Synthetic approaches to 9-arylated Cinchona alkaloids: Stereoselective addition of Grignard reagents to cinchonanones and hydroxylation of 9-phenylcinchonanes

Article abstract of DOI:10.1016/j.tetasy.2012.05.024

All 8,9-isomers of the 9-phenyl Cinchona alkaloids were obtained by autoxidation of 9-deoxy-9-phenyl-alkaloids and by the addition of Grignard reagents to the respective ketones. The diastereoselective addition of phenyl-, methyl-, and vinylmagnesium reag

Full text of DOI:10.1016/j.tetasy.2012.05.024

Tetrahedron: Asymmetry 23 (2012) 876–883
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Tetrahedron: Asymmetry
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Synthetic approaches to 9-arylated Cinchona alkaloids: stereoselective
addition of Grignard reagents to cinchonanones and hydroxylation of
9-phenylcinchonanes
a
b
a,
⇑
_
´
Przemysław J. Boratynski , Ilona Turowska-Tyrk , Jacek Skarzewski
a Department of Organic Chemistry, Faculty of Chemistry, Wrocław University of Technology, 50-370 Wrocław, Poland
b Institute of Physical and Theoretical Chemistry, Faculty of Chemistry, Wrocław University of Technology, 50-370 Wrocław, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 April 2012
Accepted 29 May 2012
All 8,9-isomers of the 9-phenyl Cinchona alkaloids were obtained by autoxidation of 9-deoxy-9-phenyl-
alkaloids and by the addition of Grignard reagents to the respective ketones. The diastereoselective addi-
tion of phenyl-, methyl-, and vinylmagnesium reagents to quinidinone and cinchoninone gave the corre-
sponding (8R,9S)-products with acceptable yields and starting material recovery. The configurations of
the compounds obtained were established by chemical correlations, NMR experiments, and were sup-
ported by DFT calculations and X-ray structures. Stereochemical models for both reactions were also
devised and discussed.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
Herein we report two synthetic approaches to the derivatives
with the 9-OH group and additional carbon substituents present
Easily available, pseudoenantiomeric natural Cinchona alkaloids,
such as quinine (QN) and quinidine (QD) have gained much inter-
est for their use in asymmetric synthesis.1 Despite significant
achievements in the catalytic applications, their derivatives are
only easily accessible in relatively limited numbers.2 In particular,
those with the extended molecular frameworks remain rather
scarcely available. We have previously reported a series of stereo-
specific carbon–carbon bond forming reactions leading to the cor-
responding 9-deoxy-9-aryl-alkaloids.3 Recently, Connon et al.
prepared a library of the corresponding compounds and evaluated
their effectiveness as chiral bifunctional organocatalysts.4 How-
ever, all of these products lack the 9-hydroxy functionality, which
is essential in many catalytic applications.
at the same position (Fig. 1).
2. Results and discussion
2.1. Synthesis
One straightforward approach to the desired 9-aryl-alkaloids is
the addition of a Grignard reagent to the corresponding ketone.5,6
The overall sequence of the transformations (Scheme 1) starts with
an alkaloid of any configuration at both the C-8 and C-9 stereogen-
ic centers. The Oppenauer oxidation5,7 deprives the compound of
chirality at the C-9 center and allows for easy epimerization at
the adjacent center, while crystallization of the ketone gives the
11
OCH3
OCH3
OCH3
10
6'
5'
3
4
7'
8'
2
H
7
5
9'
9
9
9
4'
8
8
8
N
N
N
10'
6
OH
H
OH
N
N
N
3'
2'
native alkaloid (quinidine)
9-deoxy-9-aryl-alkaloid
9-aryl-alkaloid
Figure 1.
⇑
Corresponding author.
E-mail address: jacek.skarzewski@pwr.wroc.pl (J. Skarzewski).
_
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.05.024

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P. J. Boratynski et al. / Tetrahedron: Asymmetry 23 (2012) 876–883
R1
R1
R1
R2MgX
solvent
R2
OH
O
ref 5, 7
N
N
N
R
OH
N
N
H
N
R1 = OCH3
6 R1 = H
2
1 = H, R2 = Ph
1
R
1 = OCH3, R2 = CH3
7
3 R1 = OCH3, R2 = C2H3
4
R
1 = OCH3, R2 = Ph
5 R1 = OCH3, R2 = m-C6H4NH2
Scheme 1.
ether to methylene chloride, and the desired product 4 was ob-
tained in 48% yield (entry 3). The initial low yields of the Grignard
additions, as well as the unsuccessful reaction with phenyllithium,
were most likely the result of concurrent enolate formation. In
addition to simple Grignards, heteroatom-containing reagents
were also added as exemplified by the reaction of 3-N,N-bis(tri-
methylsilyl)aminophenylmagnesium chloride (entry 5). In a simi-
lar reaction, cinchoninone 6 and phenylmagnesium bromide also
gave the single addition product 7.
