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Protonated Chiral Catalysts Versatile Tools for Asymmetric Synthesis.

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Protonated Chiral Catalysts: Versatile Tools for
Asymmetric Synthesis
Carsten Bolm,* Toni Rantanen, Ingo Schiffers, and Lorenzo Zani
asymmetric catalysis · Brønsted acids · hydrogen
bonds · organocatalysis · protonation
Asymmetric catalysis of organic reactions is one of the main research fields in
chemistry.[1] Although for many years
asymmetric catalysis was conceptually
linked to the use of chiral transitionmetal complexes, processes catalyzed by
metal-free species have recently received significant attention.[2, 3] In many
cases, the effectiveness of these catalysts
relies on the formation of strictly oriented hydrogen bonds.[4] The substrate(s) are then activated by noncovalent interactions, and in this manner
synthetically highly valuable enantioselective transformations are possible by
applying well-defined low-molecularweight nonmetallic catalysts.[5–7] A particularly elegant example of this concept
is the taddol-catalyzed asymmetric hetero-Diels–Alder reaction developed by
Rawal and co-workers.[8] In this cycloaddition, a simple chiral alcohol complexes to a carbonyl group, thus accelerating the enantioselective C C bondforming process, which gives the cyclic
product with > 92 % ee (Scheme 1).
In the cycloaddition reaction of
Rawal and co-workers, a rather small,
uncharged, (purely) organic molecule
activates the carbonyl compound and
leads to excellent enantioselectivities.
Conceptually different is the use of a
chiral Brønsted base,[9] which on its own
is catalytically inactive and requires the
addition of an acid to give an active
catalyst. The Brønsted base and acid do
[*] Prof. Dr. C. Bolm, Dipl.-Chem. T. Rantanen,
Dr. I. Schiffers, Dipl.-Chem. L. Zani
Institut fr Organische Chemie
RWTH Aachen
Landoltweg 1, 52 056 Aachen (Germany)
Fax: (+ 49) 241-8092-391
Scheme 1. Hydrogen-bond catalysis according to Rawal and co-workers. TBS = tert-butyldimethylsilyl.
not act independently, but their combination leads to a cationic species that is a
potent catalyst with remarkable activity
and (stereo)selectivity.[10] Very recently,
a number of highly exciting developments in this field have been reported
and some of them are highlighted herein.
In 2001, Yamamoto and co-workers
described the development and use of
protic acid–diamine catalysts for the
direct asymmetric aldol reaction between acetone and some aromatic and
aliphatic aldehydes.[11] Guided by earlier
observations,[12, 13] they screened several
diamines, mostly bearing a pyrrolidine
backbone, in combination with various
sulfonic acids (Scheme 2).
Among the tested diamines, which
served as Brønsted bases, those contain-
Scheme 2. Asymmetric direct aldol reaction according to Yamamoto and co-workers.
DMF = N,N-dimethylformamide.
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200500154
Angew. Chem. Int. Ed. 2005, 44, 1758 –1763
ing a secondary and a tertiary nitrogen
atom, such as 9 a–d, were found to be
excellent catalysts for the direct aldol
reaction. However, the formation of
dehydration products 7 occasionally
posed problems. The formation of such
dehydration products was avoided by
using the primary–tertiary diamine series 11 a–c, but unfortunately the reaction
rate was much lower than with the
secondary–tertiary diamine series. The
best results were obtained with the
secondary–secondary diamines 10 a–c,
albeit that considerable amounts of 7
were still formed. Diamine 8, which
bears a secondary and a primary amine
group, proved to be totally ineffective.
