Clickable 9-azido-(9-deoxy)-Cinchona alkaloids: Synthesis and conformation

Article abstract of DOI:10.1016/j.tetasy.2010.10.023

The synthesis and conformational preferences of 9-azido-(9-deoxy)-Cinchona alkaloids constituting a novel class of Cinchona alkaloid derivatives of both natural and 9-epi configurations are described. One and two-step preparative syntheses of 9-azido-(9-deoxy)-Cinchona alkaloids have been developed, allowing for their easy access on a multigram scale. The stereochemical integrity of these azides has been confirmed from their circular dichroism and specific rotation data. The conformations of the 9-azido Cinchona alkaloids, deduced from both ¹H NMR and DFT calculations, show that this class of Cinchona derivatives largely reflect the conformational preferences of the corresponding Cinchona bases; this strategy, therefore, offers a defined chiral and clickable scaffold.

Full text of DOI:10.1016/j.tetasy.2010.10.023

Tetrahedron: Asymmetry 21 (2010) 2740–2745
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Clickable 9-azido-(9-deoxy)-Cinchona alkaloids: synthesis and conformation
⇑
Karol Kacprzak , Bła z_ ej Gierczyk
Department of Chemistry, A. Mickiewicz University, ul. Grunwaldzka 6, 60-780 Pozna n´ , Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis and conformational preferences of 9-azido-(9-deoxy)-Cinchona alkaloids constituting a
novel class of Cinchona alkaloid derivatives of both natural and 9-epi configurations are described. One
and two-step preparative syntheses of 9-azido-(9-deoxy)-Cinchona alkaloids have been developed, allow-
ing for their easy access on a multigram scale. The stereochemical integrity of these azides has been con-
firmed from their circular dichroism and specific rotation data. The conformations of the 9-azido
Received 14 October 2010
Accepted 26 October 2010
Available online 20 November 2010
1
Cinchona alkaloids, deduced from both H NMR and DFT calculations, show that this class of Cinchona
derivatives largely reflect the conformational preferences of the corresponding Cinchona bases; this strat-
egy, therefore, offers a defined chiral and clickable scaffold.
Ó 2010 Elsevier Ltd. All rights reserved.
1
. Introduction
The Cinchona alkaloids comprising quinine and quinidine as its
Brunner has adopted a one-pot Mitsunobu inversion–reduction
protocol for the synthesis of 9-amino Cinchona alkaloids, without
the isolation of intermediate 9-azido derivatives (their formation
1
3
main members are a unique family of natural products which have
found numerous applications as pharmaceuticals, ‘Privileged’ type
in situ has been confirmed by IR spectroscopy). More recently,
Hoffmann et al. have also generated in situ 9-azido-(9-deoxy)-Cin-
chona alkaloids and 9-azido-(9-deoxy)-10,11-didehydro Cinchona
alkaloids by nucleophilic substitution of their corresponding 9-O-
1
2
3
organocatalysts, resolving agents , and chiral selectors in enantio-
selective analytical applications.4 In most of these applications,
parent (unmodified) alkaloids or their simple derivatives including
esters, ethers, or quaternary ammonium salts have been employed.
Most recently, however, many more complex Cinchona alkaloids
derivatives have been demonstrated to be very efficient bifunc-
tional organocatalysts, for example, 9-epi-Cinchona thioureas or
highly discriminative chiral selectors for enantioselective chroma-
tography. Less attention has been devoted to other 9-substituted
mesylates with NaN
molecular cycloaddition/rearrangement cascade.
3
and used them without isolation for an intra-
1
4
The aim of this work was to develop a scalable synthesis of
9-azido-(9-deoxy)quinine and quinidine of the both natural and
9-epi configurations, as well as their systematic characterization
in terms of their stability and stereochemical integrity. Another is-
sue to be addressed is to study the conformation of 9-azido-
5
4
,6
7
8
Cinchona alkaloids, for example, amides, imides, and imines or
(9-deoxy)-Cinchona alkaloids by using a combined approach
sulfides.9
involving NMR and DFT calculations in order to identify the
preferred geometry, helping the construction of structurally
defined Cinchona derivatives thereof.
9
-Azido-(9-deoxy)-Cinchona alkaloids seem to be an attractive
platform for their further elaboration into more complex deriva-
tives due to the high inherent reactivity of the azido group
1
0
located in a crucial part of Cinchona moiety. One of the most
straightforward ways of their further functionalization is the syn-
thesis of the corresponding 1,2,3-triazoles via click chemistry
2. Results and discussion
2.1. Synthesis
(
Huisgen 1,3-dipolar cycloaddition).11 Feasibility studies in this
area demonstrated by our group have confirmed the easy synthesis
of such types of triazolo-Cinchona hybrids.12 Encouraged by these
results, we expanded our strategy to produce more complex Cin-
chona-triazole linked derivatives and, therefore, needed a reliable
method for the multigram preparation of 9-azido Cinchona alka-
loids in pure stereochemical form. These relatively simple deriva-
tives have not been systematically described in the literature.
