A five-step synthesis of (S)-macrostomine from (S)-nicotine

Article abstract of DOI:10.1021/ol101887b

A concise synthesis of (S)-macrostomine has been accomplished in five steps from natural nicotine in 19% overall yield via a pyridyne Diels - Alder cycloaddition reaction as the key step. A Kumada cross-coupling reaction on a 1-chloroisoquinoline intermediate provided the natural product.

Full text of DOI:10.1021/ol101887b

ORGANIC
LETTERS
2010
Vol. 12, No. 20
4513-4515
A Five-Step Synthesis of
(S)-Macrostomine from (S)-Nicotine
Monica F. Enamorado, Pauline W. Ondachi, and Daniel L. Comins*
Department of Chemistry, North Carolina State UniVersity,
Raleigh, North Carolina 27695-8204
daniel_comins@ncsu.edu
Received August 11, 2010
ABSTRACT
A concise synthesis of (S)-macrostomine has been accomplished in five steps from natural nicotine in 19% overall yield via a pyridyne
Diels-Alder cycloaddition reaction as the key step. A Kumada cross-coupling reaction on a 1-chloroisoquinoline intermediate provided the
natural product.
(S)-Macrostomine (1) is a plant alkaloid containing a
benzylisoquinoline ring system that was first isolated from
the plant PapaVer macrostomum Boiss. et Huet and structur-
ally elucidated in 1974 by Santavy and co-workers.1 Later,
in 1984 the alkaloid was also isolated from the plant PapaVer
arenarium M.B.2 Santavy’s group3 reported that (S)-mac-
rostomine has a spasmolytic effect on the smooth muscle of
isolated intestines of rats and rabbits that is greater than that
of papaverin (2, Figure 1), an alkaloid used primarily in the
treatment of spasms and approved as a cerebral and coronary
vasodilator.4 (S)-Macrostomine has also been shown to have
some effects on the cardiovascular function of rabbits after
intravenous application.3 There has been no other report in
the literature on its biological activity, a shortcoming that
may be largely attributed to the lack of concise synthetic
routes to the natural product and analogues.
The first synthesis of (()-macrostomine was accomplished
in 1980 by Wykypiel and Seebach using 11 steps from
veratraldehyde.5 Two other syntheses of the racemate from
veratraldehyde were reported by Wiegrebe and co-workers6
and by Kapil and Sharma7 in 7 and 8 steps, respectively,
albeit in low overall yields. Later, in 1988 Wiegrebes’s group
published the only known enantioselective synthesis of (S)-
macrostomine in 13 steps through what they called the
Preininger alkaloid (3), a crucial intermediate for their
synthesis.8,9
Our group has in recent years been studying the synthetic
utility of (S)-nicotine (4) and its derivatives.10-12 Recently,
we reported a 6-step synthesis of (S)-brevicolline11 (5) and
two syntheses of SYB-1508Y12 (6) in 5 and 6 steps,
respectively, using (S)-nicotine as starting material. Since
(S)-macrostomine also possesses the core (S)-nicotine struc-
(1) Mnatsakanyan, V. A.; Preininger, V.; Simanek, V.; Klasek, A.;
Dolejs, L.; Santavy, F. Tetrahedron Lett. 1974, 10, 851–852.
(2) Israilov, I. S.; Manushakyan, M. A.; Mnatsakanyan, V. A.; Yusunov,
M. S. Chem. Nat. Compd. 1984, 20, 71–73.
(3) Mnatsakanyan, V. A.; Preininger, V.; Simanek, V.; Jurina, J.; Klasek,
A.; Dolejs, L.; Santavy, F. Collect. Czech. Chem. Commun. 1977, 42, 1421–
1430.
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(6) Wiegrebe, W.; Mahboobi, S.; Dannhardt, G.; Mayer, K.; Eibler, E.
Chimia 1981, 35, 288–289.
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30, 451–457. (b) Siuciak, J. A.; Chapin, D. S.; Harms, J. F.; Lebel, L. A.;
McCarthy, S. A.; Chambers, L.; Shrikhande, A.; Wong, S.; Menniti, F. S.;
Schmidt, C. J. Neuropharmacol. 2006, 51, 386–396. (c) Tang, Y.; Luan,
J.; Zhang, X. Plast. Reconstr. Surg. 2004, 114, 1166–1169.
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10.1021/ol101887b  2010 American Chemical Society
Published on Web 09/22/2010

