Easy access to 9-epimers of cinchona alkaloids: One-pot inversion by mitsunobu esterification-saponification

Article abstract of DOI:10.1055/s-0030-1259483

Cinchona alkaloids were efficiently converted into their 9-epi diastereomers. The applied one-pot procedure was based on the Mitsunobu esterification with 4-nitrobenzoic acid followed by in situ saponification of the ester. This method requires only one column chromatography, easily separating the epi-isomer from the native alkaloid and the Mitsunobu byproducts. The procedure gives higher yields and is operationally simpler than the previously used stereoselective hydrolysis of the corresponding sulfonic acid esters. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1259483

708
SHORT PAPER
Easy Access to 9-Epimers of Cinchona Alkaloids: One-Pot Inversion by
Mitsunobu Esterification–Saponification
9
-Epimerization
u
of Cinchon
k
a
A
lkaloids asz Sidorowicz, Jacek Skarżewski*
Department of Organic Chemistry, Faculty of Chemistry, Wrocław University of Technology, 50-370 Wrocław, Poland
Fax +48(71)3284064; E-mail: jacek.skarzewski@pwr,wroc.pl
Received 22 November 2010; revised 10 January 2011
hydrolysis of tosylates or mesylates of the native
Abstract: Cinchona alkaloids were efficiently converted into their
9-epi diastereomers. The applied one-pot procedure was based on
the Mitsunobu esterification with 4-nitrobenzoic acid followed by
in situ saponification of the ester. This method requires only one
epimers.3 However, in spite of recent improvements3b in
the original Suszko method,3a the whole procedure is rath-
er tedious, requiring two separate chromatographic purifi-
column chromatography, easily separating the epi-isomer from the cations.
native alkaloid and the Mitsunobu byproducts. The procedure gives
higher yields and is operationally simpler than the previously used
stereoselective hydrolysis of the corresponding sulfonic acid esters.
For our ongoing project on the synthesis of various chal-
cogen derivatives of cinchona alkaloids4 we often needed
gram amounts of the 9-epi-alkaloids. In order to simplify
their preparation we decided to examine a classical meth-
od for the inversion of chiral secondary alcohols, i.e. the
Mitsunobu esterification and subsequent ester hydroly-
sis.5 In spite of the high reputation of this well-established
approach, there were also numerous reports on the esteri-
fication/hydrolysis sequence resulting in the retention of
configuration. It especially happened for sterically hin-
dered secondary alcohols, where the oxophosphonium ac-
tivation of carboxylic acid prevails over that of the alcohol
and the alcohol acts as a nucleophile (Scheme 1).6
Key words: cinchona alkaloids, Mitsunobu reaction, inversion, al-
cohols, chiral pool
Easily available cinchona alkaloids, namely quinine
(QN), quinidine (QD), cinchonine (CN), and cinchonidine
(CD), (Figure 1) enjoy much interest as privileged cata-
lysts, effective in numerous mechanistically different,
enantioselective transformations.1 Their additional advan-
tage comes from the fact that they constitute near enantio-
mers. Often, the formation of the opposite stereoisomer of
the product can be achieved using such pseudoenantio-
meric catalysts.
