Highly enantioselective epoxidation of 2-methylnaphthoquinone (vitamin K3) mediated by new cinchona alkaloid phase-transfer catalysts

Article abstract of DOI:10.1002/chem.200600993

In the area of catalytic asymmetric epoxidation, the highly enantioselective transformation of cyclic enones and quinones is an extremely challenging target. With the aim to develop new and highly effective phase-transfer catalysts for this purpose, we co

Full text of DOI:10.1002/chem.200600993

FULL PAPER
DOI: 10.1002/chem.200600993
Highly Enantioselective Epoxidation of2-Methylnaphthoquinone (Vitamin
K ) Mediated by New Cinchona Alkaloid Phase-Transfer Catalysts
3
Albrecht Berkessel,* Maria Guixà, Friederike Schmidt, Jçrg M. Neudçrfl, and
[
a]
Johann Lex
Abstract: In the area of catalytic asym-
metric epoxidation, the highly enantio-
selective transformation of cyclic
enones and quinones is an extremely
challenging target. With the aim to de-
velop new and highly effective phase-
transfer catalysts for this purpose, we
conducted a systematic structural varia-
tion of PTCs based on quinine and
trogen atom by chiral electrophiles.
For example, the well-established 9-
anthracenylmethyl group was ex-
changed for a “chiral” anthracene in
the form of 9-chloromethyl-[(1,8-S;4,5-
R)-1,2,3,4,5,6,7,8-octahydro-1,4:5,8-di-
methanoanthracene. The asymmetric
most enantioselective catalyst for this
purpose known to date: At a catalyst
loading of only 2.50 mol%, the qui-
none epoxide was obtained in 76%
yield and with 85% ee (previously:
ꢀ34% ee), using commercial bleach
(aqueous sodium hypochlorite) as the
oxidant. To rationalize the sense of in-
duction effected by our novel phase-
transfer catalysts, a computational anal-
ysis of steric interactions in the inter-
mediate chlorooxy enolate–PTC ion
pair was conducted. Based on this anal-
ysis, the sense of induction for all 15
novel PTCs could be consistently ex-
plained.
epoxidation of vitamin K was used as
3
the test reaction for our novel PTCs.
The readily available PTC 10 (derived
from quinine in three convenient and
high-yielding steps) proved to be the
quinidine. In the total of 15 new qua-
A
C
H
T
R
E
U
N
G
ternary ammonium PTCs, modifica-
tions included, for example, the ex-
change of the quinine methoxy group
for a free hydroxyl or other alkoxy sub-
stituents, and the introduction of addi-
tional elements of chirality through al-
kylation of the alkaloid quinuclidine ni-
Keywords: alkaloids · asymmetric
catalysis · enones · epoxidation ·
phase-transfer catalysis
[4–9]
Introduction
applied.
In fact, asymmetric Weitz–Scheffer-type epoxi-
dations with chiral PTCs belong to the earliest examples of
asymmetric catalysis in general: In 1978, Wynberg et al. re-
ported the asymmetric epoxidation of chalcones 1a,b
(Scheme 1) using chiral quaternary ammonium salts derived
from quinine (2) and quinidine (3) (Figure 1). Using the
benzylquininium chloride 4a as the PTC (Scheme 1) up to
Enantiomerically pure epoxides are valuable intermediates
in the asymmetric synthesis of, for example, pharmaceuticals
and natural products in both academic and industrial labora-
[1]
tories. In most cases, epoxides are prepared by oxygen
transfer from a terminal oxidant to a C=C-double bond, and
the recent years have seen a dramatic development of vari-
ous methods for the catalytic asymmetric epoxidation of ole-
[10–12]
54% ee of epoxide 5a were achieved.
Major breakthroughs in the phase-transfer catalyzed ep-
[2,3]
fins.
For the epoxidation of electron-deficient substrates
oxidation of chalcones 1a,b resulted from work by Corey
[13]
[14,15]
such as enones, enoates or quinones, nucleophilic oxidants
such as alkaline solutions of hydroperoxides, hydrogen per-
oxide (Weitz–Scheffer epoxidation) or hypohalites are often
et al. (PTC 4b), Lygo et al. (PTC 4b),
Arai, Shioiri
[
a] Prof. Dr. A. Berkessel, Dr. M. Guixà, Dr. F. Schmidt,
Dr. J. M. Neudçrfl, Dr. J. Lex
Institut für Organische Chemie, Universität zu Kçln
Greinstrasse 4, 50393 Kçln (Germany)
Fax : (+49)221-470-5102
E-mail: Berkessel@uni-koeln.de
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Figure 1. Cinchona-alkaloids quinine (2) and quinidine (3).
Chem. Eur. J. 2007, 13, 4483– 4498
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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[16]
[9]
et al. (PTC 4c) and recently by Marouka et al. (PTC 6).
Enantiomeric excesses up to 97% were achieved in chal-
cone epoxidation using the advanced PTCs 4b–c and 6
(
Scheme 1).
3
Scheme 2. Asymmetric epoxidation of vitamin K (7) using hydrogen per-
oxide and the PTC 8.
Figure 2. Schematic representation of variations on the scaffold of cincho-
na-alkaloid PTCs.
Scheme 1. Asymmetric epoxidation of chalcone derivatives using phase-
transfer catalysts.
As it turned out, in particular the use of aqueous sodium
hypochlorite as oxidant in combination with catalyst 10
bearing a hydroxyl group at the C6’ atom of the quinoline
ring improved the enantioselectivity tremendously: up to
85% ee and 73% yield were achieved for the epoxide 9, at
a catalyst loading of 2.5 mol%. This value represents the
best enantioselectivity reported thus far (Scheme 3).
Despite these excellent results, few procedures for the
synthesis of the epoxides of quinones and quinone acetals
[17–19]
by asymmetric epoxidation appear to exist.
Oxiranes of
the latter type are valuable building blocks for pharmaceuti-
cal and natural products. 2-Methyl-1,4-naphthoquinone (vi-
tamin K (7), Scheme 2) has often served as the touchstone
3
for catalyst performance, because it is a particularly chal-
lenging substrate with respect to enantioselective epoxida-
tion. In fact, a maximum ee of 78% at 32% yield was
achiev
A
C
H
T
R
E
U
N
G
ed by Taylor et al., using carbohydrate-derived chiral
[18–19]
hydroperoxides as stoichiometric oxidizing agents.
As
far as asymmetric phase-transfer catalysis is concerned, the
best ee value (34%) at 86% yield was obtained by Arai,
Shioiri et al. using catalyst 8 and alkaline hydrogen peroxide
Scheme 3. Asymmetric epoxidation of 7 with the new phase-transfer cata-
lyst 10.
[16,20]
as the oxidant (Scheme 2).
Therefore, a highly efficient catalytic enantioselective ap-
proach still remains a challenging task. Herein we present a
detailed study regarding the catalyst and the oxidant in
order to probe the catalyst structure–reactivity relationship.
For catalyst optimization, our strategy is based on two main
ideas. First, enhancing the catalyst–substrate interaction by
additional hydrogen bonding, and second improving the
asymmetric induction by introduction of further elements of
chirality (Figure 2).
Results
Influence of the oxidant: We initially investigated the influ-
ence of several oxidants using the literature known catalysts
[
16,21]
11 and 12 (Scheme 4).
As shown in Table 1, the epoxi-
dation of 7 could be achieved in good yields using either hy-
drogen peroxide, tert-butyl hydroperoxide (TBHP), cumyl
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Chem. Eur. J. 2007, 13, 4483– 4498

Enantioselective Epoxidation
FULL PAPER
Table 1. Influence of the oxidant on the asymmetric epoxidation of 7.
droxyl function at C9 protected
ee [%] as a benzyl ether, but carrying a
[
a]
[b]
Entry
PTC
mol%
Oxidant
Solvent
t [h]
Yield [%]
Epoxide
(2R,3S)
(2R,3S)
(2S,3R)
(2S,3R)
(2S,3R)
(2S,3R)
(2S,3R)
hydroxyl group at position C6’
of the quinoline moiety, was
prepared as shown in Scheme 5.
Alkylation of 2 with benzyl
chloride yielded 19, which was
fu r6 ther converted to the phenol
1
2
3
4
5
6
7
11
11
12
12
12
12
12
5
H
2
O
2
CHCl
PhCl
CHCl
PhCl
PhCl
PhCl
PhCl
3
4
6
7
8
2387
393
5
93
90
89
92
A
H
R
U
G
21
67
66
72
76
43
3
10
10
10
1
10
10
NaOCl
NaOCl
NaOCl
NaOCl
TBHP
CHP
ACHTREUNG
3
ACHTREUNG
ACHTREUNG
ACHTREUNG
ACHTREUNG
90
ACHTREUNG
1
8
by demethylation with
[
a] LiOH (1.6 equiv) was employed as the base when hydrogen peroxide, TBHP or CHP were used as oxi-
dants. [b] The absolute configurations of epoxides 9 (2R,3S) and ent-9 (2S,3R) were assigned by comparison sodium ethyl mercaptide using
[
8,13]
with literature data.
phase.
[c] Yields and enantioselectivities were determined using GC on chiral stationary protocols developed by Deng
Scheme 4. Asymmetric epoxidation of 7 with different oxidants.
hydroperoxide (CHP) or sodium hypochlorite (Table 1, en-
tries 1, 5 and 7).
Scheme 5. Synthetic route to the catalysts 13 and 17. a) NaH, BnCl,
DMF, 1108C, 16 h; b) NaH, EtSH, DMF, 1108C, 16 h; c) 9-chloromethyl-
A remarkable improvement in the enantioselectivity was
found when sodium hypochlorite (commercial bleach) was
used as oxidant (Table 1, entries 2–5). At a catalyst loading
of 10 mol% (relative to the enone), excellent conversions
and ee values up to 72% were achieved in chlorobenzene at
À108C with catalyst 12. At lower catalyst loading (1 mol%),
an epoxide ee of 76% resulted (Table 1, entries 4 and 5).
Chlorobenzene was chosen as solvent as it consistently pro-
vided the highest ee values of the product epoxide (Table 1,
entries 2, 4–7). Obviously, the sense of induction is dominat-
ed by the configuration of the alkaloid moiety. Using qui-
nine derivative 11, epoxide enantiomer 9 is formed predomi-
nantly, whereas the pseudo-enantiomeric quinidine deriva-
tive 12 leads to epoxide ent-9, as the major enantiomer
A
H
R
U
G
[22,23]
et al. (Scheme 5).
These transformations were followed
by quaternisation of 18 and 19 with 9-chloromethylanthra-
cene to the PTCs 13 and 17. The corresponding O-benzyl
salt 14 (Figure 3) was prepared analogously from quinidine
(3).
The new ammonium salt 15 (Figure 3) was obtained from
the literature known precursor b-isocupreidine by quaterni-
sation with 9-chloromethylanthrancene (two steps from 3 in
[24]
35% overall yield). Starting from 2, the known 9-epi-qui-
(
Table 1, entries 2 and 4).
Effect of the catalyst structure
Modifications at the C9 atom: First we examined the influ-
ence of modifications at the secondary alcohol (C9) of the
PTCs on the epoxidation of vitamin K (7). Therefore, the
3
free alcohol was converted to different ethers, leading to the
novel PTCs 13–15 (Scheme 5 and Figure 3). Furthermore,
the configuration at C9 was inverted (catalyst 16, Figure 3).
The novel PTC 17 (Scheme 5), having the secondary hy-
Figure 3. Structures of catalyst 14, the b-isocupreidine salt 15 and the 9-
epi-quinine-derived ammonium salt 16.
Chem. Eur. J. 2007, 13, 4483– 4498
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www.chemeurj.org
4485

A. Berkessel et al.
[25]
nine
was quaternised with 9-chloromethylanthracene in
66% yield to give catalyst 16 (Figure 3). This salt exhibits
the non-natural configuration at the C9 atom of the alka-
loid, which was confirmed unambiguously by X-ray structur-
al analyses.
Catalytic activity ofthe salts 11–17 : As shown in Table 2, en-
tries 3–7, the enantioselectivities of the novel PTCs 13–17
were lower compared with those achieved with the literature
known catalysts 11 and 12 (Table 2, entries 1 and 2).
Table 2. Results for the asymmetric epoxidation of vitamin K
sodium hypochlorite as oxidant in chlorobenzene at À108C with catalysts
1–17.
3
(7) with
1
[
a]
[b]
Entry
PTC
t [h]
Yield [%]
Epoxide
(2R,3S)
(2S,3R)
8 2( 2S,3R)
(2R,3S)
(2R,3S)
(2S,3R)
(2S,3R)
ee [%]
1
2
3
4
5
6
7
11
12
13
14
15
16
17
6
8
3
24
24
8
90
92
A
H
R
U
G
67
72
50
41
4
AHCTREUNG
2
ACHTREUNG
81
A
T
E
N
Figure 4. Structures of the novel phase-transfer catalysts 22–27.
79 (87)
40 (48)
60 (61)
ACHTREUNG
A
T
E
N
51
20
10
ACHTREUNG
procedure by Katsuki et al. to convert (R)-BINOL 29 into
[29,30]
[
a] 10 mol% of the catalyst were used. [b] Conversion given in brackets.
triflate 30.
Kumada coupling and radical bromination
yielded the bromide 21, which was used in the subsequent
[31]
step without purification. The bromide ent-21 was synthe-
sized analogously from (S)-BINOL.
As shown in Table 2 (entry 1) the quinine-derived PTC 11
forms the epoxide enantiomer 9 predominantly in the
2R,3S)-configuration. Interestingly, the introduction of a
(
benzyl functionality at the C9 atom of the quinine-based
PTC 11 switches the sense of stereoinduction: with catalyst
11 (Table 2, entry 1), 67% ee was obtained in favour of the
epoxide 9. However, using the catalyst 13 having the quinine
scaffold and a benzyl group at C9 (Table 2, entry 3) yielded
the opposite enantiomer ent-9 in 50% ee. For the quinidine-
based O-benzylated catalyst 14, the same tendency was ob-
served (Table 2, entries 2 and 4). The 9-epi-isomer 16 pro-
duced epoxide ent-9 in 51% ee (Table 2, entry 6). In the
case of PTC 17 (alcohol functionality at C6’ and a O-benzyl
group at C9), the ee of the epoxide ent-9 decreased signifi-
cantly to 20% (Table 2, entry 7). Nearly no enantioselectivi-
ty was induced by the rigid PTC 15 (Table 2, entry 5).
Scheme 6. Synthesis of the halides 20 and 21. a) NaBH
h; b) PCl , toluene, RT, 16 h; c) (CF SO )O, Et N, CH
Hünig base, EtOH; (CF SO )O, Et N, CH
(PPh ], Et O, 0 8C, 4 h; e) NBS, AIBN, CCl
4
, MeOH, 08C,
Cl ; H , Pd/C,
d) MeMgCl, [NiCl
4
, reflux, 2 h.
3
5
3
2
3
2
2
2
[
29,30]
3
2
3
2
Cl
2
;
2
-
A
H
R
U
G
3
)
2
2
Modifications at the quinuclidine nitrogen atom: We also in-
vestigated the possibility to enhance the enantioselectivity
of the alkaloid-based catalysts by introducing further ele-
ments of chirality at the quinuclidine core. With respect to
the performance of catalysts 11 and 12, we envisaged that
the combination of quinine (2) and quinidine (3) with both
enantiomers of the chiral benzyl halides 20 and 21
Catalytic activity ofthe PTCs 22–27 : With these catalysts in
hand, we proceeded to evaluate their performance in the
asymmetric epoxidation of vitamin K (7). The results are
3
summarized in Table 3.
In all cases, naphthoquinone 7 was epoxidised in good
yields (up to 87%, see Table 3). The sense of stereoinduc-
tion is clearly dominated by the sense of chirality of the al-
kaloid moiety. Moderate enantioselectivities resulted from
the use of both diastereomers of the quininium salts 22 and
23. Clearly, 23 is the matched catalyst with a maximum of
54% ee (Table 3, entry 2), while the mismatched catalyst 22
yielded a mere 15% ee (Table 3, entry 1). Similarly pro-
nounced effects were observed for the N-binaphthylmethyl
(
Scheme 6) as chiral and bulky aromatic groups would be ef-
fective in improving the enantioselectivity. Clearly, a match-
ed–mismatched situation should result for the quaternary
catalysts 22–27 (Figure 4).
As shown in Scheme 6, we prepared 20 and ent-20 by re-
[26–28]
duction/chlorination from the corresponding aldehydes
28 and ent-28) in 70–80% overall yield. For the synthesis of
the binaphthyl electrophile 21, we followed the literature
(
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Chem. Eur. J. 2007, 13, 4483– 4498

