Total Synthesis of (±)-Phenserine via [4+1] Cyclization of a Bis(alkylthio)carbene and an Indole Isocyanate

Article abstract of DOI:10.1021/ol062915+

Figure presented A total synthesis of acetylcholine blocking agent, phenserine, has been achieved by employing a [4+1] cyclization between an appropriately substituted indole isocyanate and a bis(alkylthio)carbene.

Full text of DOI:10.1021/ol062915+

ORGANIC
LETTERS
2
007
Vol. 9, No. 7
219-1221
Total Synthesis of (
±)-Phenserine via
1
[4+
1] Cyclization of a
Bis(alkylthio)carbene and an Indole
Isocyanate
James H. Rigby* and Shyama Sidique
Department of Chemistry, Wayne State UniVersity, Detroit, Michigan 48202-3489
jhr@chem.wayne.edu
Received December 1, 2006
ABSTRACT
A total synthesis of acetylcholine blocking agent, phenserine, has been achieved by employing a [4
substituted indole isocyanate and a bis(alkylthio)carbene.
+1] cyclization between an appropriately
Alkaloids exhibiting the hexahydropyrrolo[2,3-b]indole core
Phenserine (2), the phenylcarbamate analogue of physostig-
are a growing class of natural products that display a broad
range of biological activities. Physostigmine (1) was first
mine (Figure 1), is a more potent and selective inhibitor of
1
isolated in pure form from the African Calabar bean seeds
2
Physostigma Venenosum in 1864 by Jobst and Hesse. It is
one of the earliest compounds to be identified as an inhibitor
of acetyl cholinesterase. (-)-Physostigmine is currently used
3
to treat myasthenia gravis and glaucoma. It was also found
to have promise as a therapeutic agent for Alzheimer’s
4
disease. However, the major drawbacks of this drug are a
5
low therapeutic window and short duration of action.
Figure 1. Structures of physostigmine and phenserine.
(1) For reviews, see: (a) Anthoni, U.; Christophersen, C.; Nielsen, P.
H. In Alkaloids: Chemical and Biological PerspectiVes; Pelletier, S. W.,
Ed.; Wiley: New York, 1999; Vol. 13, pp 163. (b) Takano, S.; Ogasawara,
K. In The Alkaloids; Brossi, A., Ed.; Academic: San Diego, CA, 1989;
Vol. 36, pp 225.
6
AChE and inhibits the formation of the â-amyloid precursor
7
(
(
2) Jobst, J.; Hesse, O. Justus Liebigs Ann. Chem. 1864, 129, 115.
3) (a) Axelsson, U. Acta Ophthalmol. 1969, 47, 1057. (b) Walker, M.
protein (â-APP). Consequently, it is an attractive target
molecule for synthetic study.
B. Proc. R. Soc. Med. 1934, 1, 1200.
4) (a) Greig, N. H.; Pei, X.-F.; Soncrant, T. T.; Ingram, D. K.; Brossi,
(
A. Med. Res. ReV. 1995, 15, 3. (b) Sano, N.; Bell, K.; Marder, K.; Stricks,
(6) Yu, Q.-S.; Holloway, H. W.; Flippen-Anderson, J. L.; Hoffman, B.;
Brossi, A.; Greig, N. H. J. Med. Chem. 2001, 44, 4062.
(7) Shaw, K. T. Y.; Utsuki, T.; Rogers, J.; Yu, Q.-S.; Sambamurti, K.;
Brossi, A.; Ge, Y.-W.; Lahiri, D. K.; Greig, N. H. Proc. Natl. Acad. Sci.
U.S.A. 2001, 98, 7605.
L.; Stern, Y.; Mayeux, R. Clin. Neuropharmacol. 1993, 16, 61.
(5) Al-Jafari, A.; Kamal, M. A.; Greig, N. H.; Alhomida, A. S.; Perry,
E. R. Biochem. Biophys. Res. Commun. 1998, 248, 180 and references
therein.
1
0.1021/ol062915+ CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/06/2007