Various sulfonic acids were used in
the early experiments, but trifluoromethanesulfonic acid (triflic acid) was
later found to give optimal results. The
role of the acid is probably twofold:
First, it increases the rate of enamine
formation, and second, it orients the
substrates by hydrogen bonding
(Scheme 3). Later, isolated salts such
as [9 a·HOTf]2 (15) were employed in-
direct aldol and Michael reactions. In
the Mannich reaction between acetone
or unmodified aldehydes and preformed
aldimines, surprisingly, the best catalyst
was proline itself.[15] The diamine used
by Yamamoto and co-workers only led
to moderate yields and enantiomeric
excesses, even with the help of a protic
In contrast, in direct asymmetric
aldol reactions the combination of diamine 9 a and trifluoroacetic acid was
highly efficient, whereas proline itself
gave only moderate yields and enantioselectivities.[17] Outstanding results were
obtained by the use of this catalyst in
organocatalytic direct asymmetric aldol
reactions with a,a-disubstituted aldehydes as aldol donors which led to bhydroxyaldehydes with quaternary stereogenic carbon centers.[18] The same
catalyst was also effective in the direct
asymmetric Michael reaction between
isobutyraldehyde and b-nitrostyrene
(Scheme 4).[19]
Comparably moderate enantioselectivities and yields were observed in 1,4additions of acetone and various benzyl
malonates to b-nitrostyrene. Interestingly, proline catalyzed these reactions
as well, but the resulting products had
only low ee values.[19]
The direct asymmetric Michael reaction was also studied by Kotsuki and
co-workers, who used cyclohexanones
and b-nitroolefins as reactants.[20] Chiral
pyrrolidine–pyridine bases in combination with protic acids were applied as
catalysts. Especially the results with
styrene-type nitroolefins were excellent.
Interestingly, when isovaleraldehyde
Scheme 4. Organocatalytic direct Michael additions of aldehydes to b-nitrostyrene. TFA =
trifluoroacetic acid.
was used instead of a ketone, the
enantioselectivity was very low.[21]
Perhaps the most striking application of a protonated diamine-type catalyst is the so-called “chiral proton catalysis”, a strategy recently reported by
Johnston and co-workers.[22] In this approach, a chiral catalyst is generated by
coordinating a proton, which stems from
the strong Brønsted acid TfOH, to an
axially chiral diamine (the Brønsted
base). The resulting bench-stable salt
21 is then an excellent catalyst for the
asymmetric aza-Henry reaction, and
affords the corresponding products 22
in good yields with up to 95 % ee
(Scheme 5). Although mechanistic details have not yet been disclosed, initial
experiments clearly show that the proton plays a key role in both substrate
activation and orientation, thus leading
to the observed selectivities.[23]
Of particular synthetic interest are
the organocatalysts developed by MacMillan and co-workers. They found that
Scheme 3. Proposed mechanism of the direct
aldol reaction in the presence of protonated
diamine 12 as catalyst.
stead of the chiral diamine–triflic acid
catalysts generated in situ.[14] This new
protocol had the advantage that the
enantioselectivities in the direct aldol
reaction were slightly higher and that
the handling of the corrosive and hygroscopic triflic acid could be avoided in the
catalytic reaction.
Barbas and co-workers described
the use of proline and various proline
derivatives in asymmetric Mannich reactions as well as in enantioselective
Angew. Chem. Int. Ed. 2005, 44, 1758 –1763
Scheme 5. A “chiral proton catalyst” in asymmetric aza-Henry reactions. TfO = trifluoromethanesulfonate; Boc = tert-butoxycarbonyl.
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
chiral imidazolidinones in combination
with strong Brønsted acids catalyze
important organic transformations such
as cycloadditions,[24] Friedel–Crafts alkylations,[25] Mukaiyama–Michael reactions,[26] a-chlorination of aldehydes,[27]
aldehyde–aldehyde couplings,[28] and hydride reductions.[29, 30] Scheme 6 shows
two representative reactions, which proceed under catalysis with imidazolidinones 25 (20 mol %) and 29 (5 mol %).