Enantioselective Epoxidation
FULL PAPER
Table 3. Results for the asymmetric epoxidation of 7 with sodium hypo-
chlorite as oxidant in chlorobenzene at À108C with 10 mol% of the cata-
lysts 22–27.
In analogy to the synthetic route above, the corresponding
hydrogenated PTCs 10 and 35 (quinine-based) and 36 and
7 (quinidine-based) were prepared in 34–63% overall yield
Figure 5).
3
(
Entry
PTC
t [h]
Yield [%]
Epoxide
(2R,3S)
(2R,3S)
(2S,3R)
(2S,3R)
(2S,3R)
(2S,3R)
(2S,3R)
ee [%]
1
2
3
4
5
6
7
22
23
24
7
8
8
2386
6
22
7
85
77 (86)
87
A
T
E
N
15
54
76
79
47
40
71
[
a]
ACHTREUNG
Catalytic activity ofPTCs 10, 31, 32 and 35–37 : As summar-
ACHTREUNG
[
b]
24
25
ACHTREUNG
84
83
85
ACHTREUNG
[
c]
26
27
ACHTREUNG
AHCTREUNG
[
[
a] Conversion given in brackets. [b] 1 mol% of the catalyst was used.
c] Chloroform was used as solvent.
substituted quinidinium PTCs 26 and 27 (Table 3, entries 6
and 7): in the matched case (27), epoxide ent-9 was obtained
in 71% ee, whereas its diastereomer PTC 26 generated ent-9
with only 40% ee. The best results were achieved with cata-
lyst 24. In the presence of only 1 mol% of this salt, enantio-
selectivities up to 79% ee (Table 3, entries 3–4) were ob-
served. In this case, the mismatched diastereomer 25 fur-
nished the epoxide ent-9 in good yield but with no more
than 47% ee (Table 3, entry 5).
Figure 5. Structures of the catalysts 10 and 35–37.
ized in Table 4, in the quinidine series (Table 4, entries 1–5),
the literature known catalyst 12 (Scheme 4) with a methoxy
group at the quinoline moiety (C6’) gave the best enantiose-
lectivity of 72% (Table 4, entry 1). Neither a free hydroxyl
at C6’ (PTC 31) nor a more bulky isopropyl substituent at
this position (PTC 32) could enhance the enantioselectivity
(Table 4, entries 2 and 3).
Modifications at the C6’ atom: Another variation of the cin-
chona-alkaloid scaffold involves a modification of the ether
at the C6’ position of the quinoline core. Two sets of quini-
dine-based PTCs were synthesized. In the first series, the
PTCs maintained the “natural” double bond at C10,C11. In
the second set, this position was hydrogenated. Exemplarily,
the synthetic route leading to the non-hydrogenated quini-
dine based PTCs 31 and 32 is shown in Scheme 7. First, the
methyl ether at C6’of quinidine (3) was cleaved to yield the
phenol 33. Further alkylation with 2-bromopropane gave
the ether 34. Subsequent quaternisation of 33 and 34 with 9-
chloromethylanthracene gave salts 31 and 32 in 73and 67%
yield, respectively.
Table 4. Results for the asymmetric epoxidation of 7 with sodium hypo-
chlorite as oxidant in chlorobenzene at À108C with the catalysts 10, 12,
31, 32 and 35–37.
Entry
PTC
mol%
t [h]
Yield [%]
Epoxide
(2S,3R)
(2S,3R)
(2S,3R)
(2S,3R)
(2S,3R)
(2R,3S)
(2R,3S)
ee [%]
1
2
3
4
5
6
7
12
31
32
36
37
10
35
10
5
8
18
2
28
1.5
25
8
92
89
88
74
93
73
89
A
T
E
N
72
56
59
67
60
85
59
10
2.5
10
2.5
10
Also in the case of the quinine scaffold, the effects of
these modifications were studied. To our delight, PTC 10
bearing two free hydroxyl groups (C9 and C6’) and a hydro-
genated double bond (C10,C11) afforded the highest enan-
tioselectivity of 85% ee with good yields (Table 4, entry 6).
These values are the highest reported ever in the catalytic
asymmetric epoxidation of vitamin K3 (7). On the other
hand, increasing the steric demand at the C6’ position by in-
troduction of an isopropyl ether (PTC 35), the enantioselec-
tivity dropped to 59% ee (Table 4, entry 7). Given these re-
sults, no PTCs with a sterically bulkier ether functionality at
the C6’ atom of the quinoline were tested in this reaction.
Discussion
Scheme 7. Synthetic route to the PTCs 31 and 32. a) NaH, EtSH, DMF,
Our results show that the configuration of the major epox-
ide enantiomer obtained is not necessarily determined by
1
2 3
108C, 16 h; b) Cs CO , 2-bromopropane, DMF, 608C, 40 h; c) 9-chloro-
methylanthracene, THF, reflux, 16 h.
Chem. Eur. J. 2007, 13, 4483– 4498
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4487

A. Berkessel et al.
the configuration at C8 and C9 of the alkaloid. As shown in
Table 2 (entries 1 and 3), the etherification of the hydroxyl
group at C9 led to a switch in the epoxide configuration.
We have presented herein that small variations at the
scaffold of the cinchona-alkaloid PTCs may have dramatic
effects on the enantioselectivity of the epoxidation. For in-
stance, a free phenol functionality at C6’ of the quinoline
core gave rise to remarkably increased enantioselectivity
(
10, 85% ee; Table 4, entry 6).
We applied Coreyꢁs approach to rationalise our observa-
[32,33]
tions.
Corey et al. presented a model aimed to deter-
mine the geometrical factors which are responsible for the
enantioselectivity in the catalytic, asymmetric alkylation of
glycine imine esters using cinchona-alkaloid based phase-
[32]
transfer catalysts.
In this approach, the nitrogen atom of the quinuclidine
core is regarded as the centre of a tetrahedron. A highly
enantioselective phase-transfer catalyst should be structured
in a way to provide only one open tetrahedron face for in-
teraction with the substrate. Due to the structure of the cin-
chona-alkaloids, one face is blocked by the quinuclidine ring
system. In a quaternary ammonium salt (e.g. PTC 12,
Scheme 4) a second face is shielded by the 9-anthracenyl-
[32–34]
methyl moiety.
The configuration at C9 of the alkaloid
determines the spatial arrangement of the quinoline moiety
and this substituent blocks the third face of the tetrahedron.
One face remains open for the catalyst–substrate interaction
Figure 6. Structure of the PTC 12 (top) and the energy-minimized confor-
mation of PTC 12 where the quinuclidine nitrogen atom is surrounded
by a tetrahedron (bottom).
(
in Figure 6, the face defined by C8, C2 and the benzylic C
atom CBn).
It is assumed that the oxidation described herein is—
mechanistically—an asymmetric version of the two-step
[35]
Weitz–Scheffer epoxidation: in this process, the first step
is a reversible nucleophilic attack of the anionic oxidant
À
(
OCl in our case) at the Michael system to form the eno-
lates 38 and ent-38, followed by an intramolecular nucleo-
philic substitution to yield the epoxides 9 and ent-9
(
Scheme 8). In the case of vitamin K (7), the nucleophilic
3
attack most likely occurs at C3, as C2 is sterically more hin-
[35]
dered.
Previous kinetic and mechanistic studies of the epoxida-
tion of chalcone derivatives indicate a change in the rate-de-
termining step depending on the electron density of the sub-
[36,37]
Scheme 8. Proposed mechanism of the Weitz–Scheffer epoxidation of vi-
tamin K (7).
3
strate.
Thus, for chalcones with electron-withdrawing
groups attached at the b-position of the carbonyl group, the
electron density at this carbon is reduced so that the attack
[
36,37]
of the oxidant (first step) is facilitated.
Likely, for elec-
14. Figures 7–10 show the minimum energy conformations
of the two diastereomeric enolate–catalyst complexes for
these PTCs; for better comparison the complexes with the
lowest minimum energy are depicted on the top of each
figure (10a–12a, 14a). Binding of the enolate anion to the
PTC cation involves i) Coulombic interaction (ion pairing);
ii) hydrogen bonding between the proton of the hydroxy
group at C9 of the PTC and the enolate oxygen atom (C1);
and iii) p–p stacking of the anthracenyl moiety and the aro-
matic portion of the substrate enone. The energy values, the
distances for ion pairing, hydrogen bonding and p–p stack-
ing of the above complexes are summarized in Table 5.
tron-poor a,b-unsaturated ketones, such as vitaminK (7),
3
the formation of the racemic enolate 38 is fast and reversi-
ble, whereas in contrast the intramolecular ring closure to
form the epoxide is assumed to determine the reaction rate
(
Scheme 8). In the presence of a chiral quaternary ammoni-
um salt, one of the enolates 38 or ent-38 (Scheme 8) presum-
ably coordinates preferentially to the catalyst, impeding the
reversal of the initial Michael addition, and allowing smooth
formation of the epoxide.
To shed further light on our model, we carried out confor-
mational analyses (Monte Carlo search) for the PTCs 10–12,
4488
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 4483– 4498

Enantioselective Epoxidation
FULL PAPER
Table 5. Energy values and distances for hydrogen bonding, ion pairing and p–p stacking.
and the p–p-stacking interac-
tion can occur. We assume that
the p–p-stacking interaction in
complex 14a is again responsi-
ble for the more stable coordi-
nation and the lower energy. As
shown in Figure 9, in complex
14a the benzyl group occupies
the tetrahedral face which usu-
ally accommodates the enolate.
Entry PTC Complex
E
kJmol
Ion pairing
[Š]
H Bonding (C9)
H Bonding (C6’)
p–p stacking
À1
[a]
[b]
[c]
[d]
[
]
[Š]
[Š]
[Š]
1
2
3
4
5
6
7
8
12a
12b
11a
11b
14a
14b
10a
10b
546.94
550.49
545.42
546.52
640.99
645.74
372.78
379.10
4.286
4.408
4.270
4.200
4.295
4.306
4.299
4.203
1.852
1.832
1.853–.578
1.834
–
–
–
3
–
–
3.778
–
12
11
14
10
–
3.668
–
3.576
–
–
–
1.846
1.876
1.706
1.734
[
a] Distance between the quaternary nitrogen at the quinuclidine ring and the oxygen of the enolate. [b] Dis- Therefore, the coordination has
tance between the alcoholic proton at C9 and the oxygen of the enolate. [c] Distance between the phenolic
proton at C6’ and the oxygen of the enolate. [d] Shortest distance between an aromatic carbon atom of the
substrate and a carbon atom of the anthracenyl moiety.
to take place at another tetra-
hedral face. The accessible site
is now defined by C8, C-Bn and
C6 (Figure 9, 14a bottom). It is
The resulting minimum energy conformations of PTC 12
are shown in Figure 7. As expected, both chiral enolates are
arranged such that the negative charge at the oxygen atom
at C1 of the substrate is stabilized by a contact ion pair with
the nitrogen cation of the catalyst and by hydrogen bonding
with the secondary alcohol. The aromatic part of the sub-
strate can undergo further stabilization by p–p interaction
with the anthracenyl moiety of the catalyst in the case of
complex 12a (Table 5, entries 1 and 2). The latter interac-
tions explains the lower energy for complex 12a (catalyst 12
coordinating to enolate ent-38) in comparison to complex
the same as for the pseudo-enantiomeric non-benzylated
quinine catalyst 11 (Figure 8). As a result, the configuration
of the major epoxide enantiomer changes. This is in accord-
ance with the experimental results (Table 2, entry 4).
Conformational analysis of the two possible diastereo-
meric enolate–catalyst complexes was performed for catalyst
10 as well, and they are shown in Figure 10. This conforma-
tion suggests a further stabilizing hydrogen-bonding interac-
tion between the phenolic proton and the carbonyl oxygen
atom (C4) of the substrate (Table 5, entries 7 and 8). This
additional stabilizing element in combination with the p–p-
stacking present in complex 10a could explain the excellent
enantioselectivities observed using this catalyst.
12b (ion pair of the catalyst 12 with enolate 38).
In Figure 8, the minimum energy conformations for the
catalyst–enolate complexes of the PTC 11 are shown. Also
in this case, the complex showing p–p stacking (11a) be-
tween catalyst and substrate has lower energy (Table 5,
entry 3). This spatial arrangement leads to the epoxide en-
antiomer mainly observed experimentally.
Conclusion
Our study revealed the following novel aspects of the asym-
metric phase-transfer catalyzed epoxidation:
For the pseudo-enantiomeric catalyst–enolate complexes
11a (Figure 8, quinine-based) and 12a (Figure 7, quinidine-
based) it is shown that in both cases the most readily acces-
sible tetrahedron face (C6-Bn-C8 for 11a and C2-Bn-C8 for
i) To the best of our knowledge, aqueous sodium hypo-
chlorite was not used before for the epoxidation of qui-
nones. In our hands, this oxidant gave good yields and
superior enantioselectivities in the epoxidation of vita-
12a) is responsible for the enolate coordination. The tetra-
hedron face blocked by the quinoline moiety varies, depend-
ing on the catalyst scaffold, that is, (9R) or (9S). This leads
to a different orientation of the enolates. In all cases, the
configuration of the calculated catalyst–enolate complexes
with the lowest minimum energy corresponds—without ex-
ception—to the configuration of the major epoxide enantio-
mer obtained experimentally. The above situation is the
result of the “enantiomorphism” of the catalysts 11 and 12
around the reaction centre. Overall, they are of course
pseudo-enantiomeric (diastereomeric) due to the presence
of the vinyl group at the “remote” carbon atom C3. In anal-
ogy, it is clear that the (2S,3R)-epoxide configuration
min K (7).
3
ii) A number of differently modified quinine and quinidine
phase-transfer catalysts were synthesized and were
found to be highly effective in the epoxidation of the
quinone 7. The best results were achieved with the read-
ily available ammonium salt 10, carrying a hydroxyl
group at the C6’ atom of the quinoline system. This cat-
alyst afforded the highest enantioselectivity (85% ee at
73% yield for epoxide 9) ever reported for the asym-
metric epoxidation of 7.
iii) In the mechanistic analysis presented, we successfully
adopted Coreyꢁs approach, providing a rational explana-
tion for the stereochemical course of the epoxidation
observed for different catalysts.
(
Table 2, entry 6) obtained with PTC 16 (Figure 3, epi-qui-
nine based) arises from the inverted configuration at C9.
Further minimized energy conformational analyses were
carried out for the 9-O-benzylated quinidine based catalyst
14. Due to the catalyst structure, hydrogen bonding between
In summary, we reported a comprehensive study of novel
the catalyst and the enolate is not possible (Figure 9,
Table 5, entries 5 and 6). In this case, only the ion pairing
and established cinchona-based PTCs for the asymmetric
epoxidation of enones, exemplified by vitamin K (7). This
3
Chem. Eur. J. 2007, 13, 4483– 4498
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4489

