Synthetic and Organocatalytic Studies of Quinidine Analogues with Ring-Size Modifications in the Quinuclidine Moiety

Article abstract of DOI:10.1002/chem.201601917

Six highly enantiopure analogues of [2.2.2] were synthesized with five- or seven-membered rings in the (original) quinuclidine skeleton. Five of these compounds were prepared through epoxide opening by a secondary cyclic amine, providing the nor- and homo

Full text of DOI:10.1002/chem.201601917

DOI: 10.1002/chem.201601917
Full Paper
&
Asymmetric Synthesis
Synthetic and Organocatalytic Studies of Quinidine Analogues
with Ring-Size Modifications in the Quinuclidine Moiety
Arjen C. Breman, Gydo van der Heijden, Jan H. van Maarseveen, Steen Ingemann, and
Henk Hiemstra*[a]
Abstract: Six highly enantiopure analogues of [2.2.2] were
synthesized with five- or seven-membered rings in the (origi-
nal) quinuclidine skeleton. Five of these compounds were
prepared through epoxide opening by a secondary cyclic
amine, providing the nor- and homoquinuclidine moieties
through five- and six-membered ring formation. This
method failed in the case of seven-membered ring forma-
tion, so for that particular ring size a different synthetic
route starting from 3-quinuclidone was applied. The six
novel analogues were examined as organocatalysts in four
asymmetric conjugate addition reactions and the results
compared with those of known cinchona alkaloid catalysts.
This study shows that modification of the quinuclidine ring
can have a substantial influence on catalyst activity and
enantioselectivity. To acquire more insight into the character-
istics of the new catalysts, the pKaH values were determined
by means of fluorescence spectroscopy. Furthermore,
relative reaction rates of conjugate thiol additions reactions
catalyzed by these quinidine analogues were measured
through polarimetry.
Introduction
conjugate addition reactions, we became interested in gaining
more insight into the structural features that are essential for
enantioselectivity. It is well known that both the quinuclidine
nitrogen and C-9 hydroxyl group are crucial for the reaction
rate and ee in conjugate addition reactions.[3] The basic tertiary
nitrogen atom activates the nucleophile and, at the same time,
the OH group at the C-9 position activates the electrophile
through hydrogen bonding. The catalyst is considered, there-
fore, a bifunctional catalyst and the mechanism is referred to
as dual activation.[4] Removal, protection, or epimerization of
the C-9 OH is detrimental for the rate and ee of several reac-
tions, although its replacement by another strong hydrogen-
bond donor may be beneficial.[5] Structural modifications have
also been applied to the vinyl substituent.[3b] It is remarkable
how simple modifications of this somewhat remote group can
lead to drastic changes in rate and selectivity.[3b,6]
A remarkable variety of reaction types catalyzed by (modified)
cinchona alkaloids give high levels of enantioselectivity. There-
fore, cinchona alkaloids, such as quinidine (1), are considered
to be “privileged chiral catalysts” (Figure 1).[1] However, knowl-
Figure 1. The four major alkaloids found in cinchona bark.
Many other changes have been applied to cinchona alka-
loids for the study of their role as chiral, noncovalent organo-
catalysts, for example, modifications in the quinoline ring and
introduction of other functional groups at C-9.[7] However,
a part of the molecule that has not been modified in a system-
atic way is the quinuclidine moiety. This bicyclic system on its
own contains a tertiary nitrogen atom with a pKaH of 11.0 in
water if unsubstituted.[8] The pKaH of the quinuclidine ring in
cinchona alkaloids was experimentally determined to be be-
tween eight and nine.[9] This lower pKaH in the alkaloids is as-
cribed to the electron-withdrawing groups on the C-3 and C-8
positions. Because of its bridgehead position, the nitrogen
atom is also a chiral center with the lone pair in a fixed direc-
tion. Modification of the quinuclidine ring system by removing
or adding methylene groups would provide interesting ana-
logues for studying the role of this part of cinchona alkaloids
edge of the detailed mechanism, that is, the geometry of the
actual transition states in these reactions, remains limited.
Although calculations support the outcome of noncovalent
bifunctional organocatalysis, only a few publications describe
experimental results that support the proposed mechanisms.[2]
In conjunction with our work on (modified) cinchona
alkaloids as chiral, noncovalent, bifunctional organocatalysts in
[a] Dr. A. C. Breman, G. van der Heijden, Prof. Dr. J. H. van Maarseveen,
Dr. S. Ingemann, Prof. Dr. H. Hiemstra
Van ’t Hoff Institute for Molecular Sciences
University of Amsterdam, Science Park 904
1098 XH Amsterdam (The Netherlands)
E-mail: h.hiemstra@uva.nl
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201601917.
Chem. Eur. J. 2016, 22, 1 – 11
1
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
in organocatalytic reactions (Figure 2). These modifications
should have a significant influence on both the pKaH and the
direction of the lone pair. By removing methylene groups, the
system will become more rigid, whereas the addition of CH2
groups will induce more flexibility in the bicyclic system. It was
The [2.1.2] analogue (see Figure 2) was synthesized starting
from known (+)-(R)-pyrrolidin-3-ylmethanol (5; Scheme 2).[13]
Protection of the pyrrolidine with a Teoc group,[10b–d] followed
by Swern oxidation[14] and a Wittig reaction, provided enol
Scheme 2. Synthesis of the dihydroxylation precursor for the [2.1.2] ana-
logue. NaHMDS=sodium bis(trimethylsilyl)amide, LDA=lithium diisopropyl-
amide, MsCl=methanesulfonyl chloride, Teos=trimethylsilylethoxycarbonyl.
Figure 2. Modifications of the quinuclidine ring studied herein.
ether (+)-6 in 65% yield over three steps as a 4:1 mixture of E
and
Z
isomers.[15] The enol ether was hydrolyzed with
CeCl3·7H2O and NaI. The chain-extended aldehyde was then re-
acted with the lithium salt of commercially available 4-methyl-
6-methoxyquinoline, generated by deprotonation with LDA,
giving an alcohol as a 1:1 mixture of diastereoisomers.[10b–d]
The double bond was introduced by mesylation of the alcohol
followed by elimination with KOtBu, yielding the alkene (+)-7
in 70% over four steps. Enantiomer (ꢀ)-7 was prepared in an
identical manner from known (ꢀ)-5.[13]
decided, therefore, to synthesize the analogues shown in
Figure 2. The vinyl group was not introduced in the novel de-
rivatives because it was remote from the catalytic centers and
would greatly complicate the syntheses. To study the effects of
the modifications, the analogues were examined in four
known asymmetric reactions and the results compared with
those obtained with the natural alkaloid. Also, the pKaH values
and activity of the catalysts were determined to study possible
relationships between enantioselectivity, pKaH, and efficiency of
the catalysts.
From alkene (+)-7, the diol was obtained as an inseparable
mixture of diastereoisomers (4:1) in 78% yield with the use of
AD-mix a (Scheme 3).[11] In a one-pot procedure, the epoxide 8
Results and Discussion
Synthesis of the new catalysts
For the syntheses of the novel analogues, we chose the same
strategy as that developed by the groups of Jacobsen and
Kobayashi for the total synthesis of 1 and quinine (3).[10] In this
approach, the quinuclidine ring system was prepared by regio-
selective intramolecular nucleophilic attack of the cyclic secon-
dary amine on the epoxide (Scheme 1). This epoxide was
Scheme 3. Synthesis of the [2.1.2] analogue. PPTS=pyridinium p-toluene-
sulfonate, TMSCl=trimethylsilyl chloride.
was prepared from the diol in 88% yield.[12] Finally, this epox-
ide was treated with cesium fluoride in DMF and tert-butanol
at 1108C.[10b–d] Under these conditions, the Teoc group was re-
moved and the epoxide ring opened by the unprotected
amine, leading to a 3:1 mixture of the desired [2.1.2] product
and its regioisomer 9, both as approximately 4:1 mixtures of
diastereomers. Thus, in the cyclization reaction, there was com-
petition between 5-exo-tet and 6-endo-tet processes
(Scheme 4) with a preference for 5-exo-cyclization, in agree-
ment with the Baldwin rules.[16] Separation of the four regio-
and diastereoisomers by column chromatography gave the
[2.1.2] analogue as a single isomer in 53% yield.
