Convergent diastereoselective synthesis of isopilocarpine by one-pot Michael-addition-alkylation reaction

Article abstract of DOI:10.1055/s-2004-831245

The metalated dithiane 7b available from imidazole aldehyde 6 is reacted with furanone 4 and ethyl iodide to give the lactone 8, which forms diastereoselectively. Its configuration is determined to be trans by means of a crystal structure analysis. The desulfurization of 8 leads to the alkaloid isopilocarpine 2 in three steps and 25% overall yield. The relative energies of the diastereomeric alkaloids 1 and 2 have been calculated.

Full text of DOI:10.1055/s-2004-831245

PAPER
2905
Convergent Diastereoselective Synthesis of Isopilocarpine by One-Pot
Michael-Addition-Alkylation Reaction
Convergent
D
iastereos
a
elective Sy
n
f
pilocar
p
r
ine ed Braun,*a Corinna Bühne,a Dimitrula Cougali,a Klaus Schaper,a Walter Frankb
a
Institut für Organische Chemie und Makromolekulare Chemie, Universität Düsseldorf, 40225 Düsseldorf, Germany
Fax +49(211)8115079; E-mail: braunm@uni-duesseldorf.de
b
Institut für Anorganische Chemie und Strukturchemie, Universität Düsseldorf, 40225 Düsseldorf, Germany
Received 19 July 2004
this receptor as well, although with distinctly lower bind-
ing constant.10 In view of the importance of muscarinic
agonists as potential agents for the treatment of Alzhei-
mer’s disease,11 short and efficient syntheses of the stereo-
Abstract: The metalated dithiane 7b available from imidazole al-
dehyde 6 is reacted with furanone 4 and ethyl iodide to give the lac-
tone 8, which forms diastereoselectively. Its configuration is
determined to be trans by means of a crystal structure analysis. The
desulfurization of 8 leads to the alkaloid isopilocarpine 2 in three isomeric alkaloids 1 and 2 are desirable. In this article, we
steps and 25% overall yield. The relative energies of the diastereo-
describe a highly convergent – and so far the shortest –
meric alkaloids 1 and 2 have been calculated.
route to racemic isopilocarpine 2 taking advantage of a
Key words: alkaloids, diastereoselectivity, drugs, lactones, metala-
tions
one-pot Michael-addition-alkylation protocol. As the con-
version of the trans-diastereomer 2 into cis-1 has been re-
ported,7g the route described here is also a formal
synthesis of pilocarpine.
The leaves of Pilocarpus jaborandi, a plant growing in
South American tropical rainforests and extracts prepared
from them served as drugs for multiple medicinal applica-
tions since they had been brought to Europe during the
19th century.1 The main alkaloid2 pilocarpine (1), which
was contaminated by the isomer isopilocarpine (2)
(Figure 1), was isolated by Hardy3a and Gerrard3b in 1875.
After the structure of pilocarpine had been assigned at the
beginning of the 20th century,4 its absolute configuration
[(3S,4R)-1] was elucidated in 1966 only.5 Until today,
pilocarpine (1) is the leading compound for the treatment
of glaucoma.6 Various synthetic routes have been elabo-
rated during the past seven decades.7 None of those, how-
ever, is able to compete from a commercial point of view
with the isolation from the natural source. As a conse-
quence, pilocarpine (1), used in ophthalmiatry today, is
mostly obtained from Pilocarpus microphyllus, a member
of the jaborandi family. In the course of the isolation of
the drug, the diastereomer (3R,4R)-2 inevitably forms due
to an epimerization, so that it has to be removed by frac-
tional crystallization of the alkaloid 1.2,8
The retrosynthesis outlined in Scheme 1 underlines the
highly convergent character of the anticipated concept.
The imidazole synthon 3 that acts as nucleophile was ex-
pected to add to the Michael acceptor 4 in a 1,4 manner.