A. Berkessel et al.
Figure 8. Top, middle: View of the diastereomeric enolate–catalyst com-
plexes for the PTC 11. Bottom: Illustration of the tetrahedron face (C6,
CBn and C8) in complex 11a. For the sake of clarity, the substrate C
atoms are shown in light grey.
Figure 7. Top, middle: View of the diastereomeric enolate–catalyst com-
plexes for the PTC 12. Bottom: Illustration of the tetrahedron face (C2,
CBn and C8) in complex 12a. For the sake of clarity, the substrate C
atoms are shown in light grey.
study led to the identification of the most selective catalyst
for epoxidation of the quinone 7 known to date.
4490
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Chem. Eur. J. 2007, 13, 4483– 4498

Enantioselective Epoxidation
FULL PAPER
Figure 10. View of the diastereomeric enolate–catalyst complex for cata-
lyst 10. For the sake of clarity, the substrate C atoms are shown in light
grey.
Experimental Section
General procedures: Flash chromatography was performed on silica gel
(
Macherey–Nagel MN-Kieselgel 60, 230–240 mesh). TLC was performed
on aluminium-backed silica plates (Macherey–Nagel, Polygram SIL G/
UV254), which were developed by using UV fluorescence. Melting points
were determined on a Büchi melting point apparatus and are uncorrect-
ed. Elemental analysis was performed on an Elementar Vario EL CHN
analyzer. Infrared spectra were recorded on a Perkin–Elmer Paragon
1
000 FT-IR spectrometer using the ATR technique and on a Perkin–
1
Elmer 1600 Series FT-IR spectrometer. H NMR spectra were recorded
at 300 MHz on Bruker AC 300 and DPX 300 instruments, respectively;
1
3
C NMR spectra at 75.5 MHz. Chemical shifts (d) are given in parts per
million (ppm) referenced to TMS. Low resolution mass spectra (m/z)
were recorded on an Agilent 1100 spectrometer with only molecular ions
+
[
M
] reported. High resolution mass spectra (ESI) were recorded on a
Figure 9. Top, middle: View of the diastereomeric enolate–catalyst com-
plexes for the 9-O-benzylated ammonium salt 14. Bottom: Illustration of
the tetrahedron face (C6, C8 and CBn) in complex 14a. For the sake of
clarity, the substrate C atoms are shown in light grey.
Finnigan MAT 900 ST spectrometer. Optical rotations were measured on
a Perkin–Elmer 343plus polarimeter, concentrations (c) are given in g
per 100 mL of solution. ee Values were determined by chiral GC on a
Chirasil-Dex CB column (Hewlett–Packard 5890 Series II chromato-
graph). All commercially available chemicals were used without further
purification. Anhydrous solvents were distilled from appropriate drying
agents prior to use.
Chem. Eur. J. 2007, 13, 4483– 4498
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4491

A. Berkessel et al.
2
D
0
General procedure for the quaternisation of tertiary amines
methane/methanol 9:1); m.p. > 1958C (decomp); [a] = À413( c=1.00
1
in methanol); H NMR (300 MHz, CDCl
3
): d=0.54 (t, J=7.3Hz, 3H; H-
C11), 0.87–1.32 (m, 5H; H-C7, C3, C6, C10), 1.58–1.83 (m, 3H; H-C7,
C4, C6), 2.03–2.19 (m, 1H; H-C5), 2.74–2.60 (m, 1H; H-C2), 3.36–3.45
m, 1H; H-C2), 4.35–4.62 (m, 2H; H-C8, C5), 6.23 (d, J=13.4 Hz, 1H;
H-CH An), 6.37 (d, J=13.4 Hz, 1H; H-CH An), 6.63–6.78 (m, 2H; H-
C7’, H-C9), 6.88–6.99 (m, 1H; H-Caryl), 6.99–7.11 (m, 1H; H-Caryl),
.20–7.29 (m, 1H; H-Caryl), 7.31–7.48 (m, 4H; H-Caryl), 7.56–7.65 (m,
H; H-Caryl), 7.78–7.85 (m, 1H; H-C3’), 7.85–7.93(m, 1H; OH), 8.04–
.15 (m, 1H; H-C5’), 8.25–8.38 (m, 1H; H-Caryl), 8.66–8.75 (m, 1H; H-
C2’), 8.86–8.96 (m, 1H; H-Caryl), 9.15–9.31 ppm (m, 1H; OH); C NMR
(75.5 MHz, CDCl ): d=11.4 (C11), 22.6 (C7), 23.0 (C4), 26.0 (C6), 26.8
(C10), 37.0 (C3), 50.4 (C5), 54.5 (CH An), 64.9 (C2), 66.8 (C8), 66.8
(C9), 77.20 (Caryl), 102.9 (C5’), 116.9 (C3’), 120.5 (C7’), 124.2, 124.4,
124.5, 124.9, 126.2, 127.3, 127.7, 128.5, 128.5, 129.9, 130.3 (all Caryl),
131.0 (C8’), 131.2, 132.5), 132.6 (3Caryl), 141.7 (C4’), 142.1 (C9’), 146.5
(C2’), 155.1 ppm (C6’); IR (ATR): n˜ =3132, 2956, 1618, 1526, 1464, 1448,
Under an argon atmosphere, the benzyl halide (1.10 equiv) was added to
a highly concentrated solution of the amine (1.00 equiv) in dry THF. The
reaction mixture was heated under reflux until TLC analysis showed the
complete consumption of the amine.
(
2
2
Work-up A: The yellow precipitate was filtered off and purified—if nec-
essary—by flash chromatography (CHCl
3
/MeOH 9:1) or recrystallization.
7
1
8
Work-up B: The solvent was removed under reduced pressure and the
residue purified by flash chromatography (CHCl /MeOH 9:1).
3
1
3
General procedure for the alkylation of phenols
Cesium carbonate (2.50 equiv) was added to a stirred solution of the al-
kaloid (1.00 equiv) in dry DMF (0.02m) and stirred at RT for 10 min.
The bromoalkane (2.00 equiv) was added, and the reaction mixture was
stirred for 40 h at 608C. The solvent was removed under reduced pres-
sure and the resulting solid was purified by flash chromatography
3
2
(
CHCl
General procedure for the catalytic asymmetric epoxidation of 2-methyl-
,4-naphthoquinone (7) under phase-transfer-catalyzed conditions
A stock solution 0.15m of 7 (258 mg, 1.50 mmol) and diphenyl ether
255 mg, 238 mL, 1.50 mmol, internal standard) in chlorobenzene (10 mL)
was prepared. A 10 mL round bottomed flask was cooled to À108C and
charged with the stock solution of (1.5 mL, 38.7 mg, 225 mmol,
.00 equiv) and diphenyl ether (38.3 mg, 35.7 mL, 225 mmol; internal stan-
3
/MeOH 9:1). The desired product was obtained as a solid.
1
7
C
395, 1283, 1258, 1237, 1223, 1129, 1061, 1047, 1011, 913, 895, 859, 831,
91, 743, 705, 663, 625 cm ; HR-MS (ESI, Dm=0.005): m/z: calcd for
À1
1
+
34
H
35ClN
2
O
2
: 591.3011, found: 591.301 [M ]; elemental analysis calcd
(
%) for C35
H
35ClN
2
O
2
·H
2
O (557.12): C 73.30, H 6.69, N 5.03; found: C
(
7
3.55, H 7.01, N 4.85.
CCDC-609363 contains the supplementary crystallographic data for com-
pound 10. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
7
1
dard). The phase-transfer catalyst (10 to 1 mol%) was added and the re-
action was initiated by addition of 13% aqueous sodium hypochlorite
(
500 mL, 1.09 mmol, 4.85 equiv). The mixture was vigorously stirred at
1-N-(9-Anthrylmethyl)-9-O-benzylquininium chloride (13): By following
the general procedure for the quaternisation of tertiary amines, 13 was
À108C for 4 to 24 h. Samples (150 mL) of the organic layer were with-
drawn periodically, diluted with toluene (1.00 mL), and added to saturat-
ed aqueous sodium thiosulfate (150 mL). The organic phase was analyzed
by chiral GC (GC column: CP-Chiralsil-Dex CB, nitrogen 1.2 mLmin
(
[
22]
obtained from 9-O-benzylquinine (19)
(953mg, 2. 30 mmol) using
2
0
work-up A as a yellow solid (855 mg, 58%). M.p. 121–1228C; [a]
=
D
À1
1
À297 (c=1.00 in chloroform); H NMR (300 MHz, [D
6
]DMSO): d=
constant flow modus), injector 1808C (split modus), detector (FID)
1.51–1.58 (m, 2H; H-C5, C7), 1.87 (brs, 1H; H-C4), 1.95–1.98 (m, 1H;
H-C5), 2.33–2.38 (m, 1H; H-C3), 2.42–2.47 (m, 1H; H-C7), 2.70–2.79 (m,
À1
1
808C, oven: 1458C (20 min), 108Cmin 1608C (3min)).
1
3
CH
CH
H; H-C6), 2.98–3.05 (m, 1H; H-C2), 3.95–4.01 (m, 1H; H-C2), 4.06 (s,
H; OCH ), 4.15–4.18 (m, 1H; H-C6), 4.75–4.79 (d, J=11.0 Hz, 2H; H-
Ph, C8), 4.92–4.97 (m, 2H; H-C11), 5.21–5.25 (d, J=11.1 Hz, 1H; H-
Ph), 5.63–5.77 (m, 2H; H-C10, H-CH An), 6.92–6.96 (d, J=12.1 Hz,
An), 7.44–7.77 (m, 11H; H-C9, Caryl), 7.86–7.88 (m, 2H; H-
The retention time (t
methyl-1,4-naphthoquinone (9) 18.2 min, for (2S,3R)-2,3-epoxy-2-methyl-
,4-naphthoquinone (ent-9) 17.1 min
R
) for 7 was 15.9 min, for (2R,3S)-2,3-epoxy-2-
3
2
2
1
2
and for diphenyl ether 8.79 min.
1
H; H-CH
2
ent-9: After epoxidation of 7 with cat-
alyst 12 under the conditions described
above, and work up, epoxide ent-9 was
recrystallized from ethanol and ob-
Caryl), 8.09–8.12 (d, J=9.2 Hz, 1H; H-Caryl), 8.25–8.28 (m, 2H; H-
Caryl), 8.51–8.54 (d, J=8.2 Hz, 1H; H-Caryl), 8.92–8.98 ppm (m, 3H; H-
13
Caryl); C NMR (75 MHz, [D
6
]DMSO): d=20.7 (C5), 24.5 (C7), 25.2
), 56.0 (CH An), 59.5 (C2), 68.1
Ph), 73.0 (C9), 102.9 (C5’), 116.5 (C11), 118.5, 120.1,
21.9, 124.5, 125.5, 125.3, 126.2, 127.0 (all Caryl), 127.6 (2Caryl), 127.7
2Caryl), 128.0, 128.6, 128.6, 129.4, 129.5, 130.9, 131.0, 131.1, 132.0, 132.6,
(
(
1
(
C4), 37.1 (C3), 51.8 (C6), 55.3 (OCH
C8), 70.5 (CH
3
2
tained in 98% ee. R
f
=0.70 (hexane/
2
ethyl acetate 5:1); m.p. 126–1278C
[
39]
20
05
(
ethanol) (lit: 96–978C); [a]4 =356
(
c=0.96 in chloroform, 98% ee); CD: lmax =360 nm, De=+0.84 (c=
1
1
1
33.1, 137.3 (all Caryl), 137.6 (C10), 139.5, 144.2 (2Caryl), 147.3 (C2’),
57.3ppm (C6 ’); IR (ATR): n˜ =3368, 2931, 1721, 1619, 1586, 1506, 1472,
À3
1
5
3
7
.44”10 m, CHCl
H; CH ), 3.83 (s, 1H; H-C3), 7.70–7.73 (m, 2H; H-C6, C7), 7.91–
.97 ppm (m, 2H; H-C5, C8); C NMR (75.5 MHz, CDCl
), 61.3 (C3), 61.4 (C2), 126.8 (C5), 127.4 (C8), 131.9 (C9), 132.1
3 3
, 98% ee); H NMR (300 MHz, CDCl ): d=1.71 (s,
3
À1
451, 1353, 1260, 1239, 1066, 1024, 862, 826, 738, 721, 700 cm ; HR-MS
1
3
3
): d=14.7
(
ESI, Dm=0.005): m/z: calcd for C42
H
41
N
2
O
2
: 605.3168, found: 605.317
.H O (659.3): C
(
(
(
CH
3
+
[
M
]; elemental analysis calcd (%) for C42
H
41ClN
2
O
2
2
C10), 134.3 (C6), 134.5 (C7), 191.8 (C=O), 191.9 ppm (C=O); IR
ATR): n˜ =3037, 3001, 1695, 1591, 1402, 1335, 1295, 1249, 1193, 1169,
7
6.52, H 6.57, N 4.25; found: C 76.67, H 6.46, N 4.13.
À1
1-N-(9-Anthrylmethyl)-9-O-benzylquinidinium chloride (14): By follow-
ing the general procedure for the quaternisation of tertiary amines, 14
was obtained from 9-O-benzylquinidine
work-up B as a yellow solid (520 mg, 41%). R
anol/triethylamine 8:2:0.02); m.p. 126–1278C; [a] =253( c=0.99 in
chloroform); H NMR (300 MHz, [D
C7), 1.51–1.57 (m, 1H; H-C5), 1.68–1.71 (m, 1H; H-C5), 1.82 (brs, 1H;
H-C4), 2.27–2.32 (m, 1H; H-C3), 2.57–3.08 (m, 2H; H-C7, C6), 3.02–3.08
1
5
1
1
048, 949, 853, 748, 721, 701, 629 cm ; GC-MS (capillary column HP-
MS 0.25 mm”30 m, cross-linked 5% PH ME siloxane 0.25 mm; He,
[22]
À1
À1
À1
(829 mg, 2.00 mmol) using
=0.37 (ethyl acetate/meth-
mL ; 1008C, 5 min, 208Cmin , 2008C, 15 min, 208Cmin , 2808C,
0 min); t =10.36 min, m/z: 188, 173, 160, 131, 105, 89, 76; elemental
f
R
2
0
analysis calcd (%) for C11
H
8
O
3
(188.2): C 70.21, H 4.29; found: C 70.10,
D
1
6
]DMSO): d=1.25–1.27 (m, 1H; H-
H 4.27.
CCDC-609372 contains the supplementary crystallographic data for com-
pound ent-9. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
(
m, 1H; H-C2), 4.15–4.25 (m, 4H; H-C2, OCH
C6), 4.70–5.15 (m, 5H; H-C8, H-CH Ph, C11), 5.85–5.96 (m, 2H; H-C10,
H-CH An), 6.28–6.32 (d, J=13.8 Hz, 1H; H-CH An), 7.15–7.20 (m, 1H;
3
), 4.50–4.56 (m, 1H; H-
2
2
2
[
16,39]
The analytical data were identical with those reported.
-N-(9-Anthrylmethyl)-6’-hydroxy-10,11-dihydrocinchonidinium chloride
10): By following the general procedure for the quaternisation of terti-
ary amines, 10 was obtained from 6’-hydroxy-10,11-dihydrocinchonidine
40) (584 mg, 1.65 mmol) using work-up A as a yellow solid (665 mg,
5%); recrystallized from dichloromethane/n-hexane. R =0.45 (dichloro-
H-Caryl), 7.33–7.34 (m, 1H; H-C9), 7.53–7.79 (m, 9H; H-Caryl), 7.91–
8.10 (m, 4H; H-Caryl), 8.23–8.28 (m, 2H; H-Caryl), 8.93–9.01 ppm (m,
1
(
1
3
3H; H-Caryl); C NMR (75 MHz, [D
25.6 (C4), 36.7 (C3), 55.1 (C2), 55.6 (CH
66.6 (C8), 70.3(CH Ph), 73.5 (C9), 102.9 (C5’), 116.6 (C11), 118.5, 120.3,
122.2, 123.8, 124.9, 125.2, 125.5, 126.4, 127.1, 127.7, 128.0, 128.3 (all
6
]DMSO): d=20.7 (C7), 23.4 (C5),
2
Ph), 55.6 (OCH ), 55.9 (C6),
3
(
7
2
f
4492
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 4483– 4498