In another approach, the sequence of the formation of the car-
bon–carbon and carbon–oxygen bonds was inverted. Thus, we sub-
jected the previously obtained 9-deoxy-9-aryl alkaloids3 (Fig. 1) to
9-hydroxylation. (9R)-Deoxy-9-phenyl-quinidine 8 was deproto-
nated in DMSO and the corresponding carbanion solution was sat-
urated with dry oxygen. The oxidation resulted in the formation of
two separable isomeric products 4 and 9, as confirmed by ESI-MS
(Scheme 2). One of them was identical to product 4, obtained in
the addition of the Grignard reagent to ketone 1. Similarly, (9S)-
deoxy-9-phenyl-quinine 10 was oxidized to two distinct isomeric
products 11 and 12. Both autoxidation reactions proceeded with
moderate diastereoselectivity (dr ca. 2:1) and the more polar prod-
ucts 4 and 11 were favored over the less polar 9 and 12.
Table 1
Addition of Grignard reagents to quinidinone 1 and cinchoninone 6
Entry
R2MgX
Solvent
Product
Yielda
%
1
2
3
4
5
6
CH3MgCl
PhMgCl
PhMgBr
C2H3MgBr
3-(TMS)2NC6H4MgCl
PhMgBr
THF/toluene
THF/toluene
CH2Cl2
CH2Cl2
CH2Cl2
2
4
4
3
5
7
55 (71)
25 (30)
48 (50)
37 (50)
61 (65)
30 (40)
CH2Cl2
a
Yields are preparative, content of product in crude reaction mixtures given in
parentheses is estimated by NMR integration.
(8R)-isomer 1.8,9 The reaction of 1 with methylmagnesium halide
has already been carried out by Woodward et al., however no con-
vincing evidence for the stereochemistry of the transformation
could be given at that time.5 Thus, we repeated the addition of
methylmagnesium chloride to quinidinone 1 in a THF/toluene mix-
ture and we obtained a single addition product 2 (Scheme 1).
Similarly, the reactions of vinylmagnesium and phenylmagne-
sium halides gave a single isomer of the corresponding addition
products 3 and 4. Each crude mixture obtained after aqueous
work-up contained the respective, easily separable, single diaste-
reomeric addition product (within the 1H NMR detection limit)
and the starting material only. The ketone was recovered as a mix-
ture of (8R)- and (8S)-epimers. The initial yields of the addition
were rather poor (Table 1, entry 2). After several attempts, the
yield was improved by changing the solvent from THF or diethyl
2.2. Configuration of the products
In the Grignard addition, the stereogenic center at C-9 is newly
formed. Furthermore, the adjacent center at C-8 in the starting ke-
tone is configurationally labile.9 It was previously speculated (on
the basis of the specific rotation) that the product 2 formed from
OCH3
OCH3
OCH3
1) NaH/DMSO
2) O2
+
N
N
N
21% 4, 9% 9
OH
OH
N
N
N
8
9
4
OCH3
OCH3
OCH3
N
N
N
1) NaH/DMSO
2) O2
+
11
15% , 9%
12
OH
OH
N
N
N
10
11
12
Scheme 2. Synthesis of 9-phenyl-alkaloids.

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P. J. Boratynski et al. / Tetrahedron: Asymmetry 23 (2012) 876–883
878
quinidinone 1 and methylmagnesium iodide was of the same con-
figuration as that of native quinidine.5 We have investigated the
NOE interactions for 2 (Fig. 2). The newly introduced 9-CH3 group
shows cross correlations to 8-CH and one of the hydrogen atoms of
other Grignard reagents, where a high stereoselectivity was also
achieved. The absolute configuration of 4 was also proven to be
(8R,9S) by the X-ray crystal structure (Fig. 3B).
Product 4 and starting materials 1 and 8 share the same config-
uration at the C-8 center. As one can expect, autoxidation did not
cause epimerization at the C-8 atom (cf. Scheme 2). Consequently,
the diastereomer (8R,9S)-4 must differ from 9 in the configuration
at C-9 only. An analogous stereochemical outcome was expected
for the autoxidation of (8S,9S)-10,3a where we also obtained two
C-9 epimers, respectively, 11 and 12.
H
OH
H
N
In another experiment, prior to the addition of phenylmagne-
sium chloride, ketone 1 was allowed to isomerize for a few days
in solution, giving a mixture of C-8 epimers 1 and 1a (Scheme 3),
as was earlier documented by NMR.8 This time both diastereo-
mers 4 and 11 were observed as the reaction products. Phenylal-
kaloid 11 was identical to that previously isolated from the
autoxidation of deoxy-phenyl-quinine 10. Thus it could be antic-
ipated that epimers 1 and 1a gave compounds 4 and 11 of the
same relative (unlike) configuration at the C-8 and C-9 stereo-
genic centers.
Additionally, it is known that the native alkaloids [unlike, i.e.,
(8R,9S) and (8S,9R)] are more polar than their 9-epi counterparts
[like, i.e., (8R,9R) and (8S,9S)];10 the same regularities were ob-
served here, when comparing the corresponding Rf values (see
Section 4).
H3C
H
N
H
OCH3
Figure 2. NOE interactions for 9-methylquinidine 2 in CDCl3.
the 2-CH2 group, while the latter two groups do not correlate with
each other. These unequivocally confirm the (8R)-configuration.
Correlations of 30-CH with 9-CH3 as well as correlations of 50-CH
with 8-CH are better explained by assuming the (9S)-configuration.
Finally, we unambiguously proved the configuration of the
product (8R,9S)-2 with an X-ray crystal structure (Fig. 3A). The
same stereochemical outcome was expected for the reaction of
A
B
Figure 3. Crystal structures of (A) 9-methylquinidine (2ꢀ2H2O) and (B) 9-phenylquinidine (4ꢀEtOH).