The chiral imidazolidinones can be synthesized readily in a few steps from
commercially available enantiopure
amino acids. The Brønsted acid adducts
are then either prepared as salts prior to
the reaction or generated in situ by
premixing equimolar amounts of the
two components in the reaction solvent.
Mechanistically, most transformations mentioned above proceed via
iminium ions 31,[31] and to attain high
enantioselectivities, the chiral imidazolidinone must efficiently control the
formation of only one of the two possible iminium ion stereoisomers and effectively shield one of its faces, thus
forcing the reaction partner to approach
from the other side. Interestingly, both
catalytic efficiency and stereoselectivity
depend on the Brønsted acid used which
suggests that the proton itself as well as
its counterion play a decisive role in the
For the a chlorination (Scheme 6)
the authors proposed an enamine-type
mechanism similar to that of proline-
catalyzed reactions. In this case, the
protonation of the imidazolidinonebased enamine leads to a more ordered
transition state (32) owing to the presence of an additional hydrogen bond
(Figure 1).[27]
All catalysts described so far stem
from the combination of a purely organic molecule with a strong Brønsted
acid. Corey and co-workers elaborated a
different concept of catalyst activation
by protonation based on their previous
investigations of cationic super Lewis
acid catalysts in enantioselective Diels–
Alder reactions[32] and their studies of
Figure 1. Proposed intermediates in reactions
with imidazolidinone/Brønsted acid catalysts.
Scheme 6. Two representative applications of chiral organocatalysts by MacMillan and co-workers. TMS = trimethylsilyl; DNBA = 2,4-dinitrobenzoic acid.
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
the formyl C H···O hydrogen bond as
an organizing element therein.[33] Proline-derived oxazaborolidines 33 are
especially useful catalysts for the asymmetric reduction of ketones with
BH3·THF or catecholborane as stoichiometric reducing agent.[34] In Diels–Alder
reactions of a,b-unsaturated aldehydes,
however, they show no catalytic activity.
When 33 is treated with 1 equivalent of
anhydrous triflic acid, an equilibrium
mixture of two N-protonated species 34
and 35 results, in which the latter is
“highly Lewis acidic at the boron owing
to its cationic character” (Scheme 7).[35]
a,b-Unsaturated carbonyl compounds are efficiently activated by these
protonated oxazaborolidines and even
relatively unreactive dienes, such as
butadiene and 1,3-cyclohexadiene, undergo rapid cycloaddition reactions at
low temperatures to afford products
(Scheme 8).[36]
The nature of the aryl boron substituent is of major importance for the
enantioselectivity, and the best results
are obtained with catalysts that bear an
o-tolyl group. The authors suggested a
pretransition state 46, in which the
coordinated aldehyde is fixed by a
formyl C H···O hydrogen bond and
attractive p–p donor–acceptor interactions between the electron-deficient
a,b-enal subunit and the cis aryl group
of the oxazaborolidine ring (Figure 2).
This proposal is consistent with the
stereochemical result of the catalysis
and the observation that a catalyst with
(Ar = ) 3,5-dimethylphenyl groups leads
to better ee values than one with unsubstituted phenyl groups. The fact that
an opposite face selectivity was observed in reactions with a,b-unsaturated
esters and a,b-enones was attributed to
a preferred coordination of such molecules, which lack a formyl hydrogen
atom, by formation of a hydrogen bond
between the a-olefinic hydrogen atom
and the oxazaborolidine oxygen atom as
shown in 47 (Figure 2).[37]
In the context of this overview it is
interesting that a simple change of the
counterion from triflate (TfO ) to triflimide (Tf2N ) has a remarkably beneficial effect on the catalyst stability
without lowering its potency.[38] This
increased thermal stability results in a
superior catalytic efficacy in enantioseAngew. Chem. Int. Ed. 2005, 44, 1758 –1763
Scheme 7. Oxazaborolidines and related protonated species.
Scheme 8. Protonated oxazaborolidines as catalysts for cycloaddition reactions.