Enantioselective Epoxidation
FULL PAPER
Caryl), 128.7 (2Caryl), 128.7 (2Caryl), 129.6, 129.8, 131.0, 131.1, 132.0,
f
46%); recrystallized from acetone. R =0.48 (chloroform/methanol 9:1);
2
0
1
1
32.7, 133.0 (all Caryl), 137.1 (C10), 137.3, 138.7, 144.2 (3Caryl), 147.4
m.p. > 1478C (decomp); [a] =À345 (c=0.50 in chloroform); H NMR
D
(
1
0
C2’), 157.5 ppm (C6’); IR (ATR): n˜ =2929, 2920, 1619, 1585, 1505, 1454,
3
(300 MHz, CDCl ): d=1.11–1.39 (m, 2H; H-C3, H-C7), 1.72–1.94 (m,
À1
352, 1240, 1130, 1025, 925, 868, 744, 699 cm ; HR-MS (ESI, Dm=
2H; H-C3, H-C4), 1.95–2.13 (m, 1H; H-C7), 2.15–2.29 (m, 1H; H-C5),
2.29–2.54 (m, 1H; H-C8), 2.77–2.93(m, 1H; H-C6), 4. 37 –4.52 (m, 1H;
H-C8), 4.52–4.64 (m, 1H; H-C6), 4.81–5.01 (m, 2H; H-C2, H-C11), 5.12
+
.005): m/z: calcd for C42
H
41
N
2
O
2
: 605.3168, found: 605.318 [M ]; ele-
·H O (659.3): C 76.52, H
mental analysis calcd (%) for C42
.57, N 4.25; found: C 76.42, H 6.03, N 4.16.
3S)-1-N-(9-Anthrylmethyl)-10,11-dihydro-3,9-epoxy-6’-hydroxycinchon-
inium chloride (15): By following the general procedure for the quaterni-
H
41ClN
2
O
2
2
6
(d, J=12.6 Hz, 1H; H-CH
J=12.6 Hz, 1H; H-CH Ph), 5.46–5.68 (m, 1H; H-C10), 6.05 (d, J=
3.7 Hz, 1H; H-CH An), 6.59–6.77 (m, 2H; H-CH An, H-Caryl), 6.88 (d,
2
Ph), 5.24 (d, J=16.7 Hz, 1H; H-C11), 5.37 (d,
(
2
1
2
2
ACHTREUNG
[
24]
J=2.5 Hz, 1H; H-C9), 6.97–7.21 (m, 3H; H-Caryl), 7.25–7.37 (m, 2H; H-
Caryl), 7.41–7.60 (m, 4H; H-Caryl), 7.60–7.76 (m, 3H; H-Caryl), 7.77–
8.03(m, 3H; H-Caryl), 8.26 (s, 1H; OH), 8.65 (d, J=2.2 Hz, 1H; H-C5’),
8.69 (d, J=4.5 Hz, 1H; H-C2’), 9.34 ppm (d, J=8.9 Hz, 1H; H-C8’);
sation of tertiary amines, 15 was prepared from b-isocupreidine
(
R
404 mg, 1.30 mmol) using work-up A as a yellow solid (500 mg, 72%).
2
0
f
D
=0.08 (chloroform/methanol 9:1); m.p. > 2008C (decomp); [a] =
1
À25.6 (c=1.00 in methanol); H NMR (300 MHz, CDCl
.3Hz, 3H; H-C11), 0.99–1.17 (m, 1H; H-C5), 1.21–1.51 (m, 2H; H-
C10), 1.58–1.74 (m, 1H; H-C5), 1.89–2.00 (d, J=12.8 Hz, 1H; H-C2),
3
): d=0.74 (t, J=
1
3
C NMR (75.5 MHz, CDCl
C3), 50.5 (C6), 55.6 (CH An), 61.9 (C2), 66.0 (C8), 70.8 (CH
C9), 105.5 (C5’), 117.8 (C11), 118.0, 118.2, 122.7, 123.4, 124.7, 125.2,
26.0 (all Caryl), 126.3(2Caryl), 126.7, 127. ,3 127.8, 128.2, 128.4 (all
Caryl), 129.0 (2Caryl), 129.6, 130.6, 130.8, 130.9, 131.8 (all Caryl), 133.2
3
): d=23.3 (C7), 25.5 (C5), 25.8 (C4), 38.1
7
(
(
1
2
2
Ph), 76.6
2
1
6
1
.15–2.42 (m, 3H; H-C4, C7), 2.76–2.92 (m, 1H; H-C6), 3.99 (d, J=
2.7 Hz, 1H; H-C2), 4.65–4.86 (m, 1H; H-C6), 5.39 (m, 1H; H-C8), 5.93–
.03(m, 1H; H-Caryl), 6.27 (dd, J=2.1, 9.1 Hz, 1H; H-C7’), 6.36 (d, J=
(
(
1
Caryl), 136.2 (C9), 137.0, 137.6, 143.6 (4Caryl), 145.8 (C2’), 157.2 ppm
4.3Hz, 1H; H-CH
2
An), 6.47 (s, 1H; H-C9), 6.66–6.75 (m, 1H; H-
An), 7.43–7.49 (m, 1H; H-Caryl),
.50–7.57 (m, 1H; H-Caryl), 7.62 (d, J=9.1 Hz, 1H; H-C8’), 7.66 (d, J=
.5 Hz, 1H; H-C3’), 7.70–7.79 (m, 1H; H-Caryl), 7.92 (d, J=2.2 Hz, 1H;
C6’); IR (ATR): n˜ =3041, 2949, 1617, 1465, 1448, 1287, 1258, 1237, 1226,
Caryl), 6.92 (d, J=14.3Hz, 1H; H-CH
7
4
2
À1
134, 1066, 1039, 1025, 859, 831, 790, 780, 738, 706, 662, 643 cm ; HR-
MS (ESI, Dm=0.005): m/z: calcd for C41
H
39ClN
2
O
H
2
: 591.301, found:
·2CDCl
3
+
5
91.301 [M ]; elemental analysis calcd (%) for C41
39ClN
2
O
2
H-C5’), 7.97–8.04 (m, 1H; H-Caryl), 8.22–8.31 (m, 2H; H-C10’’, Caryl),
.77 (d, J=4.5 Hz, 1H; H-C2’), 8.81–8.89 (m, 1H; H-Caryl), 10.88 ppm
(
868.0): C 59.50, H 4.99, N 3.23; found: C 59.54, H 4.87, N 3.13.
8
1
3
(
brs, 1H; OH); C NMR (75 MHz, CDCl
3
): d=6.70 (C11), 22.8 (C5),
An), 60.9 (C2), 70.2
CCDC-609365 contains the supplementary crystallographic data for com-
pound 17. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
2
3.1 (C7), 26.5 (C10), 32.0 (C4), 53.5 (C6), 55.8 (CH
2
(
(
C8), 71.2 (C9), 75.7 (C3), 102.4 (C5’), 118.2 (Caryl), 119.4 (C3’), 121.9
C7’), 124.4, 124.7, 124.8, 125.4, 126.0, 126.9, 127.6, 127.9, 129.3, 130.7,
1
31.1 (all Caryl), 131.3 (C10’’), 132.1 (C8’), 132.5, 133.1, 138.5, 142.9
9
-Chloromethyl-[(1,8-S;4,5-R)-1,2,3,4,5,6,7,8-octahydro-1,4:5,8-dimetha-
(
4Caryl), 145.7 (C2’), 158.8 ppm (C6’); IR (ATR): n˜ =2968, 1669, 1617,
noanthracene (20): A 250 mL round-bottomed flask with argon inlet was
charged with alcohol 42 (1.55 g, 6.45 mmol, 1.00 equiv) and dry toluene
1
1
6
5
591, 1525, 1509, 1463, 1446, 1396, 1353, 1331, 1282, 1228, 1146, 1098,
074, 1041, 1014, 981, 937, 924, 903, 892, 853, 830, 792, 746, 704, 661,
(
70 mL). The mixture was cooled to 08C and PCl
5
(2.70 g, 12.9 mmol,
À1
16 cm
; HR-MS (ESI, Dm=0.005): m/z: calcd for C H33ClN O :
34 2 2
2
.00 equiv) was added. After stirring at room temperature overnight, sa-
+
01.254, found: 501.255 [M ].
3
turated aqueous NaHCO (60 mL) was added at 08C, and the mixture
1
-N-(9-Anthrylmethyl)-9S-epi-quininium chloride (16): By following the
was stirred for 10 min. After separation of the phases, the aqueous layer
was extracted with toluene (20 mL). The combined organic phases were
washed with water (20 mL), dried over sodium sulfate, filtered, and con-
centrated under reduced pressure. The residue was purified by chroma-
tography on silica gel (n-hexane/dichloromethane 10:1) to give chloride
general procedure for the quaternisation of tertiary amines, 16 was ob-
tained from 9S-epi-quinine (811 mg, 2.50 mmol) using work-up A as a
yellow solid (897 mg, 66%); recrystallized from acetone. M.p. > 1458C
[
25]
2
0
1
(
decomp); [a] =À63.5 (c=1.00 in chloroform); H NMR (300 MHz,
D
[
D
6
]DMSO): d=1.09–1.14 (m, 1H; H-C7), 1.78–1.84 (m, 3H; H-C5, C4,
f
20 as a colourless solid (1.52 g, 91%). R =0.81 (dichloromethane/n-
2
0
C7), 2.08–2.11 (m, 1H; H-C5), 2.32–2.35 (m, 1H; H-C3), 2.92–2.98 (m,
hexane 1:2); m.p. 111–1128C; [a] =95.7 (c=1.01 in chloroform);
D
1
1H; H-C6), 3.14–3.22 (m, 1H; H-C2), 3.81–3.88 (m, 1H; H-C2), 4.01 (s,
3H; OCH ), 4.68–4.76 (m, 1H; H-C6), 4.96–5.03 (m, 2H; H-C11), 5.33–
5.39 (m, 1H; H-C8), 5.64–5.75 (ddd, J=6.6, 10.5, 17.2 Hz, 1H; H-C10),
5.86–5.91 (d, J=14.4 Hz, 1H; H-CH An), 6.23–6.28 (m, 1H; H-C9),
6.98–7.02 (d, J=14.4 Hz, 1H; H-CH An), 7.48–7.52 (dd, J=2.6, 9.2 Hz,
1H; H-Caryl), 7.59–7.67 (m, 2H; H-C7’, Caryl), 7.74–7.79 (m, 2H; H-
3
H NMR (300 MHz, CDCl ): d=1.10–1.12 (m, 4H; H-C2, C3, C6, C7),
3
1.45–1.48 (m, 2H; H-C11, C12), 1.68–1.71 (m, 2H; H-C11, C12), 1.84–
1.86 (m, 4H; H-C2, C3, C6, C7), 3.27 (brs, 2H; H-C4, H-C5), 3.50 (brs,
2
2H; H-C1, C8), 4.61–4.73(q, 2H; H-CH
2
Ph), 6.93ppm (s, 1H; H-Caryl);
): d=26.6 (C2, C7), 27.2 (C3, C6), 41.2 (C1,
Ph), 44.0 (C4, C5), 49.1 (C11, C12), 111.1 (C10), 122.3
1
3
2
C NMR (75 MHz, CDCl
C8), 41.2 (CH
3
2
Caryl), 7.86–7.88 (d, J=5.3Hz, 1H; OH), 7.92–7.94 (d, J=4.5 Hz, 1H;
H-C3’), 8.02–8.07 (m, 2H; H-C5’, Caryl), 8.22–8.25 (m, 2H; H-C8’,
(C9), 144.2 (C4a, C10a), 145.8 ppm (C8a, C9a); IR (KBr pellet): n˜ =2965,
2916, 2862, 1443, 1328, 1268, 1104, 942, 863, 689, 625 cm ; GC-MS (capil-
À1
1
3
Caryl), 8.86–8.95 ppm (m, 4H; H-C2’, Caryl); C NMR (75 MHz,
]DMSO): d=25.2 (C5), 25.9 (C4), 26.1 (C7), 37.5 (C3), 49.7 (C6), 60.0
OCH ), 59.3(CH An), 59.7 (C2), 70.2 (C8), 71.2 (C9), 104.1 (C5’), 117.6
C11), 120.8 (Caryl), 121.8 (C3’), 125.6, 125.9, 126.1, 126.2, 126.3, 128.1,
28.5, 128.7, 130.4, 130.5, 131.9, 132.0, 132.3, 132.7, 133.9, 134.2 (all
Caryl), 137.9 (C10), 145.3, 145.7, 148.6 (3Caryl), 158.6 ppm (C6’); IR
lary column HP-5MS 0.25 mm”30 m, cross-linked 5% PH ME siloxane
À1
À1
[
D
6
0.25 mm; helium, 1 mLmin ; 1008C, 5 min, 208Cmin , 2008C, 15 min,
À1
(
(
3
2
208Cmin , 2808C, 10 min) t
R
=13.79 min, m/z: 258, 230, 202, 178, 167,
152; elemental analysis calcd (%) for C17
found: C 79.02, H 7.35.
H19Cl (258.8): C 78.90, H 7.40;
1
9
-Chloromethyl-[(1,8-R;4,5-S)-1,2,3,4,5,6,7,8-octahydro-1,4:5,8-dimetha-
(
1
ATR): n˜ =3051, 2954, 1722, 1619, 1588, 1506, 1474, 1446, 1359, 1257,
noanthracene (ent-20): Compound ent-20 was synthesized from the alco-
hol ent-42 in the same manner as chloride 20 and was obtained as a col-
ourless solid (747 mg, 87%). The analytical data of the chloride ent-20
À1
223, 1126, 1026, 873, 745, 717cm ; HR-MS (ESI, Dm=0.005): m/z:
+
calcd for C35
calcd (%) for C35
C 73.58, H 6.61, N 4.41.
H
35
N
2
O
2
: 515.2698, found: 515.270 [M ]; elemental analysis
H
35ClN
2
O
2
·H O (569.1): C 73.86, H 6.55, N 4.92; found:
2
20
were identical to those of chloride 20, except for: [a]D =À95.0 (c=1.01
in chloroform); HR-MS (ESI, Dm=0.005): m/z: calcd for C17H19Cl:
+
CCDC-609364 contains the supplementary crystallographic data for com-
pound 16. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
258.1175; found: 258.118
19Cl (258.8): C 78.90, H 7.40; found: C 78.94, H 7.39.
-N-[9-((1,8-S;4,5-R)-1,2,3,4,5,6,7,8-octahydro-1,4:5,8-
dimethanoanthracenyl)methyl]quininium chloride (22): By following the
A
H
R
U
G
17
C H
1
AHCTREUNG
1
(
-N-(9-Anthrylmethyl)-9-O-benzyl-6’-hydroxycinchonidinium
17): By following the general procedure for the quaternisation of terti-
ary amines, 17 was obtained from 9-O-benzyl-6’-hydroxychinchonidine
chloride
general procedure for the quaternisation of tertiary amines, 22 was ob-
tained from 2 (649 mg, 2.00 mmol) and 20 using work-up A as a colour-
less solid (417 mg, 36%); recrystallized from acetone. M.p. > 2018C
(decomp); [a]D =À141 (c=0.98 in methanol); H NMR (300 MHz,
[
23]
20
1
(
18)
(1.00 g, 2.50 mmol) using work-up B as a yellow solid (713mg,
Chem. Eur. J. 2007, 13, 4483– 4498
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4493