OCH3
OCH3
N
O
AcOEt
N
O
N
N
1
1a
OCH3
OCH3
N
1
1a
PhMgCl
PhMgCl
+
+
(mixture)
N
OH
OH
N
N
4
11
1
4
(crystalline)
Scheme 3. Addition of phenylmagnesium chloride to ketones 1 and 1a.

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P. J. Boratynski et al. / Tetrahedron: Asymmetry 23 (2012) 876–883
In the solid state both 2 and 4 adopt very similar conformations,
2.3. Stereochemical models
herein referred to as anti-open11 (Fig. 3). The same type of confor-
mation was observed in the nuclear Overhauser effect experiments
for 2 in CDCl3 suggesting that the open conformation is prevalent in
solution as well (Fig. 2). Optimization of the geometries at the DFT/
B3LYP/6-31G(d,p) level of theory12 in vacuum also indicated that
the anti-open conformation was the most energetically favored
for both 9 and 12 (by ca. 5 kcal/mol) as well as for 4 and 11 (by
ca. 2 kcal/mol).
The addition of the Grignard reagents to (8R)-1 only provided
(8R,9S)-products 2, 3, 4, and 5. As we had proved, the configuration
at the C-8 center of the products is the same as in the crystalline
starting material.8 An isomerization at this center would require
a proton to be transferred from the 8-CH group and back. However,
under the Grignard reaction conditions, protonation of the enolate
is prevented until the reaction is quenched with water (Scheme 4).
Only on the addition of Grignard reagents to the mixture of 1 and
1a, were both products 4 and 11 obtained (Scheme 3).
The diastereoselectivity of the reaction at the C-9 center is in
agreement with the previous findings by Hintermann15 and by
us3 in that the complexation of magnesium to the quinuclidine
nitrogen atom determines the stereochemical outcome. It has been
demonstrated that in the addition and substitution reactions, the
carbon nucleophile always approached the reaction center from
the side of the quinuclidine nitrogen. The observed stereoselectiv-
ity of the reduction of ketone 1 was attributed to the Re attack of
hydride from the complexed aluminum species, resulting exclu-
sively in the native alkaloids.16
The tentative assignment of configuration for phenylalkaloids 9,
11, and 12 (isomers of 4) was augmented by comparison of the
experimental and theoretical (GIAO-DFT/B3LYP/6-31G(d,p)) 13C
chemical shifts.12,13 The correlations of DFT and experimental data
were very good for all compounds (R2 = 0.998). In order to empha-
size the differences in the 13C chemical shifts between the isomers
and compensate for the systematic errors of a DFT calculation,13
a
statistical approach was adopted. For each carbon atom we defined
a deviation from an averaged chemical shift taken for all four dia-
stereomers 4, 9, 11, and 12. The patterns of these deviations for the
experimental and DFT data were in good agreement for all isomers
(Fig. 4); RMS error was in the 0.58–0.77 ppm range, while the
Figure 4. 13C NMR patterns: experimental and calculated (GIAO DFT/B3LYP/6-31G(d,p)) differences of the 13C chemical shifts from the mean chemical shifts for a set of four
isomeric phenyl-alkaloids 4, 9, 11 and 12.
assignments of inappropriate configurations gave 1.26–2.65 ppm
RMS error. The configuration at the C-8 center was assigned on
the basis of the deviations of the C-2 and C-6 chemical shifts.
The patterns observed for the 9-aryl alkaloids were similar to those
observed for 9-unsubstituted alkaloids14 and were very well
matched by the DFT calculation. The relative configuration at the
C-8 and C-9 stereogenic centers was distinguished by observing
deviations in the C-8 and C-9 chemical shifts that was in qualita-
tive agreement with the computational data.
Here, the complexation of magnesium species to quinidinone 1
most likely involved two metal atoms (Scheme 4) that would en-
force the syn-orientation of the ketone oxygen and the quinucli-
dine nitrogen atoms. This conformation is distinct from that
observed in solid quinidinone.8 In such an orientation, the attack
of the carbon nucleophile would occur from the Re face. The prod-
uct formed would have a (9S)-configuration, following the substi-
tuent priority rules. Once the complex is formed, the alternative
approach from the Si face becomes very unlikely because of steric

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P. J. Boratynski et al. / Tetrahedron: Asymmetry 23 (2012) 876–883
Ph
Et2O
Mg
Br
Mg
OMe
Br
OMe
N
N
O
O
OMgBr
8
9
N
PhMgBr
9
N
H
8
Ph
N
H
MeO
H
1
4·MgBr
PhMgBr
N
PhH
OMe
N
OMe
N
MeO
BrMgO
H
N
O
O
8
8
H2O
9
N
+
9
9
8
N
H
N
1
1a
Scheme 4. Suggested intermediates in the synthesis of 4.
hindrance. Thus, the neighboring group (quinuclidine) guides reac-
tions at the 9-carbon stereocenter, whenever metal chelates could
be formed and leads to a highly stereoselective transformation.