The first attempt to synthesise 9-azido-(9-deoxy)-Cinchona
alkaloids involved the one-step Mitsunobu inversion of the parent
quinidine QD, quinine QN, and their epimers—9-epiquinidine epi-
QD and 9-epiquinine epi-QN with HN , following the protocol pub-
3
1
3
lished by Brunner et al. or by using diphenylphosphoryl azide
(DPPA) as the azide source (Scheme 1). Although these inversions
were successful and gave almost complete consumption of alka-
loids after 12 h of reaction, very laborious chromatographic purifi-
cation of the desired azides QD-2 and epi-QD-2 was required
resulting in a large consumption of solvents and moderate isolated
⇑
Corresponding author. Tel.: +48 61 8291367; fax: +48 61 829 1505.
E-mail address: karol.kacprzak@gmail.com (K. Kacprzak).
0
957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.10.023

K. Kacprzak, B. Gierczyk / Tetrahedron: Asymmetry 21 (2010) 2740–2745
2741
OMe
N
OMe
OMe
OMe
N
OH
OMs
OH
a
b
a
OMs
N
N
N
N
9
8
N
N
QD
QD-1
epi-QD
epi-QD-1
c
d
c
d
OMe
N
OMe
N
N3
N3
N
N
N
OMe
N
e
N
N
N
epi-QD-2
QD-2
QD-3
Scheme 1. Reagents and conditions: (a) MsCl, TEA, THF, rt; (b) tartaric acid, H2O, reflux 3 h; (c) DIAD, PPh
3 3 3
, HN (or DPPA), THF, rt 12 h; (d) NaN , DMF, 40–50 °C, 12–24 h.
Similar sequence has also been completed using quinine (QN) with exception of quinine-derived triazoline.
1
b a b
correspond to the L , L B bands in the naphthalene chro-
and 1
1
yields of 55–60%. Thus, we decided to use a two-step sequence
involving the O-mesylation of the alkaloids followed by nucleo-
philic substitution of 9-O-mesylates with inorganic azides
1
7
mophore. 9-Azido-(9-deoxy)-Cinchona alkaloids in addition to
the naphthalene chromophore also contain an azido group which
itself constitutes a chromophore, thus the CD of this class of
derivatives may involve the sum of their individual counterparts.
Generally, alkyl azides show two weak transitions in the ultraviolet
1
8
(
Scheme 1). 9-O-Mesylates were obtained using an efficient meth-
14,15
od developed by Hoffmann
with isolated yields of >80%. The
azidation step was then completed by using sodium azide
1.5 equiv) in DMF at 40–50 °C for 24-48 h. This route has been
1
9
(
region. The first one, located at ca. 216 nm, is associated with s-
*
found to be very efficient for the substitution of 9-O-mesylates of
naturally configured alkaloids and the resulting epi-configured 9-
azides epi-QD-2 and epi-QN-2 after simple chromatographic isola-
tion were produced in high yield with high purity (75–95%, see
Section 4). Under these conditions, epi-configured azides were sta-
ble and we did not observe the formation of the corresponding
triazolines formed by the intramolecular cycloaddition of the azide
to vinyl group (see also Ref. 14). Similarly, the azidation of 9-O-me-
syl-9-epiquinine also proceeded cleanly to give 60–65% of the de-
sired azide QN-2. Unfortunately the azidation of an analogous,
pseudoenantiomeric 9-O-mesyl-9-epiquinidine epi-QD-1 gave in
addition to the expected azide QD-2, also significant amounts
p ?p
x
transition, whereas the second at the longer wavelength
*
(ca. 287 nm) originates from the
p?p transition. The CD spectra
of 9-azido-(9-deoxy)-Cinchona alkaloids are presented in Table 1
and Figure 1. As evidenced from the data, the spectra of the azides
differ from each other in terms of position, sign, and magnitude of
the Cotton effect, but the main pattern (e.g. occurrence of the three
typical bands) shows a high degree of similarity as compared to the
native Cinchona alkaloids. The contribution of the weak transitions
originating from the presence of the azide chromophore in the CD
spectra is unfortunately not evident, as they occur in the region of
the quinoline chromophore absorption. More importantly, CD
characteristics allow easy identification of each individual azide.20
For example, in the QN-2/QD-2 pair (natural configuration at car-
bon-9, but pseudoenantiomeric relation) the long-wavelength Cot-
ton effects at ca. 330, 290, and 270 as well as the short wavelength
Cotton effect centered at 210 nm show a nearly perfect mirror-im-
age with similar magnitudes of the Cotton effect. This is not the
case for the Cotton effect at 240 nm which is positive for azide
QN-2 and QD-2. Generally, the CD characteristics of naturally con-
figured QN-2 and QD-2 largely reflect the CD spectra of the parent
(
20–40%) of the corresponding triazoline QD-3, which was the
intramolecular cycloaddition product of the azide and vinyl
1
6
group. This contrasting behavior between naturally and 9-epi
1
4
configured quinidines has already been observed by Hoffmann
who rationalized it by means of different structures of these two
stereoisomeric compounds (vide infra). Attempts to minimize this
side reaction by the use of lithium azide or HN in toluene as nucle-
3
ophiles at room temperature showed similar levels of the
formation of triazoline QD-3. On the other hand, practically quan-
titative conversion of a mixture of 9-O-mesyl-epi-quinidine/so-
dium azide or isolated azide QD-2 leading to QD-3 has been
Table 1
Electronic circular dichroism (ECD) characteristics of 9-azido-(9-deoxy)-Cinchona
observed by an increase of temperature. For example, heating 9-
a
alkaloids
2
azidoquinidine (0.03 M) in DMSO-[ H]
6
at 333 K resulted in over
Azide
CD bands
(nm)
ꢁ0.6 (337) ꢁ2.8 (267) +10.8 (243)
+0.6 (302)
+9.8 (238)b
0.6 (296)
9
5% formation of the corresponding triazoline after 24 h as moni-
1
tored by H NMR spectroscopy giving the calculated intramolecu-
a
,
D
e
(nm) p,
D
e
(nm) b,
D
e
Other,
De (nm) Confg.