Scheme 1. General Retrosynthetic Plan
induced o-(trimethylsilyl)pyridyl triflate elimination,14 in the
presence of a suitable diene would effect a Diels-Alder
cycloaddition to provide the precursor to the isoquinoline
ring system.
Our synthesis commenced with the introduction of a
chloride at the C-6 position of (S)-nicotine using Fort’s base15
as reported in our previous work (Scheme 2).10b,e A chloride
functionality at the C-6 position of 7 was essential to direct
lithiations at the C-4 and C-5 positions and to serve as a
handle in the C-C metal-catalyzed cross-coupling reaction
at the last step.
In the initial approach, 2,3-dimethoxybutadiene was
employed as the diene for the Diels-Alder cycloaddition,
as it has been reported to give cycloadducts with certain
dienophiles.16 Derivatives of (S)-6-chloronicotine substituted
at the C-4 and C-5 positions with bromine and iodine, or
with corresponding TMS and chloro groups, were employed
as pyridyne precursors. However, after extensive investiga-
tions, all efforts to achieve this cycloaddition under a variety
of conditions were unsuccessful. We attributed this failure
to the fact that 2,3-dimethoxybutadiene exists mostly in its
S-trans conformation, instead of the required S-cis conformer,
causing the cycloaddition to fail under the reaction condi-
tions.16
Figure 1. Macrostomine and related alkaloids.
ture, it was envisioned that this natural product could be
synthesized in a few steps from natural nicotine by using
directed lithiation methodology developed in our laborato-
ries.10-12
Reported herein is a 5-step synthesis of (S)-macrostomine
from (S)-nicotine. Nicotine as a chiral building block
provided the necessary stereochemistry and ring system
present in the natural product. The key step of our synthesis
involves an opportune use of a pyridyne intermediate in a
Diels-Alder reaction to provide the required isoquinoline
core heterocycle.
In our retrosynthetic plan (Scheme 1), we envisioned that
1 could be obtained from (S)-nicotine via two key reactions:
a Diels-Alder cycloaddition reaction of an intermediate
pyridyne that would provide 10 and then 1-chloroisoquinoline
11 after an aromatization step. A metal catalyzed C-C bond
formation to introduce the 3,4-methylenedioxybenzyl group
at C-1 would complete the synthesis.
As an alternative, an exploratory reaction was performed
with furan as the diene system since it is locked in a S-cis
It was anticipated that a metal-induced halide elimination13
at C-4 of a 4,6-dihalonicotine, or a corresponding fluoride-
(13) (a) Connon, S. J.; Hegarty, A. F. J. Chem. Soc., Perkin Trans. I
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Tetrahedron 2007, 63, 8065–8082. (f) Capracotta, S. S.; Comins, D. L.
Tetrahedron Lett. 2009, 50, 1806–1808. (g) Ondachi, P. W.; Comins, D. L.
Tetrahedron Lett. 2008, 49, 569–572. (h) Ondachi, P. W.; Comins, D. L.
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Org. Lett., Vol. 12, No. 20, 2010

dichloronicotine (8)10d,e was C-5 lithiated with n-BuLi at -78
°C, followed by addition of 8 equiv of 3,4-dimethoxyfuran,
and the mixture was allowed to warm to room temperature,
the product 10 was obtained in 55% yield as an inseparable
1:1 mixture of diastereomers. Attempts at aromatization of
the cycloadducts using a Zn/TiCl419 couple under reflux led
to decomposition of the starting material. Aromatization was
Scheme 2. Synthesis of (S)-Macrostomine (1) from (S)-Nicotine
20
accomplished when 10 was added to a solution of Mg/TiCl4
in THF (-78 °C to rt) to furnish key intermediate 11 in 70%
yield.
With 11 in hand, the C-C bond formation through a
Kumada21 cross-coupling reaction with piperonylmagnesium
chloride (12) was addressed. After extensive screening for
the appropriate catalyst, and optimization of conditions, a
ligand-free reaction with Ni(acac)2 as catalyst afforded the
enantiopure natural product 1 in 63% yield.
In summary, the plant alkaloid (S)-macrostomine was
synthesized via a 5-step sequence from (S)-nicotine in a 19%
overall yield. This practical synthesis was carried out with
retention of configuration on the pyrrolidine ring. Our work
constitutes the shortest synthesis of this natural product to
date, and further demonstrates the value of (S)-nicotine as a
chiral building block. Preparation of macrostomine analogues
for biological testing by using modifications of this synthetic
route is underway in our laboratories.
Acknowledgment. NMR and mass spectra were obtained
at NCSU Instrumentation laboratories, which were estab-
lished by grants from North Carolina Biotechnology Center
and National Science Foundation (Grant No. CHE-0078253).
The authors acknowledge Targacept Inc. for financial sup-
port. P.W.O. also thanks Targacept Inc. for funding of a
Research Assistantship. M.F.E. thanks NCSU for a North
Carolina State University Diversity Enhancement Grant.
conformation and is known to react with pyridynes.14
Gratifyingly, when (S)-4-bromo-6-chloro-5-iodonicotine10e
was subjected to a metal-halogen exchange at C-5 with
i-PrMgCl·LiCl at -78 °C, and then warmed to room
temperature in the presence of 10 equiv of furan, two
diastereomers of the Diels-Alder adduct were obtained in
modest yields.17 To synthesize 1 it was necessary to use a
furan derivative containing methoxy substituents at the C-3
and C-4 positions. The required 3,4-dimethoxyfuran (9) was
prepared in one step from commercially available 3,4-
dimethoxyfuran-2,5-dicarboxylic acid with use of a known
protocol.18
Supporting Information Available: Experimental pro-
cedures for 1, 8, 10, 11, and 12 and characterization and
NMR spectra for compounds 1, 10, and 11. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL101887B
Surprisingly, when (S)-4-bromo-6-chloro-5-iodonicotine10e
was subjected to similar conditions with excess 3,4-
dimethoxyfuran as the diene, the Diels-Alder adduct 10 was
obtained in very low yield. Fortunately, when (S)-4,6-
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1972, 94, 4374–4376. (c) Tamao, K.; Sumitani, K.; Kiso, Y.; Zembayashi,
M.; Fujioka, A.; Kodama, S.; Nakajima, I.; Minato, A.; Kumada, M. Bull.
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Derivatives of (S)-Nicotine from Natural Nicotine, Progress towards the
total Synthesis of (S)-Macrostomine, Ph.D. Dissertation, North Carolina
State University, Raleigh, NC, 2008.
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