A simple and efficient synthesis of (±)-mesembrine

Article abstract of DOI:10.1016/j.tetlet.2004.05.021

A simple and efficient synthesis of (±)-mesembrine 1 is described employing double Michael addition and as the key step in 18% overall yield.

Full text of DOI:10.1016/j.tetlet.2004.05.021

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5263–5265
A simple and efficient synthesis of ( )-mesembrineq
Subhash P. Chavan,* Dushant A. Khobragade, Ashok B. Pathak and U. R. Kalkote
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411008, India
Received 14 February 2004; revised 29 April 2004; accepted 6 May 2004
Abstract—A simple and efficient synthesis of ( )-mesembrine 1 is described employing double Michael addition and as the key step
in 18% overall yield.
Ó 2004 Published by Elsevier Ltd.
1. Introduction
very mild and efficient method for the synthesis of an
intermediate to a potent antidepressant.16 In this com-
munication, we describe the construction of the qua-
ternary center employing a double Michael strategy by a
mild protocol. Accordingly, Michael addition of 3,4-
dimethoxyphenyl acetonitrile 2 to methyl acrylate 3
using aqueous 10% NaOH solution and a phase transfer
catalyst furnished diester 4. The diester 4 formed crashes
out of the aqueous medium. Thus, the reaction is per-
formed under the aqueous medium and the product
formed is just filtered off and then crystallized from ethyl
acetate. Thus, this is a completely green step devoid of
any organic solvents in the reaction as well as work-up.
Alternatively, diester 4 can also be obtained efficiently
(99%) using Triton-B as a catalyst in refluxing acetoni-
trile. Dieckmann condensation gave a b-ketoester,
which exists in the enol form 5, which upon Krapcho’s
demethoxycarbonylation yielded a ketone17 6. The keto
group was protected as a 2,2-dimethyl-1,3-dioxane 7
with 2,2-dimethyl-1,3-propanediol using PPTS as a
catalyst in refluxing benzene in a Dean–Stark apparatus.
The cyano group was then reduced with DIBAL-H to
give the aldehyde 8 in quantitative yield. Aldehyde 8 was
then homologated via a one carbon Wittig reaction,
hydroboration followed by oxidative work up then gave
alcohol 10. Alcohol 10 was converted into its mesyl es-
ter, which on treatment with 40% aqueous methylamine
in a sealed tube afforded a secondary amine 11. The free
amine was protected as its carbamate 12. The dioxane 12
was deprotected in acetone–water mixture in the pres-
ence of 1–2 drops of H2SO4 to give the ketone 13. This
was converted into its silyl enol ether 14, followed by
bromination with NBS to give the a-bromoketone 15.
Since the bromo compound 15 was found to be unstable
it was immediately subjected to the next reaction.
Accordingly, treatment of 15 with Li2CO3 and LiBr in
OMe
OMe
O
N
Me
H
(-)-Mesembrine 1
The selectium alkaloids, isolated from the Mesembry-
anthemaceae family, have continued to interest syn-
thetic organic chemists as attractive molecular targets1–3
of which ())-mesembrine 1 is a naturally occurring
serotonin uptake inhibitor.4 The main challenge in the
synthesis of this octahydroindole alkaloid and other
members of the mesembrine family lies in the con-
struction of the benzylic quaternary center.5–15 A variety
of approaches have been delineated for the construction
of this molecule. Our quest for forming C–C bonds
under aqueous conditions led us to the development of a
Keywords: Alkaloids; Michael addition; Wittig reaction; Protection;
Deprotection.
q Presented at C.R.S.I., February 8, 2003, Chennai, India.
* Corresponding author. Tel./fax: +91-20-5893614; e-mail: spchavan@
dalton.ncl.res.in
0040-4039/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.05.021

