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Cupreines and Cupreidines An Emerging Class of Bifunctional Cinchona Organocatalysts.

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H. Hiemstra et al.
DOI: 10.1002/anie.200602318
Asymmetric Organocatalysis
Cupreines and Cupreidines: An Emerging Class of
Bifunctional Cinchona Organocatalysts
Tommaso Marcelli, Jan H. van Maarseveen, and Henk Hiemstra*
asymmetric catalysis · cinchona alkaloids ·
enantioselectivity · natural products · organocatalysis
Dedicated to Professor Hans Wynberg
In the steadily expanding field of organocatalysis, cinchona alkaloids
play a prominent role. Until the late 1990s, bifunctional catalysts based
on this scaffold relied exclusively on the C9-hydroxy group as the
hydrogen-bond donor. Recently, new cinchona catalysts have been
developed that feature a phenolic OH group in the C6’ position—a
structural feature that allows a diverse set of reactions to be catalyzed
in a highly stereoselective fashion. This Minireview describes the scope
and modes of action of this new class of asymmetric bifunctional
1. Introduction
Cinchona alkaloids are recognized as a privileged class of
compounds in asymmetric catalysis (Figure 1).[1] One of the
most interesting features of this well-known family of
alkaloids is their availability in two pseudo-enantiomeric
forms; cinchona catalysts can therefore provide access to both
enantiomers of a product with mostly identical selectivities.
Long before the explosion of asymmetric organocatalysis,[2]
Figure 1. The four main cinchona alkaloids and their C6’ OH derivatives. With regard to the pseudo-enantiomers, the key stereogenic
centers (N1, C8, C9) have the opposite absolute configuration while
the quinuclidine fragment (C3, C4) is identical in both.
[*] T. Marcelli, Dr. J. H. van Maarseveen, Prof. Dr. H. Hiemstra
Van’t Hoff Institute for Molecular Sciences (HIMS)
Universiteit van Amsterdam
Nieuwe Achtergracht 129, 1018WS Amsterdam (The Netherlands)
Fax: (+ 31) 20-525-5670
cinchona alkaloids were already shown
to be outstanding catalysts for enantioselective reactions. Although the
first report on asymmetric organocatalysis involving the hydrocyanation of
aldehydes catalyzed by cinchonidine dates back to 1912,[3] it is
only after 1960 that cinchona alkaloids were recognized as
useful tools for the highly enantioselective synthesis of chiral
molecules. A seminal study by Pracejus on the applications of
cinchona alkaloids in ketene chemistry[4] was followed, in the
next two decades, by several reports from Wynberg et al.,[5]
with the most impressive example being the enantioselective
Staudinger-like synthesis of b-lactones.[6] In the 1980s, the
popularity of cinchona derivatives in asymmetric catalysis
increased considerably, in particular as a result of developments in phase-transfer catalysis[7] and asymmetric dihydroxylation.[8]
To gain insight into their mode of action, the conformational behavior of the alkaloids was investigated by means of
NMR spectroscopic and computational techniques and resulted in the identification of four low-energy cinchona
conformers (Figure 2).[9] Molecular mechanics (MM) calculations suggested that quinine and quinidine preferentially
adopt a syn-closed conformation in the gas phase; however,
anti-open conformations were observed in nonpolar solvents
(by means of 1H NMR spectroscopy) for both alkaloids.[9b]
Substituents at C9 play a key role in determining the
conformation of cinchona alkaloids; in solution, esters are
present in the anti-closed form, while C9 methyl ethers prefer
an anti-open arrangement. More sophisticated ab initio
studies revealed that polar solvents stabilize the two closed
conformers.[9c] However, many other factors (such as intermolecular interactions) are responsible for the complex
conformational behavior of cinchona alkaloids in solution.
Furthermore, upon protonation, a C9 p-chlorobenzoyl ester
was shown to switch from the anti-closed to the anti-open
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 7496 – 7504
Cinchona Alkaloids
Figure 2. The four low-energy conformers of quinidine.