These findings are in contrast to the additions that do not involve
metal bidentate complexes, such as the addition of TMS–CF3 re-
agent, which results in the addition from the Si face.8
In the case of the hydroxylation reaction, it was anticipated that
the intermediate anion (or a relatively short-lived radical) would
be nearly flat. Deprotonation of 8 was evidenced by small quanti-
ties of (9S)-deoxy-9-phenylquinidine 13, an epimer of 8, found in
the reaction mixture after aqueous workup (Scheme 5). The pre-
3. Conclusion
In conclusion, a combination of the addition of Grignard re-
agents to cinchonanones and the autoxidation of 9-phenyl-cin-
chonanes gave all of the 8,9-stereoisomers of 9-phenyl-
substituted Cinchona alkaloids. The 9-substituted Cinchona alka-
loids prepared had all of their original functionalities, while offer-
ing an increased rigidity that could be important for their catalytic
applications.
OCH3
OCH3
1) O2
NaCH2SOCH3
2) H2O
Re
DMSO
Si
NaHSO3
N
N
N
H
OH
N
N
H3CO
8
H2O
4 9
/ d.r. 2:1
N
OCH3
N
N
13
Scheme 5. Intermediate anion in the autoxidation of 8.
ferred approach of the reacting species was from the side opposite
to the quinuclidine moiety, that is, Si for quinidine and Re for qui-
nine. This stereochemical behavior has already been observed for
the 9-cinchonanyl radical coupling reaction.17 However, here the
low steric demands of the reacting species (O2) preclude high
stereoselectivities.
4. Experimental
4.1. General
IR spectra were recorded on a Perkin Elmer System 2000 FTIR
spectrophotometer. 1H NMR and 13C NMR spectra were measured

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P. J. Boratynski et al. / Tetrahedron: Asymmetry 23 (2012) 876–883
on a Bruker Avance DRX 300 (1H, 300 MHz) or a Bruker Avance 600
1229, 1028, 1018, 857, 702 cmꢂ1
.
HR-MS (ESI): calcd for
(1H, 600 MHz) spectrometer using a solvent residual peak as a ref-
erence. Optical rotations were measured using an Optical Activity
Ltd Model AA-5 automatic polarimeter. High resolution mass spec-
tra were recorded using a Waters LCT Premier XE instrument in
electrospray ionization mode. Separation of products by chroma-
tography was performed on silica gel 60 (230–400 mesh) pur-
chased from Merck. Thin layer chromatography was carried out
using silica gel 60 precoated plates (Fluka). X-ray data were col-
lected at 299 K using a KM4CCD diffractometer. Crystallographic
data for the structures 2 and 4 herein have been deposited at the
Cambridge Crystallographic Data Centre as supplementary publi-
cation numbers CCDC 872905 and CCDC 872904, respectively.
[C26H28N2O2+H]+ 401.2224, found: 401.2238.
4.2.2. 9-Vinylquinidine, (8R,9S)-60-methoxy-9-vinyl-9-cinchon-
anol 3
According to the procedure for the addition of Grignard re-
agents, a solution of vinylmagnesium bromide (10 mL, 1 M in
THF, 10 mmol, 4.4 equiv) was evaporated and a solution of quinid-
inone 1 (733 mg, 2.27 mmol) in dry CH2Cl2 (17 mL) was added to
the residue. The reaction gave 297 mg of 3 (37%) as a yellowish
amorphous solid after chromatography on silica gel (CHCl3/MeOH,
10:1). Rf (CHCl3/MeOH, 10:1) 0.25. ½a D21
¼ þ97 (c 0.92, EtOH, 96%).
ꢁ
1H NMR (300 MHz, CDCl3): d 8.63 (d, J = 4.7 Hz, 1H), 7.95 (d,
J = 9.1 Hz, 1H), 7.84 (d, J = 4.7 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H),
7.24 (dd, J = 9.1, 2.4 Hz, 1H), 6.89 (dd, J = 17.7, 11.1 Hz, 1H), 5.84
(ddd, J = 17.0, 10.1, 7.7 Hz, 1H), 5.25 (d, J = 10.9 Hz, 1H), 5.03 (d,
J = 17.7 Hz, 1H), 4.88 (d, J = 11.1 Hz, 1H), 4.87 (d, J = 17.0 Hz, 1H),
ꢃ4 (br, 1H), 3.80 (s, 3H), 3.35–3.62 (m, 2H), 3.00 (m, 1H), 2.76–
2.90 (m, 2H), 2.13 (q, J = 8.4 Hz, 1H), 1.73 (m, 1H), 1.59 (m, 1H),
1.40–1.53 (m, 2H), 0.69 (m, 1H). 13C NMR (75.5 MHz, CDCl3): d
156.4, 148.7, 147.4, 144.8, 141.6, 140.1, 131.5, 126.5, 120.8,
120.4, 117.4, 114.5, 105.7, 78.7, 61.4, 55.4, 50.9, 49.9, 39.9, 28.6,
26.0, 21.7. IR (KBr): 3235, 2935, 2869, 1621, 1509, 1240, 1228,
1031, 861, 831 cmꢂ1. HR-MS (ESI): calcd for [C22H26N2O2+H]+
351.2067, found: 351.2083.
4.1.1. Quinidinone 1
This compound was obtained according to a literature proce-
dure7 on a 130 mmol scale and was recrystallized from diethyl
ether.