ꢁ
5 ꢁ1
lar reaction rate for k = 4 ꢀ 10
s
. In contrast, 9-azido-(9-
QD-2
ꢁ8.1 (208)
(8R,9S)
deoxy)epiquinidine epi-QD-2 gave only ca. 5% of the corresponding
triazoline after 7 days of heating under similar conditions.
Having in hand a reliable synthetic protocol, we checked the
stereochemical integrity of the produced 9-azido Cinchona alka-
loids by comparison of their electronic circular dichroism spectra
+
epi-QD-2 +0.3 (335) ꢁ0.8 (263) ꢁ6.3 (239) +14.5 (214)
(8R,9R)
(8S,9R)
(8S,9S)
+14.1 (200)b
ꢁ
0.1 (325)
+0.4 (337)
QN-2
—
+2.6 (244) +13.7 (212)
ꢁ1.7 (295)
+2.5 (233) +14.2 (206)b
epi-QN-2 ꢁ0.2 (337) +1.0 (278)
+2.9 (233)
+1.2 (215)b
(
CD) and specific rotation data. Circular dichroism spectra of the
parent Cinchona alkaloids usually show three distinct band, which
historically have been designated after Clar as , p and b bands, and
a
ꢁ4
All measurements in acetonitrile, c 10 M.
b
a
Shoulder.

2
742
K. Kacprzak, B. Gierczyk / Tetrahedron: Asymmetry 21 (2010) 2740–2745
Δε
1
5
0
5
0
5
QN-2
QD-2
epi-QD-2
epi-QN-2
O
O
N
1
5'
5'
H
N
H
H
N
7a
H
H
8
b
H
8
b
6a
H
6a
7
a
H
N3
H9
H
9
N3
N
H
H
3'
3'
QN-2
epi-QN-2
-
11'
H C
3
2
00
220
240
260
280
300
320
340
360 nm
O
N
O
11b
H
5
'
2a
5'
H
Figure 1. CD spectra of 9-azido-(9-deoxy)-Cinchona alkaloids (in MeCN,
c
H
H
ꢁ
4
3
ꢂ10 mol/dm ).
N3 9 H
H 9 N3 7b
H
H
7b
N
N
quinine and quinidine, both with respect to the Cotton effect se-
quence and position. A less clear situation is observed for the 9-
epi-configured azides epi-QD-2 and epi-QN-2 because they both
show less intense bands (especially epi-QN-2) making the compar-
ison and precise assignment of the bands more difficult. Neverthe-
less, the long-wavelength region of the epimers again shows
mirror-image characteristics indicating that the transitions local-
ized in this part of spectrum are sensitive to the configuration at
C-8/9 in alkaloid moiety. This is not the case for the short wave-
length Cotton effect which is positive for both epimers but differs
significantly with respect to the magnitude and position. Unfortu-
nately, the rather complex CD picture of azides studied does not al-
low correlation of the observed spectra with the conformation of
the particular azides (vide infra).
H
H
8a
8a
N
H
H
3'
3'
QD-2
epi-QD-2
Figure 2. Structure, proton numbering, and observed NOE’s in 9-azido-(9-deoxy)-
Cinchona alkaloids (see text for details).