In recent years, many new applications of cinchona
organocatalysts have been reported. In most examples, the
alkaloids (or their derivatives) were used as chiral bases.[10] In
some cases, however, the bifunctional character of the
naturally occurring alkaloids was successfully exploited. The
Henk Hiemstra was born in Dronrijp, Friesland, The Netherlands, in 1952. He studied
chemistry at the University of Groningen
and completed his PhD there with Hans
Wynberg in 1980. After a postdoctoral stay
with Barry M. Trost at the University of
Wisconsin, Madison, USA, he was appointed at the University of Amsterdam in
1982. He was promoted to full professor of
organic synthesis in 1997. His research
areas are new synthetic methodology and
the total synthesis of natural products.
Jan van Maarseveen was born in Enschede,
The Netherlands, in 1963. He studied
chemistry at the University of Nijmegen and
completed his PhD there with Binne Zwanenburg and Hans W. Scheeren in 1994.
He then joined Solvay Pharmaceuticals
(Weesp, The Netherlands) as a group leader
in the Medicinal Chemistry Department. He
was appointed associate professor at the
University of Amsterdam in 1999. His
current research interests include the development of novel synthetic methodology to
enable difficult peptide cyclizations.
Tommaso Marcelli was born in Milan, Italy,
in 1978. He studied industrial chemistry at
the University of Bologna and received his
MSc in 2002 under the supervision of
Goffredo Rosini. He then moved to the
Netherlands to join the group of Prof.
Hiemstra, where he is currently working on
his PhD thesis. His research deals with the
design of new cinchona organocatalysts for
asymmetric C C bond-forming reactions.
presence of both the quinuclidine basic nitrogen center and a
free hydroxy group on C9 was shown to be crucial for some
applications; for instance, detailed mechanistic studies on the
addition of aromatic thiols to cyclic enones revealed that the
b-hydroxyamine motif behaves as a Lewis base/Brønsted acid
bifunctional catalyst and is responsible for the good enantioselectivities observed in the reaction (up to 74 % ee).[11]
Conversion of the methoxy group at the C6’ position of
both quinine and quinidine into a reactive functionality did
not receive special attention in the early studies on cinchona
organocatalysis. Selective cleavage of the carbon–oxygen
bond to yield a phenol was first reported in 1979.[12] More
recently, Hoffmann and co-workers explored the reactivity of
cinchona alkaloids and their conversion into different derivatives, with a special focus on the synthesis of different
strained tricyclic structures.[13] To achieve that, several
quinidine derivatives were subjected to cyclization under
strongly acidic conditions. Of particular interest is the synthesis of the oxazatwistane[14] b-isoquinidine (b-IQD), a
compound with limited conformational flexibility and increased basicity and nucleophilicity, mainly due to the
reduced steric hindrance of the quinuclidine nitrogen center
and the increased ring strain of its tricyclic framework
(Figure 3).[13c]
Figure 3. Cinchona oxazatwistanes: b-isoquinidine (b-IQD) and
b-isocupreidine (b-ICPD).
The demethylated form of this cinchona derivative, bisocupreidine (b-ICPD),[15] and other simpler congeners that
comprise a C6’-hydroxy group were recently shown to be
powerful enantioselective catalysts for a wide array of
reactions. These catalysts feature two separated sites for
simultaneous activation of both nucleophile and electrophile.[16] The advantage of cupreines and cupreidines over
previously reported cinchona bifunctional catalysts (mainly
the parent alkaloids or their 10,11-dihydro derivatives) is that
they have a free site for further functionalization (C9 OH)
which can be exploited to fine tune properties such as basicity
and conformation and therefore affect the catalytic performances. This Minireview summarizes the achievements made
possible by this new class of bifunctional cinchona organocatalysts, which are referred to as cupreines in the following
pages (Table 1).
2. Baylis–Hillman Reactions
The first application of a cinchona organocatalyst that
bears a hydroxy moiety at the C6’ position was reported by
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H. Hiemstra et al.
Table 1: Structures and abbreviations of some cinchona catalysts.
Hatakeyama and co-workers in 1999.[17a] They showed that bICPD is a highly enantioselective catalyst for the Baylis–
Hillman reaction[18] of hexafluoroisopropyl acrylate (HFIPA)
with various aldehydes. The desired adducts were obtained
with excellent enantiomeric excess although in moderate
yields only, mainly owing to the formation of a dioxanone byproduct (Scheme 1).
Scheme 1. b-Isocupreidine-catalyzed Baylis–Hillman reaction.