The preparative opportunities of
these new catalyst systems were impressively demonstrated in the syntheses of
the steroids estrone and desogestrel,[39]
which is an important third-generation
oral contraceptive. In this case, oxazaborolidinium triflimide 50 was the most
effective catalyst in the preparation of
key intermediates 51 in 92–94 % yield
with 94–97 % ee (Scheme 9). It is thus
one of the most efficient synthetic
methodologies in this area at the present
In a comprehensive study, it was
shown that Diels–Alder reactions between unsymmetrical 1,3-dienes and
substituted 1,4-quinones catalyzed by
oxazaborolidinium salts generally afford
only a single highly enantiomerically
enriched regioisomer.[35c, 41] The enantioselectivity, orientational selectivity
(mode of coupling the ends of the diene
and the dienophile), and site selectivity
(only one of the two C=C subunits of the
quinone underwent reaction) were in
accordance with the mechanistic model
and enabled the authors to develop a
reliable set of selection rules that allow
the prediction of the structure and the
absolute configuration of the principal
reaction product. With this powerful
tool in hand, Corey and co-workers
modified a number of classic natural
product syntheses into enantioselective
versions and published an impressive
contribution on the use of the oxazaborolidinium catalysts in Saretts total synthesis of cortisone, Kendes dendrobine
synthesis, the preparation of (+)-myrocin C, and the synthesis of a highly
enantiomerically enriched (+)-hirsutene and ( )-coriolin precursor (45 in
Scheme 8).[42] Recently, they showed
that oxazaborolidinium cations can also
Figure 2. Preferred coordination modes of
enals and other a,b-unsaturated carbonyl
compounds to protonated oxazaborolidines.
lective Diels–Alder reactions between
dienes of low reactivity, such as 2,3dimethylbutadiene, and dienophiles that
are unreactive in the presence of the
triflate-based catalyst.
Angew. Chem. Int. Ed. 2005, 44, 1758 –1763
Scheme 9. Use of an oxazaborolidinium catalyst in steroid syntheses.
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
be applied in enantioselective cyanosilylations to generate cyanohydrins with
90–97 % ee in excellent yields. Also in
this case, the absolute configurations of
the products were correctly predicted by
the mechanistic model.[43, 44]
In conclusion, we have described the
use of new chiral catalysts, which have
already proved to be valuable for asymmetric synthesis. By combining catalytically inactive (neutral) molecules with
strong Brønsted acids, cationic species
are generated that catalyze a wide range
of synthetically powerful transformations in a highly enantioselective manner. Considering the relative youth of
this concept, we foresee many other
applications of such cationic entities and
predict a bright future for newly designed protonated chiral catalysts.[45]
[1] a) R. Noyori, Asymmetric Catalysis in
Organic Synthesis, Wiley, New York,
1994; b) Comprehensive Asymmetric
Catalysis (Eds.: E. N. Jacobsen, A.
Pfaltz, H. Yamamoto), Springer, Berlin,
1999; c) Catalytic Asymmetric Synthesis,
2nd ed. (Ed.: I. Ojima), Wiley-VCH,
New York, 2000; d) Transition Metals
for Organic Synthesis, 2nd ed. (Eds.: M.
Beller, C. Bolm), Wiley-VCH, Weinheim, 2004.
[2] For leading reviews, see: a) P. I. Dalko,
L. Moisan, Angew. Chem. 2001, 113,
3840; Angew. Chem. Int. Ed. 2001, 40,
3726; b) B. List, Synlett 2001, 1675;
c) E. R. Jarvo, S. J. Miller, Tetrahedron
2002, 58, 2481; d) B. List, Tetrahedron
2002, 58, 5573; e) P. I. Dalko, L. Moisan,
Angew. Chem. 2004, 116, 5248; Angew.
Chem. Int. Ed. 2004, 43, 5138.