Scheme 1. Synthetic approach for the formation of modified bicyclic
systems. PG=protecting group.
prepared in high enantiopurity through Sharpless asymmetric
dihydroxylation of the alkene and stereospecific ring closure of
the diol.[11,12] This strategy nicely provided the correct stereo-
chemistry at the C8 and C9 carbon atoms.
For the synthesis of the [2.2.1] analogue, the same synthetic
strategy was used as that for the [2.1.2] analogue, but now
&
&
Chem. Eur. J. 2016, 22, 1 – 11
www.chemeurj.org
2
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
zation product. Apparently, the particular conformation of the
deprotected piperidine allows the 5-exo-tet cyclization to occur
much faster than the 6-endo-tet cyclization.
To obtain the [2.3.2] and [2.2.3] analogues, a diastereoselec-
tive synthesis was performed (Scheme 7). The synthesis started
from known 4-azepinone 16,[17] which was subjected to
Horner–Wadsworth–Emmons olefination with triethyl phospho-
Scheme 4. The 5-exo-tet and 6-endo-tet cyclization processes.
starting from (ꢀ)-7 (Scheme 5). This alkene was dihydroxylated
with AD-mix a, providing the other diastereoisomer to that of
the synthesis of the [2.1.2] analogue with virtually the same
diastereoselectivity (4:1). Apparently, the stereochemistry of di-
hydroxylation is fully independent of the stereocenter in the
pyrrolidine ring. Epoxide 10 was obtained in 94% yield and
treated with CsF at 1108C. Again, competition between 5-exo-
tet and 6-endo-tet cyclization was observed. The [2.2.1] ana-
logue was obtained as a single isomer in a moderate yield of
55%.
Scheme 7. Synthesis of the [2.3.2] and [2.2.3] analogues. NMP=N-methyl-
pyrrolidin-2-one.
noacetate and NaH, providing the unsaturated ester as a mix-
ture of four isomers: the E and Z isomers of the expected exo-
cyclic alkene and the two isomerized endocyclic alkenes.[18] In
the next step all isomers were hydrogenated in the presence
of Pd/C to give ester 17 in quantitative yield. The procedure
for the addition of 4-methyl-6-methoxyquinoline was modified,
and now 2.5 equivalents of the quinoline was added.[19] We
assume that, after attack of the lithiated quinoline to the ester,
a relatively acidic benzylic proton is removed by the excess
lithiated quinoline, preventing addition of a second carbonyl.
The ketone was reduced with NaBH4 and the alcohol was elim-
inated to give alkene 18. Asymmetric dihydroxylation provided
an inseparable mixture (1:1) of diastereoisomers in 98% ee for
both diastereoisomers based on chiral HPLC. The diols were
converted into epoxides 19 in 86% yield. Cyclization of the
azepanes provided the [2.3.2] and [2.2.3] analogues in 23 and
28% yield, respectively, after separation by column chroma-
tography.
Scheme 5. Synthesis of the [2.2.1] analogue.
The synthesis of the [1.2.2] analogue started from Teoc-pro-
tected piperidinone 12 (Scheme 6).[10d] Protected piperidinone
12 was reacted with (methoxymethyl)triphenylphosphonium
chloride and NaHMDS, providing the expected enol ether. Hy-
To take advantage of this epoxide-opening cyclization strat-
egy for the synthesis of the [3.2.2] analogue, Teoc-protected
piperidinone 12 was reacted with the phosphorus ylide
formed by deprotonation of 20 by NaHMDS (Scheme 8) to pre-
pare the corresponding alkene. This alkene was reduced, fol-
lowed by removal of the acetal with sulfuric acid in aqueous
acetone, to give aldehyde 21 in 99% yield.[20] Addition of 4-
methyl-6-methoxyquinoline gave the alcohol in 68% yield,
which was eliminated to provide alkene 22 in 85% yield. Dihy-
droxylation and epoxide formation gave 23 in high yield (ee
was not determined). Next, the usual deprotection/cyclization
procedure was attempted with CsF in DMF/tBuOH at 1108C.
After stirring overnight, no trace of the bicyclic ring system
Scheme 6. Synthesis of the [1.2.2] analogue.
drolysis with CeCl3·7H2O and NaI led to aldehyde 13 in 77%
over two steps. Addition of 4-methyl-6-methoxyquinoline gave
the alcohol in 75% yield, which was subsequently eliminated
to give prochiral alkene 14 in quantitative yield. The diol was
introduced by asymmetric dihydroxylation in 97% ee based on
chiral HPLC, followed by epoxide formation in 85% yield. The
usual deprotection and cyclization procedure provided the
[1.2.2] analogue in 75% yield without a trace of the endo cycli-
Chem. Eur. J. 2016, 22, 1 – 11
www.chemeurj.org
3
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
hydrogenate the double bond in 27 with Pd/C catalyst failed.
This isomerization was achieved by treating the allylic alcohol
with KOtBu in a 10:1 mixture of THF/tBuOH. Product 28 was
obtained as a 10:1 mixture of Z/E isomers in 73% over two
steps. The mixture of isomers was reduced with hydrogen over
Pd/C in methanol in the presence of HCl to decrease the reac-
tion time. Next, the alcohol was reacted with thiocarbonyldii-
midazole in THF, providing 29 as a 2:1 mixture of diastereoiso-
mers in 64% over two steps.[25] Treatment of 29 with nBu3SnH
and a catalytic amount of AIBN in toluene at reflux led to re-
ductive removal of the thiocarbamate. Oxidation with oxygen
and NaH in DMSO at 708C following a known protocol provid-
ed a 2.5:1 mixture of the racemic [3.2.2] analogue and its epi
isomer.[26] The racemic [3.2.2] analogue was readily separated
by column chromatography and isolated as a pure compound
in 35% over two steps.[27]
Scheme 8. Attempted epoxide-opening cyclization approach leading to the
[3.2.2] analogue.
To resolve this racemate, the enantiomers were converted
into diastereomers through reaction with (S)-(+)-a-methoxy-
phenylacetic acid by using 1-ethyl-3-(3-dimethylaminopropyl)-
carbodiimide (EDC) and N-hydroxybenzotriazole (HOBt) in
CH2Cl2 (Scheme 10). The diastereoisomers were separated by
was observed in the product, but only formylation of the pi-
peridine by DMF. Changing the solvent to NMP did not provide
the desired product either, not even after stirring at 1508C.
Next, 23 was first N-deprotected and then treated with zinc tri-
fluoromethylsulfonate (Zn(OTf)2) or Y(NO3)3·6H2O in acetonitrile
at 808C.[21,22] Unfortunately, both Lewis acids failed to produce
satisfactory results. Although 7-exo-tet cyclization was expected
to be possible, in view of the Baldwin rules, we were unable to
effect the desired cyclization of compound 23.[16]
A different approach to the [3.2.2] system was then investi-
gated starting from commercially available quinuclidinone hy-
drochloride 24. Reaction of the enolate anion of 24 with qui-
nolinealdehyde 25 gave aldol condensation product 26 in
good yield (Scheme 9).[23] Ring expansion of the cyclic ketone,
according to a method recently developed by Lee et al.,[24] oc-
curred regioselectively at the side of the double bond, and
was followed by a shift of the double bond to the a,b-unsatu-
rated ketone 27 in 43% yield. The carbonyl was reduced with
NaBH4 in methanol. The double bond was then isomerized
back to the benzylic position because all attempts to directly
Scheme 10. Resolution of the racemic [3.2.2] analogue.
column chromatography. The desired diastereoisomer 30 was
1
obtained as a single isomer, according to H NMR spectrosco-
py, in 29% yield. The other fraction contained 31 and 30 as
a 4:1 mixture. Ester 30 was treated with K2CO3 in methanol to
give the [3.2.2] analogue in 89% yield and 96% ee.[28,29]
Physical data of the catalysts
With the final analogue in hand, the synthesis of the set of qui-
1
nidine analogues was complete. The H and 13C NMR spectra
of the new bases were fully analyzed with the aid of NOE
measurements and 2D techniques. Some physical data are col-
lected in Table 1. All compounds were crystalline solids with
sharp melting points and positive specific rotations. Three
known reference compounds are also included Table 1, namely,
1, dihydroquinidine (32) and [2.2.2] (Figure 2). Because the
novel quinuclidine analogues lack the vinyl substituent, ana-
logue [2.2.2] can be considered as an excellent reference com-
pound for comparison of the catalytic results. It was synthe-
sized from
1
through
a
newly developed procedure
(Scheme 11). First, the quinidine hydroxyl group was acetylated
and then the vinyl side chain was dihydroxylated by using AD-
mix a. The diol was oxidatively cleaved with NaIO4 in acetone
to give aldehyde 33 as a 9:1 isomeric mixture in 88% over
Scheme 9. New synthetic approach to the racemic [3.2.2] analogue.