Ph3P+
COOEt
N–
Ph3P
+
N
N
N
EtOOC
COOEt
EtOOC
2 R2OH
OR2
Ph P
R1COOH
3S
R
6'
R
4S
4S
COOEt
H
Ph3P+
N
EtOOC
H
N
COOEt
H
3S
6'
N
+
N
N
1S
N
1S
3
8S
9R
8R
9S
OR2
EtOOC
R2OH
R1COO–
OH
HO
R1COOH
OR2
N
N
R1COO–+
+
Ph3P OR2
Ph3P
OCOR1
nucleophile
R = OMe, quinine (QN)
R = H, cinchonidine (CD)
R = OMe, quinidine (QD)
R = H, cinchonine (CN)
SN2
O
+
Ph3P OCOR1
–OR2
nucleophile
Ph3P
O
+
+
Figure 1
R1 OR2
inversion product
SNAc
O
Their stereodifferentiating properties are mainly deter-
mined by configurations at the C8/C9 stereogenic cen-
ters.1 Thus for the native, 8,9-unlike isomers, e.g. (8S,9R)-
QN, the anti-closed conformation dominates, locating
both the quinuclidine nitrogen atom and 9-hydroxy group
far away from each other. In contrast, 9-epi-alkaloids
(8,9-like isomers) form preferential conformations with
both functionalities located closely, forming an intramo-
lecular hydrogen bond that is absent in the native alka-
loids.2 Essentially, the unnatural alkaloids of 9-epi-
configuration are available by the tartaric acid catalyzed
Ph3P
O
+
R1 OR2
retention product
Scheme 1 The simplified mechanism of the Mitsunobu esterifica-
tion, for details, see ref. 6
The database screening revealed that the application of the
Mitsunobu method to the inversion of cinchona alkaloids
has not been reported as yet. On the other hand, the
Mitsunobu reaction has already been used with these alka-
loids for the preparation of azides/primary amines (HN3
pKa 4.72, Ph3P, DIAD, followed by in situ reduction with
Ph3P; 45–65% yield)7 and thioacetates (AcSH pKa 3.33,
Ph3P, DEAD; 44–59% yield).4c Both reactions worked
well, giving selectively the SN2-type products in fair to
SYNTHESIS 2011, No. 5, pp 0708–0710
x
x
.
x
x
.2
0
1
1
Advanced online publication: 31.01.2011
DOI: 10.1055/s-0030-1259483; Art ID: T22410SS
© Georg Thieme Verlag Stuttgart · New York

SHORT PAPER
9-Epimerization of Cinchona Alkaloids
709
Table 1 Inversion of Cinchona Alkaloids by Mesyl Ester Hydrolysis and Mitsunobu Esterification/Saponificationa
Alkaloid (Rf)b
epi-Alkaloid (Rf)b
epi-Alkaloid, this work
epi-Alkaloid, two steps
Yield (%)
[a]D20 (EtOH)
Total yield (%)
[a]D20 (EtOH)
QN (0.204)
QD (0.186)
CN (0.168)
CD (0.159)
epi-QN (0.575)
epi-QD (0.584)
epi-CN (0.602)
epi-CD (0.611)
85
79
45
62
+39.2 (c 0.90)
+96.5 (c 0.60)
+113.8 (c 0.53)
+55.1 (c 0.54)
74,4c 713b
68,4c 683b
488b
+39.5 (c 0.96)4c
+96.9 (c 1.12)4c
+114.5 (c 1.07)9
+55.6 (c 0.80)4c
66,4c 388a,b
a Reaction conditions: PNBA (1.1 equiv), DEAD (1.2 equiv), Ph3P (1.3 equiv), then LiOH (5 equiv). For the details, see the experimental sec-
tion.
b Eluent: CHCl3–MeOH–Et3N, 40:1:4.
good yields regardless whether the substrate was used in fied by column chromatography resulting in samples of
either native or epi configuration. However, it should be analytical purity (Scheme 2). It is noteworthy that the na-
noted that the nucleophiles that have been used were tive and epi alkaloids markedly differ in their Rf values
much stronger than the carboxylate (carboxylic acid an- (Table 1), thus they are easily separated by chromatogra-
ion) needed for esterification.
phy on silica gel. Our present results are compared
(Table 1) with the highest reported yields of the literature
procedures (the preparation and inversions of mesylates in
two separate steps, both requiring chromatography).
While quinine and quinidine were inverted in high yield,
improved against the previous method, both cinchonine
and cinchonidine gave yields similar to the former two-
step method. Nevertheless, it is noteworthy that the
present one-pot inversion procedure requires only one
column chromatography, easily separating the epi-isomer
from the native one and the Mitsunobu byproducts.