The enolate arising from this reaction should be alkylated
in situ by alkyl halide 5. Two of the building blocks aris-
ing from the retrosynthetic disconnection of the target 2,
the furanone 4 and ethyl halide 5, are commercially avail-
able compounds. However, the imidazole synthon 3 with
a donor methylene functionality in the side chain is not di-
rectly available, as the most acidic proton of 1,5-dimeth-
ylimidazole is the ring proton in 2-position.12 As a
consequence, lithiated dithane 7b was chosen as a syn-
thetic equivalent of the donor synthon 3.
N
N
O
O
2
CH2
N
N
X
CH3
Pilocarpine (1) is a parasympathomimeticum and acts as
an agonist at the muscarinic acetylcholine receptor.9 It has
been shown more recently that isopilocarpine (2) binds to
+
+
3
5
O
O
4
N
N
N
N
Scheme 1 Retrosynthesis of isopilocarpine (2)
4
3
4
3
O
O
O
O
The synthesis of isopilocarpine (2) following the retrosyn-
thetic concept outlined above turned out to be straightfor-
ward, as shown in Scheme 2. Dithiane 7a was prepared by
protection of the aldehyde 6, which itself is available in
two steps13 from N-methylimidazole. In a one-pot proto-
col, treatment of the imidazole building block 7a with n-
BuLi led to the generation of lithiated dithiane 7b, the
pilocarpine (1)
isopilocarpine (2)
Figure 1 Diastereomers pilocarpine and isopilocarpine
SYNTHESIS 2004, No. 17, pp 2905–2909
Advanced online publication: 29.09.2004
DOI: 10.1055/s-2004-831245; Art ID: Z14404SS
x
x.
x
x
.
2
0
0
4
© Georg Thieme Verlag Stuttgart · New York

2906
M. Braun et al.
PAPER
synthetic equivalent of the donor synthon 3. Then, fura-
none 4 was added and, finally, ethyl iodide. Thus, the
product 8 was obtained in 76% isolated yield, as a result
of the anticipated Michael-addition-alkylation reaction.
According to the NMR spectra, a single product was
formed. Vinylogous additions to the furanone 4 followed
by alkylations give trans-disubstituted g-lactones as a
rule.14 Thus, the rac-trans-configuration was assigned to
the product 8. This assumption was unambiguously con-
firmed by a crystal structure analysis, whose result is
shown in Figure 2. Aside from the fact that the trans-3,4-
configuration of the furanone moiety is clearly shown, it
becomes also evident that the lactone moiety occupies the
equatorial position in the dithiacyclohexane 8, whereas
the imidazole residue is axially oriented. The synthesis of
isopilocarpine was completed by a Raney nickel desulfu-
rization, which removed both the thiophenyl and the
dithiane group and delivered the hydrochloride of the al-
kaloid 2 in 43% yield.
Figure 2 Diagram of 8. Displacement ellipsoids are drawn at the
30% probability level, radii of hydrogen atoms are chosen arbitrarily,
and the hydrogen atom labels are omitted for clarity. Selected torsion
angles [°]: C(4)-O(1)-C(1)-O(2) 174.5, C(4)-O(1)-C(1)-C(2) –5.9,
O(2)-C(1)-C(2)-C(3) 177.6, O(1)-C(1)-C(2)-C(3) –1.9, O(2)-C(1)-
C(2)-C(18) –57.5, O(1)-C(1)-C(2)-C(18) 122.9, C(1)-C(2)-C(3)-C(4)
8.1, C(18)-C(2)-C(3)-C(4) –111.8, C(1)-C(2)-C(3)-C(5) –115.7,
C(18)-C(2)-C(3)-C(5) 124.3, C(2)-C(3)-C(5)-C(6) –57.4, C(4)-C(3)-
C(5)-C(6) –176.0.