TMSCHN2 =trimethylsilyldiazomethane, AIBN=azobisisobutyronitrile
&
&
Chem. Eur. J. 2016, 22, 1 – 11
www.chemeurj.org
4
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
Table 1. Physical data of the catalysts.
[a]
Cat.
[a]D
M.p. [8C]
H-9 in 1H NMR [ppm][b]
C-9 in 13C NMR [ppm][c]
pKaH (water)
1[d]
+236.0[e]
+226.0[e]
+126.6[g]
+64.6[g]
+77.9
170–172
167–168
81–82
162–165
108–109
75–77
146–148
129–131
130–131
5.72 (brs)
5.57 (brs)
5.65 (d, J=3.8 Hz)
5.89 (brs)
5.38 (d, J=3.5 Hz)
5.95 (brs)
5.75 (brs)
6.41 (brs)
5.39 (d, J=4.5 Hz)
72.0
71.4
71.2
70.2
69.2
65.7
70.7
68.1
70.7
8.75
9.21
9.30
8.87
9.00
8.48
9.22
9.17
9.40
32[f]
[2.2.2]
[2.1.2]
[2.2.1]
[1.2.2]
[2.3.2]
[2.2.3]
[3.2.2]
+23.3
+108.2
+51.7
+109.8[g]
[a] Rotation in CHCl3. [b] H-9 refers to hydrogen at the 9-position in the natural alkaloid. [c] C-9 refers to carbon at the 9-position in the natural alkaloid.
[d] Data from ref. [10a]. [e] Rotation in EtOH. [f] Data from ref. [31]. [g] Rotation in CH2Cl2.
cyclic amine (pH@pKaH) can act as an electron donor, resulting
in an excited-state electron-transfer (ET) process to the quino-
line moiety. This process results in quenching of the quinoline
emission in polar solvents.[35] As soon as the amine is protonat-
ed, it can no longer act as an electron donor and the emission
of the quinoline moiety is recovered.
Scheme 11. Synthesis of desvinylquinidine ([2.2.2]). dppp=1,3-bis(diphenyl-
phosphino)propane.
The pKaH of 1 was measured to be 8.75 (Table 1), which was
close to reported values.[9] The pKaH of 32 showed an increase
to 9.21, which was in agreement with calculations by Mer-
schaert et al. (pKaH =9.99 (dihydrocinchonine) and 9.18 (2)),[3b]
three steps. Next, aldehyde 33 was decarbonylated by using
a rhodium(I) complex, which was formed in situ by mixing
chloro(1,5-cyclooctadiene)rhodium(I) with dppp in diglyme and
heating the mixture at reflux for 16 h.[30] Finally, the acetate
group was cleaved with K2CO3 in methanol to give [2.2.2] in
81% over two steps. The enantiomer of this compound was
synthesized previously, but the melting point and specific rota-
tion were not reported.[10c] The reported 1H NMR spectrum
showed good agreement with that obtained herein.
who proved that the vinyl group had a negative effect on the
basicity of the amine. This trend was further supported by the
pKaH value (9.30) of [2.2.2]. The nor analogues were less basic
than [2.2.2], whereas the homo analogues exhibited pKaH
values that were comparable with the pKaH of [2.2.2]. The re-
sults are in agreement with the observations of Hine and
Chen,[32] namely, that removal of one CH2 group reduces the
basicity of the amine, but the influence of an extra CH2 group
is small. The position of the modification in the bicyclic system
also influences the pKaH: the least basic catalyst is the [1.2.2]
analogue and the most basic is the [3.2.2] analogue.
Modifications in the quinuclidine ring system should also
have an effect on the basicity of the nitrogen atom. This was,
to some extent, investigated by Hine and Chen.[32] They deter-
mined the pKaH values of quinuclidine and the analogue lack-
ing one methylene group, so-called norquinuclidine. Their re-
sults showed that quinuclidine was more basic than the nor
compound (pKaH =10.9 versus 10.5). The extra CH2 group
makes the amine more electron rich, resulting in better stabili-
zation of the positive charge on the amine. If this trend is pro-
jected on the [3.2.2] series, the pKaH values should be highest
for these analogues. The calculations of Merschaert et al.
showed that the vinyl group had a negative influence on the
basicity (ACD calculations: pKaH =9.99 (dihydrocinchonine) and
9.18 (2)).[3b]
Catalysis
To gain an insight into the role of the quinuclidine ring of cin-
chona alkaloids in asymmetric organocatalysis, the analogues
were examined in four conjugate addition reactions
(Table 2).[3a,36–38] These reactions were chosen for two main rea-
sons: 1) they introduce chirality at different carbon atoms; and
2) the reactions catalyzed by the natural cinchona alkaloids are
known to give only moderate enantioselectivities, which allows
room for improvement. In thiol addition reaction A (Table 2),
chirality is introduced at the a-carbon atom through protona-
tion.[36] In this process, the parent quinidine (1) clearly per-
formed the best (45% ee), whereas removal of the ethyl or
vinyl substituents led to lower or even reversal of enantioselec-
tivity (<30% ee). In thiol addition reaction B (Table 2), chirality
Steady-state fluorescence spectroscopy was used to deter-
mine the pKaH values of the analogues.[33] This was achieved by
measuring the fluorescence spectra of the built-in quinoline
fluorophore as a function of pH.[34] The neutral form of the bi-
Chem. Eur. J. 2016, 22, 1 – 11
www.chemeurj.org
5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
of 4-tert-butylthiophenol to cyclohexenone (Table 2, reaction B)
was monitored by measuring the optical rotation of the reac-
tion mixture versus reaction time by following a known proce-
dure.[3a] The experiments were performed in duplicate and the
optical rotations were converted into percentage conversion,
plotted as a function of reaction time (Figure 3). In view of the
regular curve shape, the reactions were most probably all fol-
lowing pseudo-second-order kinetics; first order in thiol,
Table 2. Screening of the novel quinidine analogues as chiral catalysts.
1
enone, and catalyst. The time required for 50% conversion (t = )
2
is given for all catalysts in Table 3.
Figure 3 shows that the [2.2.2] bases (Table 3, entries 1, 2,
and 4) lead to the highest reaction rates. The changes of the
bridge size do not have a large effect on the rate, except for
the bridge that has the hydroxymethylquinoline substituent.
Thus, catalysts [1.2.2] and [3.2.2] give the lowest reaction
rates, but, remarkably, have the lowest and highest basicity, re-
spectively. The intermediate catalyst [2.2.2] leads to the high-
est reaction rate. This indicates that there is no clear relation-
ship between basicity and reaction rate. Structural details of
the catalysts, in particular, the distance between the quinucli-
dine nitrogen and the hydroxyl group and the relative orienta-
tion of these group are likely to be more important.
Entry
Cat.
ee [%]
42[b,d]
36[a,b]
39[b,c]
45[b,e]
1
2
3
4
5
6
7
8
9
1
32
45
41
22
19
28
13
29
ꢀ6
ꢀ13
55
45
41
57
22
35
38
40
50
49
50
53
21
3
51
41
15
31
60
66
80
27
83
52
82
62
16
[2.2.2]
[2.1.2]
[2.2.1]
[1.2.2]
[2.3.2]
[2.2.3]
[3.2.2]
Table 3 shows a summary of the catalytic performances of
the nine catalysts in thiol addition (reaction B, Table 2) with the
catalysts ordered according to compound class. Analysis of
these data reveals a noteworthy trend. The nor bases (Table 3,
entries 1–3) and the quinuclidines (Table 3, entries 4–6) show
[a] Standard reaction conditions: 0.125m substrate, thiol (1.2 equiv).
[b] The ee values were determined by chiral HPLC analysis (AD column).
[c] Standard reaction conditions: 0.52m substrate, thiol (1.15 equiv).
[d] Standard reaction conditions: 0.5m substrate, nucleophile (0.5 equiv).
