoquinone.
As recently reported,2 the triflate catalysts 2a and 2b effect highly
enantioselective Diels-Alder reaction between cyclopentadiene and
a collection of cyclic R,â-enones or R,â-unsaturated lactones.
However, these same dienophiles (which have only marginal
reactivity) resist catalytic reaction with less reactive dienes, e.g.,
2,3-dimethylbutadiene. In contrast, the use of catalysts 3a and 3b
and various R,â-enones gave much better results with 2,3-
dimethylbutadiene as test diene, as summarized in Table 4.
Until recently, the important quinone-diene subset of Diels-
Alder additions was not amenable to enantioselective catalysis. The
initial advances came with the use of Mikami’s BINOL-Cl2Ti-
(Oi-Pr)2 mixture, a catalyst of unknown structure, which gave
adducts with a very limited set of reactants, specifically with
benzoquinone or naphthoquinone and two 1-substituted butadienes
(ca. 85% ee).8,9 We now report that the use of catalysts 3a and 3b
results in outstanding enantioselectivities and yields with a range
of 1,4-benzoquinones and dienes. Table 5 displays the results of
experiments with 2,5-dimethyl-1,4-benzoquinone and dienes of
varying reactivity, which are uniformly excellent. Complementary
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C O M M U N I C A T I O N S
Figure 2. Pre-transition-state assembly for the reaction of 3a, 3-iodo-2,5-
dimethyl-1,4-benzoquionone, and 2-triisopropylsilyloxy-1,3-butadiene.
Figure 1. Two modes of reaction of a 2-substituted 1,3-butadiene with
2,5-dimethylbenzoquinone and catalyst 3a.
Table 7. Enantioselective Diels-Alder Reactions of
2,5-Dimethyl-1,4-benzoquinone, 3a (20 mol %), and Two
Unsymmetrical Dienes
Figure 3. Representative transformation of iodo-substituted quinone-
Diels-Alder adducts.
The adduct 4 can serve as a versatile synthetic intermediate
thanks to the presence of the iodine function. Figure 3 shows just
three of the many useful transformations which are possible from
this interesting chiral Diels-Alder adduct. The use of iodo- or
bromo-substituted unsymmetrical quinones in the Diels-Alder
reaction opens a range of significant new possibilities for this
important process.
The studies reported herein with 3a and 3b show that these
thermally stable and powerful chiral Lewis acids are highly promi-
sing for many enantioselective Diels-Alder reactions that were
previously beyond the reach of synthetic chemists. They provide
further support for the previously proposed1-5 predictive mecha-
nistic model.
Acknowledgment. We are grateful to Pfizer, Inc. for a generous
grant.
Table 8. Enantioselective Reactions of 3-Iodo-2,5-dimethyl-1,4-
benzoquinone, 3a (20 mol %), and Two Unsymmetrical Dienes10
Supporting Information Available: Detailed data regarding
absolute configuration, analysis, and characterization of the products
described herein (PDF, CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(1) Corey, E. J.; Shibata, T.; Lee, T. W. J. Am. Chem. Soc. 2002, 124, 3808-
3809.
(2) Ryu, D. H.; Lee, T. W.; Corey, E. J. J. Am. Chem. Soc. 2002, 124, 9992-
9993.
(3) Corey, E. J. Angew. Chem., Int. Ed. 2002, 41, 1650-1667.
(4) For R,â-enals, this model1 involves formyl CsH- -O hydrogen-bonding
and πsπ attractive interaction between the coordinated R,â-enal and the
proximate C-aryl substituent in 3. See: Corey E. J.; Lee, T. W. J. Chem.
Soc., Chem. Commun. 2001, 1321-1329.
(5) For R,â-unsaturated esters, lactones, and ketones with an R-CsH unit,
the model2 involves R-CsH- -O hydrogen-bonding and πsπ attractive
interaction between the coordinated dienophile and the proximate C-aryl
substituent in 3.
(6) See: Koppel, I. A.; Taft, R. W.; Anvia, F.; Zhu, S.-Z.; Hu, L.-Q.; Sung,
K.-S.; Des Marteau, D. D.; Yagupolski, L. M.; Yagupolski, Y. L.; Ignat’ev,
N. V.; Kondratenko, N. V.; Volkonskii, A. Y.; Vlasov, V. M.; Notario,
R.; Maria, P.-C. J. Am. Chem. Soc. 1994, 116, 3047-3057.
(7) Since the catalysts 3a and 3b and the corresponding tetracoordinated boron
species are in kinetically rapid equilibrium, all can serve as Diels-Alder
catalysts by complexing with a dienophile.
(8) Mikami, K.; Terada, M.; Motoyama, Y.; Nakai, T. Tetrahedron: Asym-
metry 1991, 2, 643-646. (b) Mikami, K.; Motoyama, Y.; Terada, M. J.
Am. Chem. Soc. 1994, 116, 2812-2820. (c) White, J. D.; Choi, Y. Org.
Lett. 2000, 2, 2373-2376.
As shown in Table 8, the reactions of 3-iodo-2,5-dimethyl-1,4-
benzoquinone with isoprene and 2-triisopropylsilyloxy-1,3-butadi-
ene are highly enantio- and position-selective. The reason for this
is that the iodine substituent in the quinone deactivates the CdC
subunit to which it is attached (CdC protection) and also blocks
catalyst coordination to the carbonyl lone pair which is syn to it.
In consequence, there is only one carbonyl lone pair in 3-iodo-
2,5-dimethyl-1,4-benzoquinone that is sterically accessible for
coordination with catalyst 3a. The structure and absolute config-
uration of the adducts 4 (from 2-triisopropylsilyloxy-1,3-butadiene
and 3-iodo-2,5-dimethyl-1,4-benzoquinone) and also 5 were de-
termined unequivocally by X-ray crystallographic analysis10 and
agree with the predictions of the mechanistic model,1-5 as sum-
marized in Figure 2 for 4.
(9) The Mikami catalyst has been found to afford much better results with
achiral 1,4-quinone monoketals as substrates. See: Breuning, M.; Corey,
E. J. Org. Lett. 2001, 3, 1559-1562.
(10) Detailed data regarding absolute configuration, analysis, and characteriza-
tion of these products are presented in the Supporting Information.
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