A more detailed insight into the conformation of the studied 9-
azido derivatives of Cinchona alkaloids has been made by analysis
of nuclear Overhauser effects between H-9, quinoline and quinucli-
dine moiety hydrogens (Fig. 2). For 9-azido-(9-deoxy)quinine QN-
0
0
2
, strong NOE’s between H-6a and H-9, H-3 , H-5 as well as H-9
2
.2. Conformation
and H-7a were observed, indicating closed conformations. Detec-
0
0
tion of H6a/H3 and H6a/H5 NOEs shows that both syn-closed
and anti-closed conformers are present in the solution. On the other
hand, the presence of open conformers is easily confirmed by H-8b
The conformational behavior of Cinchona alkaloids and their
derivatives is principally determined by the rotation of the two sin-
gle C8-C9 and C4 -C9 bonds connecting the rigid quinoline ring and
0
0
and H-9 as well as H-7a and H-3 NOEs. Since the irradiation of H-
0
quinuclidine moiety. Generally, two distinct compact conforma-
tions are denoted where the lone electron pair of the quinuclidine
nitrogen points over the quinoline ring (closed conformation)
whereas two more relaxed conformers with the quinuclidine nitro-
gen oriented away from the quinoline ring are denoted as open (see
Fig. 2). Several studies in this subject reveal that the alkaloids
of natural configuration at C9 adopted in the non-polar solvents
anti-open conformation, in contrast to the polar solvents which
may stabilize also syn-closed conformers. The 9-epimers of Cin-
chona alkaloids and their derivatives usually prefer the open
conformation as has been demonstrated for 9-epi-configured
7a does not enhance a H-5 signal, the anti-open conformer in CDCl
3
0
0
could be excluded. Analysis of the H-5 and H-3 signal intensities
after H-6a irradiation demonstrates that among closed conforma-
tions, syn-closed is preferred (the ratio of syn-closed to anti-closed
is about 2:1). The calculated ratio of open to closed conformers is
about 1:1.
2
1
22
In the case of 9-azido-(9-deoxy)quinidine QD-2, strong NOEs
were observed between H-9 and H-2a as well as H-9 and H-7b,
indicating the predominance of the open conformers. The contribu-
tion of closed conformation into the conformational equilibrium of
QD-2 in chloroform is rather small as evidenced by very weak
enhancement of the quinoline hydrogen signal after H-2a irradia-
tion. The calculated amount of closed conformer population is less
than 10%, but both the (syn and anti) species are present (both H-
7
23
amides and imides.
The different reactivities of 9-azides toward intramolecular
cycloaddition as well as conformationally dependent properties
of Cinchona alkaloids in stereoselective synthesis or in chiral recog-
nition led us to study in more detail the conformation of these
new derivatives. For this purpose, H NMR and NOESY spectros-
copy as well as molecular modeling was examined. Determination
of the coupling constant of the doublet of protons H9 and H8 is a
sensitive measure of the conformation of the Cinchona alkaloids.
We have found that independent of the configuration at C9, large
0
0
0
2a/H-5 and H-2a/H-3 NOEs were detected). Strong H-7b/H-3
2
a
0
0
0
NOEs, the absence of H-7b/H-5 NOEs, as well as H-9/H-3 (5 ) and
H-8b/H-3 (5 ) NOEs ratios indicate that the syn-open conformer is
more stable in solution.
1
0
0
Irradiation of the H-6a hydrogen of 9-azido-(9-deoxy)epiqui-
nine epi-QN-2 does not enhance any quinoline proton signals
which thus allows us to exclude the occurrence of this compound
in the closed conformation. On the other hand, the presence of an
3
JH9–H8 values varying from 10.5 to 11.5 Hz (CDCl ) indicate an anti
0
0
arrangement of these protons and as a consequence a closed con-
formation for naturally configured and open for 9-epi-configured
Cinchona azides.
open conformation is confirmed by strong H-7a/H-3 (5 ) and H-
0
6a/H-9 NOEs. As a result of an almost equal increase of H-3 and
0
H-5 intensities after H-8 (or H-7a) irradiation, the populations of

K. Kacprzak, B. Gierczyk / Tetrahedron: Asymmetry 21 (2010) 2740–2745
2743
3
syn-open and anti-open conformers in CDCl could be deduced to be
similar. The pseudoenantiomeric 9-azido-(9-deoxy)epiquinidine
epi-QD-2 shows very similar behavior. The absence of nuclear
Overhauser effects between H-2a and quinoline protons supports
the exclusive presence of open conformers. These were also con-
0
0
firmed by the detection of NOEs between H-7b and H-3 (5 ) or H-
0
1
1 and H-11b, respectively. As in the case of epi-QN-2, both syn-
open and anti-open conformers of epi-QD-2 exist in solution in sim-
ilar amounts.
2
.3. Molecular modeling
Molecular modeling studies were carried out for all diastereo-
isomeric azides QN-2 and epi-QN-2, and QD-2 and epi-QD-2. Sys-
tematic generation of the conformers has been performed by
rotating all the torsional angles which contribute to the conforma-
tion (see Fig. 3) using a molecular mechanics method (MM+). For
each individual azide, ca. 100 distinct conformers have been gener-
ated within 0–10 kcal energy range and fully optimized by using
the DFT method with the B3LYP hybrid functional and a 6-
3
1g(D,P) basis set. The lowest energy conformers of each azide
are despited in Figure 3. As expected, the computational data
strongly support the conformational characteristic of 9-azido Cin-
chona alkaloids deduced from the spectroscopic experiments
aforementioned. Moreover, it is worth noting that for the naturally
configured azides both closed and open conformations have been
identified as those of lowest energy whereas the open conformers
are the most stable for epimeric azides epi-QN-2 and epi-QD-2.