than trans-2 by 2.49 kcal/mol. We have performed an ab
initio calculation of the heat of formation of pilocarpine
and isopilocarpine. Thus a Gaussian STO-6-31G* geom-
etry optimization18 revealed a difference of 3.35 kcal/mol,
again in favor of isopilocarpine (2). Optimized geometries
of both 1 and 2 calculated by means of the ab initio meth-
od are shown in Figures 3 and 4 and confirm a conforma-
tional analysis based on NMR spectra.19 The steric
hindrance that is due to the eclipsed cis-oriented substitu-
O
S
S
X
i
N
N
H
N
N
PhS
PhS
7a: X = H
7b: X = Li
6
ii
S
S
iii
iv
N
N
PhS
OLi
N
O
S
S
v
N
Cl
PhS
N
H
O
O
N
O
O
isopilocarpine
hydrochloride (2 HCl)
.
8
Scheme 2 Synthesis of isopilocarpine (2) by one-pot Michael-addi-
tion-alkylation route. Reagents and conditions: i) HS(CH2)3SH, p-
TsOH, CHCl3, reflux, 78%; ii) n-BuLi, THF, –78 °C; iii) 4, –78 °C;
iv) EtI, –78 °C to 25 °C, 76%; v) Raney nickel, MeOH, reflux, HCl,
43%.
Figure 3 Optimized geometries of 1 according to STO-6-31G* cal-
culations.
The diastereomers 1·HCl and 2·HCl clearly differ in the
1H NMR signals of the diastereotopic protons at carbon
atom 5 of the furanone ring, each of them displaying a
doublet of doublet. It has been reported that racemic iso-
pilocarpine (2) can be converted into pilocarpine (1) by
deprotonation and subsequent reprotonation of the eno-
late.7g Although this procedure does not occur under com-
plete inversion at carbon atom 3 of the furanone ring,
subsequent chromatography and recrystallization permits
to obtain pilocarpine 1 from the trans-diastereomer 2.
Thus a novel formal route to pilocarpine is also opened.
The stereochemical lability of pilocarpine (1), i.e. its ten-
dency to a facile isomerization to isopilocarpine (2) is
well known.15,16 According to a semiempirical calculation
(AM1),17 the cis-isomer 1 has been found to be less stable
Figure 4 Optimized geometries of 2 according to STO-6-31G* cal-
culations.
Synthesis 2004, No. 17, 2905–2909 © Thieme Stuttgart · New York

PAPER
Convergent Diastereoselective Synthesis of Isopilocarpine
2907
MS (70 eV): m/z (%) = 308 (100) [M+], 233 (90), 203 (12), 201 (24),
125 (13), 121 (13), 99 (14), 98 (14), 93 (27), 91 (34), 77 (12), 71
(13).
ents at the lactone moiety of pilocarpine (1) is in evidence
therein.
In summary, the imidazole alkaloid isopilocarpine (2) has
been made accessible in a diastereoselective manner by a
straightforward synthesis taking advantage of a Michael-
addition-alkylation procedure. The hitherto shortest syn-
thesis of 2 involves three steps from known compounds or
5 steps from commercially available starting materials.
Enantioselective variants of this method are investigated
and are aimed at a short and convergent synthesis of non-
racemic isopilocarpine.
Anal. Calcd for C14H16N2S3: C, 54.51; H, 5.23; N, 9.08. Found: C,
54.26; H, 5.36; N, 9.05.