[e] Standard reaction conditions: 0.1m substrate, nucleophile (1.2 equiv).
is introduced on the b-carbon atom through the addition of
a thiophenol nucleophile.[3] Here 1 was also one of the more
selective catalysts (55% ee), but the effect of the vinyl substitu-
ent was not crucial because analogues [2.1.2] and [3.2.2],
which lacked the vinyl group, were equally good (57 and
50% ee, respectively). Reaction C (Table 2) is the Michael addi-
tion of a 1-indanone-2-carboxylic ester to methyl vinyl ketone
with chirality introduced at the nucleophilic carbon atom.[37]
Once again 1 performed rather well (49% ee), but in this case
leaving out the vinyl (or ethyl) substituent had no effect on
the ee. A remarkable result was the considerable influence of
the size of the bridges in the nor bases (varying from 51 to 21
and 3% ee). Finally, reaction D (Table 2) is a Michael addition of
malononitrile, in which chirality arises at the b-carbon of the
electrophile.[38] In this case, the synthetic bases [2.2.1] and
[2.3.2] (Table 2, entries 5 and 7) gave the highest enantioselec-
tivities (83 and 82% ee, respectively). Interestingly, the [3.2.2]
analogue gave only 16% ee, which indicated that subtle geo-
metric effects were important. As an overall conclusion, one
could argue that the influence of internal skeletal modification
of the bicyclic base on the ee is substantial and that even
larger effects might be expected from the introduction of sub-
stituents into this moiety.
Figure 3. Reaction rates for the catalyzed addition of 4-tert-butylthiophenol
to cyclohexenone (reaction B in Table 2; reaction temperature 188C; cata-
lysts ranked in order of decreasing reaction rate).
Table 3. Reaction rates (see Figure 3) in relation to ee and pKaH values for
the catalyst ordered according to compound class (quinuclidines:
entries 1–3; homo bases: entries 4–6; nor bases: entries 7–9).
1
Entry
Cat.
ee [%]
t = [min]
pKaH (water)
2
1
2
3
4
5
6
7
8
9
[2.2.1]
[2.1.2]
[1.2.2]
[2.2.2]
32
22
57
35
41
45
55
40
38
50
9.8
12.2
33.8
3.3
3.7
7.3
5.5
12.5
37.7
9.00
8.87
8.48
9.30
9.21
8.75
9.17
9.22
9.40
1
[2.2.3]
[2.3.2]
[3.2.2]
To investigate possible relationships between ee, reaction
rate, and pKaH values of the catalysts, the rate of the addition
&
&
Chem. Eur. J. 2016, 22, 1 – 11
www.chemeurj.org
6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
Spex Fluorolog 3-22 instrument was used, equipped with double
monochromators for excitation and emission and a Peltier cooled
Hamamatsu R636 photomultiplier. All reactions were carried out in
oven-dried glassware with magnetic stirring. THF was freshly dis-
tilled from sodium and benzophenone. Toluene was distilled over
CaH2 and stored over 4 ꢁ molecular sieves. DMF was dried over
molecular sieves. Other solvents were also distilled prior to use.
a direct relationship between reaction rate and basicity; the
more basic catalysts give higher reaction rates. Interestingly,
this relationship is inverse for the homo bases (Table 3, en-
tries 7–9). Although it is not surprising to see that for the more
basic catalysts deprotonation of the thiol is less important in
the rate equation, it is troublesome to use basicities in water
for toluene as a solvent. The ee values do not show a relation-
ship with either reaction rate or catalyst basicity.
Aldehyde 13
Conclusion
(Methoxymethyl)triphenylphosphonium chloride (7.2 g, 21 mmol)
was dissolved in THF (50 mL) and cooled to ꢀ788C. NaHMDS (2m
in toluene, 8.5 mL, 17 mmol) was added dropwise. The resulting
mixture was warmed to 08C and stirred for 30 min. Piperidone
12[10d] (1.7 g, 7.0 mmol) in THF (10 mL) was added and stirring was
continued for 24 h. The reaction was stopped through the addition
of a saturated aqueous solution of NH4Cl and the resulting mixture
was extracted three times with EtOAc. The combined organic
layers were washed with brine and then dried with MgSO4. Evapo-
ration of the solvent gave a residue that was filtered over silica gel
to yield the enol ether as a colorless oil. This enol ether was imme-
diately used for the next step and dissolved in acetonitrile (50 mL).
CeCl3·7H2O (650 mg, 1.75 mmol) and NaI (131 mg, 0.88 mmol)
were added and the resulting mixture was stirred overnight at
408C, followed by evaporation of the solvent. The product was pu-
rified by column chromatography (petroleum ether (PE)/EtOAc
4:1), yielding aldehyde 13 (1.39 g, 5.4 mmol, 77% over two steps)
as a colorless oil. IR (neat): n˜ =2951, 2856, 1726, 1692, 1433, 1222,
The syntheses and properties of six analogues of the cinchona
alkaloid quinidine (1) with modifications in the quinuclidine
ring system are described. The synthetic route to construct the
azabicyclic ring system was based on the intramolecular nucle-
ophilic attack of a secondary amine onto a 1,2-disubstituted
epoxide. This epoxide was generated by means of asymmetric
Sharpless dihydroxylation. Only the synthesis of the [3.2.2] an-
alogue failed with this procedure. Therefore, this analogue was
prepared as a racemate through functionalization and ring ex-
pansion of 3-quinuclidone followed by separation of the enan-
tiomers. The six analogues were examined as enantioselective
organocatalysts in four conjugate additions and the results
compared with three known reference catalysts. The pKaH
values of the nine catalysts used were determined by means
of fluorescence spectroscopy. The catalytic activity was deter-
mined for thiophenol addition to cyclohexenone by measuring
the relative reaction rates by means of polarimetry. Rate differ-
ences up to a factor of 10 were observed. Enantioselectivities
varied from close to 0 to >80%. Further studies are required
to understand the relationship between catalyst structure and
basicity on one hand and reaction rate and ee on the other
hand for the four reactions explored. Subtle geometric modifi-
cations in the catalyst structure, such as the distance and rela-
tive orientation of the basic nitrogen atom and the hydroxyl
group, seem to be important for enantioselectivity. More de-
tailed mechanistic insight will require a larger series of catalyst
structures in combination with computational studies.
838 cmꢀ1 1H NMR (400 MHz, CDCl3): d=9.87 (s, 1H), 4.20 (t, J=
;
3.6 Hz, 2H), 4.04 (d, J=10.4 Hz, 2H), 3.03 (m, 2H), 2.45 (m, 1H),
1.92 (d, J=11.2 Hz, 2H), 1.60 (m, 2H), 1.03 (t, J=3.6 Hz, 2H),
0.02 ppm (s, 9H); 13C NMR (100 MHz, CDCl3): d=202.6, 155.3, 63.6,
47.7, 42.7, 24.9, 17.6, ꢀ1.6 ppm; HRMS (FAB): m/z calcd for
C12H24NO3Si [M+H]+: 258.1525; found: 258.1526.
