selectivity to Diels-Alder reactions. Evidence of a novel
mechanism of action, involving rapid iminium formation, is
also presented.
Table 1. Hydrazide-Catalyzed Asymmetric Diels-Alder
Reactions
Scheme 1. Iminium Catalysis in Diels-Alder Cycloadditions
yield exo:endo endo ee (6)11
entry catalyst
R
(%)a
(4:6)
(%)
1
2
3
4
5
7
8
9
5
10
Ph
H
Me
Bn
25
25
18
90
1.1:1
0.9:1
1.2:1
2.1:1
1.7:1
60
3
58
82
74
CH2-1-naphthyl 82
a Combined isolated yield.
The design of our organocatalysts was driven by the goal
of increasing catalyst turnover. Catalysis in iminium-based
processes involves three phases: formation of an iminium,
such as 2 from catalyst 1 and aldehyde, cycloaddition to form
3, and finally hydrolysis to release products and regenerate
catalyst 1. It has been suggested6 that the overall efficiency
in iminium-catalyzed reactions is dictated by the rate of
iminium generation. To address this issue, we decided to
enhance the nucleophilicity of our catalyst by means of the
R-heteroatom effect.7 Such a modification would presumably
increase the rate of formation of 2, while maintaining a high
rate of conversion to 3. This hypothesis has led to the
development of a new catalyst system based on cyclic
hydrazides.8 Our catalyst design sought to incorporate a
hydrazide moiety into a chiral framework featuring a five-
membered ring. The hydrazide would provide the necessary
R-heteroatom for nucleophilic acceleration together with an
electron-withdrawing moiety to improve the rate of iminium
hydrolysis (3 f 1). Such architecture would require geminal
substitution R to the carbonyl in order to suppress â-elimina-
tion. A readily available scaffold, which provides such
features, is found in hydrazides such as 5 that are readily
synthesized in four steps from camphorsulfonic acid.
reactivity and enantioselectivity. Removal of the side chain
was deleterious to catalyst activity12 and resulted in almost
no enantioselectivity (entry 2). Small aliphatic groups at this
position gave yields and facial selectivity similar to that of
7 (entry 3). Catalyst 5, however, gave efficient conversion
to product with an enantioselectivity of 82% (entry 4). The
reaction displayed selectivity for exo isomer 4, and both the
exo and endo isomers showed similar enantioselectivities.
Increasing the size of the aromatic function relative to a
benzyl group did not improve enantioselectivity (entry 5).
The use of catalyst 5 in a variety of aqueous solvent
mixtures (9:1 solvent:H2O) was explored. We found that
aqueous mixtures of MeOH (yield 90%, endo ee 82%) and
CH3NO2 (yield 92%, endo ee 75%) gave efficient and
enantioselective conversion to products, whereas the use of
CH3CN (yield 49%, endo ee 73%), THF (yield 23%, endo
ee 83%), or CH2Cl2 (yield 64%, endo ee 75%) resulted in
only moderate yields. Enantioselectivity was less sensitive
to the nature of the solvent. Optimal catalyst performance
was noted in water, in which an enantioselectivity of 85%
and a chemical yield of 82% were achieved. Reactions in
water were biphasic, and enantioselectivity was maintained
with substrate concentrations up to 2 M.
Tuning the acid co-catalyst led to a further performance
enhancement for catalyst 5. A striking correlation was
apparent between the strength of the acid used and the
efficiency of the reaction (Table 2). Steady erosion in both
yield and enantioselectivity was observed as the acidity of
the co-catalyst was decreased. We obtained the best results
using CF3SO3H, which gave not only the best yield and
selectivity but also the cleanest and fastest reactions. To our
knowledge, such a correlation has not been previously
observed in organically catalyzed asymmetric reactions.5a
Such strong acids could have been capable of catalyzing
the Diels-Alder process, resulting in lowered enantioselec-
tivity through a competing achiral process.13 The potential
impact of this background reaction was tested using 0.2 equiv
The efficiency of this system was first evaluated using
hydrazide 79 in a Diels-Alder reaction between cinnamal-
dehyde and cyclopentadiene. This strategy proved successful
as the use of 7 resulted in catalysis of the cycloaddition with
modest enantioselectivity10 and low yield (Table 1, entry 1).11
Changes to the indicated side chain proved crucial for
(6) Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124,
1172.
(7) Fleming, I. Fronteir Orbitals and Organic Chemical Reactions;
Wiley-Interscience: Chichester, U.K., 1976.
(8) For catalysis with acyclic achiral hydrazides, see: Cavill, J. L.; Peters,
J.-U.; Tomkinson, N. C. O. J. Chem. Soc., Chem. Commun. 2003, 728.
(9) Yang, K.-S.; Chen, K. Org. Lett. 2000, 2, 729.
(10) (a) Fujioka, H.; Kotoku, N.; Fujita, T.; Inoguchi, R.; Murai, K.;
Nagatomi, Y.; Sawama, Y.; Kita, Y. Chirality 2003, 15, 60. (b) Ishihara,
K.; Kurihara, H.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 3049.
(11) Enantiomer ratios were determined on the aldehydes by chiral GLC
1
and by H 500 MHz NMR of the corresponding (+)-(R,R)-hydrobenzoin
acetals. The absolute configurations of major products 4 and 6 were
established by comparison to the NMR spectra of the (+)-(R,R)-hydroben-
zoin acetals of (S)-4 and (S)-6 prepared independently (refs 3 and 10).
(12) In contrast, acyclic hydrazides lacking substitution at this position
are effective in an achiral sense. See ref 8.
4142
Org. Lett., Vol. 7, No. 19, 2005