4.1.2. Cinchoninone 6
This compound was obtained according to a modified proce-
dure7 starting from cinchonine (34.6 g, 117 mmol). Precipitated
crude product (28.6 g) was continuously extracted with 300 mL
of diethyl ether using a Soxhlet apparatus. The extract was then
cooled and the crystalline precipitate collected. The mother liquor
was dried, evaporated and the residue was submitted to two con-
secutive recrystallizations from diethyl ether. Overall, 25.0 g of yel-
lowish crystalline cinchoninone 6 were obtained (73% yield). Mp
121–123 °C, lit.18 mp 125–125.5 °C. NMR (300 MHz, CDCl3): d
9.01 (d, J = 4.4 Hz, 1H), 8.23 (d, J = 8.5 Hz, 1H), 8.15 (d, J = 8.4 Hz,
1H), 7.75 (m, 1H), 7.68 (d, J = 4.4 Hz, 1H), 7.61 (m, 1H), 5.95 (ddd,
J = 17.5, 10.5, 7.2 Hz, 1H), 5.06–5.14 (m, 2H), 4.12–4.24 (m, 1H),
3.17 (dd, J = 17.8, 10.2 Hz, 1H), 2.73–2.95 (m, 2H), 2.54–2.69 (m,
1H), 2.34 (m, 1H), 2.09–2.20 (m, 1H), 1.80–1.96 (s, 2H), 1.61–1.73
(m, 1H), 1.39–1.58 (m, 1H).
4.2.3. 9-(3-Aminophenyl)quinidine, (8R,9S)-60-methoxy-9-(3-
aminophenyl)-9-cinchonanol 5
According to the procedure for addition of Grignard reagents, a
solution of 3-bis(trimethylsilyl)aminophenylmagnesium chloride
(10 mL, 1 M in THF, 10 mmol, 3.2 equiv) was evaporated and a
solution of quinidinone 1 (1023 mg, 3.17 mmol) in dry CH2Cl2
(15 mL) was added to the residue at 0 °C. After 26 h at room tem-
perature, a saturated NH4Cl solution was added and the mixture
was stirred for 30 min. The mixture was extracted with CH2Cl2
and dried over Na2SO4. Chromatography on silica gel (CHCl3/
MeOH, 10:1 to 5:1) afforded 804 mg of 5 (61%) as yellowish amor-
4.2. Procedure for addition of Grignard reagents
phous solid. Rf (CHCl3/MeOH, 10:1) 0.06. ½a D23
¼ þ104 (c 0.80,
ꢁ
A solution of Grignard reagent was obtained from magnesium
(240 mg, 9.9 mmol) and bromobenzene (1.1 mL, 10 mmol) in
diethyl ether (16 mL) and it was evaporated in vacuo. The residue
was cooled to 0 °C and within 2 min a freshly prepared solution of
crystalline quinidinone 1 (378 mg, 1.17 mmol) in CH2Cl2 (10 mL)
was added and the mixture was allowed to return to room temper-
ature. After 24 h, the reaction was quenched with a saturated
NH4Cl solution. The product was extracted with dichloromethane,
dried over Na2SO4 and evaporated. The residue was purified on sil-
ica gel with CHCl3/MeOH 10:1 to afford a mixture of quinidinone/
quininone followed by 9-phenylquinidine 4 223 mg, 48%.
EtOH, 96%). 1H NMR (300 MHz, CDCl3): d 8.63 (d, J = 4.5 Hz, 1H),
7.94 (br, 1H), 7.83 (d, J = 9.1 Hz, 1H), 7.11 (dd, J = 9.1, 2.9 Hz, 1H),
7.05 (d, J = 7.8 Hz, 1H), 6.98 (d, J = 7.7 Hz, 1H), 6.87–7.16 (br, 1H),
6.58 (s, 1H), 6.49 (dd, J = 7.8, 1.3 Hz, 1H), 5.43 (ddd, J = 17.3, 10.2,
7.2 Hz, 1H), 4.73 (d, J = 10.2 Hz, 1H), 4.61 (d, J = 17.2 Hz, 1H), 3.5–
5.0 (br, 3H), 3.82 (t, J = 9.8 Hz, 1H), 3.49–3.62 (m, 1H), 3.46 (s,
3H), 3.15 (m, 1H), 2.72–2.85 (m, 1H), 2.63 (br, 1H), 2.02 (m, 1H),
1.47–1.76 (m, 4H), 1.10–1.30 (br, 1H). 13C NMR (75.5 MHz, CDCl3):
d 156.3, 150.1, 147.1, 146.8, 146.5, 144.9, 139.8, 131.0, 129.1,
127.2, 121.1, 120.2, 116.6, 114.7, 114.5, 114.3, 105.2, 79.1, 61.2,
55.2, 50.6, 49.3, 39.7, 29.0, 26.1, 23.7. IR (KBr): 3335, 3211, 2935,
2868, 1621, 1605, 1508, 1453, 1240, 1226, 1029, 761 cmꢂ1. HR-
MS (ESI): calcd for [C26H29N3O2+H]+ 416.2333, found: 416.2333.