DMF = N,N-dimethylformamide.
addition of the catalyst to the Michael acceptor and subsequent reversible attack of the resulting enolate on the
aldehyde, several diastereomeric structures are present. Two
of these structures benefit from increased stabilization as a
result of an intramolecular hydrogen bond between the
alcoholate and the phenolic OH group. One of them can
easily adopt the antiperiplanar arrangement of the quaternary
nitrogen center and the a-hydrogen atom required for the
elimination to take place, leading to the preferential formation of one enantiomer. The other structure experiences
severe steric repulsions in doing so and therefore reacts with
another molecule of aldehyde to yield the dioxanone byproduct with occasionally high enantiomeric excess.
The use of Michael acceptors other than HFIPA met with
limited success. Simple a,b-unsaturated systems such as
methyl vinyl ketone gave poor results (< 50 % ee), while anaphthyl acrylate could be converted into the corresponding
Baylis–Hillman adducts with variable enantiomeric excesses
(33–92 % ee) although in low yields (17–68 %).[19] Details on
the optimization of catalyst structure, reaction partners, and
conditions, as well as an improved experimental protocol for
the reaction of HFIPA with aldehydes were reported recently
by Hatakeyama and co-workers.[17b]
This methodology was applied to the total synthesis of
( )-mycestericin E[20] and a formal synthesis of epopromycin B[21] (Scheme 2). In this case, b-ICPD was employed to
obtain high levels of diastereoselectivity in the reaction of
HFIPA with (S)-N-Fmoc-leucinal. Interestingly, the R enantiomer reacted sluggishly under the same conditions and
furnished a diastereomeric mixture of dioxanones in low
Shi et al. employed b-ICPD in the aza-Morita–Baylis–
Hillman reaction of imines with simple Michael acceptors
such as methyl vinyl ketone, methyl acrylate, and acrylonitrile
Besides its importance from a synthetic point of view (this
was the first example of a highly enantioselective catalytic
Baylis–Hillman reaction), this study clearly showed that the
presence of the phenol was essential for the enantioselectivity.
Straightforward yet elegant mechanistic studies provided
sufficient information to propose a convincing rational for the
observed asymmetric induction. In their model (Figure 4),
Hatakeyama and co-workers suggested that after conjugate
Figure 4. Explanation for the enantioselectivity in the b-isocupreidinecatalyzed Baylis–Hillman reaction.
Scheme 2. Applications of Baylis–Hillman adducts. Fmoc = 9-fluorenylmethoxycarbonyl; TBS = tert-butyldimethylsilyl.
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Cinchona Alkaloids
(Scheme 3).[22, 23] The enantioselectivity turned out to be
strongly dependent on the reaction conditions and the nature
of the reactants; the best combination was when aromatic Nsulfonyl imines were used with methyl vinyl ketone. In this
case, the aza-Morita–Baylis–Hillman adducts could be obtained in fair to high yields (58–80 %) and with synthetically
useful enantiomeric excesses (73–99 % ee).[22]
Scheme 4. Cupreine-catalyzed conjugate addition to acrolein.
Scheme 3. Enantioselective aza-Baylis–Hillman reaction.
Ts = p-toluenesulfonyl.
Hatakeyama and co-workers reported an enantioselective
aza-Morita–Baylis–Hillman reaction of HFIPA with N-phosphinoyl imines.[24] In this case, enantioselectivities were less
impressive (54–72 % ee); nevertheless, nearly enantiopure
products were obtained in satisfactory yields after one
Having successfully developed a one-pot, three-component aza-Baylis–Hillman reaction,[25] Balan and Adolfsson
implemented enantioselectivity in their protocol by replacing
1,4-diazabicyclo[2.2.2]octane (DABCO) with cinchona derivatives.[26] N-Sulfonyl imines, formed in situ from tosylamide
and an aldehyde (in the presence of a small amount of
titanium 2-propoxide and molecular sieves), reacted with
methyl acrylate in the presence of b-ICPD (15 mol %) to yield
the aza-Baylis–Hillman adducts in variable yields (12–95 %)
and with moderate enantiomeric excesses (49–74 % ee).