R
R
N
N
(8S)
1. PNBA, DEAD
Ph3P, THF
(8S)
(9R)
(9S)
OH
OH
2. LiOH, H2O
N
N
CD, R = H
QN, R = OMe
epi-CD, R = H
epi-QN, R = OMe
R
R
In order to further examine the applied reaction conditions
we tested the influence of solvents, acids, and amounts of
the reagents. Thus, attempting to improve the yield of cin-
chonine inversion, instead of tetrahydrofuran we used py-
ridine, toluene, or N,N-dimethylformamide getting 40, 22,
and 15% of epi-cinchonine, respectively. For all four al-
kaloids the experiments using 3,5-dinitrobenzoic acid or
chloroacetic acid with diethyl azodicarboxylate (1.2
equiv) and triphenylphosphine (1.3 equiv) in tetrahydro-
furan at 0 °C for 72 hours did not improve our previous re-
sults. Improved yields were also not observed with
doubled amount of PNBA/DEAD/Ph3P in tetrahydrofuran
at 0 °C for 24 hours.
1. PNBA, DEAD
OH
OH
Ph3P, THF
N
(8R)
N
(8R)
2. LiOH, H2O
(9S)
(9R)
N
N
CN, R = H
QD, R = OMe
epi-CN, R = H
epi-QD, R = OMe
Scheme 2
We decided to examine the standard esterification of the
native alkaloids with 4-nitrobenzoic acid (PNBA pKa
3.44). The first experiment performed with quinine (QN)
[PNBA (1.1 equiv), DEAD (1.2 equiv), Ph3P (1.3 equiv),
0 °C] gave the crude product containing 72% of the epi-
ester, 3% of the ester of native configuration, and 9-epi-
quinine (10%), along with native quinine (9%). The sam-
ple composition was evaluated by integration of the low-
field 1H NMR resonances originating from the respective
2¢-quinoline hydrogen atoms. The inverted quinine ester
was isolated, fully characterized, and compared with the
separately synthesized 4-nitrobenzoic acid ester of native
quinine. Both compounds were prone to hydrolysis which
explains the presence of epi-quinine and quinine in the
In summary, the developed one-pot procedure for the
Mitsunobu PNBA esterification followed by ester sapon-
ification can be recommended as an operationally simple
and quick procedure for the inversion of configuration at
the 9-stereogenic centers of cinchona alkaloids.
All solvents were purified and dried by standard methods. The start-
ing cinchona alkaloids were commercially available and were used
after drying by azeotropic distillation with toluene. Melting points
were determined using a Boetius hot-stage apparatus and are uncor-
crude product. Taking into account the steric hindrance rected. IR spectra were recorded on a Perkin Elmer 1600 FTIR spec-
trophotometer. 1H and 13C NMR spectra were measured on a Bruker
around the 9-hydroxy group we considered this outcome
CPX (1H, 300 MHz) spectrometer using TMS as internal standard.
as quite satisfactory. In turn, all four alkaloids were ester-
Optical rotations at 578 nm were measured using an Optical Activ-
ified in the same manner and subsequently the obtained
ity Ltd. Model AA-5 automatic polarimeter. HRMS were recorded
mixtures were treated in situ with aqueous 1 M lithium hy-
on a Waters LCT Premier XE (TOF/ESI) apparatus. Silica gel (60–
droxide solution. The reaction products were easily puri-
120 mesh) was used for chromatographic separation. Separations of
Synthesis 2011, No. 5, 708–710 © Thieme Stuttgart · New York

710
Ł. Sidorowicz, J. Skarżewski
SHORT PAPER
products by chromatography were performed on silica gel 60 (230–
400 mesh) purchased from Merck. TLC was performed using silica
gel 60 precoated plates (Merck).
