Total synthesis of (±)-physovenine

Article abstract of DOI:10.1002/ejoc.200900391

The Wittig olefination-Claisen rearrangement protocol was applied to the total synthesis of (±)-physovenine.

Full text of DOI:10.1002/ejoc.200900391

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200900391
Total Synthesis of (؎)-Physovenine
Mukund G. Kulkarni,*[a] Attrimuni P. Dhondge,[a] Ajit S. Borhade,[a]
Dnyaneshwar D. Gaikwad,[a] Sanjay W. Chavhan,[a] Yunnus B. Shaikh,[a] Vijay B. Nigdale,[a]
Mayur P. Desai,[a] Deekshaputra R. Birhade,[a] and Mahadev P. Shinde[a]
Keywords: Alkaloids / Olefination / Rearrangement / Ozonolysis / Reduction
The Wittig olefination–Claisen rearrangement protocol was
applied to the total synthesis of (Ϯ)-physovenine.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
venine are documented in the literature. In spite of this vo-
luminous work, even today the total synthesis of physoven-
ine is an attractive goal for demonstrating the efficacy of
newer synthetic protocols. We herein describe the successful
application of the above protocol for the synthesis of the
physovenine.
Introduction
The Wittig olefination–Claisen rearrangement protocol[1]
is now well established in our laboratory for the preparation
of 4-pentenals. These 4-pentenals have served as versatile
intermediates for the synthesis of different natural prod-
ucts.[2] This protocol is quite useful for the construction of
quaternary centers – an operation crucially required in
many natural product syntheses.[3] Many indole alkaloids
have a quaternary center at the C-3 position, and their syn-
theses have centered around the construction of such a qua-
ternary center. This gave us an opportunity to apply the
above protocol to the synthesis of physovenine, a represen-
tative of a group of indole alkaloids isolated from calabar
beans. Physovenine, with a furoindoline ring system, is a
minor component of the calabar bean alkaloids.[4] It has
interesting and potent biological properties, such as anti-
cholinergic and miotic activities.[5] Physovenine and its de-
rivatives have been found to be clinically useful for relieving
symptoms of Alzheimer’s disease.[6] Furthermore, the phar-
macological activity of physovenine is approximately equal
to that of physostigmine. Physovenine was first isolated in
1911[7] and its structure was established in 1964.[8] As a re-
sult of its biological activities and unique structure, and the
difficulty in generating the quaternary center, several meth-
odologies have been applied to the synthesis of physovenine.
These include Sharpless epoxidation,[9a] intramolecular ary-
lation,[9b] Grignard reaction,[9c] [3,3]-sigmatropic rearrange-
ment,[9d,9m,9q] catalytic asymmetric Heck reaction,[9g] Diels–
Alder reaction,[9h] radical cyclization,[9f,9k] intramolecular
Michael addition,[9l] [2+2] photocycloaddition,[9p] and cata-
lytic asymmetric alkylations.[9i,9n,9o] In all, 21 total synthe-
ses,[9] 12 diastereoselective and 9 enantioselective, of physo-
Results and Discussion
The Wittig olefination of o-nitroacetophenone (2) with
allyloxymethylenetriphenylphosphorane under standard
conditions[1] furnished the corresponding allyl vinyl ether 3,
which was found to be an inseparable mixture of E and Z
isomers. However, the NMR signals of the E and Z isomers
in the olefinic region were well separated,[10] which allowed
us to estimate the ratio of these isomers as 5:1. The mixture
of allyl vinyl ethers was heated in refluxing xylene to effect
the Claisen rearrangement 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 new aldehyde 5 in 88%
yield. This aldehyde, upon reduction with sodium boro-
hydride, in aqueous THF, afforded alcohol 6 in 92% yield.
Further, reduction of the nitro group with Raney nickel in
methanol gave the corresponding amino alcohol 7 in 80%
yield. The hydrolysis of the acetal group in 7 with p-TSA
in refluxing aqueous THF directly furnished the tricyclic
skeleton of physovenine 8 in 89% yield. A singlet at δ =
5.2 ppm for C8a-H confirmed the formation of the tetra-
hydrofuro[2,3-b]indole ring system of physovenine in one
step. N-Methylation[11] of 8 by using aqueous formalin and
10% Pd/C furnished 9 in 87% yield. The relative stereo-
chemistry between the 8a proton and the 3a methyl group
was determined by NOE experiments (Figure 1). An NOE
enhancement to the extent of 3.22% in the signal of the C-
8a proton at δ = 5.02 ppm was observed upon irradiation
of the C-3a methyl protons at δ = 1.44 ppm. Similarly, an
NOE enhancement to the extent of 3.98% in the signal of
the C-3a methyl protons at δ = 1.44 ppm was observed
[a] Department of Chemistry, University of Pune, Ganeshkhind,
Pune 411007 Maharashtra, India
Fax: +91-20-2569-1728
E-mail: mgkulkarni@chem.unipune.ernet.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900391.
Eur. J. Org. Chem. 2009, 3875–3877
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3875

M. G. Kulkarni et al.
SHORT COMMUNICATION
Scheme 1. Reagents and conditions: (a) CH2=CHCH2OCH2P+Ph3Cl–, tBuO–Na+, THF, 0 °C (65%); (b) xylene, reflux, (85%); (c) p-TSA,
ethylene glycol, toluene, reflux, (89%); (d) O3, dimethyl sulfide, DCM, (88%); (e) NaBH4, aq. THF, (92%); (f) Raney nickel, [H2], MeOH,
(80%); (g) p-TSA, aq. THF, reflux, (89%); (h) aq. HCHO, 10% Pd/C, EtOAc, [H2], room temp., (87%); (i) NBS, DMF, 0 °C; (j) CuI,
NaOMe, reflux, (70%); (k) BBr3, DCM, MeNH2, CO(COCl3)2, toluene, reflux, NaH, MeNCO, (60%).
and M. P. D. thanks University Grant Commission, New Delhi for
research fellowships.
upon irradiation of the C-8a proton at δ = 5.02 ppm. This
conclusively established that the two five-membered rings
in compound 9 are cis fused. Upon treatment with N-bro-
mosuccinimide, compound 9 gave the 5-bromo derivative,
which upon heating with sodium methoxide in the presence
of cuprous iodide[12] gave compound 10 in 70% yield. Fi-
nally, compound 10 was converted into physovenine (1) by
effecting demethylation of 10 with boron tribromide and
treatment of the resulting phenol with methyl isocyanate.[13]
The spectroscopic data of the compound so obtained were
identical with the reported data of physovenine (Scheme 1).
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Conclusions
In summary, we described a new and efficient synthesis
of physovenine. Furthermore, it is possible to extend the
present protocol developed for the synthesis of physovenine
to the synthesis of other natural products with quaternary
carbon centers at the benzylic position. On these lines, the
total synthesis of other natural products like phenserine is
being actively pursued.
Supporting Information (see footnote on the first page of this arti-
cle): Complete experimental details, including characterization of
the compounds.
Acknowledgments
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Total Synthesis of (Ϯ)-Physovenine
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Received: April 9, 2009
Published Online: July 7, 2009
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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