Non-biaryl atropisomers in organocatalysis

Article abstract of DOI:10.1002/chem.200600495

A new class of 6′-hydroxy cinchona alkaloids, with a non-biaryl atropisomeric functionalisation at position 5′ of the quinoline core can be prepared by an easy amination procedure. These are the first derivatives for which the principle of atropisomerism

Full text of DOI:10.1002/chem.200600495

FULL PAPER
DOI: 10.1002/chem.200600495
Non-Biaryl Atropisomers in Organocatalysis
Sebastian Brandes, Barbara Niess, Marco Bella, Auxiliadora Prieto,
Jacob Overgaard, and Karl Anker Jørgensen*[a]
Abstract: A new class of 6’-hydroxy
cinchona alkaloids, with a non-biaryl
atropisomeric functionalisation at posi-
tion 5’ of the quinoline core can be
prepared by an easy amination proce-
dure. These are the first derivatives for
which the principle of atropisomerism
is engrafted in the classical core of the
cinchona alkaloids. The aminated cin-
chona alkaloids are effective organoca-
talysts for the Michael addition of b-
keto esters to acrolein and methyl vinyl
ketone, in up to 93% ee (ee=enantio-
meric excess), as well as for the asym-
metric Friedel–Crafts amination of a
variety of 2-naphthols, permitting the
preparation of the latter in up to
98% ee. The aminated 8-amino-2-naph-
thol itself is the first chiral organocata-
lyst based on non-biaryl atropisomer-
ism. The two enantiomers of this chiral
primary amine can be used for the
direct a-fluorination of a-branched al-
dehydes. The fluorinated compounds
can thereby be accessed in up to
90% ee.
Keywords: amination · asymmetric
catalysis · atropisomerism · fluori-
nation · Michael addition
Introduction
Atropisomers are widely used in the field of asymmetric cat-
alysis, as ligands, additives and also as catalysts themselves.
The most famous structure by far being the 1,1’-binaphthyl
core present in BINAP[1] and BINOL ligands,[2] which are
nowadays not only used as ligands, but derivatives thereof
finding applications in various fields of chemistry.[3]
The large majority of atropisomeric structures used in
asymmetric catalysis belongs to the class of biaryl atro-
pisomers bearing a chiral axis between the two aromatic
moieties. Nonetheless, this is only a sub-class of atropisom-
ers and in recent years several groups have focussed on an-
other sub-class of atropisomers, the non-biaryl atropisomeric
anilides 1 and aromatic amides 2.[4–8]
sis,[11] medicinal chemistry[12] and a model system for allo-
steric interactions.[13]
While a variety of synthetic approaches are now available
for the biaryl atropisomers,[14] ways to access enantiopure
non-biaryl atropisomers are still limited. The enantioselec-
tive synthesis of non-biaryl atropisomers is often tedious;
besides classical separation by chiral stationary phase chro-
matography,[15] kinetic[6a,16] and thermodynamic[17] resolu-
tions, chiral pool approaches,[7,18] chiral auxiliary ap-
proaches[19] and enantioselective synthesis by desymmetrisa-
tion[8] have been reported. The enantiopurity achieved by
these procedures varies from moderate to excellent; how-
ever, the downfall mostly lies in the length of the sequences.
Recently, an elegant approach reported by Taguchi et al.
provided, by means of catalytic asymmetric N-arylation, an
easy and short access to atropisomeric anilides 1 (phenyl
series; X=tBu; R1 =alkyl, alkenyl; R2 =4-NO2C6H4).[20] In
our own laboratories, we developed the first organocatalytic
approach to non-biaryl atropisomeric structures of type 3.[21]
What started out as a textbook curiosity[9] has been devel-
oped to be a prosperous field of organic chemistry with ap-
plications in enantioselective synthesis,[10] asymmetric cataly-
[a] Dr. S. Brandes, Dr. B. Niess, Dr. M. Bella, Dr. A. Prieto,
Dr. J. Overgaard, Prof. Dr. K. A. Jørgensen
The Danish National Research Foundation
Center for Catalysis, Department of Chemistry
Aarhus University, 8000 Aarhus C (Denmark)
Fax : (+45)8619-6199
E-mail: kaj@chem.au.dk
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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The latter structures were discovered during our investiga-
tion of an easy amination procedure for 2-naphthols 4, utilis-
ing azodicarboxylates 5 as the nitrogen source [Eq. (1)]. It
was found that a tertiary amine, such as DBU or Et3N, can
catalyse this Friedel–Crafts amination.
an aminated cinchona alkaloid catalyst were detected, but
upon exposure of these cinchona alkaloids to a stoichiomet-
ric amount of DtBuAD (5b), the amination of position 5’
could be achieved quantitatively. Functionalisation of posi-
tion 5’ of the cinchona alkaloids is found rarely, and so far
only nitration,[27] diazotation[28] and bromination[29] of this
position have been described.
Until now, the four major sites of derivatisation of the cin-
chona alkaloids have been: the 9-hydroxy function (R),[30]
the 6’-hydroxy functionality (R’),[31] the quinuclidine nitro-
gen atom (R’’)[32] and the vinyl side chain.[33]
The initial results were intriguing, as the product (3a,
R1 =Et) of the reaction of 2-naphthol (4a, X=H) with di-
ethyl azodicarboxylate (5a, R1 =Et) showed diastereotopic
behaviour with regard to the methylene groups of the carba-
mate moiety. An analysis of the product by chiral HPLC re-
vealed that the product 3a existed in two enantiomeric
forms. This can only be attributed to a hindered rotation
À
around the N CAryl bond, thereby creating atropisomers. Al-
though aminated naphthalenes have been known for nearly
a century, only now have they been recognised as chiral
compounds.[22]
In the following, we will present a versatile method to
functionalise position 5’ of the quinoline core and to con-
comitantly incorporate the principle of atropisomerism into
the cinchona alkaloids. A series of these newly functional-
ised catalysts has been prepared and examined. Their per-
formance in the addition of b-keto esters to a,b-unsaturated
carbonyl compounds (Wynberg reaction)[34] and their per-
formance in the Friedel–Crafts amination of naphthols will
be outlined.
Moreover, the product of the amination reaction of 8-
amino-2-naphthol 3b (X=NH2, R1 =tBu) displayed an in-
teresting structure: the alignment of a primary amine and a
phenol in close proximity to the chiral axis and the easy
availability of both enantiomeric forms of this non-biaryl
atropisomer inspired us to seek an application in organoca-
talysis.
As the amination product of 2-naphthol 3a racemised
readily, 8-amino-2-naphthol (4b, X=NH2) was chosen as a
model system instead. Reaction with di-tert-butyl azodicar-
boxylate (5b, DtBuAD, R1 =tBu), indeed generated more
stable atropisomers.
By screening a large variety of amines, and especially cin-
chona alkaloids as catalysts, the cinchona-derived quasi-
enantiomers hydrocupreine (6) and hydrocupreidine (7)
were found to give good enantioselection in the amination
reaction.[21,23]
It has been shown that primary amino acids catalyse aldol
reactions with high enantioselectivity, especially with steri-
cally encumbered substrates.[35] Moreover, calculations of
aldol reactions catalysed by primary amines underscored the
viability of enantioselection in this reaction.[36] In contrast to
the widely used secondary amines in organocatalysis, a pri-
mary amine could offer the advantage of a less encumbered
imine/enamine intermediate, which is, for example, of inter-
est in the derivatisation of a-branched aldehydes.
With the existing knowledge in our group about a-func-
tionalisations of carbonyl compounds,[37] the fluorination of
a-branched aldehydes appeared as a promising target to
prove our idea. Although, the organocatalytic a-fluorination
of carbonyl compounds has been investigated thoroughly in
the last few years,[38] the fluorination of a-branched alde-
hydes still leaves room for improvement. We therefore in-
vestigated the possible use of the atropisomeric aminated 8-
amino-2-naphthol 3b as an organocatalyst in the fluorina-
tion of a-branched aldehydes.
The use of cinchona alkaloids in the field of organocataly-
sis[24] has, in the last few years, led to an increasing number
of derivatives, tailored to fit the need of the application.
Their core has been identified as a “privileged structure”,[25]
catalysing a plethora of reactions.[26]
During the screening of the Friedel–Crafts amination, the
structural similarity between the quinoline-6’-ol core and
the naphthol motif became obvious to us, leading to the as-
sumption that the cinchona alkaloid catalysts themselves
might be transformed during the reaction. Under the given
reaction conditions of the amination, only trace amounts of
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Non-Biaryl Atropisomers in Organocatalysis
FULL PAPER
Table 1. Investigation of the parameters governing the reaction of hydro-
In the following we will present our investigation of the
aminination of cinchona alkaloids and present the properties
of these aminated cinchona alkaloids, including the analysis
of their X-ray structures, which help to explain their catalyt-
ic and physical properties. Furthermore, the catalytic proper-
ties of the atropisomeric aminated 8-amino-2-naphthol will
be described.
cupreine (6) with di-tert-butyl azodicarboxylate (5b).[a]
Entry
Solvent
t [h]
Yield [%][b]
dr 9a/9b[c] (dr 9a/9b)[d]
Results and Discussion
1
2
3
4
5
6
7
8
9
MeOH
CH2Cl2
THF
hexane
toluene
DMF
DMSO
MeCN
MeCN
2.5
2.0
24.0
24.0
24.0
4.0
4.0
1.5
24.0
87
80
1:12
A
Aminated 6’-hydroxy cinchona alkaloids: 6’-Hydroxy cin-
chona alkaloids were aminated by a simple protocol; the
catalyst was stirred at RT in CH2Cl2 and 1.2 equivalents of
DtBuAD (5b) were added. The reaction was monitored by
TLC and during the reaction of hydrocupreidine (7) with 5b
two products 8a and b were observed by TLC [Eq. (2)].
These products were easily separated by column chromatog-
raphy and proved to be diastereomers, which were obtained
in a ratio of 8a/8b 3.5:1.
The two diastereomers showed an amazing difference in
their polarity (see Experimental Section), and thus we
named them upper (8a) and lower isomer (8b), according
to their respective TLC Rf values (8a: Rf =0.67, 8b: Rf =
0.29; EtOAc/MeOH/aq NH3 90:10:1).
n.d.[e]
traces
traces
n.d.
n.d.
92
1:2
n.d.
n.d.
1:12
1:4.8
1:17 (1:12)
1:4
n.d.
[a] Reactions were stopped after TLC control showed full consumption
of the starting material. [b] Yields after flash chromatography. [c] dr was
estimated by integration of the NMR spectra of the raw product. [d] dr
after separation by column chromatography. [e] n.d.=not determined.
eomer 9b was obtained when the reaction was conducted in
MeCN. Unfortunately, after column chromatography the 9a/
9b dr dropped from 1:17 to
1:12 (entry 8). However, in the
solid state these diastereomers
were bench stable and no iso-
merisation occurred even after
months at room temperature.
b-Isocupreidine[39] (10) and
9-benzyloxy-6’-hydroxyqui-
nine[40] (12) were also submit-
ted to the same reaction condi-
tions, yielding the 5’-aminated
We then investigated the influence of the solvent upon
the diastereomeric ratio in the reaction of hydrocupreine (6)
with DtBuAD (5b) (Table 1).
products 11 and 13, each as a set of diastereomers [Eq. (3)
and (4)].
It appears from Table 1 that
performing the reaction in
polar solvents gave good chem-
ical yields (entries 1, 2, and 8),
while apolar solvents (entries 4
and 5) gave only traces of
product, even after 24 h. The
dr (dr=diastereomeric ratio)
of 9a/9b varied between 1:17
and 1:2, showing significant de-
pendence upon the reaction
time (entries 8 and 9). Upon
prolonged stirring the lower
isomer 9b apparently started
to isomerise, leading to a di-
minished diastereomeric ratio.
The best diastereomeric ratio
in favour of the lower diaster-
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K. A. Jørgensen et al.
Other azodicarboxylates did not react as well as the tert-
butyl derivative 5b. From the reaction of dibenzyl azodicar-
boxylate (5c, R1 =Bn) with hydrocupreidine 7, only the
lower diastereomer 15 could be isolated [Eq. (5)].
upper isomers in solution. In contrast to this, the structure
of the lower diastereomer 9b shows hydrogen bonding be-
tween the oxygen atom of the 9-hydroxy group and the hy-
À
drazine N H, leaving the quinuclidine nitrogen atom unin-
volved. All structures exhibit a second intramolecular hy-
drogen bonding between the 6’-hydroxy function and the
carbonyl oxygen of the NH-carbonyl moiety. Furthermore,
the value for the torsion angle between the two carbamate
carbonyl functions bound to the hydrazine varies from 69.7
to 77.88, a distortion from the classical rectangle between
the two hydrazine carbonyl functions,[44] which also seems to
arise from the intramolecular hydrogen bonding.
The relative stereochemistry of all other aminated cincho-
na alkaloid derivatives was assigned on the basis of these
three X-ray structures and the respective TLC Rf values.
To verify if this intramolecular hydrogen bonding is also
present in solution and if it affects the basicity of the upper
diastereomer, NMR experiments were carried out in an at-
tempt to determine the pKa values of the new compounds.[45]
Upon protonation of the quinuclidine nitrogen atom the sig-
nals of the protons in close proximity to it are shifted down-
field in the NMR. When equimolar amounts of hydrocu-
preine 6 and either the upper 9a or the lower diastereomer
9b, were mixed in CD3OD and then treated with aliquots of
TFA, these chemical shifts could be recorded. Unfortunate-
ly, it was not possible to determine accurate pKa values, as
the line broadening due to the rotamers present in the new
compounds prevented such measurements. Nevertheless, a
qualitative conclusion can be drawn from the experiments.