(E)-Alkene 14
Diisopropylamine (840 mL, 6.0 mmol) was dissolved in THF (20 mL)
and cooled to ꢀ788C. nBuLi (1.6m in hexane, 3.6 mL, 5.8 mmol)
was added and the mixture was warmed to 08C. Stirring was con-
tinued for 15 min followed by cooling the mixture to ꢀ788C. 4-
Methyl-6-methoxyquinoline (1.0 g, 5.8 mmol) dissolved in THF
(5 mL) was added and stirring was continued for 1 h. A solution of
aldehyde 13 (1.04 g, 4.0 mmol) in THF (10 mL) was added dropwise
and stirring was continued for 3 h at ꢀ788C. The reaction was
stopped through the addition of a saturated solution of NH4Cl and
the mixture was allowed to reach RT and extracted three times
with EtOAc. The organic layers were combined, washed with brine,
dried with MgSO4, and the solvent was evaporated. The product
was purified by column chromatography (EtOAc) to yield the alco-
hol (1.3 g, 3.01 mmol, 75%) as sticky oil. IR (neat): n˜ =3400, 2951,
Experimental Section
General
1
The H and 13C NMR spectra (APT) were recorded (1H 400 MHz, 13C
100 MHz) at room temperature in CDCl3 as the solvent, unless indi-
cated otherwise. The NMR spectra of many of the final catalysts
were fully analyzed by using 2D techniques (COSY, HSQCGP,
NOESY) to provide chemical shift assignments for nearly all hydro-
gen and carbon atoms. Accurate mass measurements were per-
formed by HRMS with fast atom bombardment (FAB) or electro-
spray (ESI) as the ionization methods. The FAB measurements were
performed with a four-sector tandem mass spectrometer, whereas
a quadrupole time-of-flight (qTOF) instruments was used for the
ESI measurements. Low-resolution mass spectra were recorded
with an ESI LC ion trap instrument. All specific rotation values were
measured at 208C on a PerkinElmer 241 polarimeter. This polarime-
ter was also used for the reaction rate measurements. UV/Vis ab-
sorption spectra were measured on a double-beam Shimadzu UV-
2700 spectrophotometer. For fluorescence spectroscopy, a Horiba
2857, 1692, 1620, 1510, 1433, 1248, 839 cmꢀ1 1H NMR (400 MHz,
;
CDCl3): d=7.87 (d, J=4.4 Hz, 1H), 7.51 (d, J=9.2 Hz, 1H), 7.07 (dd,
J=9.2, 2.8 Hz, 1H), 7.01 (d, J=2.8 Hz, 1H), 6.91 (d, J=4.8 Hz, 1H),
5.04 (brs, 1H), 4.16 (brs, 2H), 4.07 (t, J=3.6 Hz, 2H), 3.78 (s, 3H),
3.71 (t, J=6.8 Hz, 1H), 3.12 (d, J=13.2 Hz, 1H), 2.76–2.62 (m, 3H),
1.95 (d, J=12.4 Hz, 1H), 1.75 (d, J=12.4 Hz, 1H), 1.61 (m, 1H),
1.42–1.30 (m, 2H), 0.93 (t, 3.6 Hz, 2H), ꢀ0.03 ppm (s, 9H); 13C NMR
(100 MHz, CDCl3): d=157.1, 155.3, 146.4, 144.2, 143.1, 130.4, 128.2,
122.4, 120.1, 101.6, 73.9, 63.1, 55.1 43.7, 42.5, 37.1, 28.2, 17.5,
ꢀ1.7 ppm; HRMS (FAB): m/z calcd for C23H35N2O4Si [M+H]+:
431.2366; found: 431.2359.
Chem. Eur. J. 2016, 22, 1 – 11
www.chemeurj.org
7
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
This alcohol (1.2 g, 2.79 mmol) was dissolved in anhydrous CH2Cl2
(15 mL) and cooled to 08C. Et3N (0.46 mL, 3.34 mmol) and MsCl
(0.26 mL, 3.34 mmol) were added and the resulting mixture was
stirred for 1 h. The reaction was quenched with water and the mix-
ture was warmed to RT. The layers were separated and the aque-
ous layer was extracted twice with CH2Cl2. The organic layers were
combined, washed with brine, dried with MgSO4, and concentrat-
ed. The resultant crude product was dissolved in CH2Cl2 (15 mL)
and cooled to 08C. KOtBu (1m in tBuOH, 3.3 mL, 3.34 mmol) was
added and the mixture was stirred for 2 h. The reaction mixture
was quenched with a saturated solution of NH4Cl and the layers
were separated. The organic layer was washed with a saturated so-
lution of NaHCO3 and brine and dried with MgSO4. The solvent
was evaporated and the product was purified by column chroma-
tography (EtOAc) to yield alkene 14 (1.16 g, 2.79 mmol, 99%) as
a brown oil. IR (neat): n˜ =2951, 2852, 1693, 1620, 1471, 1250, 1225,
The product was purified by column chromatography (CH2Cl2/
MeOH 40:1) to yield epoxide 15 (285 mg, 0.66 mmol, 85%) as a yel-
lowish oil. [a]D =ꢀ19.5 (c=1.0, MeOH); IR (neat): n˜ =2951, 1687,
1621, 1363, 1177, 1030, 855, 833 cmꢀ1 1H NMR (400 MHz, CDCl3):
;
d=8.74 (d, J=4.4 Hz, 1H), 8.06 (d, J=9.2 Hz, 1H), 7.42 (dd, J=9.2,
2.8 Hz, 1H), 7.31 (d, J=4.4 Hz, 1H), 7.22 (d, J=2.8 Hz, 1H), 4.32–
4.22 (m, 5H), 3.96 (s, 3H), 2.88–2.80 (m, 3H), 1.98 (d, J=13.2 Hz,
1H), 1.87 (d, J=12.8 Hz, 1H), 1.76 (m, 1H), 1.48 (m, 2H), 1.02 (t, J=
8.4 Hz, 2H), 0.05 ppm (s, 9H); 13C NMR (100 MHz, CDCl3): d=157.8,
155.4, 147.8, 143.6, 141.1, 131.6, 127.0, 121.3, 116.7, 100.7, 65.3,
63.4, 55.4, 54.2, 43.2, 38.5, 27.9, 17.6, ꢀ1.6 ppm; HRMS (FAB): m/z
calcd for C23H33N2O4Si [M+H]+: 429.2210; found: 429.2212.
Catalyst [1.2.2]
Epoxide 15 (240 mg, 0.56 mmol) was
dissolved in DMF (18 mL) and tBuOH
838 cmꢀ1 1H NMR (400 MHz, CDCl3): d=8.71 (d, J=4.4 Hz, 1H),
;
(2 mL). CsF (126 mg, 0.84 mmol) was
added, the mixture was heated to
110 8C, and stirring was continued for
24 h. The product was concentrated
8.02 (d, J=9.2 Hz, 1H), 7.40 (m, 2H), 7.30 (d, J=2.8 Hz, 1H), 7.02
(d, J=15.6 Hz, 1H), 6.21 (dd, J=15.6, 6.8 Hz, 1H), 4.31–4.20 (m,
4H), 3.98 (s, 3H), 2.91 (m, 2H), 2.52 (m, 1H), 1.90 (d, J=12.8 Hz,
2H), 1.50 (m, 2H), 1.05 (t, J=3.6 Hz, 2H), 0.07 ppm (s, 9H) 13C NMR
(100 MHz, CDCl3): d=157.5, 155.5, 147.5, 144.5, 141.8, 140.7, 131.3,
127.1, 123.5, 121.4, 117.6, 101.5, 63.4, 55.4, 43.5, 39.6, 31.4, 17.7,
ꢀ1.6 ppm; HRMS (FAB): m/z calcd for C23H33N2O3Si [M+H]+:
413.2260; found: 413.2259.
and purified by column chromatography (CH2Cl2/MeOH/NH4OH
10:1:0.1) to yield the [1.2.2] analogue (120 mg, 0.42 mmol, 75%) as
a white solid. M.p. 75–778C; [a]D = +23.3 (c=1.0, CHCl3); IR (neat):
n˜ =3329, 2962, 1621, 1509, 1242, 1227 cmꢀ1 1H NMR (400 MHz,
;
CDCl3): d=8.71 (d, J=4.4 Hz, 1H; H-2), 7.87 (d, J=9.2 Hz, 1H; H-9),
7.57 (d, J=4.4 Hz, 1H; H-3), 7.22 (s, 1H; H-6), 7.17 (dd, J=9.2,
2.4 Hz, 1H; H-8), 5.95 (brs, 1H; H-11), 3.80 (brs, 1H; H-14), 3.74 (s,
3H; H-1), 3.22 (d, J=4.0 Hz, 1H; H-12), 3.18 (m, 1H; H-13), 2.76 (m,
2H; H-13 and 14), 2.67 (s, 1H; H-15), 2.58 (m, 1H; H-18), 1.74 (m,
1H; H-17), 1.48 (m, 1H; H-18), 1.38 ppm (m, 1H; H-17) (OH is miss-
ing); 13C NMR (100 MHz, CDCl3): d=157.7 (C-7), 147.0 (C-2), 146.5
(C-4), 143.8 (C-10), 130.9 (C-9), 126.2 (C-5), 121.7 (C-7), 118.7 (C-3),
101.0 (C-6), 73.5 (C-12), 65.7 (C-11), 56.0 (C-1), 54.3 (C-13), 52.2 (C-
14), 35.8 (C-15), 29.8 (C-17), 28.4 ppm (C-18); HRMS (FAB): m/z
calcd for C17H21N2O2 [M+H]+: 285.1603; found: 285.1600.