[3] Two major journals have recently dedicated special issues to organocatalysis,
see: a) Acc. Chem. Res. 2004, 37(8);
b) Adv. Synth. Cat. 2004, 346(9–10).
[4] a) T. Steiner, Angew. Chem. 2002, 114,
50; Angew. Chem. Int. Ed. 2002, 41, 48;
b) G. A. Jeffrey, An Introduction To
Hydrogen Bonding, Oxford University,
New York, 1997; c) M. Meot-Ner
(Mautner), Chem. Rev. 2005, 105, 213.
[5] For selected examples, see: a) M. S. Sigman, E. N. Jacobsen, J. Am. Chem. Soc.
1998, 120, 5315; b) E. J. Corey, M. J.
Grogan, Org. Lett. 1999, 1, 157; c) P.
Vachal, E. N. Jacobsen, J. Am. Chem.
Soc. 2002, 124, 10 012; d) T. Okino, S.
Nakamura, T. Furukawa, Y. Takemoto,
Org. Lett. 2004, 6, 625; e) T. Okino, Y.
Hoashi, Y. Takemoto, J. Am. Chem. Soc.
2003, 125, 12 672.
[6] For the use of chiral Brønsted acid type
catalysts, see: a) N. T. McDougal, S. E.
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Schaus, J. Am. Chem. Soc. 2003, 125,
12 094; b) D. Uraguchi, M. Terada, J.
Am. Chem. Soc. 2004, 126, 5356; c) T.
Akiyama, J. Itoh, K. Yakota, K. Fuchibe,
Angew. Chem. 2004, 116, 1592; Angew.
Chem. Int. Ed. 2004, 43, 1566; d) D.
Uraguchi, K. Sarimachi, M. Terada, J.
Am. Chem. Soc. 2004, 126, 11 805.
Reviews: a) P. R. Schreiner, Chem. Soc.
Rev. 2003, 32, 289; b) M. Oestreich,
Nachr. Chem. 2004, 52, 35; c) P. M.
Pihko, Angew. Chem. 2004, 116, 2110;
Angew. Chem. Int. Ed. 2004, 43, 2062,
and references therein.
a) Y. Huang, A. K. Unni, A. N. Thadani,
V. H. Rawal, Nature 2003, 424, 146; for
recent advances in this field, see:
b) A. N. Thadani, A. R. Stankovic,
V. H. Rawal, Proc. Natl. Acad. Sci.
USA 2004, 101, 5846; c) A. K. Unni, N.
Takenaka, H. Yamamoto, V. H. Rawal,
J. Am. Chem. Soc. 2005, 127, 1336.
According to a definition proposed by
Brønsted in 1923, bases are compounds
that are able to accept a hydrogen ion:
J. N. Brnsted, Recl. Trav. Chim. PaysBas 1923, 42, 718.
This scenario parallels “ligand-accelerated catalysis” (LAC). By combining the
proton (stemming from the Brønsted
acid) and the (catalytically inactive)
chiral molecule, an equilibrium mixture
results in which the active catalyst
formed consists of a proton bound to a
chiral ligand; for a review on LAC, see:
D. J. Berrisford, C. Bolm, K. B. Sharpless, Angew. Chem. 1995, 107, 1159;
Angew. Chem. Int. Ed. Engl. 1995, 34,
a) S. Saito, M. Nakadai, H. Yamamoto,
Synlett 2001, 1245; b) M. Nakadai, S.
Saito, H. Yamamoto, Tetrahedron 2002,
58, 8167; c) S. Saito, H. Yamamoto, Acc.
Chem. Res. 2004, 37, 570.
Reference [11c] gives an excellent background to the current studies and highlights the many contributions published
by other researchers, which finally led to
the development of the present asymmetric acid–base catalysts; for further
details, this review is highly recommended.
In this context, it is also noteworthy that
an enantioselective Diels–Alder reaction catalyzed by a chiral amidinium
cation was reported as early as 2000: T.
Schuster, M. Bauch, G. Drner, M. W.