In the case of the mixture containing the upper isomer 9a,
the hydrocupreine (6) was first fully protonated, before the
signals of the upper isomer started to change, suggesting a
difference of approximately two pKa units. In contrast to
this, both compounds in the second mixture—the lower
isomer 9b and 6—were protonated from the start, suggest-
ing that the pKa values had a greater similarity to each
other (see Supporting Information). As expected, the results
of analogous experiments for 7 and either 8a or b, resem-
bled the above described behaviour. This supports the hy-
pothesis that the intramolecular hydrogen bonding, between
the quinuclidine nitrogen atom and the NH of the hydra-
zine, revealed by the X-ray structure of the upper isomers
8a and 9a, is also present in solution, thereby decreasing
the basicity of the upper isomers.
Fortunately, the upper diastereomers 8a[41] and 9a,[42] as
well as the lower diastereomer 9b[43] crystallised nicely,
making single crystal X-ray analysis possible (Figure 1).
These structures helped to elucidate the origin of the differ-
ent physical properties of the cinchona alkaloid diastereom-
ers, and as will be shown later, also their different chemical
properties. In the structures of 8a and 9a the distance be-
tween the quinuclidine nitrogen atom and the hydrogen
atom bound to the hydrazine implies a hydrogen bonding
(2.84 and 2.85 Š, respectively between the nitrogen atoms),
leading to an obstruction of the basic site of these alkaloids.
This could be an explanation for the low polarity of the
Furthermore, as soon as the upper isomer 9a was pro-
tonated, it started to isomerise to the lower diastereomer.
Consequently, at the end of the titration both mixtures, irre-
spective of which aminated isomer (9a or b) was present,
contained the same two species (6+H+ and 9+H+).
Amination of 2-naphthols: A reinvestigation of the amina-
tion of 8-amino-2-naphthol (4b) was then started, utilising
the whole new family of aminated cinchona alkaloids
(Table 2). All reactions were carried out on a 0.2 mmol scale
by using a stoichiometric amount of DtBuAD (5b) and 20
mol% of the various catalysts at À208C in 1,2-dichloro-
ethane. Full conversion was achieved overnight in the pres-
Figure 1. X-ray structures of the 5’-aminated cinchona alkaloids showing
the intramolecular hydrogen bonding: 8a (upper isomer, top), 9a (upper
isomer, middle) and 9b (lower isomer, bottom).
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Non-Biaryl Atropisomers in Organocatalysis
FULL PAPER
Table 2. Catalyst screening for the organocatalysed asymmetric Friedel–
Crafts reaction of 8-amino-2-naphthol (4b) with di-tert-butyl azodicar-
boxylate 5b.[a]
Table 3. Substrate screening for the organocatalysed asymmetric Friedel–
Crafts reaction of 8-substituted-2-naphthols 4 with di-tert-butyl azodicar-
boxylate (5b).[a]
Entry
Catalyst
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
8a (upper)
8b (lower)
9a (upper)
9b (lower)
11a (upper)
11b (lower)
13a (upper)
13b (lower)
15 (lower)
96
16
96
16
96
16
96
96
16
16
73
87
50
91
38
92
0
33
82
90
69
87
Entry Substrate X, R
Product
Catalyst 8b
Catalyst 9b
ee
Yield
ee
Yield
À63[d]
À96[d]
48
[%][b] [%][c]
[%][b,d]
[%][c]
1
2
3
4
5
NH2, H 4b
3b
3c
3d
3e
3 f
87
93
98
94
92
87
91
92
95
95
À96
À96
À98
À94
À94
91
94
80
98
93
NHMe, H 4c
NHBn, H 4d
NHC5H11, H 4e
70
n.d.
À33[d]
92
NHCH2(o-
A
9
10
C6H4OH), H 4 f
NH2, Br 4g3g
NHBoc, H 4h
Cl, H 4i
9b[e] (lower)
À96[d]
6
7
8
98
58
20
85
94
57
À96
À96
0
95
71
52
[a] Reaction carried out by using 4b (0.20 mmol), 5b (0.20 mmol) and
catalyst (0.04 mmol) in DCE (4 mL). [b] Yield of isolated product after
flash chromatography. [c] The ee was determined by HPLC. [d] The
enantiomer ent-3b with the opposite sign of optical rotation was formed.
[e] Only 5 mol% of the catalyst was used.
3h
3i
[a] Reaction carried out by using 4 (0.20 mmol), 5b (0.20 mmol) and cat-
alyst (0.04 mmol) in DCE (4 mL). [b] The ee was determined by HPLC.
[c] Yield of isolated product after flash chromatography. [d] The enan-
tiomer ent-3 with the opposite sign of optical rotation was formed.
ence of most of the lower diastereomers, whereas the reac-
tions catalysed by the upper diastereomers did not go to
completion even after four days.
ionic species in solution, permitting the formation of a two-
point-contact ion pair.[46] By this, one face of 4b would be
shielded, guiding the approaching DtBuAD (5b) to the
other face of 8-amino-2-naphthol (4b) (Figure 2, left). In the
These improved results enabled us to prepare both enan-
tiomers of the aminated 8-amino-2-naphthol 3b in over
90% ee, and exceeded especially the optical purity of ent-3b
when hydrocupreine was used as the catalyst at À208C
(from 22% ee using 6, to 96% ee using 9b, Table 2, entry 4).
It should also be noted, that the catalyst loading could be
decreased to 5 mol%, without influencing the yield or the
enantiomeric excess (entry 10). Not only was the reactivity
of the upper diastereomers considerably lower, but also the
enantioselectivity induced by these catalysts was inferior in
comparison with the lower diastereomers (entries 1–6). The
catalyst 13b with a protected 9-hydroxy function showed a
diminished reactivity, while its upper diastereomer 13a
showed no reactivity at all. The results in Table 2 show that
the catalysts 8b, 9b and 15 performed best in the Friedel–
Crafts amination of 3b and the substrate scope of this reac-
tion was investigated next (Table 3).
Figure 2. Possible intermediate in the hydrocupreidine 7 (left) and ami-
nated hydrocupreidine 8b (right) catalysed reaction of 8-amino-2-naph-
thol 4b with di-tert-butyl azodicarboxylate 5b. The parts shown in grey
lie behind the plane of the paper and the 9-hydroxy function was omitted
for clarity.
It appears from Table 3 that a large variety of optically
active, aminated 8-amino-2-naphthols 3b–h were accessible
by this reaction in high yield and enantiopurity (entries 1–
7). Even additional substituents in the naphthol ring did not
influence yield or enantioselectivity (entry 6). It has been
found that substrates containing electron-withdrawing sub-
stituents, such as the N-Boc-protected amino-naphthol 4h,
gave a lower enantioselectivity when catalyst 8b was used
(entry 7), and the 8-chloro-2-naphthol (4i) reacted sluggishly
to give a nearly racemic product with either catalyst 8b or
9b (entry 8).
case of the aminated hydrocupreidine 8b, this face shielding
would be enhanced by the 5’-substituent, explaining the in-
crease in enantioselectivity (Figure 2, right).
Ion pairing in this fashion would also explain why other
substituents than amines at position 8 do not give high enan-
tioselectivity (Table 3, entry 8).
This new class of cinchona alkaloids featuring a unique
structure has already shown interesting properties and im-
proved performance in the amination of 8-amino-2-naph-
thols. Further applications of these compounds or deriva-
tives thereof might shed light on the mechanistical aspects
of cinchona alkaloid catalysis and help tailoring catalysts to
the special needs of a reaction.
Mechanistically, it seems plausible that both hydrocu-
preine (6) and the 8-amino-2-naphthol (4b) exist as zwitter-
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K. A. Jørgensen et al.
Michael additions: To further
examine the scope and limita-
tions of this new class of cata-
lysts, their performance in the
Michael addition of b-keto
esters to acrolein was investi-
gated. The enantioselective
Scheme 1. Isolation of the Michael-addition product 18 as its acetal 19.
variant of this reaction was
first published by Bergson and
Långstrçm by using 2-(hydroxymethyl)quinuclidine as the
catalyst.[47] Although they never determined the enantiomer-
ic excess, they noted the optical activity of their products.
The first account of an application of cinchona alkaloids as
catalysts for Michael additions was given by Wynberg and
Helder. In their seminal work they added b-keto esters to
acrolein and methyl vinyl ketone, in the presence of quinine
and reported an enantiomeric excess of up to 76% ee.[34]
Most recently, this enantiomeric excess was improved by
using either phase-transfer catalysis or new derivatives of
cinchona alkaloids.[48]
By using the newly prepared cinchona derivatives, the ad-
dition of ethyl-2-oxocyclopentanone carboxylate (16) to ac-
rolein (17) was investigated (Table 4). A solvent screening
revealed that iodobenzene was an appropiate solvent for the
catalyst screening process.
acceptor was examined and reacted with good enantioselec-
tivity [Eq. (6)].
The alteration of the nucleophile, by using ethyl-2-oxocy-
clohexanone carboxylate (22) also resulted in a lower enan-
tioselectivity in comparison to ethyl-2-oxocyclopentanone
carboxylate (16) [Eq. (7)].
It appears from the results in Table 4 that the lower iso-
mers of the diastereomeric pairs of catalysts provided high
enantioselection. By using either 8b or 9b, both enantiom-
ers of the product 18 can be prepared with excellent enan-
tiomeric excess. Lowering the temperature did not have a
positive effect on the optical purity (entries 10 and 11). The
aldehyde 18 was isolated as its acetal 19 (Scheme 1), as it is
known to be susceptible to an intramolecular aldol reac-
tion.[49] Methyl vinyl ketone (20) as an additional Michael
Comparison of the optical rotation of 23 to literature
values enabled us to determine the absolute configuration
of the product to be R.[50] The other Michael-addition prod-
ucts were assigned accordingly.
Fluorination of a-branched aldehydes: As outlined in the in-
troduction, not only this new class of cinchona alkaloids can
be used as organocatalysts; the product of the amination re-
action, the aminated 8-amino-2-naphthol 3b ([Eq. (1)] and
Table 2) can also act as a new type of asymmetric organo-
catalyst.
Table 4. Michael addition of ethyl-2-oxocyclopentanone carboxylate (16)
to acrolein (17).[a]
We chose the fluorination of a-branched aldehydes to ex-
amine the applicability of these atropisomers as organocata-
lysts. So far, only two substrates, namely 2-phenylpropanal
(24a) and indan-1-carbaldehyde (24b), have been fluorinat-
ed enantioselectively, by using N-fluorobenzenesulfonimide
(25; NFSI) as the fluorine source and proline derivatives as
the catalysts (Scheme 2).[38a,b]
Intrigued by this challenge, we started to investigate dif-
ferent fluorine sources, namely NFSI (25), Selectfluor 27
and the pyridinium salt 28, applying the racemic catalyst.
Fortunately, in all cases product formation could be detect-
ed. Therefore the enantioenriched catalyst ent-3b, possess-
ing 96% ee, was used in the reaction (Table 5).
Entry
Catalyst
T [8C]
t [h]
ee [%][b]
1
2
3
4
5
6
7
8
8a (upper)
8b (lower)
9a (upper)
9b (lower)
11a (upper)
11b (lower)
13a (upper)
13b (lower)
15 (lower)
9b (lower)
9b (lower)
RT
RT
RT
RT
RT
RT
RT
RT
RT
0
16
1
À16[c]
93
16[d]
1
2
À90[c]
0
16[d]
3
À20[c]
0
16[d]
16[d]
5
À14[c]
9
10
11
54
1
2
89
89
À25
[a] Reaction carried out by using 16 (64 mmol), 17 (130 mmol) and catalyst
(0.1 equiv) in iodobenzene (0.4 mL). Completion of the reaction was de-
tected by TLC, then the reaction mixtures were filtered over a silica plug
and analysed. [b] The ee was determined by GC analysis. [c] The enan-
tiomer ent-18 with the opposite sign of optical rotation was formed.
[d] Conversion was not complete.
This initial screening gave good results, as NFSI (25) not
only led to full conversion, but the product already exhibit-
ed an enantiomeric excess not obtained so far. With NFSI
6044
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Chem. Eur. J. 2006, 12, 6039 – 6052

Non-Biaryl Atropisomers in Organocatalysis
FULL PAPER
of hexane/iPrOH 9:1 was used.
Furthermore, it was not possi-
ble to analyse all reaction
products by GC analysis,
making a derivatisation of the
raw products necessary. Two
procedures are described for
derivatisation, either reduction
to the alcohol 29 by using
[38a–d]
NaBH4
or oxidation to the
acid by using NaOCl.[38b] Both
were tried, but because of its
Scheme 2. a-Fluorination of a-branched aldehydes 24 according to Barbas and our group.[38a,b]
Table 5. Screening of fluorine sources for the organocatalytic asymmetric
Table 6. Screening of solvents for the organocatalytic asymmetric fluori-
fluorination of 2-phenylpropanal (24a).[a]
nation of 2-phenylpropanal (24a) by using NFSI (25).[a]
Entry
Solvent
Conversion [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
acetone
toluene
THF
MeCN
dioxane
DMF
CH2Cl2
EtOAc
iPrOH
MeOH
hexane
78
83
79
92
76
94
91
96
85
32
95
72
64
70
78
68
76
62
72
85
84
86
Entry
Fluorine source
Conversion [%][b]
ee [%][c]
1
2
3
25
27
28
96
6
33
72
56
16
[a] Reaction carried out by using 24a (0.25 mmol), fluorinating agent
(0.25 mmol) and ent-3b (0.05 mmol) in EtOAc (0.5 mL) for 16 h. [b] Con-
versions are stated as the ratio of product to starting material as deter-
mined by GC analysis. [c] The ee was determined by chiral GC analysis.