In particular, the lowest energy conformation of QN-2 is syn-closed
but the energy difference between the anti-closed (0.61 kcal/mol)
and anti-open conformation (1.19 kcal/mol) is relatively small
(
note that computations are preformed in vacuo). This has also
been observed for quinine derived azide QN-2 for which anti-open
and syn-closed conformers are of lowest energy, differing by about
0
.8 kcal/mol. The epimeric azides epi-QN-2 and epi-QD-2 both
show very similar conformational preferences, with the most sta-
ble syn-open conformation for epi-QN-2 and anti-open for epi-
QD-2. In this case, however, the gain in energy when compared
with their nearest closed conformations is about 1.5–2.5 kcal/mol,
thus precluding their presence under ambient conditions (in agree-
ment with experimental data, no closed conformation has not been
found by NMR).
3
. Conclusion
Synthetically interesting, especially with regards to Huisgen
1
,3-dipolar cycloaddition (click chemistry), stereoisomeric 9-azi-
do-(9-deoxy)-Cinchona alkaloids derived from both quinine and
quinidine have been prepared and systematically characterized.
These azides largely reproduce the conformational dynamics of
their precursors (parent Cinchona alkaloids) thus offering a chiral
scaffold of predictable structure for further elaboration.
Figure 3. Computed lowest-energy conformers of 9-azido-(9-deoxy)-Cinchona
alkaloids (B3LYP hybrid functional and a 6-31g(D,P) basis set).
4
4
. Experimental
distilled. Preparative column chromatography was performed on
an Argonaut system using prepacked silica gel cartridges or by con-
ventional column chromatography on silica gel.
.1. General
Quinine QN and quinidine QD were of commercial grade (Buchler
The NMR spectra were recorded at 295.0 ± 0.1 K on Bruker
Avance DRX 600 spectrometer, operating at frequencies of
GmbH) usually accompanied by <10% of 10,11-dihydro alkaloids. 9-
Epiquinine epi-QN, 9-epiquinidine (epi-QD) were prepared by the
procedure of Hoffmann.24 9-O-Mesyl Cinchona alkaloids were ob-
1
13
600.055 MHz for H and 150.899 MHz for C equipped with a
1
31
5 mm triple-resonance inverse probehead { H/ P/BB} with a
15
tained by standard mesylation as described in reference. HN
3
solu-
self-shielded z-gradient coil. Spectra were measured in freshly
tion in benzene or toluene (caution: toxic and volatile) was prepared
according to the literature.25 All other reagents were purchased
from Aldrich and Fluka and used as received. Anhydrous THF was
distilled over potassium/benzophenone, other solvents were
3
distilled CDCl , the sample concentrations were 10 mg per 600 ll
of solvent. Before NOE experiments, samples were flame-sealed
after deoxygenation by purging with pure nitrogen gas for
10 min, and then degassing using ultrasonic bath and evacuation.

2
744
K. Kacprzak, B. Gierczyk / Tetrahedron: Asymmetry 21 (2010) 2740–2745
0
0
All shifts were referenced to the internal tetramethylsilane. 1D gra-
dient selected NOESY spectra were recorded using a standard se-
quence from Bruker sequences library, mixing time (d8) was set
to 0.300 s; 256–512 scans were collected.
J = 9.2, 2.7 Hz, H-7 ), 7.39 (d, 1H, J = 4.4 Hz, H-3 ), 7.29 (d, 1H,
0
J = 2.7 Hz, H-5 ), 6.03 (ddd, 1H, J = 17.3, 10.4, 7.1 Hz, H-10), 5.22
(bd, 1H, J = 6.3 Hz, H-9), 5.13 (dt, 1H, J = 10.4, 1.4 Hz, H-11b), 5.10
(dt, 1H, J = 17.3, 1.4 Hz, H-11a), 3.95 (s, 3H, H-11 ), 3.20 (pseudoq,
0
Mass spectra were recorded on a AMD 604/402, IR spectra (KBr
pellets) were recorded on a Brucker ITS 113v spectrometer. Optical
rotation was measured using Perkin–Elmer LS-30 spectropolarim-
eter. Cache Worksystem Pro 5 (Fujitsu) and GAUSSIAN 4.0 (Gauss-
1H, J = 8.4 Hz, H-8a), 2.95 (ddd, 1H, J = 14.3, 7.9, 2.2 Hz, H-2a),
2.89 (dd, 1H, J = 14.3, 9.9 Hz, H-2b); 2.84 (m, 1H, H-6b), 2.75 (m,
1H, H-6a), 2.26 (m, 1H, H-3), 1.87 (dd, 1H, J = 13.9, 9.7 Hz, H-7b),
13
1.87 (m, 1H, H-4), 1.56 (m, 2H, H-5a,b), 1.52 (m, 1H, H-7a).