Remarkably, the aza-Baylis–Hillman adducts in all cases
have the opposite absolute configuration to the adducts
derived from aldehydes.[27] Hatakeyama and co-workers
explained this reversal by assuming that the steric hindrance
around the imine nitrogen center governs the rate of
elimination that leads to the preferential formation of one
Scheme 5. Asymmetric C C bond formation through conjugate addition. EWG = electron-withdrawing group.
notable array of small chiral building blocks. Malonates, bketoesters, b-diketones, a-nitroesters, a-cyanoesters, and acyanoketones were successfully employed as nucleophiles in
the addition to nitroalkenes, vinyl sulfones, and vinyl ketones.
In all cases, employment of cinchona alkaloids with a C6’
OMe substituent resulted in considerably lower asymmetric
induction. Wang et al. recently extended this concept to the
aza-Michael addition of benzotriazole, triazole, and tetrazole
to nitroalkenes (Table 2).[33]
In their attempt to rationalize the results obtained for the
addition of cyclic ketoesters to nitroalkenes leading to the
Table 2: Scope
3. Conjugate Additions
The ability of phenolic (C6’ OH) cinchona alkaloids to
activate Michael acceptors in enantioselective transformations was first demonstrated in 2002,[28] with the asymmetric
addition of a-cyanoketones to acrolein catalyzed by cupreine
(Scheme 4). Despite the moderate enantiomeric excesses
obtained, the reported results are particularly noteworthy
considering the ease of polymerization of acrolein in the
presence of a nucleophilic catalyst.
Two years later, Deng and co-workers published the first
of a series of papers that deal with the use of simple cupreines
as catalysts for conjugate additions (Scheme 5).[29–32] They
showed that a small set of readily available catalysts can
provide excellent enantio- and diastereoselectivity with
several combinations of reaction partners, giving access to a
Angew. Chem. Int. Ed. 2006, 45, 7496 – 7504
Catalyst (mol %)[a]
Yield [%]
ee [%][b]
de [%]
CPN (10)
BzCPN (10)
BzCPN (10)
BzCPN (10)
PHNCPN (1–10)
CPN (10)
[a] The corresponding pseudo-enantiomers afforded the opposite enantiomers with nearly identical selectivities. [b] Enantiomeric excess of the
major diastereomer.
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H. Hiemstra et al.
simultaneous generation of two contiguous tertiary and
quaternary stereocenters, Deng and co-workers proposed
that the phenolic OH group could control the stereochemistry
of the resulting product through hydrogen bonding of both
nucleophile and electrophile. As similar results were obtained
with the conformationally more rigid b-ICPD, they suggested
that in this reaction the cinchona catalyst adopts an anti-open
Such mechanistic considerations led the researchers to
also investigate the addition of carbon nucleophiles to achloroacrylonitrile. In this case, a tandem Michael addition/
asymmetric protonation led to the simultaneous generation of
two noncontiguous stereocenters (Scheme 6).[34] Excellent
4. Electrophilic Aminations
The reaction of a carbon nucleophile with an azodicarboxylate followed by reductive cleavage of the nitrogen–
nitrogen bond in the resulting hydrazine represents an elegant
approach to the creation of a nitrogen-containing quaternary
stereocenter (Scheme 8).[36] Jørgensen and co-workers
Scheme 8. Asymmetric electrophilic amination of cyanoacetates.
Boc = tert-butyloxycarbonyl; TFAA = trifluoraacetic anhydride;
py = pyridine.
Scheme 6. Tandem Michael addition/asymmetric protonation.
yields (71–96 %) and stereoselectivities (78–96 % ee, 2:1–25:1
d.r.) could be achieved with both cyclic and acyclic donors.
Furthermore, the synthetic usefulness of the resulting compounds was highlighted by a formal synthesis of ( )manzacidin A.