9
10
11
[a] Reaction carried out by using 24a (0.25 mmol), 25 (0.25 mmol) and
ent-3b (0.05 mmol) in solvent (0.5 mL) for 16 h. [b] Conversions are
stated as the ratio of product to starting material as determined by GC
analysis. [c] The ee was determined by chiral GC analysis.
(25) as the fluorine source the influence of the solvent on
the reaction course was then thoroughly examined. Table 6
shows the results for the screening of different solvents for
the organocatalytic fluorination of 24a.
ease the reduction was established as the method of choice.
Table 7 shows the enantioselective a-fluorination of alde-
hydes 24 by using NFSI 25.
To our surprise the reaction worked in all tested solvents,
with good conversions and moderate to good enantioselec-
tivity, irrespective of the polarity of the solvent. Only in
MeOH, the conversion was low, possibly due to concomitant
formation of the hemiacetal or acetal (Table 6, entry 10).
The highest enantiomeric excess was obtained when the re-
action was carried out in either MeOH, iPrOH or hexane.
By using hexane as the solvent, 90% conversion was
reached within 3 h at room temperature. The speed of the
reaction and the impossibility for acetal formation, resulted
in hexane becoming the solvent of choice. A decrease in cat-
alyst loading to 10 mol% led to a slower reaction, but with-
out diminishing the enantiomeric excess. Cooling the reac-
tion to 48C finally enhanced the enantiomeric excess to
90% ee with 95% conversion after 16 h.
Good enantioselectivity was achieved when R1 was an ar-
omatic substituent without substitution (Table 7, entry 1) or
with electron-withdrawing substituents (entries 2 and 3). The
fluorinated
1,2,3,4-tetrahydronaphthalene-1-carbaldehyde
26e could only be isolated as the aldehyde and decomposed
in our hands upon reduction to 29e. Generally, the a-fluori-
nated aldehydes themselves are known to be unstable.[51]
Nonetheless, a good enantiomeric excess of 78% was ach-
ieved for this substrate (entry 4). In the case of two aliphatic
substituents the enantioselectivity of the reaction dropped
significantly (entries 5–7). Surprisingly, linear aldehydes like
3-phenyl propanal did not react at all under the given condi-
tions and the same holds true for ketones, for example, ace-
tone or cyclohexanone. No side products could be detected
and raw yields and spectra suggested good conversions and
purities. However,only moderate yields could be isolated
after column chromatography. This could possibly originate
Under these optimised reaction conditions additional sub-
strates were examined. Unfortunately, not all substrates
were sufficiently soluble in hexane, hence a solvent mixture
Chem. Eur. J. 2006, 12, 6039 – 6052
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6045

K. A. Jørgensen et al.
Table 7. Enantioselective a-fluorination of a-branched aldehydes 24 by
using NFSI (25).[a]
An intermediate of this kind should have an E-geometry
at the enamine, which would only permit the NFSI to attack
from the Si-face of the enamine, yielding (S)-2-fluoro-2-phe-
nylpropanal ((S)-26a). This predicted configuration could be
confirmed by a single-crystal X-ray analysis of the 4-bromo-
benzoyl hydrazone derivative 31 (Figure 4).[52]
Entry Aldehyde R1
R2 Product Yield
[%][b]
ee [%][c]
1
2
3
24a
24c
24d
Ph
Me 29a
Me 29c
Me 29d
36
56
60
90
(88)[d]
78
4-NO2-C6H4
4-Br-C6H4
À
(68)[d]
90
(86)[d]
78(77)[e]
7 (3)[e]
30
55[f]
27
29
À
(CH2)3
4
5
6
24e
24 f
24g
(C6H4)
26e
Et 29 f[g]
Me 29g
Bu
CH2(4-
iPrC6H4)
cHex
Figure 4. X-ray crystallographic structure of the benzoyl hydrazone deriv-
ative 31.
(28)[d]
31[e]
7
24h
Me 29h
10
[a] Reaction carried out by using aldehyde 24 (0.50 mmol), NFSI (25;
0.60 mmol) and catalyst ent-3b (0.05 mmol, 96% ee) in hexane/iPrOH
9:1 (1.0 mL) for 16 h. [b] Yield after flash chromatography, variations
due to instability of the products. [c] The ee of the alcohol 29 (ee with 3b
[87% ee]). [d] The ee was determined by chiral HPLC analysis. [e] The ee
was determined by chiral GC analysis. [f] The aldehyde 26e was isolated
and analysed. [g] The catalyst ent-3b (0.3 equiv) was added over 72 h.
The diminished enantioselection in the reactions, for
which aliphatic a-branched aldehydes are used could be a
result of an E/Z-isomerism of the intermediate enamine.
This would cause undistinguishable faces of the enamine,
thereby preventing a stereoselective attack by the NFSI.
In summary, we have prepared a new class of compounds
consisting of nine 5’-aminated 6’-hydroxy cinchona alkaloids
which combine non-biaryl atropisomerism with the catalytic
properties of the cinchona alkaloids. A set of atropo-diaster-
eomeric cinchona alkaloids exhibits strongly differing physi-
cal and catalytical properties, due to intramolecular hydro-
gen bonding from the hydrazine NH to the quinuclidine ni-
trogen atom, present in the less polar diastereoisomer. By
this, the basic site of the molecule is blocked which was also
confirmed by NMR experiments. These new catalysts dem-
onstrated a good performance in the asymmetric Michael
addition of b-keto esters to a,b-unsaturated carbonyl com-
pounds (up to 93% ee), as well as advanced performance in
the asymmetric Friedel–Crafts amination of various 2-naph-
thols. The aminated 8-amino-2-naphthol itself was used as
an organocatalyst in the asymmetric a-fluorination of a-
branched aldehydes, yielding the fluorinated compounds in
up to 90% ee. This is the first example of an organocatalyst
in which the chirality originates from non-biaryl atrop-
isomerism. Further applications of these new catalysts and
derivatives thereof are now being investigated in our labora-
tories.
from the instability of the products towards column chroma-
tography.
Mechanistically, the chiral induction in this reaction could
originate from shielding of one of the faces of the intermedi-
ate enamine, limiting the NFSI to attack only from the op-
posite face. The X-ray structure of a functionalised product
30[21] (Figure 3, left and middle) from the amination of 8-
amino-2-naphthol shows that the substituents of the naph-
thol are oriented nearly parallel to each other and close to
rectangular to the naphthol core. Furthermore, the X-ray
structure suggests hydrogen bonding between the amide NH
moiety to the carbonyl oxygen atom of the carbonylbenzyl-
oxy (Cbz) group. The geometry of the intermediate could
possibly be stabilised by a similar intramolecular hydrogen
bonding from the enamine NH to the carbonyl oxygen atom
bound to N-1 (Figure 3, right).
Experimental Section
General: The 1H, 13C and 19F NMR spectra were recorded at 400, 100
and 377 MHz, respectively. The chemical shifts are reported in ppm
downfield to CHCl3 (d=7.26), CHDCl2 (d=5.32) or CHD2CN (d=1.94)
for 1H NMR spectra, (d=77.0), (d=53.5) or (d=1.2) for 13C NMR spec-
tra relative to the central CDCl3, CD2Cl2 or CD3CN resonance, and rela-
tive to 2,2,2-trifluoroacetophenone (d=À71.8) for 19F NMR spectra, re-
spectively. Around half of the NMR spectra show rotamers and therefore
doubling of the signal set or line broadening. Therefore all 1H and 13C
spectra with rotamer influence are available in the Supporting Informa-
Figure 3. Functionalised product 30[21] (left and middle) and possible en-
amine intermediate formed from the organocatalyst ent-3b and 2-phenyl-
propanal 24a.
6046
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Chem. Eur. J. 2006, 12, 6039 – 6052

Non-Biaryl Atropisomers in Organocatalysis
FULL PAPER
tion. Flash chromatography (FC) was carried out by using Merck silica
gel 60 (230–400 mesh). Optical rotations were measured on a Perkin–
Elmer 241 polarimeter. The enantiomeric excesses of the products were
determined by HPLC using a Daicel Chiralpak AD, Chiralcel OD or
Chiralcel OJ column with iPrOH/hexane as the eluent or by GC using an
Astec G-TA column.
MeOH/24% aq NH3 95:5:1 gave the product (0.42 g, 24%). Rf =0.16
(pentane/EtOAc 50:50); [a]2D0 =À14.6 (c=0.06 in CHCl3); 1H NMR
(400 MHz, CDCl3, 208C): d=12.12/11.89 (brs, 1H), 10.99/10.76 (s, 1H),
8.62/8.60 (d, J=4.6 Hz, 1H), 8.04/8.03 (d, J=9.2 Hz, 1H), 7.67/7.63 (d,
J=4.6 Hz, 1H), 7.46/7.44 (d, J=9.2 Hz, 1H), 6.61/6.35 (s, 1H), 3.42 (m,
1H), 3.00 (m, 1H), 2.71 (m, 2H), 2.29–2.10 (m, 2H), 2.07–1.96 (m, 1H),
1.94–1.73 (m, 2H), 1.55–1.45 (m, 15H), 1.36–1.28 (m, 1H), 1.28–1.19 (m,
2H), 1.18–1.15 (m, 5H), 0.84–0.73 ppm (m, 3H); 13C NMR (100 MHz,
CDCl3, 208C): d=161.1, 156.0, 155.5, 154.5, 154.1, 148.3, 147.8, 146.7,
146.6, 145.0, 144.7, 133.6, 133.3, 123.9, 122.9, 122.8, 119.8, 119.0, 118.4,
118.2, 82.3, 82.2, 82.1, 81.9, 70.6, 70.0, 59.8, 56.5, 56.1, 53.0, 42.5, 42.1,
37.1, 28.3, 28.1, 27.8, 27.4, 27.0, 25.8, 16.2, 16.0, 11.8 ppm; HRMS: m/z:
calcd: 543.3184; found: 543.3185 [C29H42N4O6+H]+.
Materials: Naphthols 4a and b, diazocarboxylates 5a–c, hydroquinine, hy-
droquinidine, diazabicyclo[3.2.0]undecene (DBU), the b-ketoesters 16
N
and 22, acrolein, metyl vinyl ketone, NFSI, Selectfluorꢁ, the pyridinium
salt 28, sodiumborohydride, pentane, Et2O, EtOAc, toluene, 1,2-dichloro-
ethane (DCE), CH2Cl2, MeOH, iodobenzene, acetone, THF, MeCN, di-
oxane, DMF, hexane and iPrOH were obtained from Aldrich and used as
received. Catalysts 6, 7, 10 and 12 were prepared according to literature
procedures.[23,39,40] The naphthols 4c–f were prepared by reductive amina-
tion of 4b with the corresponding aldehydes; 4g was obtained by bromi-
nation of 4b; 4h was obtained by N-Boc-protection of 4b and 4i was ob-
tained from 4b by diazotation and reaction with copper(i)chloride. a-
Branched aldehydes 24c–e and h were prepared from the corresponding
ketones by Wittig reaction with methoxymethyl triphenylphosphonium
chloride in THF by using LDA, followed by reaction with p-toluolsulfon-
ic acid in dioxane/water 1:1, following known procedures.[53]
(R)-(À)-Hydrocupreine-5’-(hydrazine-N,N’-dicarboxylic acid tert-butyl
ester) (9b): The title compound was prepared according to the general
procedure by using hydrocupreine (6; 1 g, 3.2 mmol) and DtBuAD (5b;
890 mg, 3.84 mmol). Elution with EtOAc/MeOH/24% aq NH3 95:5:1 to
EtOAc/MeOH/24% aq NH3 90:10:1 gave the product (0.98 g, 56%).
Rf =0.35 (EtOAc/MeOH/aq NH3 90:10:1); [a]2D0 =À85.6 (c=0.96 in
CHCl3); 1H NMR (400 MHz, CDCl3, 208C): d=8.59 (d, J=4.6 Hz, 1H),
7.95 (d, J=9.1 Hz, 1H), 7.48 (d, J=4.6 Hz, 1H), 7.38 (d, J=9.2 Hz, 1H),
5.61–5.43 (m, 1H), 3.38–3.20 (m, 1H), 3.13–3.00 (m, 1H), 2.99–2.85 (m,
1H), 2.60–2.41 (m, 3H), 1.98–1.88 (m, 1H), 1.87–1.76 (m, 2H), 1.75–1.63
(m, 2H), 1.56 (s, 3H), 1.53–1.32 (m, 13H), 1.28–1.21 (m, 6H), 0.93–
0.85 ppm (m, 3H); 13C NMR (100 MHz, CDCl3, 208C): d=159.2, 155.0,
146.5, 144.7, 144.1, 132.6, 126.3, 123.0, 122.7, 120.5, 82.9, 82.7, 71.2, 58.3,
57.1, 41.7, 37.1, 28.1, 27.8, 27.5, 25.2, 24.1, 21.0, 14.1, 12.1 ppm; HRMS:
m/z: calcd: 543.3184; found: 543.3187 [C29H42N4O6+H]+.