4.2.1. 9-Phenylquinidine, (8R,9S)-60-methoxy-9-phenyl-9-cinch-
onanol 4
White crystalline solid. Mp 182–186 °C (CH2Cl2/hexane). Rf
4.2.4. 9-Phenylcinchonine, (8R,9S)-9-phenyl-9-cinchonanol 7
According to a general procedure, an evaporated solution of
phenylmagnesium bromide (16 mL in Et2O, 10 mmol, 7.7 equiv)
and a freshly prepared solution of cinchoninone 6 (384 mg,
1.31 mmol) in dry CH2Cl2 (17 mL) gave after chromatography on
silicagel (CHCl3/MeOH 20:1 to 20:3) 140 mg (30%) of 7. Recrystal-
lization from ethanol provided white crystals. Mp 225–233 °C
(CHCl3/MeOH, 4:1) 0.246. ½a D26
ꢁ
¼ þ127 (c 0.7 EtOH, 96%). 1H NMR
(300 MHz, CDCl3): d 8.71 (d, J = 4.7 Hz, 1H), 8.02 (br, 1H), 7.88 (d,
J = 9.3 Hz, 1H), 7.46 (dt, J = 6.6, 1.8 Hz, 2H), 7.19–7.31 (m, 3H),
7.13 (dd, J = 9.2, 2.7 Hz, 1H), 6.82 (br, 1H), 5.43 (ddd, J = 17.3,
10.3, 7.0 Hz, 1H), 4.76 (dt, J = 10.4, 1.4 Hz, 1H), 4.62 (dt, J = 17.3,
1.4 Hz, 1H), 4.3 (br, 1H, exchangeable with D2O), 3.96 (t,
J = 10.2 Hz, 1H), 3.42 (s, 3H), 3.22 (m, 1H), 2.80–2.91 (m, 1H),
2.63–2.75 (m, 2H), 2.08 (m, 1H), 1.52–1.79 (m, 4H), 1.18–1.32
(br, 1H). 13C NMR (75.5 MHz, CDCl3): d 156.4, 149.7, 147.4, 145.5,
145.3, 139.7, 131.4, 128.6, 127.7, 127.2, 127.1, 121.1, 120.5,
114.4, 105.1, 79.3, 61.4, 55.3, 50.8, 49.5, 39.8, 29.1, 26.2, 23.8. IR
(KBr): 3143, 2932, 2870, 1622, 1509, 1449, 1432, 1357, 1242,
(EtOH). ½a 2D5
ꢁ
¼ þ11 (c 0.45, EtOH, 96%). 1H NMR (300 MHz, CDCl3):
d 8.91 (d, J = 4.7 Hz, 1H), 8.04 (d, J = 8.1 Hz, 1H), 8.04 (br, 1H), 7.60
(br, 1H), 7.48–7.55 (m, 1H), 7.43–7.48 (m, 2H), 7.15–7.30 (m, 4H),
5.88 (ddd, J = 17.2, 10.3, 7.0 Hz, 1H), 5.07 (dt J = 17.2, 1.6 Hz, 1H),
5.02 (dt, J = 10.4, 1.4 Hz, 1H), 4.2 (br, ꢃ1H), 4.00 (t, J = 9.8 Hz,
1H), 3.01–3.18 (m, 3H), 2.55 (m, 1H), 2.30 (m, 1H), 1.76 (m, 1H),

´
P. J. Boratynski et al. / Tetrahedron: Asymmetry 23 (2012) 876–883
882
1.24–1.56 (m, 4H). 13C NMR (300 MHz, CDCl3): d 151.0, 149.9,
149.1, 145.7, 142.2, 130.3, 128.6, 128.4, 127.7, 127.1, 126.4,
126.2, 125.7, 120.1, 114.6, 80.0, 61.2, 57.6, 43.7, 40.1, 28.3, 27.9,
24.9. HR-MS (ESI): calcd for [C25H26N2O+H]+ 371.2118, found:
371.2124.
121.5, 117.5, 114.6, 106.3, 78.4, 63.1, 55.3, 50.8, 48.8, 39.6, 29.4,
26.4, 24.4. IR (KBr): 3302, 2916, 2867, 1623, 1509, 1449, 1240,
1228, 1034, 998, 912, 841, 709 cmꢂ1. HR-MS (ESI): calcd for
[C26H28N2O2+H]+ 401.2224, found: 401.2235.
4.3.2. (9S)-Deoxy-9-phenylquinidine, (8R,9S)-60-methoxy-9-
phenyl-cinchonane 13
4.2.5. 9-Methylquinidine, (8R,9S)-60-methoxy-9-methyl-9-
cinchonanol 2
Off-white solidified oil. 1H NMR (300 MHz, CDCl3): d 8.79 (d,
J = 4.7 Hz, 1H), 7.94 (d, J = 9.3 Hz, 1H), 7.51 (d, J = 4.7 Hz, 1H),
7.38 (d, J = 2.6 Hz, 1H), 7.18–7.35 (m, 5H), 7.10–7.17 (m, 1H),
6.01 (ddd, J = 17.3, 10.6, 17.8 Hz, 1H), 5.06–5.16 (m, 2H), 4.65 (d,
J = 11.2 Hz, 1H), 3.89 (s, 3H), 3.64 (m, 1H), 2.75–3.13 (m, 4H),
2.25 (m, 1H), 1.76 (m, 1H), 1.48–1.70 (m, 3H), 1.13–1.28 (m, 1H).
13C NMR (300 MHz, CDCl3): d 157.5, 147.8, 147.2, 144.9, 140.83,
140.75, 131.9, 129.0, 128.69, 128.66, 127.0, 120.7, 119.5, 114.6,
102.2, 58.1, 55.5, 49.35, 49.34, 47.6, 39.8, 28.1, 27.2, 26.6. HR-MS
(ESI): calcd for [C26H28N2O+H]+ 385.2274 found 385.2281.