More recently, Deng and co-workers also reinvestigated
Michael additions to a,b-unsaturated aldehydes (including
acrolein). Careful optimization of the reaction conditions and
screening of different substituents at C9 resulted in excellent
yields and enantioselectivities with different nucleophiles (bketoesters, b-diketones, and a-cyanoacetates).[35] Interestingly, when highly nucleophilic b-ICPD, quinuclidine, or DABCO were employed as catalysts for the same transformation,
extensive polymerization of the aldehyde was observed. A
concise synthesis of (+)-tanikolide, involving a chiral aldehyde with a quaternary stereocenter as the key intermediate,
was also described (Scheme 7).
showed that racemic b-ketoesters and a-aryl-a-cyanoacetates
can be aminated in excellent yields (84–99 %) and with high
enantioselectivity (83–99 % ee) in the presence of a remarkably low amount of b-ICPD (as little as 0.5 mol %).[37] Deng
and co-workers expanded the scope of this transformation by
replacing b-ICPD with BnCPN and BnCPD.[38] The catalyst
loading occasionally had to be increased to obtain acceptable
reaction rates. Nevertheless, both product enantiomers could
thus be obtained in virtually identical yield (71–99 %) and
enantiomeric excesses (82–99 % ee). Unfortunately, the twostep reductive cleavage of the nitrogen–nitrogen bond to yield
a carbamate-protected amine (without loss of optical purity)
proceeded in somewhat disappointing yield.[36]
Jørgensen et al. also reported the first atroposelective
organocatalytic Friedel–Crafts amination of 2-naphthols[39]
(Scheme 9). Careful selection of the substituents on the
Scheme 9. Atroposelective Friedel–Crafts amination. Bn = benzyl;
DCE = dichloroethane.
Scheme 7. Cupreidine-catalyzed conjugate addition to acrolein.
aromatic ring permitted the identification of 8-amino-2naphthols as precursors for configurationally stable aryl
hydrazines. While quinine afforded nearly racemic products,
dihydrocupreidine (DHCPD) promoted this reaction with
enantiomeric excesses of up to 88 %. On the other hand,
results obtained with dihydrocupreine (DHCPN) were less
satisfactory ( 61 % ee), thus constituting a rare example of
poor pseudo-enantiomeric behavior in cinchona organocatalysis.
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Cinchona Alkaloids
Although they are unreactive under the optimized
reaction conditions, DHCPN and DHCPD were recognized
as potential substrates for this transformation. By changing
the solvent and temperature, the autocatalytic amination of
these catalysts could be carried out in good yields (80–95 %).
The C5’-aminated cinchona alkaloids 1 b and 2 b (Figure 5)
were found to be excellent pseudo-enantiomeric catalysts for
the amination of naphthols, providing access to both atropisomers of the chiral hydrazines with even higher enantiomeric excesses (87–98 % ee).
high yields (87–99 %) and with high enantiomeric excesses
(85–93 % ee).[45]
Deng and co-workers showed that, although not suitable
for aldehydes, benzoylcupreine (BzCPN) amd benzoylcupreidine (BzCPD) are excellent enantioselective organocatalysts
for the reaction of a-ketoesters with nitromethane.[46] This
methodology provides an easy access to small yet densely
functionalized molecules that feature a quaternary stereocenter. The usefulness of these building blocks was demonstrated by their straightforward conversion into highly
enantioenriched aziridines, b-lactams, and a-alkylcysteines
(Scheme 11).
Scheme 11. Asymmetric Henry reaction of a-ketoesters, and further
manipulation of the products.
Figure 5. C5’-aminated cinchona alkaloids.
5. Nitroaldol Reactions
The enantioselective addition of a nitroalkane to an
aldehyde, known as the nitroaldol (or Henry) reaction,[40] has
remained an elusive goal in organocatalysis for many years.[41]
Following pioneering studies by Matsumoto and co-workers
on the use of cinchona alkaloids in this reaction,[41b] we
investigated the use of cupreidines in the reaction of nitromethane with electron-poor aldehydes (Scheme 10). Although only moderate enantioselectivities (up to 45 % ee)
could be obtained, the results showed a clear beneficial effect
of the phenol moiety on the asymmetric induction.[42]
Replacement of the phenol with an activated thiourea[43, 44]
provided us with a catalyst that could promote the nitroaldol
reaction of various aromatic and heteroaromatic aldehydes in
Scheme 10. Enantioselective nitroaldol reaction of aromatic aldehydes.