The hexahydropyrrolo[2,3-b]indole alkaloids have been the
indole isocyanate with a nucleophilic carbene. Phenserine
possesses a methylene carbon at C (Figure 1), and access
1b,8
subject of a number of synthetic studies, including several
3
9
total syntheses of physostigmine. Total synthesis of (-)-
to this substitution pattern could be achieved by using a
nucleophilic carbene partner that could be readily reduced
to the desired oxidation level after the cyclization event. An
ideal candidate for achieving this objective is a bis(alkylthio)-
phenserine has been reported as well.10
The most synthetically challenging feature of both phys-
ostigmine and phenserine is the sterically congested all-
carbon quaternary center at C3a. Our laboratory had previ-
ously reported a method for producing quaternary centers
by reacting nucleophilic carbenes with â,â-disubstituted vinyl
12,17
carbene,
the resultant dithioacetal serving as a methylene
equivalent Via postcyclization reductive desulfurization.
Herein, an efficient total synthesis of (()-phenserine Via
[4+1] cyclization of an indole isocyanate and bis(propylthio)-
carbene is disclosed. The proposed retrosynthetic analysis
of this target is outlined in Scheme 2. The key transformation
isocyanates.1
1-13
Nucleophilic carbenes
11-15
have emerged
as powerful 1,1-dipole equivalents for the construction of
highly functionalized nitrogen heterocycles Via [4+1] cy-
clization with isocyanates, and the preparation of adducts
derived from indole isocyanates and these carbenes was
1
6
recently reported (Scheme 1).
Scheme 2. Retrosynthetic Analysis
Scheme 1. [4+1] Cyclization between an Indole Isocyanate
and Dimethoxycarbene
Inspired by these results, the synthesis of phenserine was
envisioned to proceed by the reaction of a suitably substituted
(8) For 3a-substituted pyrrolidinoindolines (other than physostigmine),
see: (a) Sun, W. Y.; Sun, Y.; Tang, Y. C.; Hu, J. Q. Synlett 1993, 337. (b)
Fuji, K.; Kawabata, T.; Ohmori, T.; Shang, M.; Node, M. Heterocycles
1
998, 47, 951. (c) Kawasaki, T.; Ogawa, A.; Takashima, Y.; Sakamoto,
M. Tetrahedron Lett. 2003, 44, 1591. (d) Austin, J. F.; Kim, S.-G.; Sinz,
C. J.; Xiao, W.-J.; MacMillan, D. W. C. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 5482. (e) Lopez-Alvarado, P.; Caballero, E.; Avendano, C.; Menendez,
in this sequence is the thermal decomposition of the 2,2-
3
12
bis(propylthio)-5,5-dimethyl-∆ -1,3,4-oxadiazoline (3) to
produce the corresponding carbene in the presence of indole
isocyanate 5, which would be expected to afford adduct 6
16
on the basis of prior related results.
The synthesis began with the preparation of indole 4 using
18
Cook’s procedure. The resulting species was then N-
methylated and saponified to obtain acid 10 in 61% yield.
Treatment of intermediate 10 with diphenylphosphorazidate
3
(DPPA) in the presence of Et N generated the requisite acyl
Heterocycles 1996, 42, 229. (b) Brossi, A.; Pei, X.-F.; Greig, N. H. Aust.
J. Chem. 1996, 49, 171. (c) Brzostowska, M.; He, X.-S.; Greig, N. H.;
Rapoport, S. I.; Brossi, A. Med. Chem. Res. 1992, 2, 238. (d) Haung, A.;
Kodanko, J. J.; Overman, L. E. J. Am. Chem. Soc. 2004, 126, 14043.
azide 11 (Scheme 3). The acyl azide 11 was refluxed in
benzene to effect Curtius rearrangement to the indole
isocyanate 5. Excess dithiooxadiazoline 3 was then added,
and the solution was refluxed for an additional 30 min to
(
11) (a) Rigby, J. H.; Cavezza, A.; Ahmed, G. J. Am. Chem. Soc. 1996,
1
18, 12848. (b) Rigby, J. H.; Cavezza, A.; Heeg, M. J. J. Am. Chem. Soc.
998, 120, 3664. (c) Rigby, J. H.; Cavezza, A.; Heeg, M. J. Tetrahedron
afford adduct 6. The crude adduct was exposed to LiAlH
4
1
Lett. 1999, 40, 2473. (d) Rigby, J. H.; Dong, W. Org. Lett. 2000, 2, 1673.
to deliver reduced tricycle 7 in 72% yield for the two steps
after purification (Scheme 4). Critical to the success of this
approach was the facility by which the quaternary center at
(
12) Rigby, J. H.; Laurent, S. J. Org. Chem. 1999, 64, 1766.
(13) For a review of vinyl isocyanate chemistry, see: Rigby, J. H. Synlett
2
1
000, 1.
(14) Rigby, J. H.; Laurent, S.; Cavezza, A.; Heeg, M. J. J. Org. Chem.
C3a was constructed. The efficiency of the carbene/isocyanate
998, 63, 5587.
(
15) For an overview of nucleophilic carbene chemistry, see: Warkentin,
J. In AdVances in Carbene Chemistry; Brinker, U. H., Ed.; JAI: Greenwich,
998; Vol. 2, pp 245.
16) Rigby, J. H.; Burke, P. J. Heterocycles 2006, 67, 643.
(17) Rigby, J. H.; Danca, M. D. Tetrahedron Lett. 1999, 40, 6891.
(18) Zhao, S.; Liao, X.; Wang, T.; Flippen-Anderson, J.; Cook, J. M. J.
Org. Chem. 2003, 68, 6279.
1
(
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Org. Lett., Vol. 9, No. 7, 2007

Scheme 3. Preparation of the Acyl Azide
Scheme 5. Synthesis of Phenserine
cyclization for making quaternary centers is a noteworthy
11-13
featureofthesereactionsthathasbeenexploitedpreviously.
With the tricyclic core of phenserine in place, compound
7
was N-methylated to furnish 12 in 93% yield. The stage
LiAlH
4
in refluxing THF produced esermethole (9) in
was then set for the reductive cleavage of the carbon-sulfur
bonds that were indroduced during the carbene addition step.
This was achieved in routine fashion by treatment with Raney
Ni. Further reduction of the lactam carbonyl group with
quantitative yield (Scheme 5).
Finally, using conditions reported by Overman and co-
1
0d
workers, esermethole was transformed in two steps, and
in 62% yield, to (()-phenserine (2). The spectral data of
this material were identical with those reported by Overman
1
0d
and co-workers.
In summary, we have developed a novel and efficient total
synthesis of (()-phenserine Via a [4+1] cyclization of an
indole isocyanate and bis(propylthio)carbene.
Scheme 4
Acknowledgment. The authors wish to thank the Na-
tional Science Foundation for their generous support of this
research.
Supporting Information Available: General experimen-
tal procedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL062915+
Org. Lett., Vol. 9, No. 7, 2007
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