A novel and efficient total synthesis of (±)-physostigmine

Article abstract of DOI:10.1016/j.tetlet.2009.03.012

Application of the Wittig olefination-Claisen rearrangement protocol for the total synthesis of (±)-physostigmine.

Full text of DOI:10.1016/j.tetlet.2009.03.012

Tetrahedron Letters 50 (2009) 2411–2413
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A novel and efficient total synthesis of ( )-physostigmine
*
Mukund G. Kulkarni , Attrimuni P. Dhondge, Ajit S. Borhade, Dnyaneshwar D. Gaikwad, Sanjay W. Chavhan,
Yunnus B. Shaikh, Vijay B. Ningdale, Mayur P. Desai, Deekshaputra R. Birhade, Mahadev P. Shinde
Department of Chemistry, University of Pune, Ganeshkhind, Pune 411 007, Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Application of the Wittig olefination–Claisen rearrangement protocol for the total synthesis of ( )-
Received 14 October 2008
Revised 23 February 2009
Accepted 4 March 2009
Available online 9 March 2009
physostigmine.
Ó 2009 Elsevier Ltd. All rights reserved.
The Physostigma genus (Fabaceae) produces many indole alka-
loids, of which Physostigmine 1 is one of the main constituents.
It was first isolated in 1864 from the seeds of the African Calabar
bean Physostigma venenosum and was structurally characterized
in 1925.1 The hexahydropyrrolo[2,3-b]indoline ring system, pres-
ent in 1 is found in a large number of indole alkaloids with a wide
variety of structural formats.2–5 These alkaloids have interesting
potent biological properties, such as anticholinergic and miotic
activities.6 These compounds and their derivatives have been
found to be clinically useful for relieving symptoms of Alzheimer’s
disease.7 Like many biologically important indole alkaloids, physo-
stigmine 1 has a quaternary carbon center at the C-3a position. The
effective construction of such a quaternary center has been one of
the pivotal issues in the total synthesis of these alkaloids. As a re-
sult of their biological activities, unique structure and the difficulty
of generating a quaternary center, several syntheses of physostig-
mine have been reported. Similarly, various racemic and/or chiral
methods have been developed8–10 for the construction of the core
ring system of these alkaloids, namely, hexahydropyrrolo[2,3-
b]indoline. These include a catalytic asymmetric Heck reaction,
catalytic asymmetric alkylation and allylation, chiral auxiliary-in-
duced asymmetric alkylation and rearrangement, asymmetric
addition–cyclization, desulfurization–cyclization, [3,3] sigmatropic
rearrangements, hetero-Pauson–Khand reaction, [4+1] cycloaddi-
tion reaction, intramolecular cyanoamidation, Diels–Alder reac-
tion, Grignard reaction, intramolecular 1,3-dipolar addition,
nucleophilic substitution, lipase-catalyzed desymmetrization pro-
tocol, domino reaction involving a sequence of olefination–isomer-
ization, Claisen rearrangement and intramolecular Michael
addition. After the pioneering synthesis of physostigmine by Julian
in 1935,9a most of the above-mentioned methods for the construc-
tion of hexahydropyrrolo[2,3-b]indoline have been applied to the
synthesis of physostigmine. An impressive total of 71 syntheses
of physostigmine, 33 racemic9and 38 chiral,10 have been reported
in the literature. In spite of this voluminous work, even today the
total synthesis of physostigmine is an attractive goal for demon-
strating the efficacy of newer synthetic methodologies.
We have developed a methodology for the construction of a
quaternary carbon center by using the Wittig olefination–Claisen
rearrangement protocol.11 This methodology provides a powerful
tool for the synthesis of natural products especially those with a
quaternary carbon center(s). Herein we describe the successful
application of this protocol for the synthesis of the acetylcholines-
terase inhibitor physostigmine 1.
The Wittig olefination of o-nitroacetophenone 2 with ally-
loxymethylenetriphenylphosphorane under standard conditions11
furnished the corresponding allyl vinyl ether 3, which was found
to be an inseparable mixture of E- and Z-isomer. However, the
NMR signals of E- and Z-isomer in the olefinic region were well
separated and it allowed us to estimate the ratio of these isomers12
(5:1). The mixture of allyl vinyl ethers was heated in refluxing xy-
lene to effect the Claisen rearrangement and to get 4-pentenal 4 in
85% yield. After protecting the aldehyde group in 4 as its acetal, the
double bond was ozonolyzed to get a new aldehyde 5. This alde-
hyde on reduction with sodium borohydride in aqueous THF, gave
alcohol 6 in a near quantitative yield. The conversion of alcohol 6
into amine 7 was achieved in two steps subjecting the alcohol to
Mitsunobu conditions (DIAD, triphenylphosphine, and phthali-
mide) at room temperature and subsequently refluxing the inter-
mediate phthalimide derivative in methylamine to get the
corresponding amine 7 in 68% yield. Further, reduction of the nitro
group with Raney nickel in methanol afforded diamine 8. The
hydrolysis of acetal in 8 with p-TSA in refluxing aqueous THF di-
rectly furnished the tricyclic compound 9 in 65% yield. A singlet
at d 5.0 for C8a–H confirmed the formation of a hexahydropyrrol-
o[2,3-b]indole ring system of physostigmine in one step. Bis-N-
methylation13 of 9, using aqueous formalin and 10% Pd–C fur-
nished desoxyeseroline 10. Following the known protocol14, the
compound 10 was converted to physostigmine. Compound 10 on
treatment with N bromosuccinimide gave the 5-bromo derivative,
which on heating with sodium methoxide in the presence of
* Corresponding author. Tel./fax: +91 020 2569 1728.
E-mail address: mgkulkarni@chem.unipune.ernet.in (M.G. Kulkarni).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.012