General procedure for the amination of the cinchona alkaloids: The cin-
chona alkaloid (1.0 equiv) was placed in a 25 mL round-bottomed flask.
The solid was suspended in dichloromethane (10 mL per 1 g cinchona al-
kaloid) and then azodicarboxylate (5; 1.2 equiv) was added. When the
starting material could no longer be detected by TLC or when the sus-
pension turned into a dark orange solution, the solvent was evaporated
and the raw product purified by FC.
(S)-(À)-b-Isocupreidine-5’-(hydrazine-N,N’-dicarboxylic acid tert-butyl
ester) (11a): The title compound was prepared according to the general
procedure by using b-isocupreidine (10; 100 mg, 0.32 mmol) and
DtBuAD (5b; 89 mg, 0.38 mmol). Elution with pentane/EtOAc 50:50 to
EtOAc/MeOH/24% aq NH3 95:5:1 gave the product (79 mg, 45%). Rf =
0.32 (pentane/EtOAc 50:50); [a]2D0 =À32.5 (c=1.03 in CHCl3); 1H NMR
(400 MHz, CDCl3, 208C): d=11.08/10.87 (s, 1H), 10.85/10.72 (s, 1H),
8.66/8.64 (d, J=4.5 Hz, 1H), 8.03/7.99 (d, J=9.2 Hz, 1H), 7.76/7.74 (d,
J=4.5 Hz, 1H), 7.40/7.39 (d, J=9.2 Hz, 1H), 5.97/5.83 (s, 1H), 3.52/3.50
(d, J=13.8 Hz, 1H), 3.04–2.83 (m, 3H), 2.67/2.59 (d, J=13.8 Hz, 1H),
2.08–1.96 (m, 1H), 1.71–1.59 (m, 3H), 1.56–1.46 (m, 16H), 1.15–1.10 (m,
5H), 0.97/0.92 ppm (t, J=7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3,
208C): d=161.6, 161.1, 156.5, 155.9, 154.7, 146.4, 146.4, 146.3, 144.4,
144.1, 141.7, 133.9, 133.5, 125.0, 122.4, 119.3, 119.1, 118.5, 117.8, 82.7,
82.5, 77.9, 77.7 72.1, 72.0, 56.8, 56.7, 53.6, 53.6, 45.8, 33.5, 33.1, 28.2, 28.1,
28.1, 27.7, 27.6, 27.5, 27.4, 23.2, 22.2, 22.1, 7.3 ppm; HRMS: m/z: calcd:
541.3026; found: 541.3033 [C29H40N4O6+H]+.
Characterisation data for the cinchona alkaloid derivatives
(S)-(+)-Hydrocupreidine-5’-(hydrazine-N,N’-dicarboxylic acid tert-butyl
ester) (8a): The title compound was prepared according to the general
procedure by using hydrocupreidine (7; 1.0 g, 3.20 mmol) and DtBuAD
(5b; 890 mg, 3.84 mmol). Elution with pentane/EtOAc 50:50 to EtOAc/
MeOH/24% aq NH3 95:5:1 gave the product (1.24 g, 72%). Rf =0.67
(EtOAc/MeOH/aq NH3 90:10:1); Rf =0.18 (pentane/EtOAc 50:50);
1
[a]2D0 =+81.9 (c=1.0 in CH2Cl2); H NMR (400 MHz, CD2Cl2, 208C): d=
10.75/10.60 (s, 1H), 8.37 (d, J=4.6 Hz, 1H), 7.89/7.88 (d, J=9.2 Hz, 1H),
7.58/7.53 (d, J=4.5 Hz, 1H), 7.28/7.26 (d, J=9.2 Hz, 1H), 5.63/5.61 (brs,
1H), 3.69/3.53 (brs, 1H), 3.03–2.93 (m, 1H), 2.92–2.84 (m, 1H), 2.72–2.64
(m, 1H), 2.60–2.51 (m, 1H), 2.51–2.43 (m, 1H), 2.39–2.31/2.26–2.18 (m,
1H), 1.66–1.57 (m, 1H), 1.55–1.43 (m, 2H), 1.42–1.35 (m, 11H), 1.34–
1.26 (m, 7H), 0.98 (s, 3H), 0.99–0.95/0.95–0.89 (m, 1H), 0.82/0.75 ppm (t,
3H, J=7.3 Hz); 13C NMR (100 MHz, CD2Cl2, 208C): d=161.2, 161.1,
155.8, 155.4, 154.4, 153.9, 149.3, 148.5, 146.9, 146.6, 144.8, 144.6, 133.3,
133.1, 124.2, 124.0, 122.4, 120.0, 119.4, 118.9, 118.6, 82.4, 82.2, 82.0, 81.9,
71.0, 70.3, 60.2, 60.0, 50.1, 49.6, 48.3, 47.9, 37.4, 37.3, 28.1, 28.0, 27.9, 27.8,
27.6, 26.4, 25.2, 25.2, 16.5, 16.5, 12.0, 11.9 ppm; HRMS: m/z: calcd:
543.3184; found: 543.3181 [C29H42N4O6+H]+.
(R)-(À)-b-Isocupreidine-5’-(hydrazine-N,N’-dicarboxylic acid tert-butyl
ester) (11b): The title compound was prepared according to the general
procedure by using b-isocupreidine (10; 100 mg, 0.32 mmol) and
DtBuAD (5b; 89 mg, 0.38 mmol). Elution with EtOAc/MeOH/24% aq
NH3 95:5:1 to EtOAc/MeOH/24% aq NH3 90:10:1 gave the product
(78 mg, 45%). Rf =0.35 (EtOAc/MeOH/aq NH3 90:10:1); [a]2D0 =À2.8
(c=0.59 in CHCl3); 1H NMR (400 MHz, CDCl3, 208C): d=10.67 (brs,
1H), 9.30 (brs, 1H), 8.69/8.66 (d, J=4.6 Hz, 1H), 8.04/8.03 (d, J=9.1 Hz,
1H), 7.53/7.49 (d, J=4.6 Hz, 1H), 7.44 (t, J=8.7 Hz, 1H), 5.85/5.78 (s,
1H), 3.53–3.42 (m, 2H), 3.16–2.92 (m, 2H), 2.62 (dd, J=4.8 Hz, J=
13.9 Hz, 1H), 2.18–2.06 (m, 2H), 1.70–1.58 (m, 3H), 1.51/1.50/1.48 (s,
14H), 1.27 ppm (s, 4H); 13C NMR (100 MHz, CDCl3, 208C): d=159.7,
159.5, 156.1, 155.4, 154.2, 153.6, 146.7, 146.6, 145.2, 145.1, 140.9, 140.7,
134.2, 133.7, 127.3, 126.8, 122.9, 122.9, 121.5, 121.4, 119.9, 118.8, 83.3,
83.1, 82.8, 82.5, 78.7, 78.5, 74.2, 74.1, 56.3, 56.3, 54.1, 46.6, 46.6, 31.2, 31.2,
28.1, 28.1, 27.8, 26.9, 26.9, 24.9, 24.8, 23.7, 23.7, 7.4, 7.3 ppm; HRMS:
m/z: calcd: 541.3026; found: 541.3023 [C29H40N4O6+H]+.
(R)-(+)-Hydrocupreidine-5’-(hydrazine-N,N’-dicarboxylic acid tert-butyl
ester) (8b): The title compound was prepared according to the general
procedure by using hydrocupreidine (7; 1.0 g, 3.20 mmol) and DtBuAD
(5b; 890 mg, 3.84 mmol). Elution with EtOAc/MeOH/24% aq NH3
95:5:1 to EtOAc/MeOH/24% aq NH3 90:10:1 gave the product (0.37 g,
21%). Rf =0.29 (EtOAc/MeOH/aq NH3 90:10:1); Rf =0.61 (EtOAc/
MeOH/aq NH3 50:50:1); [a]2D0 =+134.2 (c=1.6 in CHCl3); 1H NMR
(400 MHz, CDCl3, 208C): d=8.40 (m, 1H), 7.86 (d, J=9.1 Hz, 1H), 7.44
(d, J=3.8 Hz, 1H), 7.33 (d, J=9.1 Hz, 1H), 5.71/5.54 (s, 1H), 3.27 (brs,
1H), 3.15–2.98 (m, 1H), 2.95–2.58 (m, 3H), 2.13–1.99/1.97–1.86 (m, 1H),
1.83/1.76 (brs, 1H), 1.72–1.58 (m, 2H), 1.58–1.49 (m, 6H), 1.48–1.33 (m,
13H), 1.24 (s, 6H), 0.92–0.78 ppm (m, 3H); 13C NMR (100 MHz, CDCl3,
208C): d=159.3, 155.2, 146.5, 144.7, 132.8, 126.5, 123.5, 122.9, 120.6,
120.1, 83.0, 82.6, 70.3, 58.8, 58.2, 50.4, 50.0, 48.6, 37.3, 37.5, 28.2, 28.1,
27.9, 27.0, 26.6, 25.9, 25.5, 25.0, 24.9, 23.3, 12.1, 11.9 ppm; HRMS: m/z:
calcd: 543.3184; found: 543.3115 [C29H42N4O6+H]+.
(R)-(+)-9-Benzyl-6’-hydroxyquinine-5’-(hydrazine-N,N’-dicarboxylic acid
tert-butyl ester) (13a): The title compound was prepared according to the
general procedure by using 9-benzyl-6’-hydroxyquinine (12; 305 mg,
0.76 mmol) and DtBuAD (5b; 210 mg, 0.91 mmol). Elution with pen-
tane/EtOAc/aq NH3 80:20:1 to 40:60:1 gave the product (48 mg, 10%).
Rf =0.65 (pentane/EtOAc 50:50); [a]2D0 =+49.8 (c=0.15 in CHCl3);
(S)-(À)-Hydrocupreine-5’-(hydrazine-N,N’-dicarboxylic acid tert-butyl
ester) (9a): The title compound was prepared according to the general
procedure by using hydrocupreine 6 (1.0 g, 3.20 mmol) and DtBuAD
(5b; 890 mg, 3.84 mmol). Elution with pentane/EtOAc 50:50 to EtOAc/
Chem. Eur. J. 2006, 12, 6039 – 6052
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6047

K. A. Jørgensen et al.
1H NMR (400 MHz, CDCl3, 208C): d=11.96/11.73 (s, 1H), 11.02/10.82 (s,
1H), 8.68/8.64 (d, J=4.5 Hz, 1H), 8.08 (dd, J=1.3 Hz, J=9.2 Hz, 1H),
7.65/7.58 (d, J=4.5 Hz, 1H), 7.50/7.48 (dd, J=9.2 Hz, 1H), 7.42–7.30 (m,
5H), 5.76–5.62 (m, 1H), 5.50/5.45 (s, 1H), 5.00–4.88 (m, 2H), 4.49–4.39
(m, 2H), 3.40–3.28 (m, 1H), 3.10–3.00 (m, 1H), 2.87–2.70 (m, 2H), 2.62–
2.50 (m, 1H), 2.37–2.10 (m, 2H), 1.96–1.75 (m, 2H), 1.59–1.49 (m, 15H),
1.28 ppm (s, 5H); 13C NMR (100 MHz, CDCl3, 208C): d=161.0, 156.0,
155.4, 154.5, 153.9, 146.8, 145.0, 141.3, 141.1, 138.0, 137.7, 133.9, 133.6,
128.5, 128.4, 127.8, 127.6, 127.3, 127.1, 123.0, 118.2, 114.7, 114.5, 82.4,
82.4, 82.1, 79.5, 78.9, 71.7, 71.1, 60.2, 59.9, 54.8, 54.3, 42.5, 42.1, 39.6, 30.3,
28.3, 28.3, 28.3, 28.2, 28.0, 26.9, 26.8, 17.5, 17.3 ppm; HRMS: m/z: calcd:
631.3496; found: 631.3470 [C36H46N4O6+H]+.
412.1840 [C20H27N3O5+Na]+; the ee was determined by HPLC using a
Chiralcel OD column (hexane/iPrOH 80:20); flow rate: 1.0 mLminÀ1
tmajor =5.8 min, tminor =7.5 min.
;
N-(8-Methylamino-2-hydroxy-1-naphthyl)hydrazine-N,N’-dicarboxylic acid
tert-butyl ester (3c): The title compound was prepared according to the
general procedure by using 8-methylamino-2-naphthol (4c; 35 mg,
0.20 mmol) and 8b (22 mg, 0.04 mmol). Elution with pentane/Et20 80:20
gave the product (74 mg, 91%). Rf =0.35 (pentane/Et20 50:50); [a]D20
=
À71.2 (c=1.0 in CDCl3); 1H NMR (400 MHz, CDCl3, 608C): d=9.16
(brs, 1H), 7.69 (d, J=8.9 Hz, 1H), 7.32 (s, 1H), 7.29 (d, J=7.9 Hz, 1H),
7.25–7.00 (m, 2H), 6.81 (d, J=7.4 Hz, 1H), 4.35 (brs, 1H), 2.95 (s, 3H),
1.50/1.45 ppm (s, 18H); 13C NMR (100 MHz, CDCl3, 608C): d=157.6,
154.4, 152.5, 143.5, 131.3, 131.2, 130.9, 123.7, 120.6, 119.3, 109.9, 83.0,
82.8, 32.7, 28.2, 28.0 ppm; HRMS [C21H29N3O5+Na]+: calcd: 426.2005;
found: 426.2014; the ee was determined by HPLC using a Chiralcel OD
column (hexane/iPrOH 90:10); flow rate: 1.0 mLminÀ1; tminor =6.5 min,
tmajor =7.9 min.