trans-3-Ethyl-4-[2-(1-methyl-2-phenylsulfanyl-imidazol-5-yl)-
1,3-dithian-2-yl]-dihydrofuran-2-one (8)
A 100-mL flask was charged with 7a (1.234 g, 4.2 mmol), equipped
with a magnetic stirrer, connected to the combined N2/vacuum line,
and closed with a septum. The air in the flask was replaced by N2
and THF (20 mL) was added through a cannula. The mixture was
cooled to –78 °C, n-BuLi (2.5 mL of a 1.6 M solution in n-hexane)
was added dropwise by syringe, and stirring was continued for 2.5
h at –78 °C. Furanone 4 (0.336 g, 4.0 mmol) dissolved in 2 mL of
THF was injected, and the mixture was stirred for another 2.5 h at
–78 °C. After ethyl iodide (0.625 g, 4.0 mmol) had been added by
syringe, the solution was allowed to reach r.t. overnight. Water (50
mL) was added, the solution was extracted three times with a total
amount of 120 mL of EtOAc, and the combined organic layers were
dried with MgSO4. The solvent was removed in a rotary evaporator
and the residue was purified by column chromatography to give a
colorless solid 8 (1.275 g; 76%); mp 135 °C (after recrystallization
from Et2O); Rf 0.2 (Et2O–n-hexane, 10:1).
Melting points (uncorrected) were determined with a Büchi melting
point apparatus. NMR spectra were recorded in CDCl3 or D2O so-
lution (internal standard) with a Bruker DRX 500 spectrometer. IR
spectra were recorded with a Bruker Vector 22. Mass spectra were
measured with a Varian MAT 311 spectrometer. TLC plates silica
gel F254 (Merck) were used for the identification of products. Col-
umn chromatography was performed using Macherey–Nagel Kie-
selgel 60 and Merck Kieselgel 60, mesh size 0.04–0.063. Elemental
analyses were carried out with a Perkin-Elmer CHN-Analysator
263 at the Institut für Pharmazeutische Chemie (Universität Düssel-
dorf).
IR (KBr): 2964, 2908, 1759, 1582, 1477, 1439, 1383, 1265, 1183,
1037, 991, 741, 706, 688 cm–1.
All reactions involving organolithium compounds were carried out
under an atmosphere of anhyd N2. THF was pre-dried with KOH
and distilled under N2 from Na/benzophenone. It was taken from the
distillation flask, which was closed by a septum with syringes or
cannulas. n-BuLi was purchased as solution in hexane, Raney nick-
el as a suspension in water. Reactions at temperatures below 0 °C
were monitored by a thermocouple connected to a resistance ther-
mometer (Ebro). 1-Methyl-2-phenylsulfanylimidazole (6) was pre-
pared from N-methylimidazole according to ref.13a 3-Methyl-2-
phenylsulfanylimidazole-4-carbaldehyde (7) was synthesized ac-
cording to ref.13b
1H NMR (CDCl3): d = 0.78 (t, J = 7.4 Hz, 3 H, CH2CH3), 1.31–1.51
(m, 2 H, CH2CH3), 1.84–2.08 (m, 2 H, SCH2CH2CH2S), 2.70–3.00
(m, 6 H, SCH2CH2CH2S, 3-H, 4-H), 3.85 (s, 3 H, NCH3), 4.22 (dd,
J = 8.5 Hz, J = 10.0, 1 H, 5-H), 4.64 (dd, J = 5.0 Hz, J = 10.0 Hz, 1
H, 5-H), 7.19–7.30 (m, 5 H, phenyl-H), 7.54 (s, 1 H, imidazyl-H).
13C NMR (CDCl3): d = 10.72 (CH3), 24.18 (CH2CH3), 24.73
(SCH2CH2CH2S), 27.77 (SCH2CH2CH2S), 28.01 (SCH2CH2CH2S),
34.72 (NCH3), 42.5 (SCS), 47.76 (C-4), 54.75 (C-3), 67.35 (C-5),
127.58, 129.78, 143.04 (phenyl-C), 132.02 (5-imidazyl-C), 134.06
(2-imidazyl-C), 135.94 (4-imidazyl-C), 178.25 (CO).
MS (70 eV): m/z (%) = 420 (34) [M+], 307 (100), 233 (17), 109 (6),
91 (8), 77 (6).