Gbel, Org. Lett. 2000, 2, 179. Subsequently, the applicability of a C2-symmetric bis(amidinium) catalyst was demonstrated: S. B. Tsogoeva, G. Drner,
M. Bolte, M. W. Gbel, Eur. J. Org.
Chem. 2003, 1661. In both studies, however, the turnover numbers of the catalysts as well as the enantioselectivities
were low or moderate at best.
[14] The salts were prepared by first reacting
diamine 9 a with excess (> 2 equiv)
TfOH. The resulting diammonium salt
was then mixed with an additional
equimolar amount of diamine 9 a to
yield the desired amine–acid of composition 15. Any variation of this ratio
resulted in a decrease of the reaction
rate. For example, a salt with a 1:2
(amine/acid) stoichiometry did not show
any catalytic activity.
[15] a) W. Notz, F. Tanaka, S.-I. Watanabe,
N. S. Chowdari, J. M. Turner, R. Thayumanavan, C. F. Barbas III, J. Org. Chem.
2003, 68, 9624; b) N. S. Chowdari, J. T.
Suri, C. F. Barbas III, Org. Lett. 2004, 6,
[16] W. Notz, K. Sakthivel, T. Bui, G. Zhong,
C. F. Barbas III, Tetrahedron Lett. 2001,
42, 199.
[17] B. List, R. A. Lerner, C. F. Barbas III, J.
Am. Chem. Soc. 2000, 122, 2395.
[18] N. Mase, F. Tanaka, C. F. Barbas III,
Angew. Chem. 2004, 116, 2474; Angew.
Chem. Int. Ed. 2004, 43, 2420.
[19] N. Mase, R. Thayumanavan, F. Tanaka,
C. F. Barbas III, Org. Lett. 2004, 6, 2527.
[20] T. Ishii, S. Fujioka, Y. Sekiguchi, H.
Kotsuki, J. Am. Chem. Soc. 2004, 126,
[21] A protonated chiral pyrrolidine has also
been used in catalyzed asymmetric epoxidations. In this case, however, it
appears to only serve as carrier and
activator of the peroxymonosulfate anion, and no additional interaction with
the olefinic substrate has been described: V. K. Aggarwal, C. Lopin, F.
Sandrinelli, J. Am. Chem. Soc. 2003, 125,
7596, and references therein.
[22] B. M. Nugent, R. A. Yoder, J. N. Johnston, J. Am. Chem. Soc. 2004, 126, 3418.
[23] The authors report that the use of the
chiral ligand alone furnished a result
comparable to the uncatalyzed reaction
(less than 5 % yield at 20 8C after
5 days).
[24] a) K. A. Ahrendt, C. J. Borths, D. W. C.
MacMillan, J. Am. Chem. Soc. 2000, 122,
4243; b) W. S. Jen, J. J. M. Wiener,
D. W. C. MacMillan, J. Am. Chem. Soc.
2000, 122, 9874; c) A. B. Northrup,
D. W. C. MacMillan, J. Am. Chem. Soc.
2002, 124, 2458.
[25] a) N. A. Paras, D. W. C. MacMillan, J.
Am. Chem. Soc. 2001, 123, 4370; b) J. F.
Austin, D. W. C. MacMillan, J. Am.
Chem. Soc. 2002, 124, 1172; c) N. A.
Paras, D. W. C. MacMillan, J. Am.
Chem. Soc. 2002, 124, 7894.
[26] S. P. Brown, N. C. Goodwin, D. W. C.
MacMillan, J. Am. Chem. Soc. 2003, 125,
[27] M. P. Brochu, S. P. Brown, D. W. C.
MacMillan, J. Am. Chem. Soc. 2004,
126, 4108.
Angew. Chem. Int. Ed. 2005, 44, 1758 –1763
[28] I. K. Mangion, A. B. Northrup, D. W. C.