C
2
6
0
0
0
ian) was used for the molecular modeling.
NMR (CDCl
3
): 158.11 (C-6 ), 147.58 (C-2 ), 144.93 (C-4 ), 142.15
0
0
0
0
(
C-9 ), 140.23 (C-10), 132.09 (C-8 ), 127.13 (C-10 ), 121.72 (C-7 ),
0
0
4
.2. General procedure for the synthesis of 9-azido-(9-deoxy)-
119.39 (C-3 ), 114.83 (C-11), 101.16 (C-5 ), 65.10 (br, C-9), 58.58
0
Cinchona alkaloids by the substitution of the corresponding 9-
O-mesylates (Method A)
(C-8), 55.64 (C-11 ), 49.86 (C-6), 48.71 (C-2), 39.70 (C-3), 27.87
23 5
(C-4), 26.33 (C-5), 24.19 (C-7); HRMS (EI) calcd for C20H N O
ꢁ1
3
49.1903, found 349.1899, IR (KBr)
1588, 1473, 1450, 1259, 1228, 1133, 1088, 1032, 850, 830;
= +28.0 (c 1, CHCl ).
m (cm ) 2940, 2102, 1620,
A stirred solution of 2.5 g of 9-O-mesylquinidine (6.2 mmol,
1
equiv) in 12 ml of anhydrous DMF was treated with 0.6 g of
[a
]
D
3
NaN (9.23 mmol, 1.5 equiv). The mixture was stirred on oil bath
3
at 45–55 °C until all the mesylate was consumed (12–48 h, TLC
monitoring), after which filtration of salts, and evaporation of
DMF under reduced pressure (water bath 50 °C) took place. The
crude azide was dissolved in a small portion of dichloromethane
and purified by liquid chromatography on silica gel using 5% meth-
anol in dichloromethane. Yield: 1.63 g (75%) as yellowish, dense
oil.
4.6. (8S,9S)-9-Azido-(9-deoxy)epiquinine epi-QN-2
1
Method A, yellowish oil, yield 2.53 g (95%), H NMR (CDCl
3
): d
0
0
8.79 (d, 1H, J = 4.5 Hz, H-2 ), 8.09 (d, 1H, J = 9.1 Hz, H-8 ), 7.48 (br,
0
0
1H, H-5 ), 7.43 (dd, 1H, J = 9.1, 2.6 Hz, H-7 ), 7.34 (d, 1H,
0
J = 4.5 Hz, H-3 ), 5.76 (ddd, 1H, J = 17.4, 10.4, 7.4 Hz, H-10), 5.02
(br, 1H, H-9), 5.01 (dt, 1H, J = 17.4, 1.4 Hz, H-11a), 4.98 (dt, 1H,
0
J = 10.4, 1.4 Hz, H-11b), 3.97 (s, 3H, H-11 ), 3.38 (pseudoq, 1H,
4
.3. General procedure for the synthesis of 9-azido-(9-deoxy)-
J = 9.6 Hz, H-8b), 3.22 (m, 1H, H-6a), 3.32 (dd, 1H, J = 14.0,
10.7 Hz, H-2a); 2.91 (m, 1H, H-6b), 2.85 (ddd, 1H, J = 14.0, 4.4,
Cinchona alkaloids by Mitsunobu inversion (Method B)
2
.5 Hz, H-2b), 2.30 (m, 1H, H-3), 1.67 (m, 1H, H-4), 1.59 (m, 2H,
The reaction is preformed under an inert atmosphere. To the
stirred solution of 0.51 g of 9-epi-quinidine (1.57 mmol, 1 equiv)
and 0.62 g of triphenylphosphine (2.36 mmol, 1.5 equiv) in 15 ml
of anhydrous THF cooled on an ice-bath to 0 °C, 0.41 mL of DPPA
H-5a,b), 1.40 (m, 1H, H-7b), 0.78 (ddm, 1H, J = 13.9, 7.7 Hz, H-7a).
1
3
0
0
0
C NMR (CDCl
3
): 158.09 (C-6 ), 147.94 (C-2 ), 145.01 (C-4 ),
0
0
0
141.32 (C-10), 140.36 (C-9 ), 132.08 (C-8 ), 127.55 (C-10 ), 121.82
0
0
0
(C-7 ), 120.89 (br, C-3 ), 114.26 (C-11), 101.60 (C-5 ), 63.67 (br, C-
0
(
1.88 mmol, 1.2 equiv) was added by syringe (or alternatively
9), 59.11 (C-8), 55.99 (C-2), 55.57 (C-11 ), 40.91 (C-6), 39.35 (C-
3
ml of hydrazoic acid ꢂ4%, ꢂ3 mmol in benzene—caution: volatile
3), 27.94 (C-5), 27.18 (C-4), 26.15 (C-7); HRMS (EI) calcd for
ꢁ1
poison) followed by the slow addition of DIAD (0.45 ml, 1.2 equiv).