A. Berkessel et al.
[
D
6
]DMSO): d=0.86–1.24 (m, 4H; H-
C7’’), 2.35–2.43 (m, 1H; H-C7), 2.68–2.77 (m, 1H; H-C3), 3.02–3.12 (m,
1H; H-C6), 3.39 (brs, 2H; H-C4’’, C5’’), 3.50–3.80 (m, 3H; H-C2, C1’’,
C2’’, C3’’, C6’’, C7’’), 1.42–1.61 (m,
5
6
2
2
1
3
H; H-C7, C11’’, C12’’), 1.88–1.98 (m,
H; H-C5, C4, C2’’, C3’’, C6’’, C7’’),
.15–2.23(m, 2H; H-C7, C5), 2.7–3
.77 (m, 1H; H-C3), 3.20–3.22 (m,
H; H-C2), 3.48–3.55 (m, 1H; H-C2),
.81–4.03 (m, 5H; H-C6, C1’’, C8’’,
3
C8’’), 3.94–4.01 (m, 1H; H-C6), 4.11 (s, 3H; OCH ), 4.14–4.21 (m, 1H;
H-C8), 4.40–4.46 (m, 1H; H-C2), 4.78 (d, J=12.9 Hz, 1H; H-CH Ph),
2
5.11–5.27 (m, 3H; H-CH Ph, C11), 6.02–6.14 (ddd, J=6.9, J=10.5, J=
2
17.2 Hz, 1H; H-C10), 6.61 (s, 1H; H-C9), 7.23(s, 1H; H-C10 ’’), 7.39–7.40
(d, J=3.6 Hz, 1H; OH), 7.47–7.54 (m, 2H; H-C5’, C7’), 7.80–7.82 (d, J=
4.5 Hz, 1H; H-C3’), 8.00–8.03(d, J=9.0 Hz, 1H; H-C8’), 8.81–8.82 ppm
1
3
C4’’, C5’’), 4.04 (s, 3H; OCH
.34 (m, 2H; H-C8, H-C6), 4.40–4.44
d, J=12.9 Hz, 1H; H-CH Ph), 5.00–
.09 (m, 2H; H-C11), 5.65–5.70 (d, J=
2.6 Hz, 1H; H-CH Ph), 5.74–5.86
3
), 4.29–
(d, J=4.5 Hz, 1H; H-C2’); C NMR (75 MHz, [D ]DMSO): d=21.8
6
4
(
5
1
(C7), 24.2 (C5), 26.9 (C4), 27.4 (C3’’, C6’’), 27.9 (C2’’, C7’’), 37.8 (C3),
43.4 (C1’’, C8’’), 44.8 (C4’’, C5’’), 48.6 (C11’’ or C12’’), 50.7 (C11’’ or
2
C12’’), 54.9 (C2), 56.3(OCH 3), 57.0 (C6), 59.6 (CH Ph), 65.9 (C9), 67.5
2
2
(C8), 103.4 (C5’), 115.1 (Caryl), 117.3(C10 ’’), 117.8 (C11), 121.2 (C3’),
(
7
7
ddd, J=7.1, J=10.3, J=17.1 Hz, 1H; H-C10), 6.67–6.69 (m, 1H; H-C9),
122.4 (C7’), 126.3(Caryl), 1 32 .1 (C8 ’), 138.2 (C10), 144.6, 144.6 (2Caryl),
146.2 (2Caryl), 148.2 (2Caryl), 148.3(C2 ’), 158.2 ppm (C6’); IR (CsI
pellet): n˜ =3320, 3175, 2964, 2870, 1623, 1509, 1474, 1432, 1332, 1243,
.22–7.48 (m, 4H; H-Caryl, OH), 7.82–7.83(d, J=4.5 Hz, 1H; H-Caryl),
.99–8.02 (d, J=9.0 Hz, 1H; H-C8’), 8.81–8.83ppm (d, J=4.5 Hz, 1H;
1
3
À1
H-C2’); C NMR (75 MHz, [D
6
]DMSO): d=20.5 (C7), 24.3(C5), 25.9
C4), 26.0 (C2’’, C7’’), 26.8 (C3’’, C6’’), 37.3 (C5), 41.1 (C1’’, C8’’), 43.1
C4’’, C5’’), 47.6 (C11’’ or C12’’), 50.1 (C11’’ or C12’’), 51.3(C6), 55.2
OCH ), 58.6 (C2), 59.7 (CH Ph), 63.2 (C9), 68.7 (C8), 101.9 (C5’), 114.1,
16.4 (2Caryl), 116.6 (C11), 120.4, 122.0, 125.2, 131.1 (4Caryl), 137.3
1227, 1113, 1029, 1004, 935, 870, 827 cm ; HR-MS (ESI, Dm=0.005): m/
+
(
(
(
z: calcd for C H N O : 547.3325, found: 547.332 [M ]; elemental analy-
3
7
43
2
2
sis calcd (%) for C H ClN O ·H O (601.2): C 73.92, H 7.54, N 4.66;
3
7
43
2
2
2
3
2
found: C 73.75, H 7.47, N 4.58.
1
CCDC-609368 contains the supplementary crystallographic data for com-
pound 24. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
(
(
1
C10), 143.6, 144.4, 147.4 (3Caryl), 147.7 (4Caryl), 157.0 ppm (C6’); IR
ATR): n˜ =3076, 2957, 2866, 1620, 1589, 1506, 1471, 1456, 1429, 1330,
À1
254, 1238, 1224, 1179, 1111, 1027, 907, 860, 825, 730, 696 cm ; HR-MS
(
ESI, Dm=0.005): m/z: calcd for C37
H
43
N
2
O
2
: 547.3325, found: 547.332
·H O (601.2): C
1
-N-[9-((1,8-R;4,5-S)-1,2,3,4,5,6,7,8-octahydro-1,4:5,8-dimethanoanthra-
cenyl)methyl]quinidinium chloride (25): By following the general proce-
dure for the quaternisation of tertiary amines, 25 was obtained from 3
+
[
M
]; elemental analysis calcd (%) for C37
H
43ClN
2
O
2
2
A
H
R
U
G
ACHTREUNG
7
3.92, H 7.54, N 4.66 found: C 73.96, H 7.55, N 4.62.
CCDC-609366 contains the supplementary crystallographic data for com-
pound 22. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
(
(
811 mg, 2.50 mmol) and ent-20 using work-up A as a colourless solid
574 mg, 39%); recrystallized from methanol. M.p. > 2018C (decomp);
20
1
[
a]D =126 (c=0.89 in methanol); H NMR (300 MHz, [D
6
]DMSO): d=
1
.03–1.12 (m, 5H; H-C7, C2’’, C3’’, C6’’, C7’’), 1.55–1.93(m, 11H; H-
1
-N-[9-((1,8-R;4,5-S)-1,2,3,4,5,6,7,8-octahydro-1,4:5,8-dimethanoanthra-
cenyl)methyl]quininium chloride (23): By following the general proce-
dure for the quaternisation of tertiary amines, 23 was obtained from 2
C11’’, C12’’, C2’’, C3’’, C6’’, C7’’, C7, C4), 2.39–2.47 (m, 1H; H-C5), 2.71–
2.79 (m, 1H; H-C3), 3.12–3.22 (m, 1H; H-C6), 3.36–3.38 (m, 2H; H-C5’’,
C4’’), 3.44–3.51 (m, 1H; H-C2), 3.84 (brs, 2H; H-C1’’, C8’’), 4.12–4.18
A
C
H
T
R
E
U
N
G
ACHTREUNG
(
(
462 mg, 1.42 mmol) and ent-20 using work-up A as a colourless solid
332 mg, 40%); recrystallized from acetone. M.p. > 2058C (decomp);
(m, 5H; H-C6, OCH , C8), 4.27–4.33 (m, 1H; H-C2), 4.53–4.57 (d, J=
3
12.0 Hz, 1H; H-CH Ph), 5.18–5.35 (m, 3H; H-CH Ph, C11), 6.10–6.18
2
2
2
0
1
[
1
a] =À268 (c=0.97 in methanol); H NMR (300 MHz, [D
6
]DMSO): d=
(ddd, 1H; H-C10), 6.64–6.65 (m, 1H; OH), 7.22 (s, 1H; H-C10’’), 7.41–
7.48 (m, 3H; H-C9, C5’, C7’), 7.79–7.80 (d, J=4.5 Hz, 1H; H-C3’), 7.99–
8.01 (d, J=9.3Hz, 1H; H-C8 ’), 8.81–8.82 ppm (d, J=4.5 Hz, 1H; H-
D
.07–1.10 (m, 4H; H-C2’’, C3’’, C6’’, C7’’), 1.35–1.88 (m, 9H; H-C2’’, C3’’,
C6’’, C7’’, C7, C4, C5), 2.00–2.01 (m, 1H; H-C3), 2.21–2.23 (m, 2H; H-
C11’’, C12’’), 2.70–2.77 (m, 1H; H-C6), 3.29–3.33 (m, 4H; H-C1’’, C8’’,
C4’’, C5’’), 3.58–3.63 (m, 2H; H-C11’’, C12’’), 3.77–3.86 (m, 2H; H-C2),
1
3
C2’); C NMR (75 MHz, [D ]DMSO): d=21.6 (C7), 24.6 (C5), 26.9 (C4),
6
27.4 (C3’’, C6’’), 27.9 (C2’’, C7’’), 37.7 (C3), 43.2 (C1’’, C8’’), 44.5 (C4’’,
4
.02 (s, 3H; H-OCH
3
), 4.21–4.28 (m, 1H; H-C6), 4.48–4.56 (m, 1H; H-
Ph), 5.00–5.10 (m, 2H; H-C11),
Ph), 5.73–5.84 (ddd, J=7.1, 10.3,
7.1 Hz, 1H; H-C10), 6.66–6.67 (m, 1H; H-C9), 7.11–7.27 (m, 2H; H-
C5’’), 48.6 (C11’’ or C12’’), 50.9 (C11’’ or C12’’), 55.4 (C2), 55.0 (C6), 56.1
(OCH ), 60.2 (CH Ph), 65.1 (C9), 68.2 (C8), 102.6 (C5’), 115.1 (Caryl),
117.4 (C10’’), 117.8 (C11), 121.1 (C3’), 122.9 (C7’), 126.2 (Caryl), 132.1
(C8’), 138.5 (C10), 144.6, 144.8 (2Caryl), 146.5 (2Caryl), 148.3 (C2’),
148.3(2Caryl), 158.1 ppm (C6 ’); IR (CsI pellet): n˜ =3420, 3134, 2960,
C8), 4.63–4.68 (d, J=12.9 Hz, 1H; H-CH
2
3
2
5
1
.36–5.40 (d, J=12.9 Hz, 1H; H-CH
2
C10’’, OH), 7.48–7.50 (m, 2H; H-Caryl), 7.80–7.81 (d, J=4.5 Hz, 1H; H-
Caryl), 8.00–8.03(d, J=9.6 Hz, 1H; H-C8’), 8.81–8.83ppm (d, J=4.5 Hz,
2868, 1622, 1593, 1508, 1474, 1458, 1432, 1241, 1112, 1028, 932, 862, 824,
1
3
À1
1H; H-C2’); C NMR (75 MHz, [D
25.6 (C2’’, C7’’), 25.6 (C4), 26.8 (C3’’, C6’’), 37.3 (C3), 41.1 (C1’’, C8’’),
43.1 (C4’’, C5’’), 45.2 (C11’’ or C12’’), 47.0 (C11’’ or C12’’), 50.5 (CH Ph),
55.2 (OCH ), 59.4 (C6), 59.6 (C2), 63.7 (C9), 68.1 (C8), 102.7 (C5’), 114.2
6
]DMSO): d=20.5 (C7), 24.3(C5),
7
5
19 cm
;
HR-MS (ESI, Dm=0.005): m/z: calcd for
C
37
H
43
N
2
O
2
:
+
47.3325, found: 547.332 [M ]; elemental analysis calcd (%) for
·MeOH (615.2): C 74.18, H 7.70, N 4.55; found: C 74.63, H
2
37 2 2
C H43ClN O
3
7
.58, N 4.66.
-N-((R)-Methyl-2-[1,1’]-binaphthyl)quinidinium bromide (26):
00 mL round-bottomed flask was charged with (S)-2-methyl-[1,1’]-bi-
(25 mL). N-
Bromosuccinimide (1.29 g, 6.70 mmol, 1.20 equiv) and AIBN (64.0 mg,
50 mmol, 0.07 equiv) were added to the solution. The reaction was stir-
(
1
Caryl), 114.3(C11), 116.4 (C10 ’’), 120.3, 121.5, 125.2, 131.2 (4Caryl),
37.2 (C10), 143.6, 144.2, 146.8 (3Caryl), 147.3 (Caryl), 157.0 ppm (C6’);
1
1
A
IR (ATR): n˜ =3085, 2954, 2860, 1619, 1589, 1507, 1470, 1430, 1330, 1238,
naphthalene (ent-43; 1.50 g, 5.59 mmol, 1.00 equiv) and CCl
4
À1
1
224, 1110, 1026, 912, 860, 826, 730, 697 cm ; HR-MS (ESI, Dm=0.005):
+
m/z: calcd for C37
43 2 2
H N O : 547.3325, found: 547.332 [M ].
3
CCDC-609367 contains the supplementary crystallographic data for com-
pound 23. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
red and heated to reflux for one hour. After cooling to 08C, the precipi-
tates were filtered off and the filtrate was concentrated under reduced
pressure to give the bromide 21. The latter was used directly for the sub-
sequent reaction without any purification. The crude bromide was dis-
solved in dry tetrahydrofuran (25 mL), quinidine (3, 1.06 g, 3.26 mmol,
1.00 equiv) was added, and the reaction was stirred and heated under
reflux under argon atmosphere overnight. After cooling to room temper-
ature, the solids were collected, washed with tetrahydrofuran and recrys-
1
-N-[9-((1,8-S;4,5-R)-1,2,3,4,5,6,7,8-octahydro-1,4:5,8-dimethanoanthra-
cenyl)methyl]quinidinium chloride (24): By following the general proce-
dure for the quaternisation of tertiary amines, 24 was obtained from 3
A
C
H
T
R
E
U
N
G
ACHTREUNG
(
(
413mg, 1.27 mmol) and 20 using work-up A as a colourless solid
349 mg, 47%); recrystallized from acetone. R =0.26 (ethyl acetate/
tallized from dichloromethane to give the ammonium salt 26 as a colour-
f
2
0
20
methanol 8:2); m.p. > 2028C (decomp); [a] =286 (c=0.68 in metha-
nol); H NMR (300 MHz, [D
less solid (1.22 g, 32%). M.p. > 1928C (decomp); [a] =249 (c=1.00 in
D
D
1
1
6
]DMSO): d=1.02–1.13(m, 5H; H-C7, C2 ’’,
methanol); H NMR (300 MHz, [D
6
]DMSO): d=0.71–0.89 (m, 1H; H-
C3’’, C6’’, C7’’), 1.54–1.91 (m, 11H; H-C11’’, C12’’, C5, C4, C2’’, C3’’, C6’’,
C7), 1.60–1.79 (m, 3H; H-C5, C4), 1.89–1.97 (m, 1H; H-C7), 2.21–2.29
4494
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 4483– 4498