5-(1,3-Dithian-2-yl)-1-methyl-2-phenylsulfanyl-imidazole (7a)
A 250-mL two-necked flask was charged with 6 (2.00 g, 9.16
mmol), p-toluenesulfonic acid monohydrate (1.90 g, 10 mmol) and
anhyd CHCl3 (150 mL). The flask was closed with a septum and
equipped with a magnetic stirrer and a Soxhlet extractor filled with
molecular sieves 4 Å with a reflux condenser that was closed with
a drying tube (CaCl2). 1,3-Propanedithiol (1.48 g, 13.74 mmol) was
injected by syringe, and the solution was refluxed for 4 h. After
cooling to r.t., a 3 N solution of NaOH (50 mL) was added. The lay-
ers were separated, the organic phase was dried with MgSO4 and
concentrated in a rotary evaporator. The crude product thus ob-
tained was purified by column chromatography or recrystallization
to yield colorless crystalline 7a (2.21 g, 78%); mp 124 °C; Rf 0.57
(Et2O–n-hexane, 15:2).
Anal. Calcd for C20H24N2O2S3: C, 57.11; H, 5.75; N, 6.66. Found:
C, 56.90; H, 5.81; N, 6.60.
Crystal Structure Determination of Compound 820
Crystals of 8 suitable for X-ray study were selected by means of a
polarization microscope. They were investigated on a Stoe Imaging
Plate Diffraction System using graphite monochromatized Mo Ka
radiation (l = 0.71073 Å). Unit cell parameters were determined by
a least-squares refinement on the positions of 8000 strong reflec-
tions, distributed equally in reciprocal space. An anorthic lattice
was found compatible with space groups P1 and P–1. The latter was
confirmed in the course of the structure refinement. Crystal data:
Mr(C20H24N2O2S3) = 420.59, a = 6.4707 (13) Å, b = 8.0160 (14) Å,
c = 20.466 (4) Å, a = 85.61 (3)°, b = 81.69 (3)°, g = 78.23(3), V =
1027.1(4) Å3, Z = 2, Dx = 1.360 g cm–3, m = 0.379 mm–1, T = 291 K,
colorless crystal of dimensions 0.5 mm × 0.3 mm × 0.1 mm. 14608
intensity data (Qmin = 2.60°, Qmax = 25.91°) were collected and Lp
corrections were applied. The structure was solved by direct
methods21 and approximate positions of all the hydrogen atoms
were found via difference Fourier-synthesis. Refinement (285 pa-
rameters, all of 3714 unique reflections used) by full-matrix least-
squares calculations on F2,22 converged to the following final indi-
IR (KBr): 2933, 2903, 2825, 1579, 1479, 1450, 1275, 1024, 772,
739, 698, 687 cm–1.
1H NMR (CDCl3): d = 1.90–1.98 (m, 1 H, SCH2CHHCH2S), 2.13–
2.29 (m, 1 H, SCH2CHHCH2S), 2.93 (ddd, J = 14.5 Hz, J = 5.0 Hz,
J = 3.2 Hz, 2 H, SCHHCH2CHHS), 3.02 (ddd, J = 14.5 Hz, J = 11.7
Hz, J = 2.7 Hz, 2 H, SCHHCH2CHHS), 3.69 (s, 3 H, NCH3), 5.18
(s, 1 H, SCHS), 7.13–7.27 (m, 5 H, phenyl-H), 7.29 (s, 1 H, imi-
dazyl-H).