(S)-(À)-9-Benzyl-6’-hydroxyquinine-5’-(hydrazine-N,N’-dicarboxylic acid
tert-butyl ester) (13b): The title compound was prepared according to the
general procedure by using 9-benzyl-6’-hydroxyquinine (12; 305 mg,
0.76 mmol) and DtBuAD (5b; 210 mg, 0.91 mmol). Elution with pen-
tane/EtOAc/aq NH3 40:60:1 to 0:100:1 gave the product (328 mg, 68%).
Rf =0.22 (pentane/EtOAc 50:50); [a]2D0 =À62.3 (c=1.02 in CHCl3);
1H NMR (400 MHz, CDCl3, 208C): d=11.40/11.14 (s, 1H), 8.71–8.67 (m,
1H), 8.07/8.03 (d, J=9.4 Hz, 1H), 7.57/7.55 (d, J=4.9 Hz, 1H), 7.47/7.41
(d, J=9.2 Hz, 1H), 7.31–7.21 (m, 3H), 7.19–7.12 (m, 2H), 5.85–5.72 (m,
1H), 5.37–5.46 (m, 1H), 5.04–4.90 (m, 2H), 4.14–3.98 (m, 2H), 3.42–3.02
(m, 3H), 2.84–2.56 (m, 2H), 2.35–2.08 (m, 2H), 1.87–1.68 (m, 3H), 1.52–
1.44 (m, 13H), 1.13 ppm (s, 7H); 13C NMR (100 MHz, CDCl3, 208C): d=
161.2, 160.3, 156.8, 156.6, 154.3, 154.0, 146.7, 145.2, 145.0, 143.6, 142.7,
141.6, 141.5, 137.5, 137.4, 134.1, 133.7, 128.9, 128.7, 128.3, 128.3, 127.8,
127.7, 127.6, 125.5, 123.3, 123.0, 120.2, 119.7, 119.4, 119.0, 114.6, 114.3,
83.2, 82.8, 82.7, 82.0, 78.6, 78.3, 69.5, 69.0, 59.0, 58.6, 56.1, 55.1, 42.3, 42.1,
40.0, 39.5, 30.3, 28.2, 28.1, 27.7, 27.6, 27.1, 27.1, 20.5, 19.8 ppm; HRMS:
m/z: calcd: 631.3496; found: 631.3503 [C36H46N4O6+H]+.
N-(8-Benzylamino-2-hydroxy-1-naphthyl)hydrazine-N,N’-dicarboxylic acid
tert-butyl ester (3d): The title compound was prepared according to the
general procedure by using 8-benzylamino-2-naphthol (4d; 50 mg,
0.20 mmol) and 8b (22 mg, 0.04 mmol). Elution with pentane/Et20 75:25
gave the product (88 mg, 92%). Rf =0.27 (pentane/Et20 50:50); [a]D20
=
1
À58.6 (c=0.50 in CDCl3); H NMR (400 MHz, CDCl3, 608C): d=9.19 (s,
1H), 7.70 (d, J=8.9 Hz, 1H), 7.50–7.40 (m, 4H), 7.40–7.30 (m, 2H),
7.30–7.19 (m, 3H), 6.86 (d, J=7.5 Hz, 1H), 4.59 (brs, 1H), 4.37 (d, J=
12.8 Hz, 2H), 1.50 (s, 9H), 1.34 ppm (s, 9H); 13C NMR (100 MHz,
CDCl3, 608C): d=157.7, 153.7, 152.8, 142.3, 139.2, 131.3, 131.2, 131.0,
128.9, 128.0, 127.6, 124.4, 123.5, 123.4, 120.9, 120.4, 119.4, 110.7, 82.8,
82.6, 50.1, 28.2, 27.8 ppm; HRMS: m/z: calcd: 502.2318; found: 502.2314
[C27H33N3O5+Na]+; the ee was determined by HPLC using a Chiralcel
OD column (hexane/iPrOH 85:15); flow rate: 1.0 mLminÀ1
7.0 min, tmajor =7.8 min.
; tminor =
(R)-(+)-Hydrocupreidine-5’-(hydrazine-N,N’-dicarboxylic acid benzyl
ester) (15): The title compound was prepared according to the general
procedure by using hydrocupreidine (7; 147 mg, 0.47 mmol) and DBnAD
(5c; 168 mg, 0.56 mmol). Elution with EtOAc/MeOH/24% aq NH3
100:0:0 to 80:20:1 gave the product (143 mg, 50%). Rf =0.60 (EtOAc/
MeOH/aq NH3 50:50:1); [a]2D0 =+54.3 (c=0.55 in CHCl3); 1H NMR
(400 MHz, CDCl3, 608C): d=8.59 (d, J=4.6 Hz, 1H), 7.97 (d, J=9.2 Hz,
1H), 7.87 (d, J=4.5 Hz, 1H), 7.47 (d, J=9.2 Hz, 1H), 7.42–6.98 (m, 9H),
6.80–6.30 (m, 1H), 5.40–5.03 (m, 3H), 4.67 (s, 4H), 3.93 (dd, J=8.9 Hz,
J=11.8 Hz, 1H), 3.77–3.56 (m, 0.5H), 3.43 (t, J=11.4 Hz, 1H), 3.25–2.82
(m, 1H), 2.54–2.24 (m, 0.5H), 1.96–1.50 (m, 6H), 1.20–1.06 (m, 1H),
0.93 ppm (t, J=7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3, 608C): d=
161.0, 160.4, 159.6, 159.2, 158.7, 158.7, 158.1, 147.5, 146.9, 146.0, 145.8,
144.1, 142.7, 137.3, 137.0, 136.8, 136.3, 133.5, 133.4, 129.7, 129.6, 129.6,
129.5, 129.3, 129.3, 128.9, 128.8, 128.2, 128.0, 127.7, 125.8, 125.7, 125.5,
124.3, 124.2, 123.5, 123.1, 122.1, 121.9, 121.8, 121.7, 70.7, 70.4, 69.3, 68.9,
68.3, 67.9, 65.2, 62.0, 61.6, 61.2, 51.9, 51.6, 26.4, 26.3, 26.1, 25.3, 24.6, 24.5,
22.2, 18.8, 18.4, 18.4, 17.9, 11.8 ppm; HRMS [C35H38N4O6+H]+: calcd:
611.2870; found: 611.2866.
N-(8-(2,2-Dimethylpropylamino)-2-hydroxy-1-naphthyl)hydrazine-N,N’-di-
carboxylic acid tert-butyl ester (3e): The title compound was prepared ac-
cording to the general procedure by using 8-(2,2-dimethylpropylamino)-
2-naphthol (4e; 46 mg, 0.20 mmol) and 8b (22 mg, 0.04 mmol). Elution
with pentane/Et20 90:10 gave the product (87 mg, 95%). Rf =0.40 (pen-
tane/Et20 50:50); [a]2D0 =À100.0 (c=0.92 in CDCl3); 1H NMR (400 MHz,
CDCl3, 208C): d=9.28 (s, 1H), 7.71 (d, J=8.9 Hz, 1H), 7.63/7.46 (s, 1H),
7.29 (d, J=8.0 Hz, 1H), 7.26–7.18 (m, 2H), 6.81 (d, J=7.4 Hz, 1H), 4.43
(s, 1H), 3.10–2.96 (m, 1H), 2.88 (d, J=10.7 Hz, 1H), 1.58 (s, 1H), 1.47 (s,
9H), 1.41 (s, 5H), 1.14 ppm (s, 9H); 13C NMR (100 MHz, CDCl3, 208C):
d=157.4, 153.9, 151.8, 143.2, 131.4, 131.1, 130.7, 123.7, 120.4, 120.0, 119.5,
109.6, 109.1, 83.0 57.9, 57.7, 31.0, 28.1, 27.9 ppm; HRMS: m/z: calcd:
482.2631; found: 482.2599 [C25H37N3O5+Na]+; the ee was determined by
HPLC using a Chiralcel OD column (hexane/iPrOH 98:2); flow rate:
1.0 mLminÀ1; tmajor =6.3 min, tminor =7.6 min.
N-(8-(2’-Hydroxybenzylamino)-2-hydroxy-1-naphthyl)hydrazine-N,N’-di-
carboxylic acid tert-butyl ester (3 f): The title compound was prepared ac-
cording to the general procedure by using 8-(2-hydroxybenzylamino)-
naphthalen-2-ol (4 f; 53 mg, 0.20 mmol) and 8b (22 mg, 0.04 mmol). Elu-
tion with pentane/Et20 85:15 gave the product (94 mg, 95%) of product.
Rf =0.20 (pentane/Et20 50:50); [a]2D0 =+22.0 (c=1.48 in CHCl3);
1H NMR (400 MHz, CDCl3, 608C): d=7.69 (d, J=8.9 Hz, 2H), 7.32 (d,
J=7.7 Hz, 1H), 7.26–7.18 (m, 3H), 6.95–6.89 (m, 3H), 4.51 (d, J=
12.4 Hz, 1H), 4.30 (d, J=12.5 Hz, 1H), 4.13 (q, J=7.1 Hz, 1H), 1.50 (s,
9H), 1.27 ppm (s, 9H); 13C NMR (100 MHz, CDCl3, 608C): d=157.9,
155.2, 154.6, 152.6, 131.4, 131.3, 130.9, 129.9, 129.0, 124.7, 123.6, 121.1,
120.7, 119.1, 116.3, 111.1, 82.9, 82.7, 47.1, 28.2, 27.8 ppm; HRMS: m/z:
calcd: 518.2267; found: 518.2278 [C27H33N3O6+Na]+; the ee was deter-
mined by HPLC using a Chiralpak AD column (hexane/iPrOH 95:5);
flow rate: 1.0 mLminÀ1; tmajor =17.6 min, tminor =20.5 min.
General procedure for the amination of 2-naphthols: The catalyst (DBU
for racemates; 0.04 mmol, 0.2 equiv) was added to naphthol
4
(0.20 mmol) in a 4 mL vial, and then everything was dissolved in 1,2-di-
chloroethane (4.0 mL, 0.05m). The vial was closed with a screw lid and
put into a freezer at À208C, where the solution was stirred for at least
30 min. After this period the DtBuAD (5b; 46 mg, 0.20 mmol) was
added and the solution stirred overnight. The product was purified by
FC.
N-(8-Amino-2-hydroxy-1-naphthyl)hydrazine-N,N’-dicarboxylic acid tert-
butyl ester (3b): The title compound was prepared according to the gen-
eral procedure by using 8-amino-2-naphthol (4b; 32 mg, 0.20 mmol) and
8b (22 mg, 0.04 mmol). Elution with pentane/Et20=75:25 gave the prod-
uct (68 mg, 87%). Rf =0.38 (pentane/Et20 50:50); [a]2D0 =À64.3 (c=2.0 in
CDCl3, sample with 84% ee); 1H NMR (400 MHz, CDCl3, 208C): d=
9.39 (s, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.66 (s, 1H), 7.35 (d, J=7.8 Hz,
1H), 7.23 (d, J=8.4 Hz, 1H), 7.12 (t, J=7.4 Hz, 1H), 6.83 (d, J=7.3 Hz,
1H), 3.88 (s, 2H), 1.48/1.39 ppm (s, 18H); 13C NMR (100 MHz, CDCl3,
208C): d=157.6, 154.4, 152.1, 139.0, 131.0, 130.8, 123.3, 121.9, 119.4,
116.4, 82.7, 82.6, 28.1, 27.9 ppm; HRMS: m/z: calcd: 412.1848; found:
N-(8-Amino-5,7-dibromo-2-hydroxy-1-naphthyl)hydrazine-N,N’-dicarbox-
ylic acid tert-butyl ester (3g): The title compound was prepared according
to the general procedure by using 8-amino-5,7-dibromo-2-naphthol (4g;
63 mg, 0.20 mmol) and 8b (22 mg, 0.04 mmol). Elution with pentane/Et20
75:25 gave the product (91 mg, 85%). Rf =0.30 (pentane/Et20 50:50);
[a]2D0 =À56.0 (c=4.10 in CDCl3); 1H NMR (400 MHz, CDCl3, 208C): d=
6048
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ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 6039 – 6052

Non-Biaryl Atropisomers in Organocatalysis
FULL PAPER
9.66 (s, 1H), 8.14 (d, J=9.3 Hz, 1H), 7.71 (s, 1H), 7.38 (s, 1H), 7.34 (d,
J=9.3 Hz, 1H), 4.43 (s, 2H), 1.48 ppm (s, 18H); 13C NMR (100 MHz,
CDCl3, 208C): d=157.8, 153.9, 149.6, 143.1, 139.9, 136.7, 130.6, 130.3,
127.4, 125.5, 122.8, 122.3, 121.1, 113.9, 85.1, 83.5, 28.1, 28.0, 27.9 ppm;
HRMS: m/z: calcd: 570.0038; found: 570.0074 [C20H2579Br80BrN3O5+Na]+
; the ee was determined by HPLC using a Chiralcel OD column (hexane/
iPrOH 90:10); flow rate: 1.0 mLminÀ1; tminor =3.6 min, tmajor =4.1 min.
showed full conversion and the reaction mixture was purified by FC. Elu-
tion with pentane/Et20 80:20 to 50:50 gave the product (29 mg, quant.
yield). Rf =0.25 (pentane/Et20 50:50); [a]2D0 =À4.4 (c=1.41 in CHCl3);
1H NMR (400 MHz, CDCl3, 208C): d=4.14 (dq, J=0.8 Hz, J=7.1 Hz,
2H), 2.68 (ddd, J=5.7 Hz, J=9.6 Hz, J=17.8 Hz, 1H), 2.36 (m, 1H),
2.11 (s, 1H), 2.07 (m, 1H), 1.92 (m, 4H), 1.22 ppm (t, J=7.1 Hz, 3H).