was stirred at 0 °C for 20 min, at r.t. for 3 h, and then again cooled
to 0 °C. 1 M LiOH in H2O (5.0 mL) and MeOH (1.0 mL) were add-
ed and the mixture was stirred at r.t. overnight. Organic solvents
were evaporated in vacuo and the residue was quenched with H2O
(5 mL) and CH2Cl2 (15 mL). The organic phase was separated,
washed with brine, and dried (K2CO3). The solvent was removed in
vacuo and the product was purified by column chromatography [sil-
ica gel, 1. CHCl3–t-BuOMe, 3:1 (to remove Ph3PO and most of the
diethyl hydrazine-1,2-dicarboxylate), then 2. CHCl3–MeOH–Et3N,
40:1:4 (to isolate the corresponding epi-alkaloid)].
9-epi-Quinine 4-Nitrobenzoic Acid Ester
A stirred suspension of quinine (1.0 mmol, 324.4 mg), Ph3P (1.3
mmol, 262.3 mg), and PNBA (1.1 mmol, 183.8 mg) in anhyd THF
(10 mL) was placed in an ice-water bath for 10 min. Then DEAD
(1.1 mmol, 171 mL) was added dropwise via syringe. After the ad-
dition of DEAD, the homogenic mixture was stirred at 0 °C for 20
min, then at r.t. overnight. The solvent was removed in vacuo and
the crude product was isolated by column chromatography (EtOAc)
giving after vacuum drying an oil (353 mg, 74%); Rf = 0.118
(EtOAc).
When the above procedure was scaled up to 1 g of the alkaloid (ca.
3 mmol), all the reagents but THF solvent (15 mL) were used in
triplicate amounts.
[a]D20 –79.9 (c 0.8, CH2Cl2).
IR: 2938, 1723, 1621, 1526, 1268, 1102, 718 cm–1.
Acknowledgment
We are grateful to the Polish Ministry of Science and Higher Edu-
cation for financial support; Grant No. N204 161036. Ł.S. thanks
for a fellowship co-financed by European Union within European
Social Fund.
1H NMR (300 MHz, CDCl3): d = 0.81–0.86 (m, 1 H), 1.42–1.51 (m,
1 H), 1.52–1.61 (m, 2 H), 1.62–1.69 (m, 1 H), 2.25–2.32 (m, 1 H),
2.71–2.83 (m, 2 H), 3.21 (dd, J = 14.01, 10.2 Hz, 1 H), 3.29–3.41
(m, 1 H), 3.59 (q, J = 9.3 Hz, 1 H), 3.99 (s, 3 H), 4.95–5.05 (m, 2
H), 5.75–5.87 (m, 1 H), 6.72 (d, J = 10.2 Hz, 1 H), 7.38 (dd, J = 9.3,
2.7 Hz, 1 H), 7.50 (d, J = 4.5 Hz, 1 H), 7.64 (d, J = 2.7 Hz, 1 H),
8.02 (d, J = 9.3 Hz, 1 H), 8.14–8.24 (m, 4 H), 8.77 (d, J = 4.5 Hz, 1
H).
13C NMR (75.5 MHz, CDCl3): d = 164.2, 158.3, 150.6, 147.6,
145.0, 141.6, 141.0, 135.5, 132.0, 131.0, 127.8, 123.5, 122.0, 120.5,
114.6, 101.6, 72.5, 59.3, 56.1, 55.7, 41.4, 39.6, 28.0, 27.3, 25.3.
HRMS: m/z [M + H]+ calcd for C27H28N3O5: 474.2029; found:
474.2041.
References
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(b) Hoffmann, H. M. R.; Frackenpohl, J. Eur. J. Org. Chem.
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Organocatalysis; Song, C. E., Ed.; Wiley-VCH: Weinheim,
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(2) Caner, H.; Biedermann, P. U.; Agranat, I. Chirality 2003, 15,
637; and refs cited therein.
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Sci. Math. Nat., Ser. A 1936, 403; Chem. Abstr. 1937, 31,
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Asymmetry 2009, 20, 1992.