trans-Epoxide 15
Alkene 14 (1.16 g, 2.8 mmol) was dissolved in tBuOH (10 mL). A
mixture of AD-mix
a (8 g) and methanesulfonamide (1.3 g,
14.0 mmol) in tBuOH (18 mL) and water (18 mL) was added and
the resultant mixture was stirred for 24 h at 08C. Sodium sulfite
(10 g) was added and stirring was continued for an additional
hour. Water was added and the mixture was extracted three times
with CH2Cl2. The organic layers were combined, washed with brine,
dried with MgSO4, and evaporated. The product was purified by
column chromatography (CH2Cl2/MeOH/Et3N 20:1:0.5) to yield the
diol (860 mg, 1.9 mmol, 69%) as a white foam. ee=97% (deter-
mined by HPLC Chiral Daicel ODH, iPrOH/n-heptane 15:85
(0.50 mLminꢀ1, l=220 nm), tr major=29.7 min and tr minor=
23.8 min); m.p. 68–718C; [a]D =ꢀ12.0 (c=0.5, MeOH); IR (neat):
n˜ =3369, 2952, 1673, 1593, 1510, 1472, 1278, 1248, 1227, 835,
Aldehyde 33
Quinidine (1, 2.0 g, 6.2 mmol) was dissolved in a 1:1 mixture
(20 mL) of acetic anhydride and pyridine. 4-Dimethylaminopyridine
(DMAP; 122 mg, 1 mmol) was added and the resulting mixture was
stirred overnight. The solvent was removed and the residue was
dissolved in CH2Cl2 and extracted with a saturated solution of
NaHCO3. The water layer was extracted three times with CH2Cl2.
The organic layers were combined, washed with brine, dried with
Na2SO4, and concentrated in vacuo. The residue was dissolved in
tBuOH (20 mL) and the resulting solution was added to a solution
(80 mL) of tBuOH and water containing AD-mix a (18.0 g) and
methanesulfonamide (2.94 g, 31.0 mmol). The mixture was stirred
overnight and quenched with sodium sulfite (15 g). Water (200 mL)
and CH2Cl2 (200 mL) were added and the layers were separated.
The water layer was extracted three more times with CH2Cl2. The
organic layers were combined, dried with Na2SO4, and concentrat-
ed. The crude product was dissolved in a 1:1 mixture (20 mL) of
acetone/water and cooled to 08C. NaIO4 (1.32 g, 6.1 mmol) was
added and the resulting mixture was stirred at RT for 2 h. Acetone
was removed and a saturated solution of NaHCO3 and CH2Cl2 were
added. The layers were separated and the aqueous layer was ex-
tracted twice with CH2Cl2. The organic layers were combined, dried
with Na2SO4, and concentrated. Purification by column chromatog-
raphy (CH2Cl2/MeOH 20:1) provided aldehyde 33 (2.0 g, 5.5 mmol,
88% over three steps) as a 9:1 mixture of isomers as a white solid.
731 cmꢀ1 1H NMR (400 MHz, CDCl3): d=8.23 (brs, 1H), 7.54 (dd,
;
J=9.2, 6.8 Hz, 1H), 7.38 (d, J=3.2 Hz, 1H), 7.14 (d, J=9.2 Hz, 1H),
6.88 (s, 1H), 5.40 (s, 1H), 4.26 (brs, 2H), 4.19 (t, J=8.0 Hz, 2H), 3.87
(s, 3H), 3.72 (d, J=7.2 Hz, 1H), 2.78 (m, 2H), 2.15 (d, J=12.8 Hz,
1H), 1.99 (m, 2H), 1.46 (m 1H), 1.26 (m, 1H), 1.01 (t, J=8.0 Hz, 2H),
0.06 ppm (s, 9H) (OH groups are missing); 13C NMR (100 MHz,
CDCl3): d=157.4, 155.6, 146.9, 142.8, 130.4, 125.8, 121.0, 118.9,
100.8, 76.2, 68.7, 63.5, 55.4, 43.8, 38.9, 28.7, 17.7, ꢀ1.5 ppm; HRMS
(FAB): m/z calcd for C23H35N2O5Si [M+H]+: 447.2315; found:
447.2321.
This diol (350 mg, 0.78 mmol) was dissolved in anhydrous CH2Cl2
(5 mL). Trimethyl orthoacetate (300 mL, 2.53 mmol) and PPTS
(19 mg, 0.078 mmol) were added and the mixture was stirred over-
night. The product was concentrated and dissolved in anhydrous
CH2Cl2 (5 mL). TMSCl (320 mL, 2.53 mmol) was added and stirring
was continued for 24 h. The solvent was evaporated and the crude
mixture was dissolved in methanol (5 mL). K2CO3 (539 mg,
3.9 mmol) was added and the resultant mixture was stirred for 2 h.
The reaction was quenched with a saturated solution of NH4Cl and
the mixture was extracted three times with CH2Cl2. The organic
layers were combined, washed with brine, and dried with MgSO4.
1
IR (neat): n˜ =2940, 1743, 1719, 1621, 1228, 1028, 731 cmꢀ1; H NMR
&
&
Chem. Eur. J. 2016, 22, 1 – 11
www.chemeurj.org
8
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
(400 MHz, CDCl3): d=9.88 (s, 0.9H), 9.82 (s, 0.1H), 8.74 (d, J=
4.6 Hz, 1H), 8.03 (d, J=9.2 Hz, 1H), 7.52 (d, J=2.5 Hz, 1H), 7.40
(dd, J=9.2, 2.5 Hz, 1H), 7.31 (d, J=4.5 Hz, 1H), 6.56 (d, J=6.5 Hz,
1H), 4.03 (s, 2.7H), 3.97 (s, 0.3H), 3.66 (m, 1H), 3.26 (m, 1H), 2.91
(m, 1H), 2.76 (m, 2H), 2.49 (m, 2H), 2.17 (s, 3H), 1.83 (brs, 1H),
1.68–1.54 ppm (m, 3H); 13C NMR (100 MHz, CDCl3): d=203.4, 20.3,
169.7, 157.8, 147.2, 144.4, 143.6, 131.5, 126.7, 121.9, 121.7, 118.3,
118.1, 101.0, 73.4, 58.5, 55.5, 50.2, 48.8, 42.1, 25.7, 24.6, 23.2,
20.8 ppm; HRMS (ESI): m/z calcd for C21H25N2O4 [M+H]+: 369.1809;
found: 369.1813.
Itot ¼ axIprotonated þ bxIneutral
ð1Þ
All samples were measured twice, the pKaH values were averaged,
and standard deviations were used as the error.
Methyl 3-(benzylthio)-2-(1,3-dioxoisoindolin-2-yl)propanoate
(36)
Catalyst (6.0 mmol, 5.0 mol%) and 34 (29 mg, 0.125 mmol) were
dissolved in toluene (1.0 mL) and the mixture was cooled to 08C.
Phenylmethanethiol 35 (16 mL, 0.14 mmol) was added and the mix-
ture was stirred for 24 h. The mixture was filtered over silica gel
and concentrated to give addition product 36 (ee determined by
HPLC Chiral Daicel AD, iPrOH/n-heptane 10:90 (1.00 mLminꢀ1, l=
220 nm), tr major=20.5 min and tr minor=16.8 min).
Desvinylquinidine ([2.2.2])
Argon was bubbled through diglyme
(30 mL) for 30 min. Next chloro(1,5-
cyclooctadiene)rhodium(I)
dimer
(39 mg, 0.05 mmol) and dppp
(90 mg, 0.22 mmol) were added and
the bubbling of argon was contin-
3-[(4-tert-Butylphenyl)thio]cyclohexanone (39)
ued for 15 min. Aldehyde 34 (800 mg, 2.17 mmol) was added and
the mixture was heated at reflux overnight. The solution was
cooled to RT and water (200 mL) and CH2Cl2 (200 mL) were added.
The layers were separated and the aqueous layer was extracted
twice with CH2Cl2. The organic layers were combined, washed with
brine, dried with Na2SO4, and concentrated. The residue was dis-
solved in MeOH (10 mL) and cooled to 08C. K2CO3 (1.5 g,
10.9 mmol) was added and the mixture was stirred at RT for 2 h.