The ee was determined by GC using an Astec G-TA column (708C to
1708C, 108CminÀ1, then 10 min 1708C): tminor =16.5 min, tmajor =16.7 min.
The spectroscopic data were in agreement with the literature.[54]
N-(8-(Carbamic acid tert-butyl ester)-2-hydroxy-1-naphthyl)hydrazine-
N,N’-dicarboxylic acid tert-butyl ester,( 3h): The title compound was pre-
pared according to the general procedure by using (7-hydroxy-naphtha-
len-1-yl)carbamic acid tert-butyl ester (4h; 52 mg, 0.20 mmol) and 8b
(22 mg, 0.04 mmol). Elution with pentane/Et20 67:33 gave the product
(92 mg, 94%). Rf =0.31 (pentane/Et20 50:50); [a]2D0 =+1.7 (c=0.62 in
CHCl3); 1H NMR (400 MHz, CDCl3, 608C): d=9.64 (brs, 1H), 7.74 (d,
J=8.9 Hz, 1H), 7.67 (d, J=8.2 Hz, 1H), 7.54–7.48 (m, 1H), 7.39 (brs,
1H), 7.28 (t, J=7.8 Hz, 1H), 7.23 (d, J=9.0 Hz, 1H), 6.56 (brs, 1H), 1.61
(s, 9H), 1.57–1.40 ppm (m, 18H); 13C NMR (100 MHz, CDCl3, 208C):
d=137.8, 131.6, 131.4, 130.7, 129.1, 129.0, 128.2, 125.2, 122.9, 119.6, 86.8,
82.8, 82.6, 81.1, 28.3, 28.1, 27.7 ppm; HRMS: m/z: calcd: 512.2373; found:
512.2368 [C25H35N3O7+Na]+; the ee was determined by HPLC using a
2-Oxo-1-(3-oxopropyl)cyclohexanecarboxylic acid ethyl ester (23): The
catalyst 8b (7 mg, 0.013 mmol, 0.1 equiv) and iodobenzene (0.8 mL) were
added to ethyl-2-oxocyclohexanone carboxylate (22; 20 mL, 0.128 mmol)
in a 4 mL vial, and the solution was stirred for 30 min. Then acrolein 17
(17 mL, 0.256 mmol, 2 equiv) was added and the solution stirred for 16 h
at room temperature. After this time, TLC control showed full conver-
sion and the reaction mixture was purified by FC. Elution with pentane/
Et20 80:20 to 50:50 gave the desired product (26 mg, 91%). Rf =0.22
(pentane/Et20 50:50); [a]2D0 =+81.7 (c=0.86 in CHCl3); 1H NMR
(400 MHz, CDCl3, 208C): d=9.72 (s, 1H), 4.22–4.16 (m, 2H), 2.62–2.56
(m, 5H), 2.17–2.16 (m, 1H), 2.04–1.97 (m, 1H), 1.91–1.84 (m, 1H), 1.76–
1.75 (m, 1H), 1.65–1.59 (m, 1H), 1.48–1.44 (m, 1H), 1.26 ppm (t, J=
7.2 Hz, 3H); the ee was determined by GC using an Astec G-TA column
Chiralpak AD column (hexane/iPrOH 95:5); flow rate: 1.0 mLminÀ1
tminor =11.3 min, tmajor =14.1 min.
;
(708C to 1708C, 10 8CminÀ1, then 25 min 1708C): tminor =18.1 min, tmajor
=
N-(8-Chloro-2-hydroxy-1-naphthyl)hydrazine-N,N’-dicarboxylic acid tert-
butyl ester (3i): The title compound was prepared according to the gener-
al procedure by using 8-chloro-2-naphthol (4h; 36 mg, 0.20 mmol) and
8b (22 mg, 0.04 mmol). The reaction was stirred for 8 d at À208C without
reaching full conversion by TLC. Elution with pentane/Et20 91:9 gave the
product (47 mg, 57%). Rf =0.70 (pentane/Et20 50:50); [a]2D0 =+15.6 (c=
0.58 in CHCl3); 1H NMR (400 MHz, CDCl3, 208C): d=10.17/10.05 (s,
1H), 7.77/7.76 (d, J=9.0 Hz, 1H), 7.69/7.68 (dd, J=1.2 Hz, J=8.0 Hz,
1H), 7.54/7.51 (dd, J=1.2 Hz, J=8.5 Hz, 1H), 7.29/7.28 (d, J=9.0 Hz,
1H), 7.20/7.18 (t, J=8.1 Hz, 1H), 6.98/6.96 (s, 1H), 1.54/1.53/1.52/
1.28 ppm (s, 18H); 13C NMR (100 MHz, CDCl3, 208C): d=159.2, 158.7,
155.6, 155.0, 154.4, 131.9, 131.5, 131.0, 130.7, 130.3, 130.1, 128.7, 128.5,
128.0, 127.7, 125.6, 125.4, 123.0, 122.9, 120.1, 119.0, 83.5, 83.3, 82.6, 82.4,
28.1, 28.1, 27.8 ppm; HRMS: m/z: calcd: 431.1350; found: 431.1348
[C20H25ClN2O5+Na]+; the ee was determined by HPLC using a Chiralcel
18.5 min. The spectroscopic data were in agreement with the literature.[55]
General procedure for the a-fluorination of a-branched aldehydes 24:
The catalyst (0.1 equiv), hexane (0.9 mL) and iPrOH (0.1 mL) were
added to the a-branched aldehyde 24 (0.50 mmol) in a 4 mL vial. After
30 min stirring at 28C, NFSI 25 (189 mg, 0.60 mmol, 1.2 equiv) was added
and the reaction mixture stirred overnight.
Workup A: The mixture was filtered and the residue rinsed with hexane.
The solvents were evaporated.
Workup B: The mixture was diluted with Et2O and washed with saturat-
ed NH4Cl/KI solution. The aqueous phase was extracted with Et2O and
the combined organic phases washed with sat. Na2S2O3 solution, sat.
Na2CO3 solution and sat. NaCl solution. The solvents were evaporated
after drying over Na2SO4.
Reduction: The raw aldehyde 26 was dissolved in MeOH and NaBH4
(2.0 equiv) was added. After full conversion was detected by TLC,
KHSO4 solution (1m) and CH2Cl2 were added and the aqueous phase
was extracted with CH2Cl2. The organic phase was dried over Na2SO4, fil-
tered and the solvent evaporated. The crude product was purified by FC.
OD column (hexane/iPrOH 99:1); flow rate: 1.0 mLminÀ1
8.3 min, tmajor =10.0 min.
; tminor =
Michael additions
1-(2-[1,3]Dioxolan-2-yl-ethyl)-2-oxocyclopentanecarboxylic acid ethyl
ester (19): Catalyst 8b (27 mg, 0.05 mmol, 0.1 equiv) and iodobenzene
(2.5 mL) were added to ethyl-2-oxocyclopentanone carboxylate (16;
74 mL, 0.50 mmol) in a 4 mL vial, and the solution was stirred for 30 min.
Acrolein (17; 67 mL, 1.0 mmol, 2.0 equiv) was then added and the solu-
tion was stirred for a further 1 h at room temperature. After this time,
TLC control showed full conversion and the reaction mixture was puri-
fied over a short silica plug, eluting with Et2O. The Et2O was evaporated
and then 2-ethyl-2-methyl-1,3-dioxolane (75 mL, 0.6 mmol, 1.2 equiv) and
p-toluolsulfonic acid (19 mg, 0.1 equiv) were added. The solution was stir-
red for 4 h, until GC control showed full conversion and the raw product
was then purified by FC. Elution with pentane/Et20 50:50 gave the prod-
uct (92 mg, 87%). Rf =0.14 (pentane/Et20 50:50); [a]2D0 =À14.3 (c=1.0 in
CHCl3); 1H NMR (400 MHz, CDCl3, 208C): d=4.77 (t, J=4.4 Hz, 1H),
4.08 (q, J=7.1 Hz, 2H), 3.90–3.82 (m, 2H), 3.81–3.73 (m, 2H), 2.48–2.40
(m, 1H), 2.39–2.29 (m, 1H), 2.24–2.13 (m, 1H), 2.01–1.77 (m, 4H), 1.73–
1.56 (m, 2H), 1.45–1.55 (m, 1H), 1.17 ppm (t, J=7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3, 208C): d=214.5, 170.7, 103.8, 64.7, 61.2, 59.6, 37.7,
32.8, 29.0, 27.5, 19.4, 13.9 ppm; HRMS: m/z: calcd: 279.1208; found:
279.1207 [C13H20O5+Na]+; the ee was determined by GC analysis using
an Astec G-TA column (708C to 1808C, 10 8CminÀ1, then 20 min 1808C):
tminor =21.6 min, tmajor =21.8 min.
2-Fluoro-2-phenylpropan-1-ol (29a): The title compound was prepared
according to the general procedure by using 2-phenylpropanal (24a;
67 mg, 0.50 mmol) and workup procedure A. Elution with pentane/Et20
75:25 gave the product (28 mg, 36%). Rf =0.39 (pentane/Et20 50:50);
1
[a]2D0 =+10.4 (c=0.51 in CHCl3); H NMR (400 MHz, CDCl3, 208C): d=
7.39–7.32 (m, 5H); 3.89–3.70 (m, 2H); 1.85 (b, 1H); 1.70 ppm (d, J=
22.8 Hz, 3H); 13C NMR (100 MHz, CDCl3, 208C): d=141.4 (d, J=
21.7 Hz); 128.4 (d, J=1.5 Hz); 124.4 (d, J=9.2 Hz); 97.9 (d, J=172 Hz);
69.6 (d, J=25.1 Hz); 23.1 ppm (d, J=24.4 Hz); 19F NMR (377 MHz,
CDCl3, 208C): d=À157.6 ppm; HRMS: m/z: calcd: 177.0692; found:
177.0671 [C9H11FO+Na]+; the ee was determined by HPLC using a Chir-
alpak AD column (hexane/iPrOH 95:5); flow rate: 1.0 mLminÀ1; tmajor
12.6 min, tminor =14.3 min.
=
2-Fluoro-2-(4’-nitrophenyl)propan-1-ol (29c): The title compound was
prepared according to the general procedure and workup procedure B by
using 2-(4’-nitrophenyl)propanal (24c; 90 mg, 0.50 mmol), which could
only be obtained in 75% purity, the impurity being 4-nitroacetophenone.
Elution with pentane/Et20 75:25 to 50:50 gave the product (67 mg, 56%).
Rf =0.14 (pentane/Et20 50:50); [a]2D0 =À8.7 (c=1.00 in CHCl3); 1H NMR
(400 MHz, CDCl3, 208C): d=8.25 (d, J=8.9 Hz, 2H), 7.55 (d, J=8.9 Hz,
2H), 3.86 (dd, J=2.6 Hz, 3J
C
2-Oxo-1-(3-oxobutyl)cyclopentanecarboxylic acid ethyl ester,( 21): Cata-
lyst 8b (7 mg, 0.013 mmol, 0.1 equiv) and iodobenzene (0.8 mL) were
added to ethyl-2-oxocyclopentanone carboxylate (16; 20 mL, 0.128 mmol)
in a 4 mL vial, and the solution was stirred for 30 min. Methyl vinyl
ketone (20; 21 mL, 0.256 mmol, 2 equiv) was then added and the solution
stirred for 21 h at room temperature. After this time, TLC control
AHCTREUNG
d=148.8 (d, J=22.0 Hz), 147.2, 125.6 (d, J=9.9 Hz), 123.5, 97.5 (d, J=
175 Hz), 68.8 (d, J=24.8 Hz), 23.1 ppm (d, J=24.4 Hz); 19F NMR
(377 MHz, CDCl3, 208C): d=À158.2 ppm; the ee was determined by
HPLC using a Chiralcel OD column (hexane/iPrOH 90:10); flow rate:
1.0 mLminÀ1; tminor =13.5 min, tmajor =15.2 min.
Chem. Eur. J. 2006, 12, 6039 – 6052
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6049

K. A. Jørgensen et al.
2-Fluoro-2-(4’-bromophenyl)propan-1-ol (29d): The title compound was
prepared according to the general procedure by using 2-(4’-bromophe-
nyl)propanal (24d; 107 mg, 0.50 mmol) and workup procedure A. Elution
with pentane/Et20 80:20 gave the product (70 mg, 60%). Rf =0.20 (pen-
tane/Et20 50:50); [a]2D0 =À12.4 (c=0.70 in CHCl3); 1H NMR (400 MHz,
CDCl3, 208C): d=7.50 (d, J=8.5 Hz, 2H), 7.23 (d, J=8.3 Hz, 2H), 3.84–
208C): d=99.9 (d, J=168 Hz), 66.9 (d, J=23.4 Hz), 42.9 (d, J=21.2 Hz),
27.7 (d, J=7.7 Hz), 26.4, 26.3, 26.2, 17.6 ppm (d, J=24.8 Hz); 19F NMR
(377 MHz, CDCl3, 208C): d=À158.1 ppm; the ee was determined by GC
using a Astec G-TA column (708C to 1008C, 88CminÀ1, then 25 min
1008C): tminor =22.1 min, tmajor =23.9 min.