The reaction was carried out according to Woodward0s proce-
dure.5 From quinidinone 1 (440 mg, 1.37 mmol) and methylmag-
nesium chloride (3.0 mL, 3 M in Et2O, 9.0 mmol, 6.5 equiv)
280 mg (55%) of 2 were obtained.
Dihydrate ½a 2D3
ꢁ
¼ þ151 (c 0.49, EtOH, 96%); anhydrous lit.5
[a]
D = +168, = +170 (c 0.5, EtOH, 96%). 1H NMR (600 MHz, CDCl3):
d 8.70 (d, J = 4.7 Hz, 1H), 8.03 (d, J = 9.3 Hz, 1H), 7.71 (br, 1H),
7.67 (br, 1H), 7.34 (dd, J = 9.3, 2.5 Hz, 1H), 5.73 (ddd, J = 17.3,
10.5, 7.7 Hz, 1H), 4.87 (d, J = 10.5 Hz, 1H), 4.79 (d, J = 17.3 Hz,
1H), 3.92 (s, 3H), ꢃ3.4 (br, 1H), 3.28 (t, J = 9.1 Hz, 1H), 3.09 (m,
1H), 3.01 (m, 1H), 2.79–2.90 (m, 2H), 2.13 (m, 1H), 1.95 (s, 3H),
1.78 (m, 1H), 1.67 (m, 1H), 1.51–1.56 (m, 2H), 1.01 (m, 1H). 1H
4.4. Autoxidation of 9-deoxy-9-phenyl-quinine
According to the procedure for autoxidation of 8, (9S)-phenyl-9-
deoxy-quinine3 10 (52.5 mg, 0.13 mmol) and sodium dimsylate
obtained from 63 mg of sodium hydride (1.6 mmol, 12 equiv) gave
(9R)-phenyl-quinine 11 (7.2 mg, 13%) and (9S)-phenyl-quinine 12
(4.5 mg, 9%).
NMR (600 MHz, C6D6):
d 8.74 (d, J = 4.6 Hz, 1H), 8.33 (d,
J = 9.1 Hz, 1H), 7.87 (br, 1H), 7.47 (br, 1H), 7.22 (dd, J = 9.1,
2.7 Hz, 1H), 5.92 (m, 1H), 4.95 (d, J = 10.5 Hz, 1H), 4.91 (d,
J = 17.4 Hz, 1H), 3.45 (s, 3H), 3.36 (m, 1H), 3.18 (br, 1H), ꢃ3.0 (br,
1H), 2.79 (m, 1H), 2.74 (dd, J = 13.6, 10.3 Hz, 1H), 2.60 (m, 1H),
1.92 (m, 1H), 1.81–1.88 (m, 1H) 1.86 (s, 3H), 1.42 (m, 1H), 1.12–
1.16 (m, 2H), 0.71 (m, 1H). 13C NMR (150 MHz, CDCl3): d 156.8,
150.9, 147.5, 145.3, 140.3, 132.1, 127.0, 120.6, 119.9, 114.3,
104.3, ꢃ77.3, 63.4, 55.4, 51.2, 41.8, 39.9, 29.6, 28.8, 26.3, 22.1.
4.4.1. 9-Phenylquinine, (8S,9R)-60-methoxy-9-phenyl-9-cinch-
onanol 11
White crystalline solid. Rf (CHCl3/MeOH, 4:1) 0.377, ½a D26
¼ ꢂ27
ꢁ
(c 0.4 EtOH, 96%), ½a D20
ꢁ
¼ ꢂ9:1 (c 1 CH2Cl2), 1H NMR (300 MHz,
CDCl3) d 8.81 (d, J = 4.7 Hz, 1H), 8.02 (br, 1H), 7.93 (d, J = 9.2 Hz,
1H), 7.44–7.48 (m, 2H), 7.19–7.33 (m, 3H), 7.16 (dd, J = 9.2,
2.8 Hz, 1H), 6.81 (br, 1H), 5.92 (ddd, J = 17.2, 10.5, 6.5 Hz, 1H),
5.11 (dt, J = 17.2, 1.8 Hz, 1H), 5.08 (dt, J = 10.5, 1.8 Hz, 1H), 4.04
(m, 1H), 3.48 (s, 3H), 3.10–3.24 (m, 3H), 2.55–2.68 (m, 1H), 2.35
(m, 1H), 2.1–3.8 (br, 1H), 1.82 (m, 1H), 1.19–1.67 (m, 4H). 13C
NMR (75.5 MHz, CDCl3) d 156.5, 149.4, 147.4, 145.7, 145.3, 142.2,
131.5, 128.5, 127.5, 126.9, 121.3, 120.4, 114.7, 104.8, 79.7, 61.1,
57.6, 55.3, 43.6, 39.9, 28.3, 27.8, 25.1, (1 signal overlap). IR (KBr):
3138, 2920, 2859, 1621, 1509, 1449, 1244, 1229, 1032, 837,
4.3. Autoxidation of 9-deoxy-9-phenyl-quinidine 8
Sodium hydride (60% dispersion in oil, 137 mg, 3.45 mmol,
8.8 equiv) was washed with hexane in an N2-filled glovebag, sus-
pended in dry DMSO (1.5 mL), stirred at 75 °C for 1.5 h, and cooled
to room temperature. Then a solution of (9R)-deoxy-9-phenylalka-
loid3 7 (151.6 mg, 0.39 mmol) in DMSO (1.5 mL) was added and the
mixture turned dark red. After stirring for 20 min, dry oxygen was
slowly passed through a solution for 48 h. The mixture initially
warmed up and a gradual discoloration occurred. Then a solution
of sodium hydrogen sulfite in water (1 mL, 40%) was added and
the mixture was agitated for 30 min, and then alkalized with aque-
ous sodium hydroxide (10%) solution. The mixture was then ex-
tracted with ethyl acetate (6 ꢄ 15 mL). The combined organic
phases were washed with brine and dried over Na2SO4 giving after
evaporation approximately 100 mg of residue. Column chromatog-
raphy on silica gel with CHCl3/MeOH 10:1 afforded a mixture con-
taining 9-epi-phenyl-alkaloid 9, followed by pure (9S)-phenyl-
quinidine 4 (32.2 mg, 21%). The epi-alkaloid fraction (ꢃ60 mg)
was again chromatographed on silica gel with CHCl3/MeOH 20:1
and gave pure (9R)-phenyl-quinidine 9 (14.5 mg, 9%) and (9S)-9-
deoxy-9-phenylquinidine 13 (18.4 mg, 12%).
