Addition of metallo enolates to chiral 1-acylpyridinium salts: Total synthesis of (+)-cannabisativine

Article abstract of DOI:10.1021/ol0056271

formula presented A novel route to the first asymmetric synthesis of (+)-cannabisativine (1) is described. The total synthesis of 1 was accomplished with a high degree of regio- and stereoselectivity in 19 steps and 9% overall yield.

Full text of DOI:10.1021/ol0056271

ORGANIC
LETTERS
2000
Vol. 2, No. 6
855-857
Addition of Metallo Enolates to Chiral
1-Acylpyridinium Salts: Total Synthesis
of (+)-Cannabisativine
Jeffrey T. Kuethe and Daniel L. Comins*
Department of Chemistry, North Carolina State UniVersity,
Raleigh, North Carolina 27695-8204
daniel_comins@ncsu.edu
Received February 4, 2000
ABSTRACT
A novel route to the first asymmetric synthesis of (+)-cannabisativine (1) is described. The total synthesis of 1 was accomplished with a high
degree of regio- and stereoselectivity in 19 steps and 9% overall yield.
The polyamine alkaloid (+)-cannabisativine (1) was isolated
from Cannabis satiVa L. in 1975, and its structure was
determined by X-ray diffraction analysis.1 Spurred by its
unique architecture, synthetic efforts ensued and resulted in
two racemic syntheses from the laboratories of Natsume2
and Wasserman.2b A few years later, the absolute stereo-
chemistry of 1 was established through the synthesis of (-)-
cannabisativine by Hamada and co-workers.3
reaction is useful for the enantioselective preparation of 2-
substituted piperidines containing functionality and stereo-
centers in the C-2 side chain. The piperidine core of
cannabisativine, with its 1,2-diol side chain, appeared to be
an attractive target for this methodology. Herein is described
the first asymmetric synthesis of natural (+)-cannabisativine
(1). The four stereocenters and the carbon-carbon double
bond are introduced with a high degree of stereo- and
regiochemical control.
The synthesis began as shown in Scheme 1. The enantio-
pure 1-acylpyridinium salt 25 was treated with zinc enolate
3 to give dihydropyridone 4 in 85% yield.6 Conversion of 4
to Weinreb’s amide 5 proceeded in near quantitative yield.4,7
(2) (a) Ogawa, M.; Kuriya, N.; Natsume, M. Tetrahedron Lett. 1984,
25, 969. (b) Wasserman, H. H.; Leadbetter, M. R. Tetrahedron Lett. 1985,
26, 2241.
(3) Hamada, T.; Zenkoh, T.; Sato, H.; Yonemitsu, O. Tetrahedron Lett.
1991, 32, 1649.
(4) Comins, D. L.; Kuethe, J. T.; Hong, H.; Lakner, F. J. J. Am. Chem.
Soc. 1999, 121, 2615 and references therein.
(5) Comins, D. L.; Joseph, S. P.; Goehring, R. R. J. Am. Chem. Soc.
1994, 116, 4719.
Recently, we have been investigating the addition of
metallo enolates to chiral 1-acylpyridinium salts.4 This
(6) The yield is of diastereomerically pure 4 isolated by radial preparative
layer chromatography. The reaction proceeded in >95% de; see ref 4.
(7) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815. (b)
Shimizu, T.; Osako, K.; Nakata, T. Tetrahedron Lett. 1997, 38, 2685 and
references therein.
(1) (a) Lotter, H. L.; Abraham, D. J.; Turner, C. E.; Knapp, J. E.; Schiff,
P. L.; Slatkin, D. J. Tetrahedron Lett. 1975, 7, 2815. (b) Turner, C. E.;
Hsu, M.-F. H.; Knapp, J. E.; Schiff, P. L.; Slatkin, D. L. J. Pharm. Sci.
1976, 65, 1084.
10.1021/ol0056271 CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/15/2000