3.66 (m, 2H), 2.16 (s, 1H), 1.66 ppm (d, 3J
(H,F)=22.6 Hz, 3H);
A
13C NMR (100 MHz, CDCl3, 208C): d=140.5 (d, J=22.1 Hz), 131.5 (d,
J=1.3 Hz), 126.3 (d, J=9.3 Hz), 121.9 (d, J=1.5 Hz), 97.5 (d, J=
173 Hz), 69.2 (d, J=25.0 Hz), 23.0 ppm (d, J=24.7 Hz); 19F NMR
(377 MHz, CDCl3, 208C): d=À157.8 ppm; the ee was determined by
HPLC using a Chiralpak AD column (hexane/iPrOH 95:5); flow rate:
1.0 mLminÀ1; tmajor =13.8 min, tminor =18.1 min.
Acknowledgements
This work was made possible by a grant from The Danish National Re-
search Foundation. B.N. would like to thank the DAAD for financial sup-
port. Financial support for the X-ray analysis by the Carlsberg Founda-
tion is gratefully acknowledged.
1-Fluoro-1,2,3,4-tetrahydronaphthalene-1-carbaldehyde (26e): The title
compound was prepared according to the general procedure by using
1,2,3,4-tetrahydronaphthalene-1-carbaldehyde (24e; 80 mg, 0.50 mmol).
After the reaction was finished, saturated NaHCO3 solution was added
to the reaction mixture. The aqueous phase was extracted with Et2O, the
combined organic phases were dried over MgSO4 and the solvent was
evaporated. The crude product was purified by FC. Elution with pentane/
Et20 30:1 gave the product (49 mg, 55%). The product contained 5% of
the starting aldehyde. Rf =0.50 (pentane/Et20 6:1); [a]2D0 =À9.1 (c=1.06
[1] a) R. Noyori, H. Takaya, Acc. Chem. Res. 1990, 23, 345–350; b) M.
Berthod, G. Mignani, G. Woodward, M. Lemaire, Chem. Rev. 2005,
105, 1801–1836.
[2] a) Y. Chen, S. Yekta, A. K. Yudin, Chem. Rev. 2003, 103, 3155–
3211; b) J. M. Brunel, Chem. Rev. 2005, 105, 857–897.
in CHCl3); 1H NMR (400 MHz, CDCl3, 208C) d=9.71 (d, 3J
(F,H)=
T
ˇ
ˇ
´
ˇ
ˇ
[3] a) P. Kocovsky, S. Vyskocil, M. Smrcina, Chem. Rev. 2003, 103,
3213–3245; for recent applications in organocatalysis see: b) M.
Rueping, E. Sugiono, C. Azap, T. Theissmann, M. Bolte, Org. Lett.
2005, 7, 3781–3783; c) T. Kano, J. Takai, O. Tokuda, K. Maruoka,
Angew. Chem. 2005, 117, 3115–3117; Angew. Chem. Int. Ed. 2005,
44, 3055–3057.
6.0 Hz, 1H), 7.23–7.11 (m, 5H), 2.81–2.66 (m, 2H), 2.16–2.04 (m, 2H),
1.84–1.02 ppm (m, 2H); 13C NMR (100 MHz, CDCl3, 208C) d=197.9 (d,
J=38.8 Hz), 138.9 (d, J=3.9 Hz), 129.6 (d, J=3.0 Hz), 129.6, 128.5 (d,
J=4.0 Hz), 126.7 (d, J=2.3 Hz), 95.5 (d, J=182 Hz), 29.5 (d, J=
21.0 Hz), 28.8, 18.4 ppm (d, J=2.8 Hz); 19F NMR (377 MHz, CDCl3,
208C): d=À142.3 ppm; the ee was determined by GC using a Astec G-
[4] a) D. P. Curran, H. Qi, S. J. Geib, N. C. DeMello, J. Am. Chem. Soc.
1994, 116, 3131–3132; b) D. P. Curran, G. R. Hale, S. J. Geib, A.
Balog, Q. B. Cass, A. L. G. Degani, M. Z. Hernandez, L. C. G. Frei-
tas, Tetrahedron: Asymmetry 1997, 8, 3955–3975; c) D. P. Curran,
S. J. Geib, N. C. DeMello, Tetrahedron 1999, 55, 5681–5704; d) D. P.
Curran, W. Liu, C. H.-T. Chen, J. Am. Chem. Soc. 1999, 121, 11012–
11013; e) D. P. Curran, C. H.-T. Chen, S. J. Greib, A. J. B. Lapierre,
Tetrahedron 2004, 60, 4413–4424.
[5] a) J. Clayden, N. Westlund, F. X. Wilson, Tetrahedron Lett. 1996, 37,
5577–5580; b) A. Ahmed, R. A. Bragg, J. Clayden, L. W. Lai, C.
McCarthy, J. H. Pink, N. Westlund, S. A. Yasin, Tetrahedron 1998,
54, 13277–13294; c) J. Clayden, C. McCarthy, M. Helliwell, Chem.
Commun. 1999, 2059–2060.
[6] a) A. D. Hughes, D. A. Price, O. Shishkin, N. S. Simpkins, Tetrahe-
dron Lett. 1996, 37, 7607–7610; b) D. J. Bennett, A. J. Blake, P. A.
Cooke, C. R. A. Godfrey, P. L. Pickering, N. S. Simpkins, M. D.
Walker, C. Wilson, Tetrahedron 2004, 60, 4491–4511.
[7] a) M. Fujita, O. Kitagawa, H. Izawa, A. Dobashi, H. Fukaya, T. Ta-
guchi, Tetrahedron Lett. 1999, 40, 1949–1952; b) O. Kitagawa, H.
Izawa, K. Sato, A. Dobashi, T. Taguchi, M. Shiro, J. Org. Chem.
1998, 63, 2634–2640.
TA column (708C to 1308C, 58CminÀ1, then 20 min 1308C): tminor
19.2 min, tmajor =19.7 min.
=
2-Ethyl-2-fluorohexan-1-ol (29 f): The title compound was prepared ac-
cording to the general procedure by using 2-ethylhexanal (24 f; 78 mL,
0.50 mmol) and workup procedure B. After 24 and 48 h another 0.1
equivalents of catalyst were added. Elution with pentane/Et20 85:15 gave
the product (20 mg, 27%). Rf =0.41 (pentane/Et20 50:50); [a]2D0 =+1.3
(c=0.45 in CHCl3); 1H NMR (400 MHz, CDCl3, 208C): d=3.60 (d, 3J-
A
4H), 0.93–0.87 ppm (m, 6H); 13C NMR (100 MHz, CDCl3, 208C): d=
99.8 (d, J=168 Hz), 66.1 (d, J=24.0 Hz), 32.7 (d, J=22.4 Hz), 26.1 (d,
J=23.3 Hz), 25.3 (d, J=6.6 Hz), 23.1, 14.0, 7.60 ppm (d, J=8.0 Hz);
19F NMR (377 MHz, CDCl3, 208C): d=À161.6 ppm; HRMS of the 4-bro-
mobenzoylhydrazone:
calcd:
calcd:
365.0641;
367.0621;
found:
found:
365.0655
367.0618
[C15H2079BrFN2O+Na]+,
[C15H2081BrFN2O+Na]+; the ee was determined by GC using a Astec G-
TA column (708C to 1008C, 108CminÀ1, then 20 min 1008C): tminor
8.8 min, tmajor =9.0 min.
=
2-Fluoro-3-(4’-isopropylphenyl)-2-methyl-propan-1-ol (29g): The title
compound was prepared according to the general procedure by using 2-
methyl-3-(4’-isopropylphenyl)propanal (24g; 100 mL, 0.50 mmol) and
workup procedure B. Elution with pentane/Et20 75:25 gave the product
(30 mg, 29%). Rf =0.40 (pentane/Et20 50:50); [a]2D0 =+9.1 (c=1.45 in
CHCl3); 1H NMR (400 MHz, CDCl3, 208C): d=7.17 (s, 4H), 3.59 (d, J=
19.6 Hz, 2H), 2.99–2.84 (m, 3H), 1.90 (brs, 1H), 1.28 (d, J=21.5 Hz,
3H), 1.25 ppm (d, J=6.9 Hz, 6H); 13C NMR (100 MHz, CDCl3, 208C):
d=147.2, 133.2 (d, J=5.9 Hz), 130.3, 126.3, 97.4 (d, J=170 Hz), 67.5 (d,
J=23.8 Hz), 41.9 (d, J=22.9 Hz), 33.7, 24.0, 20.9 ppm (d, J=23.9 Hz);
19F NMR (377 MHz, CDCl3, 208C): d=À154.6 ppm; HRMS: m/z: calcd:
233.1318; found: 233.1323 [C13H19FO+Na]+; the ee was determined by
HPLC using a Chiralcel OJ column (hexane/iPrOH 99:1); flow rate:
1.0 mLminÀ1; tminor =16.7 min, tmajor =19.5 min.
[8] a) H. Koide, M. Uemura, Chem. Commun. 1998, 2483–2484; b) T.
Hata, H. Koide, N. Taniguchi, M. Uemura, Org. Lett. 2000, 2, 1907–
1910; c) T. Hata, H. Koide, M. Uemura, Synlett 2000, 1145–1147;
d) H. Koide, T. Hata, K. Yoshihara, K. Kamikawa, M. Uemura, Tet-
rahedron 2004, 60, 4527–4541.
[9] E. L. Eliel, S. H. Wilen, Stereochemistry of Organic Compounds,
Wiley, New York, 1994.
[10] a) O. Kitagawa, S.-i. Momose, Y. Fushimi, T. Taguchi, Tetrahedron
Lett. 1999, 40, 8827–8831; b) J. Clayden, C. McCarthy, J. G. Cum-
ming, Tetrahedron Lett. 2000, 41, 3279–3283; c) J. Clayden, M. Hel-
liwell, C. McCarthy, N. Westlund, J. Chem. Soc. Perkin Trans. 1
2000, 3232–3249; d) O. Kitagawa, H. Izawa, T. Taguchi, M. Shiro,
Tetrahedron Lett. 1997, 38, 4447–4450.
2-Cyclohexyl-2-fluoropropan-1-ol (29h): The title compound was pre-
pared according to the general procedure by using 2-cyclohexylpropanal
(24h; 71 mg, 0.50 mmol) and workup procedure A. Elution with pentane/
Et20 85:15 gave the desired product (8 mg, 10%). Rf =0.30 (pentane/Et20
50:50); [a]2D0 =À15.0 (c=0.32 in CHCl3); 1H NMR (400 MHz, CDCl3,
[11] a) J. Clayden, P. Johnson, J. H. Pink, M. Helliwell, J. Org. Chem.
2000, 65, 7033–7040; b) Y. Chen, M. D. Smith, K. D. Shimizu, Tetra-
hedron Lett. 2001, 42, 7185–7187; c) W.-M. Dai, K. K. Y. Yeing, J.-T.
Liu, Y. Zhang, I. D. Williams, Org. Lett. 2002, 4, 1615–1618; d) T.
Mino, Y. Tanaka, T. Yabusaki, D. Okumura, M. Sakamoto, T. Fujita,
Tetrahedron: Asymmetry 2003, 14, 2503–2506; e) W.-M. Dai,
K. K. Y. Yeung, Y. Wang, Tetrahedron 2004, 60, 4425–4430.
208C): d=3.73–3.52 (m, 2H), 1.84–1.64 (m, 5H), 1.23 (d, 3J
(H,F)=
A
22.8 Hz, 3H), 1.28–1.11 ppm (m, 6H); 13C NMR (100 MHz, CDCl3,
6050
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 6039 – 6052

Non-Biaryl Atropisomers in Organocatalysis
FULL PAPER
[12] a) Y. Ikeura, Y. Ishichi, T. Tanaka, A. Fujishima, M. Murabayashi,
M. Kawada, T. Ishimaru, I. Kamo, T. Doi, H. Natsugari, J. Med.
Chem. 1998, 41, 4232–4239; b) Y. Ikeura, T. Ishimaru, T. Doi, M.
Kawada, A. Fujishima, H. Natsugari, Chem. Commun. 1998, 2141–
2142; c) Y. Ishichi, Y. Ikeura, H. Natsugari, Tetrahedron 2004, 60,
4481–4490; d) J. S. Albert, C. Ohnmacht, P. R. Bernstein, W. L.
Rumsey, D. Aharony, B. B. Masek, B. T. Dembofsky, G. M. Koether,
W. Potts, J. L. Evenden, Tetrahedron 2004, 60, 4337–4347.
[13] J. Clayden, A. Lund, L. Vallverdffl, M. Helliwell, Nature 2004, 431,
966–971.
[14] For reviews on this topic see: a) C. Rosini, L. Franzini, A. Raffaelli,
P. Salvadori, Synthesis, 1992, 503–517; b) G. Bringmann, A. J. Price
Mortimer, P. A. Keller, M. J. Gresser, J. Garner, M. Breuning,
Angew. Chem. 2005, 117, 5518–5563; Angew. Chem. Int. Ed. 2005,
44, 5384–5427.
1987, 325–326; c) S. J. Rowan, P. A. Brady, J. K. M. Sanders, Angew.
Chem. 1996, 108, 2283–2285; Angew. Chem. Int. Ed. Engl. 1996, 35,
2143–2145. For 9-amino compounds see: d) H. Brunner, J. Bügler,
B. Nuber, Tetrahedron: Asymmetry 1995, 6, 1699–1702. For urea
and thiourea see: e) B. Vakulya, S. Varga, A. Csampai, T. Soos, Org.