The solution was left to stir overnight. Solvent was removed on
rotatory evaporator (bath <30 °C) and the residue was purified by
column chromatography on silica gel using 5% MeOH in dichloro-
methane as the solvent. Products in the forms of dense oils were
prepared with yields of 50–60%.
C
20
H
23
N
5
O 349.1903, found 349.1903, IR (KBr)
2100, 1674, 1621, 1590, 1508, 1475, 1432, 1259, 1242, 1228,
1134, 1083, 1032, 918, 853, 831, 755; [ = +77.5 (c 1, CHCl ).
m (cm ) 2942,
a]
D
3
4.7. (8S,9R)-9-Azido-(9-deoxy)quinine QN-2
1
Method B, yellowish oil, yield 50%, H NMR (CDCl
3
): d 8.79 (d,
0
0
4
.4. (8R,9R)-9-Azido-(9-deoxy)epiquinidine epi-QD-2
1H, J = 4.6 Hz, H-2 ), 8.07 (d, 1H, J = 8.6 Hz, H-8 ), 7.41 (dd, 1H,
J = 8.6, 2.7 Hz, H-7 ), 7.39 (d, 1H, J = 4.6 Hz, H-3 ), 7.32 (d, 1H,
J = 2.7 Hz, H-5 ), 5.82 (ddd, 1H, J = 17.5, 10.2, 7.5 Hz, H-10), 5.19
0
0
1
0
0
H NMR (CDCl
3
): d 8.79 (d, 1H, J = 4.3 Hz, H-2 ), 8.07 (d, 1H,
0
0
J = 9.1 Hz, H-8 ), 7.45 (br s, 1H, H-5 ), 7.42 (dd, 1H, J = 9.1, 4.3 Hz,
H-7 ), 7.37 (d, 1H, J = 4.3 Hz, H-3 ), 5.87 (ddd, 1H, J = 17.2, 10.8,
(br d, 1H, J = 7.2 Hz, H-9), 5.01 (dt, 1H, J = 17.5, 1.4 Hz, H-11a),
0
0
0
4.99 (dt, 1H, J = 10.2, 1.4 Hz, H-11b), 3.95 (s, 3H, H-11 ), 3.27 (pseu-
6
.3 Hz, H-10), 5.11 (dt, 1H, J = 10.4, 1.7 Hz, H-11b), 5.10 (dt, 1H,
doq, 1H, J = 7.4 Hz, H-8b), 3.12 (m, 1H, H-6a), 3.06 (dd, 1H, J = 13.5,
9.9 Hz, H-2b); 2.64 (m, 2H, H-2a, H-6b), 2.27 (br m, 1H, H-3), 1.90
(m, 1H, H-7b), 1.86 (m, 1H, H-4), 1.70 (m, 1H, H-5a), 1.57 (ddm, 1H,
0
J = 17.2, 1.7 Hz, H-11a), 5.08 (br, 1 H, H-9), 3.97 (s, 3H, H-11 ),
3
.26 (pseudoq, 1H, J = 9.3 Hz, H-8a), 3.15 (dd, 1H, J = 14.5, 10.4 Hz,
H-2b), 3.07 (dd, 1H, J = 13.5, 2.4 Hz, H-6a), 3.01 (ddd, 1H, J = 13.5,
.6, 7.9 Hz, H-6b), 2.94 (dd, 1H, J = 14.5, 7.6, 2.1 Hz, H-2a), 2.32
m, 1H, H-3), 1.65 (m, 1H, H-4), 1.55 (m, 2H, H-5a,b), 1.13 (ddd,
1
3
J = 13.6, 7.8 Hz, H-7a), 1.53 (m, 1H, H-5b). C NMR (CDCl
3
): 158.04
0
0
0
0
9
(
(C-6 ), 147.48 (C-2 ), 144.83 (C-4 ), 141.82 (C-9 ), 141.50 (C-10),
0
0
0
0
131.99 (C-8 ), 127.03 (C-10 ), 121.65 (C-7 ), 119.46 (C-3 ), 114.49
13
0
1
H, J = 13.8, 8.8, 1.8 Hz, H-7b), 0.94 (m, 1H, H-7a). C NMR
(C-11), 101.04 (C-5 ), 65.28 (br, C-9), 58.41 (C-8), 56.48 (C-2),
0
0
0
0
0
(
CDCl
3
): 158.11 (C-6 ), 147.46 (C-2 ), 144.98 (C-4 ), 140.92 (C-9 ),
55.59 (C-11 ), 41.98 (C-6), 39.48 (C-3), 27.59 (C-5), 27.50 (C-4),
0
0
0
1
40.34 (C-10), 132.09 (C-8 ), 127.54 (C-10 ), 122.08 (C-7 ), 120.71
24.93 (C-7).HRMS (EI) calcd for C20
H
23
N
5
O 349.1903, found
0
0
ꢁ1
(
br, C-3 ), 114.77 (C-11), 101.29 (C-5 ), 62.40 (br, C-9), 59.85 (br,
349.1893, IR (KBr)
m
(cm ) 2941, 2103, 1724, 1621, 1590, 1508,
0
C-8), 55.57 (C-11 ), 49.34 (C-6), 47.39 (C-2), 39.18 (C-3), 27.19
1473, 1455, 1432, 1256, 1242, 1228, 1132, 1084, 1031, 989, 912,
(
3
1
C-4), 26.41 (C-5), 25.14 (C-7); HRMS (EI) calcd for C20
H
23
N
5
O
852, 832, 737; [ ).