reduction of the alkyne bond could be achieved via catalytic
hydrogenation to give 10. The TIPS group was now removed
with TFA (CHCl3, reflux, 12 h) to provide bicyclic carbamate
11 (Scheme 2). At this stage, an acetic acid unit needed to
Scheme 1
Scheme 2
be introduced stereoselectively at C-6 of 11, and regiospecific
incorporation of a C-3,4 olefin into the piperidine ring was
required. Selenenylation of 11 via its enolate provided phenyl
selenides 12 as a 3/1 mixture of diastereomers. A latent acetic
acid unit was introduced at C-6 with complete stereoselec-
tivity using a Mukaiyama-Michael reaction.11 Addition of
BF3 etherate to a mixture of 12 and O-silyl ketene acetal
1312 (CH2Cl2, -78 °C, 30 min) followed by acidic workup
afforded piperidones 14 in quantitative yield. Luche reduction
of 14 gave an 85% crude yield of two alcohols, 15 and 16,
which were used directly as a mixture in the next step. A
one-pot procedure was developed to convert crude 15/16 into
the desired tetrahydropyridine 18 (Scheme 3). The crude
mixture (15/16) in toluene was treated with 1,1′-thiocar-
bonyldiimidazole (DMAP, toluene, reflux, 8 h) to give the
corresponding thiocarbamates 17, which were reduced in situ
on addition of Bu3SnH/AIBN (reflux, 10 min) to afford
tetrahydropyridine 18 in 85% overall yield.11b The ester 18
was converted to amide 20 via its acid chloride and amino
alcohol 1913 using Schotten-Baumann conditions (NaOH,
CH2Cl2, rt).
Addition of pentynyllithium (5 equiv) to 5 provided ketone
6, which was reduced under Luche conditions to give diol 7
(>95% de) in excellent yield.8 The previous three steps could
be accomplished in high overall yield due to the C-5 TIPS
group which protects the dihydropyridone against nucleo-
philic attack. On treatment of 7 with sodium hydride, cyclic
carbamate 8 was formed and isolated in 88% yield. In
addition, the released chiral auxiliary, (+)-TCC,9 was
recovered (94%). The remaining secondary hydroxyl group
of 8 was protected as its benzyl ether using benzyl tri-
chloroacetimidate to afford 9.10 With the TIPS group still
protecting the enone system of dihydropyridone 9, clean
(8) This highly stereoselective reduction is likely a result of a chelation-
controlled addition mechanism.
(9) Comins, D. L.; Salvador, J. M. J. Org. Chem. 1993, 58, 4656.
(10) Iversen, T.; Bundle, D. R. J. Chem. Soc., Chem. Commun. 1981,
1240.
(11) (a) Saigo, K.; Osaki, M.; Mukaiyama, T. Chem. Lett. 1976, 163.
(b) Kuethe, J. T.; Comins, D. L. Org. Lett. 1999, 1, 1031.
(12) The 1-methoxy-1-trimethylsiloxyethene (13) was prepared by a
literature procedure: Collins, D. J.; Cullen, J. D. Aust. J. Chem. 1988, 41,
735.
(13) Lesher, G. Y.; Surrey, A. R. J. Am. Chem. Soc. 1955, 77, 636.
856
Org. Lett., Vol. 2, No. 6, 2000

Scheme 3
Scheme 4
agreement with the literature values [mp 167-68 °C; [R]D
+55.1 (c 0.53, CHCl3)].1a
In summary, the first asymmetric synthesis of (+)-
cannabisativine (1) has been accomplished in 19 steps with
a high degree of stereocontrol. Key to the success of this
total synthesis was the metallo enolate addition to chiral
acylpyridinium salt 2. This allowed the preparation of
dihydropyridone building block 4 which contains two
contiguous stereocenters of the right absolute stereochemistry
for the natural product target. The conversion of dihydro-
pyridone 7 to bicyclic carbamate 8 was also of strategic
importance. In one step, one secondary alcohol was protected,
the chiral auxiliary was released, and a bicyclic system was
formed with the proper conformational bias to allow the last
stereocenter to be introduced with complete control of
stereochemistry. This strategy should be useful for the
enantioselective preparation of other complex alkaloids.
Efforts in this direction are ongoing in our laboratories.
The oxazolidinone ring of 20 was opened in the presence
of the tertiary amide group by treatment with refluxing
aqueous KOH to provide aminodiol 21.14 The 13-membered
lactam ring of 1 was constructed using a method similar to
that reported by Weinreb for the synthesis of anhydro-
cannabisativene.15 Treatment of 21 with triflate 22 (1.6 equiv)
in the presence of Hunig’s base afforded the tertiary amine
23. After conversion to the primary mesylate 24 (Scheme
4), cyclization was carried out in acetonitrile/K2CO3 to
provide lactam 25 in 70% yield.
Global deprotection using sodium in liquid ammonia gave
a 76% yield of (+)-cannabisativine (1), which exhibited
spectral data in agreement with reported data for authentic
material.2b The melting point (165-66 °C) and optical
rotation, [R]2D3 +51.8 (c 0.425, CHCl3), were also in
Acknowledgment. We express appreciation to the Na-
tional Institutes of Health (Grant GM 34442) for financial
support of this research. We are grateful to Dr. H. Wasserman
for 500 MHz 1H NMR spectral data of cannabisativine. NMR
and mass spectra were obtained at NCSU instrumentation
laboratories, which were established by grants from the North
Carolina Biotechnology Center and the National Science
Foundation (Grants CHE-9121380 and CHE-9509532).
Special thanks to Robert Johnson and Wendy White (Glaxo-
Wellcome, Inc.) for HRMS analyses of compounds 23 and
25.
Supporting Information Available: Characterization
data for compounds 4-12, 14-16, 18, 20-21, 23-25, and
1
1, H and 13C NMR spectra of 6-10, 12, 14-16, 18, 20-
21, 23-25, and 1. This material is available free of charge
via the Internet at http://pubs.acs.org.
(14) The corresponding secondary amide suffers significant hydrolysis
under these conditions.
(15) Bailey, T. R.; Garigipati, R. S.; Morton, J. A.; Weinreb, S. M. J.
Am. Chem. Soc. 1984, 106, 3240.
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