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Jpn. 1972, 45, 245. For general reviews on the Mitsunobu
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70, 3079. (c) Schenk, S.; Weston, J.; Anders, E. J. Am.
Chem. Soc. 2005, 127, 12566.
Quinine 4-Nitrobenzoic Acid Ester
PNBA (167 mg, 1 mmol) and SOCl2 (2.0 mL) placed in a 2-neck
round-bottom flask were refluxed for 3 h and excess SOCl2 was re-
moved in vacuo. After drying for 2 h in vacuo CH2Cl2 (5.0 mL) was
added. The round-bottom flask was secured with drying tube
(CaCl2), cooled in an ice bath, Et3N (210 mL, 1.5 mmol), and then
quinine (1.0 mmol, 342 mg) in CH2Cl2 (5.0 mL) were added drop-
wise. The mixture was stirred 15 min at 0 °C, then overnight at r.t.
The resulting mixture was washed with H2O (2 ×) and brine (1 ×),
and dried (Na2SO4). The solvent was evaporated in vacuo and the
product was isolated by column chromatography (silica gel, EtOAc)
yielding the ester (298 mg, 63%); mp 151–153 °C (CHCl3–hexane);
Rf = 0.091 (EtOAc).
[a]D20 +150.0 (c 0.5, CH2Cl2).
IR: 2941, 1727, 1621, 1527, 1268, 1100, 718 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.50–1.70 (m, 3 H), 1.85–2.05 (m,
2 H), 2.25–2.35 (m, 1 H), 2.60–2.75 (m, 2 H), 3.05–3.20 (m, 2 H),
3.55 (q, J = 2.1 Hz, 1 H), 3.98 (s, 3 H), 5.00–5.10 (m, 2 H), 5.80–
5.92 (m, 1 H), 6.75 (d, J = 7.20 Hz, 1 H), 7.38 (dd J = 9.3, 2.7 Hz,
1 H), 7.42 (d, J = 4.5 Hz, 1 H), 7.50 (d, J = 2.7 Hz, 1 H), 8.02 (d,
J = 9.3 Hz, 1 H), 8.20–8.33 (m, 4 H), 8.74 (d, J = 4.5 Hz, 1 H).
13C NMR (75.5 MHz, CDCl3): d = 163.9, 158.1, 150.8, 147.5,
144.9, 143.0, 141.6, 135.1, 132.0, 130.8, 127.0, 123.8, 121.9, 118.8,
114.8, 101.4, 75.4, 59.4, 56.7, 55.7, 42.6, 39.6, 28.0, 27.6, 24.6.
(7) (a) Brunner, H.; Bügler, J. Bull. Soc. Chim. Belg. 1997, 106,
77. (b) For a recent example, see: Kacprzak, K.; Gierczyk,
B. Tetrahedron: Asymmetry 2010, 21, 2740.
(8) (a) Röper, S.; Franz, M. H.; Wartchow, R.; Hoffmann, H. M.
R. J. Org. Chem. 2003, 68, 4944. (b) Franz, M. H.; Röper,
S.; Wartchow, R.; Hoffmann, H. M. R. J. Org. Chem. 2004,
69, 2983.
HRMS: m/z [M + H]+ calcd for C27H28N3O5: 474.2029; found:
474.2041.
Inversion of Cinchona Alkaloids; General Procedure
To a stirred suspension of the alkaloid (1 mmol), Ph3P (1.3 mmol)
and PNBA (1.1 mmol) in THF (10 mL) placed in an ice-water bath
was added DEAD (1.1 mmol) dropwise via syringe. The mixture
(9) Hiratake, J.; Inagaki, M.; Yamamoto, Y.; Oda, J. J. Chem.
Soc., Perkin Trans. 1 1987, 1053.
Synthesis 2011, No. 5, 708–710 © Thieme Stuttgart · New York