a
]
D
= ꢁ28.2 (c 1.1, CHCl
3
ꢁ1
49.1903, found 349.1894, IR (KBr)
621, 1508, 1475, 1433, 1258, 1227, 1137, 1090, 1030, 852, 828;
= +55.7 (c 1, CHCl ).
m (cm ) 2938, 2100, 1675,
4.8. QD-3 (triazoline)
[a
]
D
3
1
0
H NMR (DMSO-d
6
): d 8.77 (d, 1H, J = 4.6 Hz, H-2 ), 8.02 (d, 1H,
0
0
4
.5. (8R,9S)-9-Azido-(9-deoxy)quinidine QD-2
J = 9.2 Hz, H-8 ), 7.59 (d, 1H, J = 4.6 Hz, H-3 ), 7.47 (dd, 1H, J = 9.2,
.7 Hz, H-7 ), 7.27 (d, 1H, J = 2.7 Hz, H-5 ), 6.34 (s, 1H, H-9), 4.49
0
0
2
1
Method B, yellowish oil, 300 mg (55%), H NMR (CDCl
3
): d 8.79
(dd, 1H, J = 20.8, 13.5 Hz, H-11b), 4.48 (m, 1H, H-10), 4.11 (dd,
1H, J = 20.8, 12.8 Hz, H-11a), 3.94 (s, 3H, H-11 ), 3.35 (d, 1H,
0
0
0
(
d, 1H, J = 4.4 Hz, H-2 ), 8.06 (d, 1H, J = 9.2 Hz, H-8 ), 7.40 (dd, 1H,

K. Kacprzak, B. Gierczyk / Tetrahedron: Asymmetry 21 (2010) 2740–2745
2745
J = 10.0 Hz, H-8a), 2.84 (dd, 1H, J = 13.0, 9.6 Hz, H-6b), 2.72 (m, 1H,
H-6a), 2.67 (dd, 1H, J = 14.4, 7.9 Hz, H-2b); 2.32 (d, 1H, J = 14.4 Hz,
H-2a), 2.00 (m, 1H, H-4), 1.95 (m, 1H, H-7b), 1.71 (m, 1H, H-3), 1.52
11. (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004–
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13. Brunner, H.; Bügler, J.; Nuber, B. Tetrahedron: Asymmetry 1995, 6, 1699–1702.
14. Roper, S.; Franz, M. H.; Wartchow, R.; Hoffmann, H. M. R. Org. Lett. 2003, 5,
2
1
2
1
3
(
(
1
(
5
2
1
m, 1H, H-5b), 1.37 (m, 1H, H-5a), 1.18 (m, 1H, H-7a). C NMR
0
0
0
0
CDCl
3
): 157.57 (C-6 ), 147.80 (C-2 ), 146.07 (C-4 ), 143.80 (C-9 ),
2773–2776.
0
0
0
0
31.61 (C-8 ), 125.82 (C-10 ), 121.39 (C-7 ), 120.19 (C-3 ), 101.03
15. Franz, M. H.; Röper, S.; Wartchow, R.; Hoffmann, H. M. R. Journal. Org. Chem.
0
C-5 ), 72.47 (C-11), 62.88 (br, C-9), 58.52 (C-10), 55.63 (C-8),
2004, 69, 2983–2991.
16. (a) Basak, A.; Roy, S. K.; Das, S.; Hazra, A. B.; Ghosh, S. C.; Jha, S. Chem. Commun.
0
5.57 (C-11 ), 47.49 (C-6), 45.36 (C-5), 39.09 (C-3), 26.19 (C-4),
2007, 622; (b) Markidis, T.; Mikros, E.; Kokotos, G. Heterocycles 2003, 60, 2637–
ꢁ1
3.59 (C-5), 22.74 (C-7); IR (KBr)
m (cm ) 1620, 1591, 1506,
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497, 1470, 1434, 1426, 1302, 1232, 1136, 1049, 1024, 827, 712
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1
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Research support from European Commission (project click-fun
Grant No. 206943) is gratefully acknowledged. The authors are in-
debted to Dr. Paweł Skowronek for their help in molecular
modeling.
1332–1340.
20. The purities of all synthesized azides have also been checked by RP-HPLC,
indicating >95% purity for all samples.
2
1. Due to the limited space, the conformations of Cinchona alkaloids are not
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