The reaction was quenched with water and the mixture was ex-
tracted three times with CH2Cl2. The organic layers were combined,
washed with brine, dried with Na2SO4, and concentrated. Purifica-
tion with column chromatography (CH2Cl2/MeOH/NH4OH 100:3:1)
provided [2.2.2] (518 mg, 1.74 mmol, 81%) as a white solid. M.p.
81–828C; [a]D = +126.6 (c=0.37, CH2Cl2); IR (neat): n˜ =3076, 2935,
Catalyst (6.4 mmol, 1.0 mol%) and 37 (65 mL, 0.67 mmol) were dis-
solved in toluene (1.28 mL). Compound 38 (133 mL, 0.77 mmol)
was added and the mixture was stirred overnight. The mixture was
filtered over silica gel and concentrated to give thioether 39 (ee
determined by HPLC Chiral Daicel AD, iPrOH/n-heptane 2:98
(1.00 mLminꢀ1
8.5 min.
, l=220 nm), tr major=6.9 min and tr minor=
Methyl 1-oxo-2-(3-oxobutyl)-2,3-dihydro-1H-indene-2-car-
boxylate (42)
Catalyst (5.0 mmol, 1.0 mol%) and 41 (95 mg, 0.5 mmol) were dis-
solved in toluene (2.0 mL). Compound 40 (81 mL, 1.0 mmol) was
added and the mixture was stirred overnight. The mixture was fil-
tered over silica gel and concentrated to give 42 (ee determined
1621, 1508, 1259, 1241, 729 cmꢀ1 1H NMR (500 MHz, CDCl3): d=
;
8.64 (d, J=4.5 Hz, 1H; H-2), 7.96 (d, J=9.0 Hz, 1H; H-9), 7.54 (d,
J=4.5 Hz, 1H; H-3), 7.30 (dd, J=9.0, 2.5 Hz, 1H; H-8), 7.20 (d, J=
2.5 Hz, 1H; H-6), 5.67 (d, J=4.0 Hz, 1H; H-11), 3.85 (s, 3H; H-1),
3.57 (m, 1H; H-14), 3.16 (m, 1H; H-12), 2.91 (m, 1H; H-13), 2.83 (m,
1H; H-13), 2.77 (m, 1H; H-14), 2.64 (brs, 1H), 1.87 (m, 2H; H-15, H-
16), 1.64 (m, 1H; H-18), 1.42–1.55 (m, 3H; 2ꢂH-17, H-18), 1.30 ppm
(m, 1H; H-16); 13C NMR (125 MHz, CDCl3): d=157.7 (C-7), 147.7 (C-
4), 147.5 (C-2), 144.1 (C-10), 131.5 (C-9), 126.6 (C-5), 121.5 (C-8),
118.5 (C-3), 101.3 (C-6), 71.7 (C-11), 59.7 (C-12), 55.7 (C-1), 50.7 (C-
13), 44.0 (C-14), 26.3 (C-16), 26.1 (C-18), 25.4 (C-17), 21.9 ppm (C-
15); HRMS (ESI): calculated C18H23N2O2 [M+H]+: 299.1754; found:
299.1749.
by HPLC Chiral Daicel AD-H, iPrOH/n-heptane 15:85 (1.00 mLminꢀ1
l=220 nm), tr major=12.8 min, tr minor=11.3 min).
,
2-(3-Oxo-1,3-diphenylpropyl)malononitrile (45)
Catalyst (10.0 mmol, 10.0 mol%) and 43 (21 mg, 0.1 mmol) were
dissolved in toluene (1 mL). Malononitrile 44 (8 mg, 0.12 mmol)
was added and the mixture was stirred overnight. The mixture was
filtered over silica gel and concentrated to give 45 (ee determined
by HPLC Chiral Daicel AD, iPrOH/n-heptane 20:80 (1.00 mLminꢀ1
l=220 nm), tr major=10.2 min, tr minor=13.6 min).
,
General procedure for the determination of catalyst activity
pKaH determination
For the determination of the activity of the catalysts, a polarimeter
was used to measure relative reaction rates.[3a] The polarimeter was
equipped with a cooling unit to maintain the temperature at 188C
throughout the whole measurement. The measurements were car-
ried out in a 10 cm jacketed cell. The polarimeter was connected
to a computer through a Labjack and the software provided by
Labjack was used to record the optical rotations every 10 s.
The cinchona-type base was dissolved in DMSO (10 mmolmLꢀ1). An
aliquot (5 mL) of that solution was dissolved in a 0.1m solution of
NaOH (2.5 mL) in a sample cuvette. An absorption spectrum was
measured between l=260 and 450 nm. The concentration of the
sample was adjusted so that the maximum absorption was below
0.1. Next, the pH value was measured and then the emission spec-
trum was measured between l=325 and 550 nm with excitation
at l=310 nm. A small amount of HCl solution (different concentra-
tions of HCl solutions were used) was added and the procedure
was repeated until the sample solution reached pH 7 or below.
The emission spectra were integrated and corrected for the dilu-
tion factor. The corrected integrated emissions (Itot) were plotted as
a function of pH. The pKaH values were determined by curve fitting
according to Equation (1):
Just before the reaction was carried out, the catalyst was dissolved
in 1m HCl and extracted three times with CH2Cl2. The pH was ad-
justed with ammonia to 12 and the aqueous layer was extracted
three times with CH2Cl2. The organic layers were combined,
1
washed with brine, dried with Na2SO4, and concentrated. H NMR
spectra were taken to check the purity of the catalyst. Compounds
37 and 38 were freshly distilled before use.
Chem. Eur. J. 2016, 22, 1 – 11
www.chemeurj.org
9
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
[8] C. A. Grob, Helv. Chim. Acta 1985, 68, 882–886.
Cyclohexenone 37 (505 mL, 5.23 mmol) and cinchona catalyst
(0.0523 mmol) were dissolved in toluene (5 mL). A solution of 38
(1.01 mL, 6.01 mmol) in toluene (5 mL) was added and the mixture
was shaken. The reaction solution was placed in the polarimeter
cell and the optical rotation was measured as a function of time.
The time was measured between the addition of 38 and the place-
ment of the cell in the polarimeter and the time was later correct-
ed. All reaction rates of the catalysts were measured twice and the
conversions for both experiments were averaged. The conversion
[9] R. J. Prankerd in Profiles of Drug Substances, Excipients and Related Meth-
odology, Vol 33, (Ed.: H. G. Brittain), Elsevier Inc., 2007, pp. 354–356.
[10] a) I. T. Raheem, S. N. Goodman, E. N. Jacobsen, J. Am. Chem. Soc. 2004,
126, 706–707; b) J. Igarashi, M. Katsukawa, Y. G. Wang, H. P. Acharya, Y.
Kobayashi, Tetrahedron Lett. 2004, 45, 3783–3786; c) J. Igarashi, Y. Ko-
bayashi, Tetrahedron Lett. 2005, 46, 6381–6384; d) K. Furukawa, M. Kat-
sukawa, M. Nuruzzaman, Y. Kobayashi, Heterocycles 2007, 74, 159–166.
[11] H. C. Kolb, M. S. van Nieuwenhze, K. B. Sharpless, Chem. Rev. 1994, 94,
2483–2547.
1
[12] H. C. Kolb, K. B. Sharpless, Tetrahedron 1992, 48, 10515–10530.
[13] L. Nielsen, L. Brehm, P. Krogsgaard-Larsen, J. Med. Chem. 1990, 33, 71–
77.
was plotted as a function of time. The 50% (t = ) conversion point
2
was taken as a fixed point to compare the reaction rates of the cat-
alysts.
[14] K. Omura, D. Swern, Tetrahedron 1978, 34, 1651–1660.
[15] K. A. Fairweather, L. N. Mander, Org. Lett. 2006, 8, 3395–3398.
[16] a) J. E. Baldwin, J. Chem. Soc. Chem. Commun. 1976, 734–736; b) K. C.
Nicolaou, C. V. C. Prasad, P. K. Somers, C.-K. Hwang, J. Am. Chem. Soc.
1989, 111, 5330–5334.
Acknowledgements
The National Research School Combination Catalysis (NRSC-C)
is gratefully acknowledged for financial support. We thank
Jan A. J. Geenevasen, Els Engelen-Goris, and Jan M. Ernsting for
their help with the NMR studies and Elwin Janssen (VU Univer-
sity, Amsterdam) for mass spectral measurements. Dr. Tatu
Kumpulainen is gratefully acknowledged for his help in the de-
termination of the pKaH values.
