Synthesis of (±)-esermethole via an intramolecular carbamoylketene-alkene [2+2] cycloaddition

Article abstract of DOI:10.3987/COM-12-12599

A synthesis of (±)-esermethole (2), a synthetic precursor of physostigmine (1), has been accomplished by using an intramolecular carbamoylketene-alkene [2+2] cycloaddition followed by nitrone-mediated regioselective ring expansion for the construction of the basic carbon framework of 2 as the key steps.

Full text of DOI:10.3987/COM-12-12599

HETEROCYCLES, Vol. 85, No. 12, 2012
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HETEROCYCLES, Vol. 85, No. 12, 2012, pp. 2927 - 2932. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 6th October, 2012, Accepted, 24th October, 2012, Published online, 25th October, 2012
DOI: 10.3987/COM-12-12599
SYNTHESIS OF (±)-ESERMETHOLE VIAAN INTRAMOLECULAR
CARBAMOYLKETENE-ALKENE [2+2] CYCLOADDITION
Tsukasa Ozawa, Makoto Kanematsu, Hiromasa Yokoe, Masahiro Yoshida
and Kozo Shishido*
Graduate School of Pharmaceutical Sciences, The University of Tokushima,
1-78-1 Sho-machi, Tokushima 770-8505, Japan
Abstract – A synthesis of (±)-esermethole (2), a synthetic precursor of
physostigmine (1), has been accomplished by using an intramolecular
carbamoylketene-alkene [2+2] cycloaddition followed by nitrone-mediated
regioselective ring expansion for the construction of the basic carbon framework
of 2 as the key steps.
Physostigmine (1)1 is a representative of the Calabar bean alkaloid isolated from the African tropical vine
Physostigma venenosum. Physostigmine is not only an important anticholinesterase compound with
several clinical uses, but also a promising therapeutic agent for Alzheimer’s disease.2 Because
physostigmine has a simple but intriguing molecular structure and biological profile, a number of
synthetic efforts of the alkaloid and its synthetic precursor esermethole (2), which can readily be
converted to 1 via a two-step sequence, have been reported in racemic3 and optically active forms4 so far
(Figure 1).
Figure 1. Physostigmine and esermethole
During the course of our synthetic studies directed towards the Calabar bean alkaloids,5 we previously
reported a synthesis of the tetrahydro-2H-furo[2,3-b]indole 7, which has been converted to physovenine

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(8) via a two-step sequence, employing an intramolecular carbamoylketene-alkene [2+2] cycloaddition
reaction (4!5!6) followed by a Baeyer-Villiger oxidation as the key steps.6 The originally developed
[2+2] cycloaddition seemed to be a useful methodology not only for the synthesis of other Calabar bean
alkaloids but also for related alkaloids,7 however, its inefficiency for the preparation of 2-alkenylaniline
derivatives, e.g. 2-isopropenyl-4-methoxyaniline 3 (in 43% overall yield for seven steps from
m-hydroxyacetophenone)6 remains a drawback. (Scheme 1) In this report, we describe a synthesis of
(±)-esermethole (2) employing an intramolecular carbamoylketene-alkene [2+2] cycloaddition and a
nitrone-mediated regioselective ring expansion of the cyclobutanone 6 to !-lactam fused onto indoline as
the key steps.
Scheme 1. Formal synthesis of physovenine via the intramolecular carbamoylketene-alkene [2+2]
cycloaddition
Our retrosynthetic analysis is shown in Scheme 2. We envisaged that esermethole 2 might be derived
from the lactam carbamate 9, which would be assembled from the [2+2] cycloadduct 6 through a
regioselective ring expansion. It was thought that the procedure to make the synthesis of 10 more efficient
would be the Suzuki-Molander coupling of t-butyl 2-iodo-4-methoxyphenylcarbamate (12)8 with
potassium isopropenyltrifluoroborate (11)9 (Scheme 2).
Scheme 2. Retrosynthetic analysis