Enantioselective Epoxidation
FULL PAPER
(
m, 1H; H-C3), 2.76–2.83 (m, 1H; H-C2), 2.99–3.07 (m, 1H; H-C2),
C10), 6.23(d, J=13.2 Hz, 1H; H-CH
2
An), 6.39 (d, J=13.2 Hz, 1H; H-
3
4
4
6
.37–3.41 (m, 1H; H-C6), 3.75–3.81 (m, 1H; H-C8), 3.95 (s, 3H; OCH
.09–4.11 (m, 1H; H-C6), 4.18–4.24 (d, J=17.3Hz, 1H; H-C11), 4.75–
.81 (m, 2H; H-C11, H-CH Ph), 5.33–5.46 (m, 2H; H-C10, H-CH Ph),
.14 (s, 1H; OH), 6.29 (s, 1H; H-C9), 7.06–7.09 (d, J=8.5 Hz, 1H; H-
3
),
CH An), 6.63–6.81 (m, 2H; H-C9, H-C7’), 6.89–7.01 (m, 1H; H-Caryl),
2
7.01–7.14 (m, 1H; H-Caryl), 7.20–7.33 (m, 1H; H-Caryl), 7.35–7.52 (m,
3H; H-Caryl, OH), 7.53 (d, J=9.1 Hz, 1H; H-C8’), 7.58–7.67 (m, 1H; H-
Caryl), 7.87–7.93(d, J=4.5 Hz, 1H; H-C3’), 7.93–8.03 (s, 1H; H-C10’’),
8.06–8.23(m, 2H; H-C5 ’, Caryl), 8.72 (d, J=4.5 Hz, 1H; H-C2’), 9.07 (d,
2
2
Caryl), 7.21–7.24 (d, J=8.5 Hz, 1H; H-Caryl), 7.29–7.39 (m, 3H; H-C5’,
H-Caryl), 7.45–7.54 (m, 3H; H-C3’, Caryl), 7.60–7.65 (m, 1H; H-Caryl),
1
3
J=9.1 Hz, 1H; H-C8’), 9.17 ppm (brs, 1H; OH); C NMR (75.5 MHz,
CDCl ): d=22.0 (C7), 24.1 (C5), 26.9 (C4), 37.9 (C3), 54.0 (CH An), 54.4
7
8
8
.69–7.77 (m, 2H; H-Caryl), 7.96–7.99 (d, J=9.1 Hz, 1H; H-Caryl), 8.07–
.19 (m, 4H; H-Caryl), 8.26–8.29 (d, J=8.5 Hz, 1H; H-C8’), 8.72–
.73ppm (d, J=4.4 Hz, 1H; H-C2’); C NMR (75 MHz, [D
3
2
(C2), 58.1 (C6), 66.7 (C8), 67.2 (C9), 103.3 (C5’), 116.7 (C11), 117.6
(Caryl), 119.5 (C3’), 120.6 (C7’), 123.7, 124.4, 124.5, 124.9, 126.2, 127.5,
127.8, 128.5, 128.6, 129.8, 130.3 (all Caryl), 130.7 (C8’), 131.3 (C10’’),
132.3, 132.6 (2Caryl), 135.1 (C10), 141.7, 141.8 (2Caryl), 146.4 (C2’),
156.1 ppm (C6’); IR (ATR): n˜ =3161, 1617, 1526, 1464, 1447, 1398, 1237,
1
3
6
]DMSO):
),
6.2 (C6), 60.3(CBn), 64.9 (C9), 66.4 (C8), 102.2 (C5 ’), 115.6 (C11),
d=20.6 (C7), 23.0 (C5), 25.4 (C4), 35.9 (C3), 54.2 (C2), 55.5 (OCH
3
5
1
1
1
20.3, 121.1, 124.6 (3Caryl), 125.2 (s, Caryl), 125.9, 125.9, 126.1, 126.5,
26.8, 126.9, 127.3, 128.0, 128.2, 128.6, 128.8, 129.3, 131.2, 131.3, 132.1,
32.5, 133.1, 133.3, 133.7 (all Caryl), 136. 2 (C10), 141.7, 143.1, 143.5
À1
1223, 1131, 998, 924, 854, 792, 737, 707, 618 cm ; HR-MS (ESI, Dm=
+
0.005): m/z: calcd for C H ClN O : 501.154, found: 501.155 [M ]; ele-
3
4
33
2
2
(
3Caryl), 147.1 (C2’), 157.2 ppm (C6’); IR (CsI pellet): n˜ =3253, 3069,
34 33 2 2 2
mental analysis calcd (%) for C H ClN O ·H O (555.11): C 73.56, H
2
1
0
976, 2933, 2876, 1621, 1605, 1508, 1460, 1435, 1346, 1242, 1227, 1126,
6.36, N 5.05; found: C 73.41, H 6.15, N 5.00.
À1
064, 1024, 935, 916, 873, 842, 806, 789, 763 cm ; HR-MS (ESI, Dm=
1
-N-(9-Anthrylmethyl)-6’-isopropoxycinchoninium chloride (32): By fol-
+
.005): m/z: calcd for C41
H
39
N
2
O
2
: 591.3011, found: 591.301 [M ]; ele-
lowing the general procedure for the quaternisation of tertiary amines, 32
was obtained from 6’-isopropoxycinchonine (34) (200 mg, 567 mmol)
mental analysis calcd (%) for C41
2 2 2
H39BrN O ·H O (691.7): C 71.40, H
5
.99, N 4.06 found: C 71.90, H 6.01, N 4.03.
f
using work-up B as a yellow solid (219 mg, 67%). R =0.16 (chloroform/
2
0
CCDC-609369 contains the supplementary crystallographic data for com-
pound 26. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
methanol 9:1); m.p. >1658C (decomp); [a] =368 (c=0.30 in methanol);
D
1
H NMR (300 MHz, CDCl ): d=0.89–1.04 (m, 1H; H-C5), 1.14–1.30 (m,
3
1H; H-C7), 1.33 (d, J=6.0 Hz, 3H; H-C13), 1.39 (d, J=6.0 Hz, 3H; H-
C13), 1.56–1.64 (m, 1H; H-C4), 1.64–1.78 (m, 1H; H-C7), 1.78–1.92 (m,
1H; H-C3), 2.10–2.24 (m, 1H; H-C6), 2.25–2.39 (m, 1H; H-C5), 2.75–
2.88 (m, 1H; H-C2), 3.92–4.08 (m, 1H; H-C6), 4.43–4.63 (m, 2H; H-C2,
C8), 4.66–480 (sep, J=6.0 Hz, 1H; H-C12), 4.89–5.07 (m, 2H; H-C11),
1
-N-((S)-Methyl-2-[1,1’]-binaphthyl)quinidinium bromide (27): This com-
pound was synthesized in the same manner as described for 26, starting
from (R)-2-methyl-[1,1’]-binaphthalene (43). In the case of 27, after the
reaction with 3, the solvents were removed under reduced pressure. The
2
5.63–5.80 (m, 1H; H-C10), 6.41–6.58 (m, 2H; H-CH An), 6.93–7.06 (m,
crude material was dissolved in CH
2
Cl
2
(5 mL) and added dropwise to di-
1H; H-C9), 7.19–7.27 (m, 2H; H-Caryl), 7.27–7.34 (m, 1H; H-Caryl),
7.37–7.45 (m, 2H; H-Caryl), 7.59–7.64 (m, 1H; H-Caryl), 7.66–7.75 (m,
1H; H-Caryl), 7.90–7.96 (m, 1H; H-Caryl), 7.99–8.03(m, 1H; H-Caryl),
8.04–8.13(m, 2H; H-Caryl), 8.17–8.28 (m, 1H; H-Caryl), 8.5 3– 8.60 (m,
ethyl ether (80 mL). The resulting precipitates were filtered off and
washed with diethyl ether. The remaining solid was purified by chroma-
tography on silica gel (ethyl acetate/methanol 8:2). Recrystallization
from acetone resulted in the salt 27 as a colourless solid (187 mg, 7%).
1H; H-Caryl), 8.77–8.89 ppm (m, 1H; H-Caryl); the OH proton could
2
0
1
13
M.p. > 1758C (decomp); [a] =155 (c=1.06 in methanol); H NMR
not be detected; C NMR (75.5 MHz, CDCl
3
): d=22.2 (C13), 22.3
An), 54.7
D
(
300 MHz, [D
6
]DMSO): d=0.78–0.85 (m, 1H; H-C7), 1.48–1.51 (m, 2H;
(C13), 22.3 (C5), 24.3 (C7), 26.3 (C4), 38.2 (C3), 54.7 (CH
2
H-C5), 1.73–1.74 (m, 1H; H-C4), 2.04–2.12 (m, 1H; H-C7), 2.56–2.61 (m,
(C2), 56.8 (C6), 69.0 (C8, C9), 70.6 (C12), 106.8, 117.6 (2Caryl), 118.0
(C11), 121.3, 121.7, 124.9 (3Caryl), 125.1 (Caryl), 125.4, 127.4, 127.5,
127.9, 128.8, 129.0, 130.5, 130.6 (all Caryl), 131.2 (2Caryl), 132.8, 133.0
(2Caryl), 133.5 (C10), 135.8, 143.2, 144.2, 156.0 ppm (4Caryl); IR (ATR):
n˜ =3152, 2972, 1669, 1616, 1505, 1505, 1457, 1372, 1310, 1275, 1238, 1200,
1
4
5
6
2
H; H-C3), 3.17–3.21 (m, 2H; H-C6), 3.72–3.90 (m, 3H; H-C2, H-C8),
.04 (s, 3H; OCH ), 4.97 (s, 2H; H-CH Ar), 5.10–5.23(m, 2H; H-C11),
3
2
.88–5.99 (ddd, J=6.9, 10.4, 17.3Hz, 1H; H-C10), 6.08 (s, 1H; H-C9),
.33 (s, 1H; OH), 7.03–7.06 (d, J=9.0 Hz, 1H; H-Caryl), 7.16–7.20 (d,
H; H-C5’, Caryl), 7.33–7.39 (m, 2H; H-Caryl), 7.44–7.65 (m, 4H; H-
À1
1108, 1048, 999, 966, 928, 866, 827, 792, 731, 699 cm ; HR-MS (ESI,
+
Caryl), 7.70–7.73(m, 2H; H-Caryl), 7.94–7.97 (d, J=9.0 Hz, 1H; H-
Caryl), 8.05–8.19 (m, 4H; H-Caryl), 8.26–8.29 (d, J=9.0 Hz, 1H; H-C8’),
Dm=0.005): m/z: calcd for C37
H
39ClN
2
O
2
: 543.301, found: 543.302 [M ].
6’-Isopropoxycinchonine (34): By following the general procedure for the
1
3
[22]
8
.71–8.73ppm (d, J=6.0 Hz, 1H; H-C2’);
]DMSO): d=20.7 (C7), 22.9 (C5), 25.7 (C4), 36.6 (C3), 54.2 (C2), 55.8
OCH ), 56.6 (C6), 60.8 (CH Ar), 64.9 (C9), 66.4 (C8), 102.2 (C5’), 116.6
C11), 120.2, 121.1, 124.3, 125.1, 125.2, 125.3, 126.0, 126.6, 126.7, 126.9,
C NMR (75 MHz,
alkylation of phenols, 34 was obtained from 6’-hydroxycinchonine (33)
[
D
6
(1.00 g, 3.24 mmol) as a colourless solid (993 mg, 87%). R =0.84 (chloro-
f
[
40]
20
(
(
3
2
form/methanol 9:1); m.p. 1668C (lit.:
1548C); [a]D =181 (c=0.30 in
1
chloroform); H NMR (300 MHz, CDCl
3
): d=1.00–1.15 (m, 1H; H-C7),
1
1
27.3, 128.1, 128.2, 128.7, 129.1, 129.5, 131.1, 131.2, 132.1, 133.7, 133.3,
33.5, 133.9 (all Caryl), 137.3 (C10), 141.5, 143.0, 143.4 (3Caryl), 147.1
1
1
2
.28, 1.30 (2”s, 6H; H-C13), 1.35–1.57 (m, 2H; H-C5), 1.63–1.76 (m,
H; H-C4), 1.92–2.08 (m, 1H; H-C7), 2.10–2.28 (m, 1H; H-C3), 2.62–
.72 (m, 1H; H-C6), 2.73–2.92 (m, 2H; H-C2, C6), 2.93–3.08 (m, 1H; H-
(
C2’), 157.2 ppm (C6’); IR (CsI pellet): n˜ =3410, 3061, 2750, 1735, 1621,
À1
1
605, 1511, 1473, 1354, 1242, 1138, 1024, 933, 833, 783, 719 cm ; HR-MS
C8), 3.22–3.42 (m, 1H; H-C2), 4.58 (sep, J=6.0 Hz, 1H; H-C12), 4.94–
5
7
(
ESI, Dm=0.005): m/z: calcd for C41H N O : 591.3011, found: 591.3011
39 2 2
.08 (m, 2H; H-C11), 5.54 (d, 1H; H-C9), 5.92–6.10 (m, 1H; H-C10),
.11–7.24 (m, 2H; C5’, C7’), 7.45 (d; J=2.6 Hz, 1H; H-C3’), 7.87 (d, J=
+
[
M ].
CCDC-609370 contains the supplementary crystallographic data for com-
pound 27. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
9.1 Hz 1H; H-C8’), 8.49 ppm (d, J=4.5 Hz, 1H; H-C2’); the OH proton
could not be detected; C NMR (75.5 MHz, CDCl ): d=21.1 (C7), 21.5
3
(C13), 22.0 (C13), 25.4 (C5), 28.2 (C4), 40.0 (C3), 49.6 (C2), 50.2 (C6),
59.7 (C8), 70.0 (C12), 71.9 (C9), 103.5 (C5’), 114.4 (C11), 118.4 (C3’),
1
3
1
1
22.5, 126.5 (2Caryl), 131.3 (C8’), 140.6 (C10), 143.8 (Caryl), 147.3 (C2’),
47.7 (Caryl), 155.7 ppm (C6’); IR (ATR): n˜ =3070, 2973, 2933, 2869,
1
-N-(9-Anthrylmethyl)-6’-hydroxycinchoninium chloride (31): By follow-
ing the general procedure for the quaternisation of tertiary amines, 31
was obtained from 6’-hydroxycinchonine (33)
using work-up A as a yellow solid (633 mg, 73%). R
[
22]
1712, 1635, 1617, 1588, 1505, 1455, 1383, 1371, 1326, 1300, 1238, 1222,
1
639 cm ; HR-MS (ESI, Dm=0.005): m/z: calcd for C H N O : 353.223,
found: 353.223 [M+H ].
(500 mg, 1.61 mmol)
=0.05 (chloroform/
197, 1134, 1110, 1048, 1019, 998, 968, 909, 860, 829, 798, 761, 731, 663,
f
À1
2
0
methanol 9:1); m.p. >1708C (decomp); [a] =352 (c=1.00 in methanol);
22 28
2
2
D
+
1
3
H NMR (300 MHz, CDCl ): d=0.60–0.80 (m, 1H; H-C7), 1.35–1.53 (m,
1
1
1
4
H; H-C5), 1.55–1.64 (m, 1H; H-C4), 1.61–1.78 (m, 2H; H-C3, C5),
.90–2.07 (m, 1H; H-C7), 2.30–2.45 (m, 2H, H-C2, C6), 3.90–4.10 (m,
H; H-C6), 4.24–4.39 (m, 1H; H-C2), 4.39–4.55 (m, 1H; H-C8), 4.78–
.92 (m, 1H; H-C11), 4.96–5.09 (m, 1H; H-C11), 5.45–5.68 (m, 1H; H-
1-N-(9-Anthrylmethyl)-6’-isopropoxy-10,11-dihydrocinchonidinium chlo-
ride (35): By following the general procedure for the quaternisation of
tertiary amines, 35 was obtained from 6’-isopropoxy-10,11-dihydrocincho-
nidine (41) (500 mg, 1.41 mmol) using work-up B as a yellow solid
Chem. Eur. J. 2007, 13, 4483– 4498
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4495

