Allyl vinyl ethers via Wittig olefination: A short and efficient synthesis of (±)-mesembrine

Article abstract of DOI:10.1016/S0040-4039(02)00227-7

A Wittig olefination-Claisen rearrangement approach has been successfully applied to a short and efficient synthesis of (±)-mesembrine.

Full text of DOI:10.1016/S0040-4039(02)00227-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2297–2298
Allyl vinyl ethers via Wittig olefination: a short and efficient
synthesis of ( )-mesembrine
Mukund G. Kulkarni,* Ravindra M. Rasne, Saryu I. Davawala and Aniruddha K. Doke
Department of Chemistry, University of Pune, Pune 411 007, India
Received 19 January 2002; accepted 30 January 2002
Abstract—A Wittig olefination-Claisen rearrangement approach has been successfully applied to a short and efficient synthesis of
( )-mesembrine. © 2002 Elsevier Science Ltd. All rights reserved.
Recently, we reported an efficient method for the
preparation of allyl vinyl ethers.1 Such allyl vinyl ethers
once formed easily undergo Claisen rearrangement to
give 4-pentenals. By taking advantage of this fact we
have prepared2 many 4-pentenals with built-in contigu-
ous quaternary centers. Creation of such quaternary
centers is a serious challenge in organic synthesis.3–5
These 4-pentenals have served as key intermediates in
the synthesis of natural products6,7 with sterically
crowded cyclopentanoid rings. Syntheses of several
other natural products with sterically crowded ring
systems carbocyclic or heterocyclic could be accessed
through this methodology. The alkaloid mesembrine is
an octahydroindole based natural product comprising
1% of the dry weight of plant material from certain
plants of the Sceletium genus, namely S. namaquense, S.
strictum and S. tortuosum.8 Structure elucidation,9,10
including the determination of the absolute config-
uration11 of mesembrine spanned over 10 years and
finally structure 1 was established for the compound.
Pure mesembrine, though devoid of any interesting
biological properties, has attracted enormous attention
from synthetic chemists for the past three decades. As
a direct result of this, in all, 28 syntheses12–39 of
Scheme 1. Reagents and conditions: (i) CH2:CHCH2OCH2P+Ph3Cl−, tBuO−K+, THF, 0°C, 1 h (93%); (ii) xylene reflux, 7 h (98%);
(iii) MVK, cat. ethanolic KOH, ether, 0°C–rt, 24 h (85%); (iv) cat. OsO4 and 1.5 equiv. NaIO4, 5 h (60%); (v) Jones’ reagent CrO3,
H2SO4, acetone, 4 h (60%); (vi) MeNH2 excess, MeOH, 80°C, 12 h in sealed tube (quantitative yield); (vii) a. 2-ethyl-2-methyl-1,3-
dioxolane, p-TSA, reflux, 2 h, b. LAH excess, THF:Et2O (2:1) reflux, 23 h, c. 10% HCl, rt, 2 days (72%).
* Corresponding author. Tel./fax:+91 020 5691728; e-mail: mgkulkarni@chem.unipune.ernet.in
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00227-7

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M. G. Kulkarni et al. / Tetrahedron Letters 43 (2002) 2297–2298
this compound are known. We herein report a short and
efficient synthesis of ( )-mesembrine 1 (Scheme 1).
7. Kulkarni, M. G.; Pendharkar, D. S. J. Chem. Soc., Perkin
Trans. 1 1997, 3127–3128.
8. Bodendorf, K.; Krieger, W. Arch. Pharm. 1957, 290, 441–
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The reaction of veratraldehyde 2 with allyloxymethyl-
enetriphenylphosphonium chloride1 using potassium t-
butoxide as a base furnished the allyl vinyl ether 3 as an
inseparable mixture of E- and Z-isomers (1H NMR) in
good yield. The ill-resolved nature of the proton NMR
spectrum of this mixture in the olefinic range (l 5.6 to
l 6.7) prevented us from estimating the ratio of the
geometric isomers. Nevertheless, this mixture of the allyl
vinyl ethers 3 smoothly underwent Claisen rearrange-
ment in refluxing xylene to furnish the 2-aryl-4-pentenal
4 in quantitative yield. The 4-pentenal 4 on treatment
with methyl vinyl ketone and a catalytic amount of
ethanolic KOH underwent tandem Michael addition–
intramolecular aldol condensation39 to give the allyl
cyclohexenone 5 in 85% yield. This cyclohexenone has
previously been prepared20 in six steps with an overall
yield of 10%. In the present case it was obtained in an
overall yield of 80% in just three steps. The allyl
cyclohexenone was treated with a catalytic amount of
osmium tetroxide and 1.5 equivalents of sodium metape-
riodate to give the unstable aldehyde 6 in 60% yield. As
treatment of this aldehyde with basic Ag2O did not lead
to any meaningful isolable product, it was subjected to
oxidation with Jones’ reagent. To our pleasant surprise
this resulted in the formation of the lactone 7 rather than
the carboxylic acid. Apparently, the carboxylic acid
formed on oxidation underwent in situ 1,4-addition to
the enone to give the lactone 7. Heating the lactone with
excess methylamine in methanol at 80°C in a sealed tube
for 12 h gave the lactam 8. The conversion of this lactam
8 to ( )-mesembrine was achieved by the method
reported by Oh-ishi.17,18 Thus, the lactam was subjected
to ketal exchange with 2-ethyl-2-methyl-1,3-dioxolane.
The excess dioxolane was removed under vacuum and
the crude lactam was reduced with excess lithium alu-
minium hydride in refluxing THF:Et2O (2:1) for 23 h.
Acid hydrolysis of the crude ketal amine so obtained
gave ( )-mesembrine 1 in an overall yield of 72% from
the lactam 8. The protocol described here is a short and
efficient route for the synthesis of ( )-mesembrine 1.
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