[17] G. G. Dubinina, W. Y. Yoshida, W. J. Chain, Tetrahedron Lett. 2010, 51,
5325–5327.
[18] This was also reported in: K. A. Gupta, A. K. Saxena, P. C. Jain, N. Anand,
Ind. J. Chem. Sect. B 1987, 26, 344–347.
[19] S. M. Sarkar, Y. Taira, A. Nakano, K. Takahashi, J. Ishihara, S. Hatakeyama,
Tetrahedron Lett. 2011, 52, 923–927.
[20] M. Al Batal, P. G. Jones, T. Lindel, Eur. J. Org. Chem. 2013, 2533–2536.
[21] P. Webber, M. J. Krische, J. Org. Chem. 2008, 73, 9379–9387.
[22] M. J. Bhanushali, N. S. Nandurkar, M. D. Bhor, B. M. Bhanage, Tetrahedron
Lett. 2008, 49, 3672–3676.
[23] D. R. Bender, D. L. Coffen, J. Org. Chem. 1968, 33, 2504–2509.
[24] H. Liu, C. Sun, N.-K. Lee, R. F. Henry, D. Lee, Chem. Eur. J. 2012, 18,
11889–11893.
Keywords: amino alcohols · asymmetric synthesis · basicity ·
Michael addition · organocatalysis
[25] P. L. Stotter, M. D. Friedman, D. E. Minter, J. Org. Chem. 1985, 50, 29–31.
[26] a) J. Gutzwiller, M. R. Uskokovic, J. Am. Chem. Soc. 1978, 100, 576–582;
b) G. Stork, N. Niu, A. Fujimoto, E. R. Koft, J. M. Balkovec, J. R. Tata, G. R.
Dake, J. Am. Chem. Soc. 2001, 123, 3239–3242.
[1] a) T. P. Yoon, E. N. Jacobsen, Science 2003, 299, 1691–1693; b) Cinchona
Alkaloids in Synthesis & Catalysis: Ligands, Immobilization and Organoca-
talysis, (Ed.: C. E. Song), Wiley-VCH: Weinheim, 2009; c) T. Marcelli, H.
Hiemstra, Synthesis 2010, 1229–1279; d) S. Ingemann, H. Hiemstra In
Comprehensive Enantioselective Organocatalysis (Ed.: P. I. Dalko), Wiley-
VCH: Weinheim, 2013, pp. 119–160.
[2] a) P. Hammar, T. Marcelli, H. Hiemstra, F. Himo, Adv. Synth. Catal. 2007,
349, 2537–2548; b) J.-Z. Zhu, Y. Zhang, C. Liu, A.-M. Zheng, W. Wang, J.
Org. Chem. 2012, 77, 9813–9825; c) W. Li, D. Huang, Y. Lv, Org. Biomol.
Chem. 2013, 11, 7497–7506; d) B. Dedeoglu, S. Catak, A. Yildirim, C.
Bolm, V. Aviyente, ChemCatChem 2015, 7, 4173–4179; e) K. N. Houk,
M. N. Grayson, J. Am. Chem. Soc. 2016, 138, 1170–1173.
1
[27] The assignment of the relative stereochemistry is based on the H NMR
coupling constant of the proton adjacent to the hydroxyl group (3J=
4.5 Hz) in combination with the usual stereochemical preference in the
oxidation reaction.[26]
[28] When the esterification was performed without N-hydroxybenzotriazole
and at RT, partial epimerization of (S)-(+)-a-methoxyphenylacetic acid
occurred and the [3.2.2] analogues were obtained in 80% ee.
[29] The correct enantiomer was determined on the basis of the sign of its
specific rotation (Table 1) and the direction of asymmetric induction in
thiol addition (Table 2, reaction B).
[3] a) H. Hiemstra, H. Wynberg, J. Am. Chem. Soc. 1981, 103, 417–430; b) A.
Merschaert, P. Delbeke, D. Daloze, G. Dive, Tetrahedron Lett. 2004, 45,
4697–4701.
[30] P. Fristrup, M. Kreis, A. Palmelund, P.-O. Norrby, R. Madsen, J. Am. Chem.
Soc. 2008, 130, 5206–5215.
[4] a) T. Okino, Y. Hoashi, Y. Takemoto, J. Am. Chem. Soc. 2003, 125, 12672–
12673; b) T. Okino, Y. Hoashi, T. Furukawa, X. Xu, Y. Takemoto, J. Am.
Chem. Soc. 2005, 127, 119–125.
[5] For the thiourea moiety at C-9, see: a) B.-J. Li, L. Jiang, M. Liu, L.-S.
Chen, Y. Wu, Synlett 2005, 603–606; b) B. Vakulya, S. Varga, A. Csampai,
T. Soos, Org. Lett. 2005, 7, 1967–1969; c) S. H. McCooey, S. J. Connon,
Angew. Chem. Int. Ed. 2005, 44, 6367–6370; Angew. Chem. 2005, 117,
6525–6528; d) J. Ye, D. J. Dixon, P. S. Hynes, Chem. Commun. 2005, 35,
4481–4483.
[31] A. Berkessel, B. Seelig, S. Schwengberg, J. Hescheler, A. Sachinidis,
ChemBioChem 2010, 11, 208–217.
[32] J. Hine, Y.-J. Chen, J. Org. Chem. 1987, 52, 2091–2094.
[33] J. R. Lakowicz, Principles of Fluorescence Spectroscopy, Springer, New
York; 3rd Ed., 2006.
[34] J. L. Wilcox, P. C. Bevilacqua, J. Am. Chem. Soc. 2013, 135, 7390–7393.
[35] a) W. Qin, A. Vozza, A. M. Brouwer, J. Phys. Chem. C 2009, 113, 11790–
11795; b) T. Kumpulainen, A. M. Brouwer, Phys. Chem. Chem. Phys. 2012,
14, 13019–13026.
[36] H. Pracejus, F. W. Wilcke, K. Hanemann, J. Prakt. Chem. 1977, 319, 219–
229.
[6] L. Hintermann, J. Ackerstaff, F. Boeck, Chem. Eur. J. 2013, 19, 2311–
2321.
[7] See for example, a) B. Lygo, J. Crosby, T. R. Lowdon, P. G. Wainwright, Tet-
rahedron 2001, 57, 2391–2402; b) T. Marcelli, J. H. van Maarseveen, H.
Hiemstra, Angew. Chem. Int. Ed. 2006, 45, 7496–7504; Angew. Chem.
2006, 118, 7658–7666; c) Z. Rodrꢃguez-Docampo, C. Quigley, S. Tallon,
S. J. Connon, J. Org. Chem. 2012, 77, 2407–2414; d) C. Palacio, S. J.
Connon, Eur. J. Org. Chem. 2013, 77, 5398–5413; e) A. C. Breman,
S. E. M. Telderman, R. P. M. van Santen, J. I. Scott, J. H. van Maarseveen,
S. Ingemann, H. Hiemstra, J. Org. Chem. 2015, 80, 10561–10574.
[37] H. Wynberg, R. Helder, Tetrahedron Lett. 1975, 16, 4057–4060.
[38] A. Russo, A. Perfetto, A. Lattanzi, Adv. Synth. Catal. 2009, 351, 3067–
3071.
Received: April 25, 2016
Published online on && &&, 0000
&
&
Chem. Eur. J. 2016, 22, 1 – 11
www.chemeurj.org
10
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
FULL PAPER
&
Asymmetric Synthesis
A. C. Breman, G. van der Heijden,
J. H. van Maarseveen, S. Ingemann,
H. Hiemstra*
Barking up the right tree: Six quinidine
analogues were synthesized that lacked
the vinyl group and had five- or seven-
membered rings in the (original) quinu-
clidine skeleton. These enantiopure
amino alcohols were examined as
organocatalysts in four asymmetric
conjugate addition reactions and the
results compared with those of known
cinchona alkaloid catalysts (see scheme;
EWG=electron-withdrawing group).
&& – &&
Synthetic and Organocatalytic Studies
of Quinidine Analogues with Ring-Size
Modifications in the Quinuclidine
Moiety
Chem. Eur. J. 2016, 22, 1 – 11
www.chemeurj.org
11
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