13C NMR (CDCl3):
d = 24.90 (SCH2CH2CH2S), 31.33
2
2
(SCH2CH2CH2S), 31.92 (NCH3), 40.57 (SCS), 126.71, 128.18,
129.29, 139.44 (phenyl-C), 129,64 (5-imidazyl-C), 132.26 (2-imi-
dazyl-C), 134.41 (4-imidazyl-C).
cators: R1[Fo > 2s(Fo )] = 0.047, wR2 = 0.105 (all data), w = 1/
2
[s2(Fo ) + (0.025 P)2 + 1.0P] where P = (Fo2 + 2Fc2)/3, S = 1.003,22
largest peak and hole in the final difference map are 0.292 e/Å2 and
–0.340 e/Å3, respectively. Anisotropic displacement parameters
were used for all non-hydrogen atoms. Together with their parent
Synthesis 2004, No. 17, 2905–2909 © Thieme Stuttgart · New York

2908
M. Braun et al.
PAPER
carbon atoms all H atoms were treated as rigid groups with fixed
idealised C-H distances. The H atoms of methyl groups were al-
lowed to move collectively around the neighboring C-C axis. The
isotropic displacement parameters of the H atoms were kept equal
to 120% of the equivalent isotropic displacement parameters of the
parent ‘aromatic’, tertiary or secondary carbon atom and equal to
150% of the parent primary carbon atom, respectively. Scattering
factors, dispersion corrections and absorption coefficients were tak-
en from International Tables for Crystallography (1992, Vol. C,
Tables 6.114, 4.268 and 4.2.4.2).
(7) (a) Preobrashenskij, N. A.; Wompe, A. F.; Preobrashenskij,
W. A.; Schtschukina, M. N. Ber. Dtsch. Chem. Ges. 1933,
66, 1536. (b) Dey, A. N. J. Chem. Soc. 1937, 1057.
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P. J. Org. Chem. USSR 1972, 8, 1112. (d) DeGraw, J. I.
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trans-3-Ethyl-4-[(1-methylimidazol-5-yl)methyl]dihydrofuran-
2-one (Isopilocarpine) (2)
(j) Gmeiner, P.; Feldman, P. L.; Chu-Moyer, M. Y.;
Rapoport, H. J. Org. Chem. 1990, 55, 3068. (k) Dener, J.
M.; Zhang, L.-H.; Rapoport, H. J. Org. Chem. 1993, 58,
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A 100-mL flask was equipped with a magnetic stirrer and charged
with a 10% aq suspension of Raney nickel (30 mL). The supernatant
water was removed by decantation and MeOH was added to the res-
idue. Again, the liquid phase was removed by decantation, and this
procedure was repeated three times. Finally, the residue was sus-
pended in anhyd MeOH and a solution of 8 (1.54 g, 3.66 mmol) in
anhyd MeOH (50 mL) was added. After refluxing the mixture for 4
h under vigorous stirring, it was cooled to r.t. and the solid was al-
lowed to sediment. The supernatant solution was filtered through
celite in a microfilter. The solid residue and the celite were washed
twice with MeOH. The combined filtrates were evaporated and dis-
solved in 1 N HCl acid. The acidic solution was basified by addition
of solid Na2CO3 and extracted three times with a total volume of
100 mL of EtOAc. The combined organic layers were extracted
with 10% HCl acid (25 mL). Finally, the acidic aqueous layer was
concentrated in a rotary evaporator and exposed to oil pump vacu-
um for several hours to give isopilocarpine hydrochloride (1·HCl)
in 43% yield (0.385 g). The product was identical with isopilo-
carpine according to its NMR spectra in D2O when compared with
those described in the literature.19 No traces of pilocarpine (1) were
detected.
(8) (a) Chemnitius, F. J. Prakt. Chem. 1928, 226, 20.
(b) Scheerer, J. Ph.D. Dissertation; Universität Würzburg:
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Acknowledgment
This work was supported by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie. We would like to thank
Sylvia Dahlhäuser and Dr. Peter Mühlenbrock for having carried
out preceding experiments.
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Synthesis 2004, No. 17, 2905–2909 © Thieme Stuttgart · New York

PAPER
Convergent Diastereoselective Synthesis of Isopilocarpine
2909
M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.;
obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK (fax: +44(1223)336033 or
e-mail: deposit@ccdc.cam.ac.uk).
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Synthesis 2004, No. 17, 2905–2909 © Thieme Stuttgart · New York