2412
M. G. Kulkarni et al. / Tetrahedron Letters 50 (2009) 2411–2413
O
O
O
O
CHO
O
CHO
O
a
b
c
e
f
OH
NO2
NO2
NO2
d
NO2
NO2
4
3
5
6
2
O
O
O
MeNHCO2
l
MeO
O
h
j
N
N
N
g
NH2
R
NH2
N
N
N
R
k
NH2
NO2
11
9 R = H
10 R = Me
8
1
7
i
Reagents and condition: (a) CH2=CHCH2OCH2P+Ph3Cl-, t-BuO-Na+, THF, 0OC; (b) Xylene, reflux; (c) p-TSA, ethylene
glycol, Toluene, reflux; (d) O3, dimethyl sulfide, 00C, DCM; (e) NaBH4, aq. THF; (f) DIAD, PPh3, phthalimide, methylamine,
reflux; (g) Raney nickel, [H2], MeOH; (h) p-TSA, aq. THF, reflux; (i) aq. HCHO, 10% Pd-C, EtOAc, [H 2]; (j) NBS, DMF, 00C;
(k) CuI, NaOMe, reflux; (l) BBr3, CH2Cl2, 00C- rt. NaH, MeNCO.
251–270; (d) Yu, Q.-S.; Luo, W.; Holloway, H. W.; Utsuki, T.; Perry, T.; Lahiri, D.
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cuprous iodide gave esermethole 11. Finally esermethole was con-
verted to physostigmine 1 by effecting demethylation of 11 with
boron tribromide and treatment of the resulting phenol with
methylisocyanate.10a–g The spectral data of the compound so ob-
tained were identical with the reported data for physostigmine. In
summary, we have described a new and efficient synthesis of phy-
sostigmine. Further, it is possible to extend the present protocol
developed for the synthesis of physostigmine to the synthesis of
other natural products with quaternary carbon at the benzylic posi-
tion. On these lines, the total syntheses of other natural products
such as Physovenine and phenserine are being actively pursued.
Acknowledgments
The authors A.P.D., M.P.S., A.S.B., D.D.G., S.W.C., Y.B.S., V.B.N.,
and D.R.B. thank CSIR, New Delhi and M.P.D. thanks UGC, New Del-
hi, for research fellowships.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.03.012.
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