A. Berkessel et al.
(
(
545 mg, 66%). R
f
=0.20 (chloroform/methanol 9:1); m.p.
>
1508C
(brm, 3H; H-Caryl, OH), 8.49–8.58 (m, 1H; H-Caryl), 8.70–8.82 ppm
2
0
1
13
decomp); [a] =À409 (c=1.00 in methanol); H NMR (300 MHz,
(m, 1H; H-Caryl); C NMR (75.5 MHz, CDCl
3
): d=11.1 (C11), 22.0
D
CDCl
3
): d=0.42 (t, J=7.2 Hz, 3H; H-C11), 0.92–1.12 (m, 2H; H-C10),
(C7), 22.1 (C13), 22.4 (C13), 23.9 (C4), 24.3 (C10), 24.8 (C5), 36.2 (C3),
54.6 (CH An), 56.8 (C2), 56.9 (C6), 69.1 (C8), 69.5 (br; C9), 70.6 (C12),
1
2
1
.13–1.44 (m, 9H; H-C7, C3, C5, C13), 1.67–1.78 (m, 1H; H-C4), 2.02–
.27 (m, 2H; H-C5, C7), 2.29–2.59 (m, 2H; H-C2, OH), 2.68–2.84 (m,
H; H-C6), 2.85–2.98 (m, 1H; H-C2), 4.08–4.22 (m, 1H; H-C8), 4.81
2
106.7, 118.1, 121.2, 121.5, 124.9, 125.0, 125.2, 125.3, 127.4, 127.5, 127.7,
128.8, 129.0 (all Caryl), 130.6 (2Caryl), 131.2, 131.6, 132.7, 133.0, 143.1,
144.4, 147.4 (all Caryl), 155.94 ppm (C6’); IR (ATR): n˜ =3062, 2968,
1706, 1670, 1616, 1588, 1457, 1382, 1238, 1222, 1200, 1109, 1047, 966, 929,
(
1
sep, J=6.0 Hz, 1H; H-C12), 4.93–5.10 (m, 1H; H-C6), 5.84 (d, J=
3.7 Hz, 1H; H-CH An), 6.84 (d, J=13.7 Hz, 1H; H-CH An), 6.95 (d,
J=6.0 Hz, 1H; H-C9), 7.28 (dd, J=2.5, 9.2 Hz, 1H; H-C7’), 7.33–7.42
m, 2H; H-Caryl), 7.44–7.54 (m, 1H; H-Caryl), 7.58–7.67 (m, 1H; H-
Caryl), 7.73(d, J=2.3Hz, 1H; H-C5 ’), 7.75–7.84 (m, 1H; H-Caryl), 7.85–
2
2
À1
895, 866, 828, 732, 700, 618 cm ; HR-MS (ESI, Dm=0.005): m/z: calcd
+
(
for C37
calcd (%) for C37
C 74.12, H 7.68, N 4.39.
’-Isopropoxy-10,11-dihydrocinchonine (39): By following the general
procedure for the alkylation of phenols, 39 was obtained from 6’-hy-
H
41ClN
2
O
2
: 545.617, found: 545.316 [M ]; elemental analysis
H
2 2 2
41ClN O ·H O (581.2): C 74.16, H 7.23, N 4.68; found:
7
2
1
(
(
(
1
1
3
1
6
5
.93(m, 2H; H-C3 ’, Caryl), 7.96 (d, J=9.2 Hz, 1H; H-C8’), 7.75–7.84 (m,
H; H-Caryl), 8.52 (d, J=4.5 Hz, 1H; H-C2’), 9.09 ppm (d, J=9.1 Hz,
6
1
3
3
H; H-Caryl); C NMR (75.5 MHz, CDCl ): d=11.0 (C11), 21.8, 25.8
C7, C5), 22.1 (2”C13), 23.3 (C4), 26.3 (C10), 36.5 (C3), 52.7 (C6), 57.1
CH An), 6 3. 3(C2), 65.7 (C9), 70.7 (C12), 71.3(C8), 105.5 (C5 ’), 118.0
Caryl), 120.1 (C3’), 121.2 (C7’), 123.6, 125.0, 125.7, 125.9, 126.5, 127.7,
[22]
droxy-10,11-dihydrocinchonine (33)
(755 mg, 2.03mmol) as a colour-
2
less solid (720 mg, 84%). =0.56 (chloroform/methanol 9:1); m.p.
R
f
[41]
20
D
[41]
30
1
(
778C (lit.: 1818C); [a] =188 (c=2.00 in ethanol) (lit.: [a]D =206
c=2.00 in ethanol); H NMR (300 MHz, CDCl
28.5, 128.8, 129.9, 130.8, 131.1, 131.9 (all Caryl), 132.0 (C8’), 132.8,
33.2, 143.5, 144.0 (4Caryl), 147.6 (C2’), 156.2 ppm (C6’); IR (ATR): n˜ =
1
3
): d=0.83(t, J=6.9 Hz,
3
1
1
3
5
2
1
H; H-C11), 0.97–1.09 (m, 1H; H-C7), 1.17–1.32 (m, 6H; H-C13), 1.32–
.53 (m, 5H; H-C3, C5, C10), 1.63–1.71 (m, 1H; H-C4), 1.88–2.01 (m,
H; H-C7), 2.59–2.93(m, 3H ; H-C2, C6), 2.94– .30 6 (m, 1H; H-C8),
.06–3.20 (m, 1H; H-C6), 4.56 (sep, J=6.0 Hz, 1H; H-C12), 5.63(d, J=
.6 Hz, 1H; H-C9), 7.19 (dd, J=2.4, 7.6 Hz, 1H; H-C7’), 7.24 (d, J=
.6 Hz, 1H; H-C5’), 7.49 (d, J=4.4 Hz, 1H; H-C3’), 7.90 (d, J=9.1 Hz,
H; H-C8’), 8.57 ppm (d, J=4.5 Hz, 1H; H-C2’); the OH proton could
050, 2961 (CH
3
), 1616 (CÀC), 1588, 1505, 1457 (CH
3
), 1382, 1329, 1259,
237 (CÀO), 1221 (CÀO), 1197, 1109, 1047, 966, 897, 860, 824, 793, 730,
À1
99, 621 cm ; HR-MS (ESI, Dm=0.005): m/z: calcd for C37
H
41ClN
2
O
2
:
+
45.317, found: 345.316 [M ]; elemental analysis calcd (%) for
1
37 2 2 2 2
C H41ClN O · = H O (590.2): C 75.30, H 7.17, N 4.75; found: C 74.83, H
6
.97, N 4.61.
1
3
CCDC-609371 contains the supplementary crystallographic data for com-
pound 35. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
3
not be detected; C NMR (75.5 MHz, CDCl ): d=10.9 (C11), 20.8 (C7),
21.6, 22.0 (C13), 25.1 (C10), 26.3 (C4), 27.1 (C5), 37.4 (C3), 50.3 (C2),
51.2 (C6), 59.7 (C8), 70.0 (C12), 71.9 (C9), 103.5 (C5’), 118.4 (C3’), 122.6
(C7’), 126.6 (Caryl), 131.3 (C8’), 143.8 (Caryl), 147.3 (C2’), 147.7 (Caryl),
1
1
8
55.7 ppm (C6’); IR (ATR): n˜ =3156, 2929, 2869, 1711, 1616, 1588, 1503,
1
-(9-Anthrylmethyl)-6’-hydroxy-10,11-dihydrocinchoninium chloride (36):
454, 1382, 1371, 1328, 1237, 1221, 1198, 1135, 1111, 1047, 967, 939, 883,
By following the general procedure for the quaternisation of tertiary
amines, 36 was obtained from 6’-hydroxy-10,11-dihydrocinchonine (40)
À1
59, 829, 732, 701, 639 cm ; HR-MS (ESI, Dm=0.005): m/z: calcd for
+
C
22
H
30
N
2
O
2
: 355.239, found: 355.239 [M+H ].
(
200 mg, 640 mmol) using work-up A as a yellow solid (310 mg, 90%).
2
D
0
R
f
=0.41 (chloroform/methanol 9:1); m.p. > 1958C (decomp); [a] =361
6’-Hydroxy-10,11-dihydrocinchonine (40): A solution of 10,11-dihydro-
1
[42]
(
c=0.50 in methanol); H NMR (300 MHz, CDCl
3
): d=0.43(t, J=
quinidine (419 mg, 1.28 mmol, 1.00 equiv) in dry CH
placed into a Schlenk flask at À788C. Under vigorous stirring, BBr
(1.0m in CH Cl ; 5.13mL, 5.13mmol, 1.23g, 4.00 equiv) was added
slowly. The reaction mixture was allowed to warm up to room tempera-
ture. It was then refluxed at 408C for 1 h and was cooled to 58C. While
stirring and maintaining the temperature, a 10% solution of aqueous
sodium hydroxide (10 mL) was added. The basic aqueous solution was
2 2
Cl (40.0 mL) was
7
1
1
3
1
.3Hz, 3H; H-C11), 0.61–0.77 (m, 1H; H-C7), 0.79–1.00 (m, 1H; H-C 3) ,
3
.06–1.42 (m, 3H; H-C5, C10), 1.44–1.57 (m, 1H; H-C4), 1.59–1.77 (m,
H; H-C5), 1.82–2.06 (m, 1H; H-C7), 2.23–2.50 (m, 2H; H-C2, C6),
.81–4.14 (m, 2H; H-C2, C6), 4.28–4.48 (m, 1H; H-C8), 6.07–6.24 (d, J=
2
2
3.1 Hz, 1H; H-CH
m, 2H; H-C7’, C9), 6.87–7.12 (m, 2H; H-Caryl), 7.17–7.32 (m, 1H; H-
Caryl), 7.35–7.53 (m, 4H; H-Caryl), 7.59 (d, J=8.2 Hz, 1H; H-Caryl),
2 2
An), 6.34 (d, J=13.1 Hz, 1H; H-CH An), 6.59–6.82
(
2 2
separated from the organic phase and washed with CH Cl (15 mL). Hy-
7
4
1
.80–7.94 (m, 2H; H-Caryl), 8.04–8.22 (m, 2H; H-Caryl), 7.70 (d, J=
drochloric acid (2m) was added dropwise until a colourless solid precipi-
tated (approx. pH 8). Extraction with chloroform, drying of the organic
phase with magnesium sulfate and evaporating to dryness yielded the de-
.5 Hz, 1H; H-Caryl), 9.06 (d, J=9.0 Hz, 1H; H-Caryl), 9.16 ppm (brs,
1
3
H; OH); C NMR (75.5 MHz, CDCl
3
): d=10.9 (C11), 21.9 (C7), 23.8
An), 56.3(C2), 58.2
C6), 66.8 (C8), 67.3 (C9), 103.2, 116.9, 119.5, 120.8, 123.8, 124.5, 124.5,
(
C4), 24.0 (C10), 24.7 (C5), 36.0 (C3), 53.8 (CH
2
f
sired product 39 as a colourless solid (227 mg, 57%). R =0.21 (chloro-
[
43]
20
D
(
form/methanol 9:1); m.p. 1728C (lit.:
1708C); [a] =230 (c=1.00 in
[44]
20
1
1
1
3
1
8
25.0, 126.3, 127.5, 127.6, 128.5, 128.6, 129.8, 130.3, 130.5, 131.2, 132.4,
32.6, 141.4, 142.1, 146.1 (all Caryl), 156.2 ppm (C6’); IR (ATR): n˜ =
087, 2956 (CH
methanol) (lit.:
CDCl
[a]D =243( c=1.00 in ethanol); H NMR (300 MHz,
): d=0.64–0.94 (m, 4H; H-C7, C11), 1.13–1.34 (m, 3H; H-C3, C5),
3
3
), 2931 (CH
2
), 1618 (CÀC), 1591, 1525, 1506, 1463, 1447,
1.36–1.53 (m, 2H; H-C10), 1.58–1.66 (m, 1H; H-C4), 2.12–2.36 (m, 2H;
H-C2, C7), 2.40–2.61 (m, 1H; H-C2), 2.72–2.90 (m, 1H; H-C6), 2.92–3.06
(m, 1H; H-C8), 3.46–3.63 (m, 1H; H-C6), 5.94–6.09 (m, 1H; H-C9),
6.83–7.15 (brm, 2H; OH), 7.19 (d, J=8.9 Hz, 1H; H-C7’), 7.30 (s, 1H;
H-C5’), 7.48 (d, J=4.9 Hz, 1H; H-C3’), 7.80 (d, J=4.5 Hz, 1H; H-C8’),
394, 1258, 1236, 1223 (OÀH), 1158, 1129, 1047, 1023, 1007, 992, 961, 907,
À1
64, 829, 791, 726, 663, 641, 623 cm ; HR-MS (ESI, Dm=0.005): m/z:
+
calcd for C34
H
35ClN
2
O
2
: 503.2698, found: 503.269 [M ].
1
(
-N-(9-Anthrylmethyl)-6’-isopropoxy-10,11-dihydrocinchoninium chloride
37): By following the general procedure for the quaternisation of terti-
ary amines, 37 was obtained from 6’-isopropoxy-10,11-dihydrocinchonine
39) (300 mg, 846 mmol) using work-up B as a yellow solid (329 mg,
7%). R =0.21 (chloroform/methanol 9:2); m.p. >1508C (decomp);
1
3
8
.49 ppm (d, J=4.5 Hz, 1H; H-C2’); C NMR (75.5 MHz, CDCl
3
): d=
1
1.8 (C11), 18.1 (C7), 24.7 (C10), 25.5 (C4), 25.9 (C5), 36.5 (C3), 49.3
(
1
C2), 50.4 (C6), 59.5 (C8), 69.9 (C9), 103.9 (C5’), 117.7 (C3’), 123.6 (C7’),
26.6 (C10), 131.4 (C8’), 142.8 (Caryl), 146.0 (C2’), 146.5 (Caryl),
(
6
f
2
0
1
158.5 ppm (C6’); IR (ATR): n˜ =2948, 2928, 2869, 1615, 1585, 1463, 1329,
[
a] =363 (c=1.00 in methanol); H NMR (300 MHz, CDCl
3
): d=0.50
D
À1
1
227, 1113, 1079, 1051, 1024, 997, 931, 831, 734, 698, 643 cm ; HR-MS
(
t, J=7.3Hz, 3H; H-C11), 0.88–1.09 (m, 2H; H-C 3, C7), 1.19–1.44 (m,
(
ESI, Dm=0.005): m/z: calcd for C19H N O : 313.192, found: 313.192
24 2 2
9
H; H-C5, C10, C13), 1.49–1.58 (m, 1H; H-C4), 1.59–1.72 (m, 1H; H-
+
[
M+H ].
C5), 2.01–2.19 (m, 1H; H-C6), 2.20–2.37 (m, 1H; H-C7), 2.72–2.90 (m,
1
4
1
H; H-C2), 3.81–3.98 (m, 1H; H-C6), 4.13–4.28 (m, 1H; H-C2), 4.39–
.52 (m, 1H; H-C8), 4.75 (sep, J=6.0 Hz, 1H; H-C12), 6.37 (d, J=
3.6 Hz, 1H; CH An), 6.43(d, J=13.4 Hz, 1H, CH An), 6.97 (brs, 1H;
2 2
6’-Isopropoxy-10,11-dihydrocinchonidine (41): By following the general
procedure for the alkylation of phenols, 41 was obtained from 6’-hy-
droxy-10,11-dihydrocinchonidine (1.10 g, 3.41 mmol) as a colourless solid
2
0
H-C9), 7.17–7.31 (m, 3H; H-Caryl), 7.32–7.44 (m, 2H; H-Caryl), 7.56–
.64 (m, 1H; H-Caryl), 7.64–7.72 (m, 1H; H-Caryl), 7.89–7.95 (m, 1H;
H-Caryl), 7.95–8.01 (m, 1H; H-Caryl), 8.01–8.06 (m, 1H; H-Caryl), 8.12
(1.21 g, 97%). R
À116 (c=1.00 in ethanol); H NMR (300 MHz, CDCl
7.2 Hz, 3H; H-C11), 1.01–1.17 (m, 2H; H-C10), 1.20–1.40 (m, 9H; H-C7,
f
D
=0.05 (chloroform/methanol 9:1); m.p. 848C; [a] =
1
7
3
): d=0.68 (t, J=
4496
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 4483– 4498