Angew. Chem. Int. Ed. 2006, 45, 7496 – 7504
Unlike in the case of conjugate addition, in the nitroaldol
reaction b-ICPD afforded products with considerably lower
optical purity than those obtained with simpler cupreidines
(both with aldehydes and a-ketoesters). Although not
supported by direct experimental evidence, this suggests that
a “closed” conformation of the catalyst may be required for
an efficient asymmetric induction (this conformation is
impossible to adopt for b-ICPD owing to its tricyclic
6. Miscellaneous
Romo and co-workers developed an elegant asymmetric
organocatalytic protocol for the nucleophile-catalyzed aldol
lactonization.[47] Good to excellent enantiomeric excesses
were obtained with different quinidine derivatives substituted
with a methoxy group at the C6’ position. Interestingly, when
b-ICPD was used as the catalyst, a complete reversal in the
sense of asymmetric induction was observed (Scheme 12).[47b]
Analysis of 1H NMR coupling constants and NOE spectra did
not provide the authors with a satisfying explanation for the
observed enantioselectivities, but suggested that O-acetylquinidine and b-ICPD discriminate between the two prochiral
faces according to completely different mechanisms, as
previously observed for other reactions, such as the Michael
addition of thiols to enones.[10a]
Enantiomerically enriched hydroxylated b-dicarbonyl
compounds were obtained by Taylor by reacting a cyclic bketoester with tert-butyl hydroperoxide in the presence of
catalytic amounts of a quinidine derivative (Scheme 13).[48]
Although the importance of the phenolic OH in the catalyst
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
H. Hiemstra et al.
7. Conclusions and Outlook
Scheme 12. Asymmetric nucleophile-catalyzed aldol lactonization.
Scheme 13. Enantioselective a-hydroxylation of b-ketoesters.
was not mentioned, cupreidines consistently outperformed
their C6’ OMe counterparts in the examples described
Baylis–Hillman adducts, upon conversion of the alcohol
into a leaving group, can be substrates for asymmetric allylic
substitutions.[49] Trost et al. employed palladium complexes to
convert these compounds into highly enantiomerically enriched intermediates for the total synthesis of biologically
relevant targets.[50] More recently, Lu and co-workers described the first enantioselective allylic substitution catalyzed
by a cinchona alkaloid, namely b-ICPD. O-Boc-protected
Baylis–Hillman adducts were treated with a variety of
nucleophiles to afford chiral a-methylene esters in good
yields (84–96 %) although with only moderate enantiomeric
excesses (51–72 % ee).[51] According to the proposed mechanism, the presence of an electron-withdrawing ester on the
olefin allows b-ICPD to attack the activated double bond
(first SN2’ step) and displace the leaving group. The consequent loss of carbon dioxide generates a basic tert-butoxide
anion, which is able to deprotonate the pro-nucleophile; the
second SN2’ step leads to formation of the product and
regeneration of the catalyst (Scheme 14).
Scheme 14. Organocatalytic asymmetric allylic substitution.
In only a short time since their first application, cupreines
and cupreidines have been shown to be powerful catalysts for
a plethora of asymmetric transformations. Note that almost
all of the catalysts described in this Minireview can be
accessed in one or two easy steps from commercially available
alkaloids. In particular, b-ICPD offers an attractive combination of high reactivity and selectivity, therefore allowing
reactions to be carried out with minimal catalyst loading and
thus overcoming one of the major limitations of most
organocatalysts. Also, for many transformations, cupreines
display a level of chemo-, regio-, and enantioselective control
that is unmatched by metal complexes or other organocatalysts.
To further exploit the potential of these catalysts (and to
design new ones), detailed mechanistic investigations would
be desirable. While many DFT and NMR studies have been
reported for enamine catalysis,[52] the understanding of the
processes governing enantioselectivity in cinchona bifunctional organocatalysis is often not satisfactory. We believe
that the examples here described represent only a minor
portion of the asymmetric catalytic transformations made
possible by these alkaloids; it is likely that new cupreine
derivatives and combinations of reaction partners have to be
expected in the near future.[53]
The National Research School Combination Catalysis
(NRSC-C) is gratefully acknowledged for financial support.
Received: June 9, 2006
Published online: October 19, 2006
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Cinchona Alkaloids
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this may lead to ambiguity as CD is the commonly accepted
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2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
H. Hiemstra et al.
[53] Note added in proof: After this manuscript was accepted, three
examples of cupreine-catalyzed asymmetric transformations
were reported: a) Kornblum–Delamare rearrangement: S. T.
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2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 7496 – 7504
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