707 cmꢂ1 HR-MS (ESI): calcd for [C26H28N2O2+H]+ 401.2224,
.
found: 401.2234.
4.4.2. epi-9-Phenylquinine, (8S,9S)-60-methoxy-9-phenyl-9-
cinchonanol 12
White crystalline solid. Rf (CHCl3/MeOH, 4:1) 0.450. ½a D23
¼ þ13
ꢁ
(c 0.2 EtOH, 96%). 1H NMR (300 MHz, CDCl3): d 8.77 (d, J = 4.7 Hz,
1H), 7.87 (d, J = 9.2 Hz, 1H), 7.55 (d, J = 2.8 Hz, 1H), 7.31–7.43 (m,
3H), 7.10–7.26 (m, 4H), 6.08 (ddd, J = 17.2, 10.6, 6.6 Hz, 1H), 5.19
(dt, J = 10.6, 1.5 Hz, 1H), 5.17 (dt, J = 17.2, 1.5 Hz, 1H), 3.73 (t,
J = 9.4 Hz, 1H), 3.61 (s, 3H), 3.13 (dd, J = 13.5, 9.9 Hz, 1H), 2.96–
3.04 (m, 1H), 2.81–2.93 (m, 1H), 2.37 (m, 1H), 2.02–2.14 (m, 1H)
1.93 (m, 1H) 1.63–1.73 (m, 1H), 1.13–1.37 (m, 3H). 13C NMR
(75.5 MHz, CDCl3): d 156.8, 150.0, 147.1, 146.1, 143.9, 141.9,
131.2, 128.8, 127.7, 127.6, 127.0, 121.5, 117.6, 115.0, 106.3, 78.9,
62.8, 57.5, 55.4, 43.1, 39.8, 28.4, 27.5, 25.3. IR (KBr): 3296, 2922,
2861, 1621, 1508, 1240, 1224, 1035, 839, 709, 701 cmꢂ1. HR-MS
(ESI): calcd for [C26H28N2O2+H]+ 401.2224, found: 401.2233.
4.3.1. epi-9-Phenylquinidine, (8R,9R)-60-methoxy-9-phenyl-9-
cinchonanol 9
White crystalline solid. Rf (CHCl3/MeOH, 4:1) 0.309.
½
a 2D4
ꢁ
¼ þ110 (c 0.3 EtOH, 96%). 1H NMR (300 MHz, CDCl3): d 8.76
(d, J = 4.7 Hz, 1H), 7.87 (d, J = 9.2 Hz, 1H), 7.59 (d, J = 2.8 Hz, 1H),
7.46 (d, J = 4.6 Hz, 1H), 7.42 (br d, J = ꢃ6.9 Hz, 2H), 7.17–7.27 (m,
3H), 7.15 (dd, J = 9.2, 2.8 Hz, 1H), 5.18 (ddd, J = 17.3, 10.4, 7.0,
1H), 4.71 (d, J = 10.4 Hz, 1H), 4.49 (d, J = 17.3 Hz, 1H), 3.68 (m,
1H), 3.61 (s, 3H), 3.08 (m, 1H), 2.78–2.91 (m, 1H), 2.67 (dd,
J = 13.6, 9.8 Hz, 1H), 2.50–2.60 (m, 1H), 2.09 (q, J = 8.2 Hz, 1H)
1.59–2.01 (m, 5H). 13C NMR (75.5 MHz, CDCl3): d 156.7, 149.8,
146.8, 146.1, 144.0, 139.1, 131.0, 127.64, 127.59, 127.52, 127.0,
Acknowledgements
We are grateful to the Polish Ministry of Science and Higher
Education for financial support; Grant N N204 161036. We would
like to thank Wroclaw Networking and Supercomputing Center
for the allotment of computer time.

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P. J. Boratynski et al. / Tetrahedron: Asymmetry 23 (2012) 876–883
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