Lett. 2005, 7, 1967–1969; f) S. H. McCooey, S. J. Connon, Angew.
Chem. 2005, 117, 6525–6528; Angew. Chem. Int. Ed. 2005, 44, 6367–
6370; g) J. Ye, D. J. Dixon, P. S. Hines, Chem. Commun. 2005, 4481–
4483.
[31] For ethers see: a) M. P. Arrington, Y. L. Bennani, T. Gçbel, P.
Walsh, S.-H. Zhao, K. B. Sharpless, Tetrahedron Lett. 1993, 34,
7375–7378. For esters see: b) O. Hesse, Justus Liebigs Ann. Chem.
1880, 205, 314–357; c) O. Hesse, Justus Liebigs Ann. Chem. 1885,
230, 55–73; d) Ludwiczak, J. Suszko, Rocz. Chem. 1935, 15, 209–
216; e) Prajer, J. Suszko, Rocz. Chem. 1952, 26, 555–558. For thio-
ureas see: f) T. Marcelli, R. N. S. van der Haas, J. H. van Maar-
seveen, H. Hiemstra, Angew. Chem. 2006, 118, 943–945; Angew.
Chem. Int. Ed. 2006, 45, 929–931; for 6’-/9-OH modification see for
example: g) H. Li, Y. Wang, L. Tang, L. Deng, J. Am. Chem. Soc.
2004, 126, 9906–9907.
[15] a) M. A. Cuyegkeng, A. Mannschreck, Chem. Ber. 1987, 120, 803–
809; b) W. H. Pirkle, C. J. Welch, A. J. Zych, J. Chromatogr. 1993,
648, 101–109.
[16] a) S. Thayumanavan, P. Beak, D. P. Curran, Tetrahedron Lett. 1996,
37, 2899–2902; b) V. Chan, J. G. Kim, C. Jimeno, P. J. Carroll, P. J.
Walsh, Org. Lett. 2004, 6, 2051–2053.
[32] For benzyl PTC see: a) E. J. Corey, F. Xu, M. C. Noe, J. Am. Chem.
Soc. 1997, 119, 12414–12415; b) U.-H. Dolling, P. Davis, E. J. J. Gra-
bowski, J. Am. Chem. Soc. 1984, 106, 446–447; c) M. J. OꢂDonnell,
I. A. Esikova, A. Mi, D. F. Shullenberger, S. Wu, J. Am. Chem. Soc.
1989, 111, 2353–2355. For anthracyl PTC see: d) E. J. Corey, M. C.
Noe, A. Y. Ting, Tetrahedron Lett. 1996, 37, 1735–1738; B. Lygo,
P. G. Wainwright, Tetrahedron Lett. 1997, 38, 8595–8598. For chloro
compounds see: e) H. Wack, A. E. Taggi, A. M. Hafez, W. J. Drury,
III, T. Lectka, J. Am. Chem. Soc. 2001, 123, 1531–1532. For fluoro
compounds see: f) D. Cahard, C. Audouard, J.-C. Plaquevent, N.
Roques, Org. Lett. 2000, 2, 3699–3701; g) B. Mohar, J. Baudoux, J.-
C. Plaquevent, D. Cahard, Angew. Chem. 2001, 113, 4339–4341;
Angew. Chem. Int. Ed. 2001, 40, 4214–4216.
[33] For examples of the variation of the vinyl side chain see: literature
reference [31a] and a) W. M. Braje, J. Frackenpohl, O. Schrake, R.
Wartchow, W. Beil, H. M. R. Hoffmann, Helv. Chim. Acta 2000, 83,
777–792; b) J. Frackenpohl, W. M. Braje, H. M. R. Hoffmann, J.
Chem. Soc. Perkin Trans. 1 2001, 47–65.
[34] a) H. Wynberg, R. Helder, Tetrahedron Lett. 1975, 16, 4057–4060;
b) K. Hermann, H. Wynberg, J. Org. Chem. 1979, 44, 2238–2244.
[35] a) F. R. Clemente, K. N. Houk, J. Am. Chem. Soc. 2005, 127, 11294–
11302; b) A. Córdova, W. Zou, I. Ibrahem, E. Reyes, M. Engquist,
W.-W. Liao, Chem. Commun. 2005, 3586–3588.
[17] J. Clayden, P. M. Kubinski, F. Sammiceli, M. Helliwell, L. Diorazio,
Tetrahedron 2004, 60, 4387–4397.
[18] A. D. Hughes, N. S. Simpkins, Synlett 1998, 967–968.
[19] a) J. Clayden, L. W. Lai, Angew. Chem. 1999, 111, 2755–2757;
Angew. Chem. Int. Ed. 1999, 38, 2556–2558; b) J. Clayden, L. W.
Lai, M. Helliwell, Tetrahedron 2004, 60, 4399–4412.
[20] O. Kitagawa, M. Takahashi, M. Yoshikawa, T. Taguchi, J. Am.
Chem. Soc. 2005, 127, 3676–3677.
[21] S. Brandes, M. Bella, A. Kjærsgaard, K. A. Jørgensen, Angew.
Chem. 2006, 118, 1165–1169; Angew. Chem. Int. Ed. 2006, 45, 1147–
1151.
[22] For earlier reports on related structures see: a) O. Diels, I. Back,
Ber. Dtsch. Chem. Ges. B 1921, 54, 213–226; b) H. Mitchell, Y. Leb-
lanc, J. Org. Chem. 1994, 59, 682–687; c) Y. Leblanc, N. Boudreault,
J. Org. Chem. 1995, 60, 4268–4271; d) W. J. Kinnart, C. M. Kinnart,
J. Organomet. Chem. 2003, 665, 233–236. For atropisomeric 1-aryl-
imidazoline/lidine-2-ones/thiones see: e) M. Avalos, R. Babiano, P.
Cintas, J. L. JimØnez, J. C. Palacios, G. Silvero, C. Valencia, Tetrahe-
dron 1999, 55, 4377–4400; f) M. Avalos, R. Babiano, P. Cintas, F. J.
Higes, J. L. JimØnez, J. C. Palacios, G. Silvero, C. Valencia, Tetrahe-
dron 1999, 55, 4401–4426; g) M. Avalos, R. Babiano, P. Cintas,
M. B. Hursthouse, J. L. JimØnez, M. E. Light, J. C. Palacios, G. Sil-
vero, Tetrahedron 2005, 61, 7931–7944; h) M. Avalos, R. Babiano, P.
Cintas, M. B. Hursthouse, J. L. JimØnez, M. E. Light, J. C. Palacios,
G. Silvero, Tetrahedron 2005, 61, 7945–7959.
[36] S. Bahmanyar, K. N. Houk, J. Am. Chem. Soc. 2001, 123, 11273–
11283.
[37] a) M. Marigo, K. A. Jørgensen, Chem. Commun. 2006, 2001–2011;
b) J. FranzØn, M. Marigo, D. Fielenbach, T. C. Wabnitz, A. Kjærs-
gaard, K. A. Jørgensen, J. Am. Chem. Soc. 2005, 127, 18296–18304.
[38] a) M. Marigo, D. Fielenbach, A. Braunton, A. Kjærsgaard, K. A.
Jørgensen, Angew. Chem. 2005, 117, 3769–3772; Angew. Chem. Int.
Ed. 2005, 44, 3703–3706; b) D. D. Steiner, N. Mase, C. F. Barbas,
III, Angew. Chem. 2005, 117, 3772–3776; Angew. Chem. Int. Ed.
2005, 44, 3706–3710; c) T. D. Beeson, D. W. C. MacMillan, J. Am.
Chem. Soc. 2005, 127, 8826–8828; d) D. Enders, M. R. M. Hüttl,
Synlett 2005, 991–993; e) P. M. Pihko, Angew. Chem. 2006, 118,
558–561; Angew. Chem. Int. Ed. 2006, 45, 544–547; f) J.-A. Ma, D.
Cahard, Chem. Rev. 2004, 104, 6119–6146, and references therein.
[39] For the preparation of b-isocupreidine see: Y. Iwabuchi, M. Nakata-
ni, N. Yokoyama, S. Hatakeyama, J. Am. Chem. Soc. 1999, 121,
10219–10220, and references therein.
[23] For the preparation of hydrocupreine and hydrocupreidine see: M.
Heidelberger, W. A. Jacobs, J. Am. Chem. Soc. 1919, 41, 817–833.
[24] For recent reviews see for example, a) P. I. Dalko, L. Moisan,
Angew. Chem. 2001, 113, 3840–3864; Angew. Chem. Int. Ed. 2001,
40, 3726–3748; b) P. I. Dalko, L. Moisan, Angew. Chem. 2004, 116,
5248–5286; Angew. Chem. Int. Ed. 2004, 43, 5138–5175; c) A. Ber-
kessel, H. Grçger, Asymmetric Organocatalysis, Wiley-VCH, Wein-
heim, 2005; d) J. Seayad, B. List, Org. Biomol. Chem. 2005, 3, 719–
724.
[25] T. P. Yoon, E. N. Jacobsen, Science 2003, 299, 1691–1693.
[26] a) K. Kacprzak, J. GawroÇski, Synthesis 2001, 961–998; b) S. France,
D. J. Guerin, S. J. Miller, T. Lectka, Chem. Rev. 2003, 103, 2985–
3012; c) H. M. R. Hoffmann, J. Frackenpohl, Eur. J. Org. Chem.
2004, 4293–4312.
[27] a) G. Giemsa, J. Halberkann, Chem. Ber. B 1920, 53, 732–750;
b) W. A. Jacobs, M. Heidelberger, J. Am. Chem. Soc. 1920, 42,
1481–1489.
[40] For the preparation of 9-benzyloxy-6’-hydroxy-quinine see: X. Liu,
H. Li, L. Deng, Org. Lett. 2005, 7, 167–170.
[41] CCDC-603654 contains the supplementary crystallographic data for
this structure. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
[42] CCDC-603655 contains the supplementary crystallographic data for
this structure. These data can be obtained free of charge from The
[28] a) G. Giemsa, J. Halberkann, Chem. Ber. B 1919, 52, 906–923; b) M.
Heidelberger, W. A. Jacobs, J. Am. Chem. Soc. 1919, 41, 2131–2147.
[29] R. Weller, Chem. Ber. B 1921, 54, 230–239.
[30] For ethers see: a) H. C. Kolb, M. S. VanNieuwenhze, K. B. Sharpless,
Chem. Rev. 1994, 94, 2483–2547. For silyl ethers see b) T. H. Chan,
Q.-J. Peng, D. Wang, J. A. Guo, J. Chem. Soc. Chem. Commun.
Chem. Eur. J. 2006, 12, 6039 – 6052
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6051

K. A. Jørgensen et al.
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
[43] CCDC-603656 contains the supplementary crystallographic data for
this structure. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
[44] Y. Shvo in The Chemistry of Hydrazo,Azo and Azoxy groups (Ed.:
S. Patai), Wiley, New York, 1975, pp. 1017–1095.
[45] a) C. Drzewiczak, A. Suszko-Purzycka, J. Skolik, Polish J. Chem.
1993, 67, 45–52; b) V. K. Aggarwal, I. Emme, S. Y. Fulford, J. Org.
Chem. 2003, 68, 692–700; c) C. L. Perrin, M. A. Fabian, Anal.
Chem. 1996, 68, 2127–2134.
[46] a) Y. Iwabuchi, M. Nakatani, N. Yokoyama, S. Hatakeyama, J. Am.
Chem. Soc. 1999, 121, 10219–10220; b) H. Li, Y. Wang, L. Tang, F.
Wu, X. Liu, C. Guo, B. M. Foxman, L. Deng, Angew. Chem. 2005,
117, 107–110; Angew. Chem. Int. Ed. 2005, 44, 105–108; c) Y.
Wang, X. Liu, L. Deng, J. Am. Chem. Soc. 2006, 128, 3928–3930.
[47] B. Långstrçm, G. Bergson, Acta Chem. Scand. 1973, 27, 3118–3119.
[48] a) G. Szçllçsi, M. Bartók, Chirality 2001, 13, 614–618; b) T. Ooi, T.
Miki, M. Taniguchi, M. Shiraishi, M. Takeuchi, K. Maruoka, Angew.
Chem. 2003, 115, 3926–3928; Angew. Chem. Int. Ed. 2003, 42, 3796–
3798; c) F. Wu, H. Li, R. Hong, L. Deng, Angew. Chem. 2006, 118,
961–964; Angew. Chem. Int. Ed. 2006, 45, 947–950.
[49] W. Kraus, H. Patzelt, H. Sadlo, H. Sawitzki, G. Schwinger, Liebigs
Ann. Chem. 1981, 1826–1837.
[50] J. Christoffers, A. Mann, Chem. Eur. J. 2001, 7, 1014–1027.
[51] The instability of the products has been described previously: F. A.
Davis, P. V. N. Kasu, G. Sundarababu, H. Qi, J. Org. Chem. 1997, 62,
7546–7547, and references therein.
[52] CCDC-603657 contains the supplementary crystallographic data for
this structure. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
[53] S. Danishefsky, D. F. Harvey, J. Am. Chem. Soc. 1985, 107, 6647–
6652.
[54] T. Suzuki, T. Torii, Tetrahedron: Asymmetry 2001, 12, 1077–1081.
[55] D. Bensa, J. Rodriguez, Synth. Commun. 2004, 34, 1515–1533.
Received: April 7, 2006
Published online: June 21, 2006
6052
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 6039 – 6052