Enantioselective Epoxidation
FULL PAPER
[
31,45]
C3, C5, C13), 1.55–1.69 (m, 3H; H-C7, C4, C5), 2.17–2.30 (m, 1H; H-
C2), 2.39–2.58 (m, 1H; H-C6), 2.83–3.02 (m, 2H; H-C8, C2), 3.27–3.46
(R)-2-Methyl-[1,1’]-binaphthalene (43):
In a 250 mL three-necked
[
29,30]
flask, equipped with an argon inlet, (S)-monotriflate 30
(5.20 g,
(
5
m, 1H; H-C6), 4.57 (sep, J=6.0 Hz, 1H; H-C12), 4.96 (brs, 1H; OH),
.39 (d, J=3.7 Hz, 1H; H-C9), 7.08–7.22 (m, 2H; H-C5’, C7’), 7.35 (d,
J=4.5 Hz, 1H; H-C3’), 7.79 (d, J=8.9 Hz, 1H; H-C8’), 8.38 ppm (d, J=
.3Hz, 1H; H-C2 ’); C NMR (75.5 MHz, CDCl ): d=12.0 (C11), 21.3,
3
8.3 (C7, C5), 21.3 (C13), 21.5 (C13), 25.4 (C4), 27.6 (C10), 37.8 (C3),
12.9 mmol, 1.00 equiv) was dissolved in dry diethyl ether (65 mL). At
08C, bis(triphenylphosphine)nickel(II) dichloride (423mg, 646 mmol,
5 mol%) was added, followed by the dropwise addition of a 3.00m solu-
tion of MeMgCl (12.9 mL, 38.8 mmol, 3.00 equiv) in tetrahydrofuran.
The reaction mixture was allowed to warm to room temperature and was
stirred for 4 h. This mixture was then poured into an ice-cooled 5% HCl
solution (80 mL). The phases were separated, and the aqueous layer was
extracted with diethyl ether (2”20 mL). The combined organic phases
were dried over sodium sulfate, filtered and concentrated under reduced
pressure. The residue was purified by chromatography on silica gel (n-
hexane) to give methyl binaphthalene 43 as a colourless solid (2.43g,
1
3
4
2
4
(
(
3.3 (C6), 57.8 (C2), 59.8 (C8), 70.0 (C12), 72.0 (C9), 103.8 (C5’), 118.4
C3’), 122.5 (C7’), 126.6 (C10), 131.2 (C8’), 143.8, 148.1 (C4’, C9’), 147.2
C2’), 155.7 ppm (C6’); IR (ATR): n˜ =3172, 2927 (CH ), 2869 (CH ),
2
3
1
(
617 (C-C), 1588, 1504, 1455 (CH
CÀO), 1195, 1135, 1135, 1112, 1086, 1043, 968, 880, 853, 828, 642 cm
3
), 1381, 1375, 1328, 1237 (CÀO), 1222
À1
;
HR-MS (ESI, Dm=0.005): m/z: calcd for C22
3
30 2 2
H N O : 355.239, found:
[
31]
20
+
70%). M.p. 132–1348C (lit:
132–1378C); [a]D =À45.7 (c=1.00 in
55.238 [M+H ].
-Hydroxymethyl-[(1,8-S;4,5-R)-1,2,3,4,5,6,7,8-octahydro-1,4:5,8-dimeth-
(1.59 g, 41.9 mmol,
[
31]
20
1
chloroform) (lit:
300 MHz, CDCl
[a]D =À43.9 (c=1.00 in chloroform); H NMR
9
(
3
): d=2.11 (s, 3H; CH
3
), 7.14–7.30 (m, 4H; H-Caryl),
A
C
H
T
R
E
U
N
G
anoanthracene (42): To a suspension of LiAlH
.59 equiv) in dry tetrahydrofuran (30 mL), aldehyde 28
.23mmol, 1.00 equiv) in dry tetrahy-
4
7
7
.37–7.51 (m, 4H; H-Caryl), 7.59–7.64 (dd, J=8.4, 6.9 Hz, 1H; H-Caryl),
[
26–28]
4
(2.20 g,
13
.86–7.97 ppm (m, 4H; H-Caryl); C NMR (75 MHz, CDCl
), 124.8, 125.6, 125.7, 125.8, 125.9, 126.0, 126.1, 127.4, 127.5, 127.6,
27.7, 128.1, 128.5, 131.9, 132.5, 133.4, 133.7, 134.4, 136.0, 137.4 ppm (all
3
): d=20.5
9
(
CH
3
drofuran (20 mL) was added at 08C.
The reaction was stirred for two hours
at room temperature under argon at-
mosphere. After cooling to 08C, the re-
1
Caryl); IR (ATR): n˜ =3049, 3006, 2915, 2856, 1924, 1815, 1590, 1504,
1
7
424, 1370, 1256, 1159, 1142, 1131, 1027, 1014, 949, 863, 802, 810, 790,
À1
79, 772, 743, 674, 619 cm
; GC-MS (capillary column HP-5MS
maining LiAlH
addition of water (70 mL). After
0 min of stirring, the reaction mixture
was filtered over Celite and washed
4
was decomposed by
0.25 mm”30 m, cross-linked 5% PH ME siloxane 0.25 mm; He,
À1
À1
À1
1 mLmin ; 1008C, 5 min, 208Cmin , 2008C, 15 min, 208Cmin , 2808C,
1
10 min) t =24.32 min, m/z: 268, 253; elemental analysis calcd (%) for
R
C H (268.4): C 93.99, H 6.01 found: C 93.69, H 6.09.
2
1
16
with water and tetrahydrofuran. Diethyl ether (10 mL) was added, the
phases were separated and the aqueous layer was extracted with diethyl
ether (2”15 mL). The combined organic phases were dried over sodium
sulfate, filtered and concentrated under reduced pressure. The residue
was purified by chromatography on silica gel (dichloromethane/n-hexane
(
S)-2-Methyl-[1,1’]-binaphthalene (ent-43): Compound ent-43 was synthe-
sized from the (R)-monotriflate ent-30 in the same manner as (R)-2-
methyl-[1,1’]-binaphthalene 43. A colourless solid (3.76 g, 79%) was ob-
tained. The analytical data of this compound were identical to those of
2
0
(R)-2-methyl-[1,1’]-binaphthalene 43, except for: [a] =46.5 (c=1.03in
D
3
:1, then dichloromethane/n-hexane 10:1) to give alcohol 42 as a colour-
chloroform); elemental analysis calcd (%) for C H (268.4): C 93.99, H
2
1
16
less solid (1.69 g, 76%). R
f
=0.31 (dichloromethane/n-hexane 10:1); m.p.
6.01 found: C 93.70, H 5.95.
2
0
1
1
21–1228C; [a] =75.1 (c=1.00 in chloroform); H NMR (300 MHz,
D
3
CDCl ): d=1.05–1.09 (m, 4H; H-C2, C3, C6, C7), 1.44–1.47 (m, 2H; H-
C11, C12), 1.67–1.69 (m, 2H; H-C11, C12), 1.83–1.89 (m, 4H; H-C2, C3,
C6, C7), 3.27 (brs, 2H; H-C4, C5), 3.53 (brs, 2H; H-C1, H-C8), 4.67–4.76
(
m, 2H; H-CH
2
3
Ph), 6.92 ppm (s, 1H; H-Caryl); the OH proton could not
Acknowledgements
1
be detected; C NMR (75 MHz, CDCl
C6), 41.2 (C1, C8), 43.9 (C4, C5), 49.1 (C11, C12), 60.4 (CH
C10), 125.1 (C9), 143.9 (C4a, C10a), 145.7 ppm (C8a, C9a); IR (KBr
3
): d=27.11 (C2, C7), 27.2 (C3,
2
Ph), 113.5
This work was supported by the Fonds der Chemischen Industrie. Gener-
ous gifts of cinchona alkaloids by Buchler GmbH, Braunschweig are
gratefully acknowledged.
(
pellet): n˜ =3175, 2963, 2917, 2862, 1470, 1444, 1325, 1298, 1267, 1249,
À1
1
0
1
1
0
104, 1045, 1012, 944, 864, 719 cm ; GC-MS (capillary column HP-5MS
.25 mm”30 m, cross-linked 5% PH ME siloxane 0.25 mm; helium,
À1
À1
À1
mLmin ; 1008C, 5 min, 208Cmin , 2008C, 15 min, 208Cmin , 2808C,
0 min) t =13.99 min, m/z: 240, 212, 184, 166, 154; HR-MS (ESI, Dm=
.005): m/z: calcd for C17
[1] C. Bonini, G. Righi, Tetrahedron 2002, 58, 4981–5021.
[2] T. Katsuki, in Comprehensive Asymmetric Catalysis (Eds.: E. N. Ja-
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R
+
H
20O: 240.1514 found 240.152 [M ]; HPLC
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1
À1
.00 mLmin ; t
R
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9
-Hydroxymethyl-[(1,8-R;4,5-S)-1,2,3,4,5,6,7,8-octahydro-1,4:5,8-dimetha-
noanthracene (ent-42): A 100 mL round-bottomed flask with argon inlet
was charged with aldehyde ent-28
and dry methanol (25 mL). The reaction mixture was cooled to 08C and
sodium borohydride (270 mg, 7.05 mmol, 5.00 equiv) was added portion-
wise. After stirring at room temperature for 3h, a 10% HCl solution
[
26–28]
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[
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HPLC Column: Chiralpak-AD, eluent: n-hexane/isopropanol 100:2, flow:
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Received: July 11, 2006
Revised: December 20, 2006
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4498
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 4483– 4498