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Ortho-lithiation of the N-Boc-p-anisidine 13 gave the iodide 12, which was treated with potassium
isopropenyltrifluoroborate 11 and 5 mol% of PdCl2(dppf) in the presence of cesium carbonate in refluxing
aqueous tetrahydrofuran (THF) to give the coupled product 10 in 90% yield. Removal of the Boc-group
with trifluoroacetic acid provided 3 in four steps in 69% overall yield from p-anisidine and thus our
objective of improvement of efficiency was achieved. Carbomethoxylation, alkylation with methyl
bromoacetate followed by alkaline hydrolysis provided the carboxylic acid 4, a precursor of the ketene.
Treatment of 4 with oxalyl chloride in refluxing benzene produced the acid chloride which, after removal
of excess reagent and the solvent by evaporation, was immediately treated with triethylamine in refluxing
benzene in one pot6,7 to give the cyclobutanone 6 in 90% overall yield from 15. To explore a mild and
efficient method for the [2+2] cycloaddition, we examined a procedure via a mixed anhydride.10
Treatment of the carboxylic acid 4 with ethyl chloroformate and triethylamine at room temperature for
seven hours produced 6 in 65% yield in a single operation (method a). The best result was obtained when
4 was treated with 2-nitrobenzenesulfonyl (nosyl) chloride11 and triethylamine in benzene at room
temperature providing 6 in 82% yield (method b) (Scheme 3).
Scheme 3. Synthesis of ketene precursor 4 and the [2+2] cycloaddition
With the requisite tricyclic compound 6 in hand, we advanced to the key ring expansion. The
cyclobutanone was converted to the oxime 16,12 the configuration of which, determined by 1H NMR using
a shift reagent Eu(dpm)3,13 proved to be Z.14 On exposure of 6 to the conditions of Beckmann
rearrangement (SOCl2, benzene, rt, 11 h), the desired tricyclic lactam 17 was not obtained at all but the

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ring-opened hemiaminal 18, which was characterized as the methyl acetal 19,15 was produced in 56%
yield for the two steps (Scheme 4).
Scheme 4. Attempted Beckmann rearrangement
Unsuccessful attempts at Beckmann rearrangement led us to find a regioselective ring expansion from 6
to the lactam. We found that a rearrangement through a nitrone7,16 can be applied to the conversion; thus,
treatment of 6 with N-methylhydroxylamine hydrochloride, NaHCO3, and 3A molecular sieves in ethanol
at 50 °C provided the nitrone 20, which, without purification, was immediately reacted with
p-toluenesulfonyl chloride (p-TsCl) and 4-pyrrolidinopyridine in refluxing chloroform to give the
requisite !-lactam 9 in 75% yield for the two steps. Thus, we were able to overcome a key hurdle and
demonstrated that the procedure could be successfully applied to install the
hexahydropyrrolo[2,3-b]indole backbone. Finally, reaction of 9 with lithium aluminum hydride (LAH) in
refluxing THF produced esermethole (2) in 80% yield. The spectroscopic properties of synthetic 2 were
completely identical with those reported in the literature4a (Scheme 5).
Scheme 5. Ring expansion via nitrone rearrangement and synthesis of esermethole

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In summary, a synthesis of (±)-esermethole (2) has been accomplished in 12 steps in 33% overall yield
from p-anisidine as an application of the intramolecular carbamoylketene-alkene [2+2] cycloaddition
which has been developed in our laboratories. The unique features of this work include the use of
originally developed [2+2] cycloaddition and a regioselective nitrone-mediated ring expansion for the
construction of the basic carbon framework of the target molecule. We were also able to demonstrate that
the mixed anhydride method using the nosyl group would be a mild (at room temperature) and efficient
(by a single operation in one pot) alternative method for the generation of carbamoylketenes. The
synthetic route developed here is general and efficient and can be applied to the synthesis of both Calabar
bean alkaloids and related alkaloids.
ACKNOWLEDGEMENTS
A JSPS Fellows Grant-in-Aid (22-9957) to T.O. is gratefully acknowledged. This work was supported
financially by a Grant-in-Aid from the Program for Promotion of Basic and Applied Research for
Innovations in the Bio-oriented Industry (BRAIN).
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1
12. IR (neat) 3336, 1708 cm-1 ; H NMR (CDCl3, 400 MHz) ! 1.67 (s, 3H), 3.02 (d, 1H, J = 17.2 Hz),
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13
1H, J = 7.6 Hz); C NMR (CDCl3, 100 MHz) ! 23.2 (CH3), 44.0 (C), 44.1 (CH2), 52.6 (CH3), 55.6
(CH3), 69.9 (CH), 109.3 (CH), 113.0 (CH), 115.8 (CH), 136.2 (C), 137.7 (C), 152.8 (C), 154.4 (C),
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1
15. IR (neat) 2928, 2360, 1714 cm-1 ; H NMR (CDCl3, 400 MHz) ! 1.40 (s, 3H), 2.70 (d, 1H, J = 22.0
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13
(d, 1H, J = 8.1 Hz), 7.61 (br, 1H); C NMR (DMSO-d6, 100 MHz, 60 ºC) ! 21.1 (CH3), 25.2 (CH2),
46.1 (C), 52.5 (CH3), 55.3 (CH3), 57.5 (CH3), 97.0 (CH), 108.8 (CH), 112.8 (CH), 115.8 (CH), 118.5
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