5264
S. P. Chavan et al. / Tetrahedron Letters 45 (2004) 5263–5265
O
O
OMe
OMe
NC
NC
Ar
NC
Ar
NC
Ar
a
d
c
OMe
OMe
b
+
O
OH
3
O
Ar
2
4
5
6
O
OH
O
O
O
O
O
O
O
O
NC
Ar
g
f
e
Ar
Ar
Ar
O
9
10
7
8
Me
NCbz
Me
Me
NCbz
NCbz
14
NHMe
O
O
O
O
k
l
j
h, i
O
OTMS
Ar
Ar
Ar
Ar
13
12
11
Me
NCbz
Me
NCbz
Me
H
Br
N
o
n
m
O
O
O
Ar
Ar
Ar
16
(+) -1
15
-
OMe
Ar =
OMe
Scheme 1. Reagents and conditions: (a) 10% aq NaOH, TBAHSO4, 0 °C, 30 min, 76%; (b) NaH, DME, reflux, 3 h, 89%; (c) NaCl, H2O, DMSO,
140 °C, 6 h, 87%; (d) HOCH2C(CH3)2CH2OH, PPTS, benzene, reflux, 3 h, 95%; (e) DIBAL-H, DCM, 0 °C, 30 min, 100%; (f) Ph3PþCH2IÀ, NaNH2,
Et2O–THF(1:1), 0 °C, 10 min, 82%; (g) BH3ÆMe2S, THF, 0 °C, then 30% H2O2, 30% NaOH, 75%; (h) Et3N, MeSO2Cl, DCM, 0 °C, 30 min, 100%; (i)
40% aq MeNH2, THF–H2O, in sealed tube, 80 °C, 2 h; (j) ClCOOCH2Ph, K2CO3, 0 °C to rt, 4 h, 88%; (k) CH3COCH3–H2O, 1–2 drops H2SO4,
reflux, 24 h, 85%; (l) Et3N, TMSCl, CH3CN, reflux, 2 h, 100%; (m) NBS, THF, 0 °C, 10 min, 100%; (n) Li2CO3, LiBr, DMF, 110 °C, 2 h, 75%; (o)
BF3ÆOEt2, Me2S, DCM, 0 °C to rt, 1 h, 95%.
DMF18 smoothly afforded enone 16. Deprotection of
the carbamate was achieved with BF3ÆOEt2 in the pres-
ence of Me2S19 to furnish the amine, which subsequently
underwent facile intramolecular Michael addition20;21 to
obtain the target molecule 1 (Scheme 1). The spectral
data of ( )-1 thus obtained matched well with the re-
ported data.22
S.P.C. is gratefully acknowledged. We are also indebted
to Alkali Metals, Hyderabad for generous gift of soda-
mide and triphenylphosphine.
References and notes
1. Kulkarni, M. G.; Rasne, R. M.; Davawala, S. I.; Doke, A.
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cited therein.
2. Conclusion
2. Taber, D. F.; Neubert, T. D. J. Org. Chem. 2001, 66, 143–
147, and references cited therein.
3. Rigby, J. H.; Dong, W. Org. Lett. 2000, 2, 1673–1675, and
references cited therein.
4. Gericke, N. P.; Van Wyk, B. E. World Patent 9,746,234,
1997; Chem. Abstr. 1998, 128, 80030.
In conclusion, we have demonstrated that ( )-mesem-
brine can be efficiently synthesized by double Michael
addition under aqueous condition as the key step in 18%
overall yield.
5. Posner, G. H.; Kogan, T. P.; Hulce, M. Tetrahedron Lett.
1984, 25, 383–386.
6. Pfau, M.; Revial, G.; Guingant, A.; d’Angelo, J. J. Am.
Chem. Soc. 1985, 107, 273–274.
Acknowledgements
D.A.K. and A.B.P. thank C.S.I.R., New Delhi, for
providing fellowships. Funding from Y.S.A., C.S.I.R. to
7. Koga, K.; Tomioka, K.; Cho, Y. S.; Sato, F. J. Org.
Chem. 1988, 53, 4094–4098.

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22. Spectral data for ( )-mesembrine: IR (CHCl3) 2959, 1716,
1519, 1254, 1217, 755, 666 cmÀ1
;
1H NMR (CDCl3,
500 MHz) d 2.05–2.18 (m, 4H), 2.23–2.29 (m, 1H), 2.34
(s, 3H), 2.35–2.42 (m, 2H), 2.62 (t, J ¼ 4:6 Hz, 2H), 3.02 (t,
J ¼ 3:7 Hz, 1H), 3.15–3.23 (m, 1H), 3.84 (s, 3H), 3.86 (s,
3H), 6.81 (d, J ¼ 8:3 Hz, 1H), 6.85 (dd, J ¼ 8:3 Hz and
J ¼ 2:0 Hz, 1H), 6.87 (d, J ¼ 2:0 Hz, 1H); 13C NMR
211.08, 149.43, 147.97, 140.02, 118.27, 111.54, 110.50,
70.46, 56.34, 56.16, 54.89, 47.84, 40.65, 40.24, 39.08, 36.35,
35.30; MS (EI) m=z 289 (Mþ), 274, 254, 218, 204, 128, 91,
70, 59.