MacMillan, Angew. Chem. 2004, 116,
6890; Angew. Chem. Int. Ed. 2004, 43,
[29] S. G. Ouellet, J. B. Tuttle, D. W. C. MacMillan, J. Am. Chem. Soc. 2005, 127, 32.
[30] After the reports by MacMillan, imidazolidinone catalysts were also applied by
other groups; for examples, see: a) [4+3] cycloadditions: M. Harmata, S. K.
Ghosh, X. Hong, S. Wacharasindhu, P.
Kirchhfer, J. Am. Chem. Soc. 2003, 125,
2058; b) intramolecular Michael reactions: M. T. Hechavarria Fonseca, B.
List, Angew. Chem. 2004, 116, 4048;
Angew. Chem. Int. Ed. 2004, 43, 3958;
c) tranfer hydrogenations: J. W. Yang,
M. T. Hechavarria Fonseca, N. Vignola,
B. List, Angew. Chem. 2005, 117, 110;
Angew. Chem. Int. Ed. 2005, 44, 108.
[31] The activation of the unsaturated carbonyl compound is suggested to originate from a lowering of the LUMO
upon conversion of the substrate into
the corresponding, and much more reactive, iminium ion.
Angew. Chem. Int. Ed. 2005, 44, 1758 –1763
[32] a) Y. Hayashi, J. J. Rohde, E. J. Corey, J.
Am. Chem. Soc. 1996, 118, 5502; b) E. J.
Corey, Angew. Chem. 2002, 114, 1724;
Angew. Chem. Int. Ed. 2002, 41, 1650.
[33] E. J. Corey, T. W. Lee, Chem. Commun.
2001, 1321.
[34] For a review, see: E. J. Corey, C. J. Helal,
Angew. Chem. 1998, 110, 2092; Angew.
Chem. Int. Ed. 1998, 37, 1986.
[35] a) E. J. Corey, T. Shibata, T. W. Lee, J.
Am. Chem. Soc. 2002, 124, 3808;
b) D. H. Ryu, T. W. Lee, E. J. Corey, J.
Am. Chem. Soc. 2002, 124, 9992;
c) D. H. Ruy, E. J. Corey, J. Am. Chem.
Soc. 2003, 125, 6388.
[36] Triflic acid was more effective than the
weaker methanesulfonic acid in generating an active Diels–Alder catalyst.
[37] Evidence for this hypothesis stems from
X-ray crystal-structure investigations of
the BF3 complexes of methyl cinnamate,
benzylidene acetone, and dibenzylidene
acetone, in which the short distances
between the a-olefinic hydrogen atom
and the nearest fluorine atom suggests
such an attractive interaction.
[38] Catalyst 35 a is too unstable to be used
above 4 8C, whereas species 35 c functions well at 25 8C.[35c]
[39] In this context, a stereoselective Diels–
Alder reaction as key step in the synthesis of the steroid skeleton of norgestrel by Gbel and co-workers[13] should
be mentioned again.
[40] Q.-Y. Hu, P. D. Rege, E. J. Corey, J. Am.
Chem. Soc. 2004, 126, 5984.
[41] D. H. Ryu, G. Zhou, E. J. Corey, J. Am.
Chem. Soc. 2004, 126, 4800.
[42] Q.-Y. Hu, G. Zhou, E. J. Corey, J. Am.
Chem. Soc. 2004, 126, 13 708.
[43] D. H. Ryu, E. J. Corey, J. Am. Chem.
Soc. 2004, 126, 8106.
[44] For a recent extension of this study
involving a combination of an alkaloidderived ligand and a strong Brønsted
acid, see: J. Huang, E. J. Corey, Org.
Lett. 2004, 6, 5027.
[45] For a recent demonstration of the ability
of protons to conformationally reorient
chiral ligands, see: M. Dggeli, T. Christen, A. von Zelewsky, Chem. Eur. J.
2005, 11, 185.
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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