First Diastereoselective Chiral Synthesis of (-)-Securinine

Article abstract of DOI:10.1021/ol0361251

(Equation presented) A diastereoselective total synthesis of securinine in optically pure form was achieved by employing ring-closing metathesis of the corresponding dienyne compound as a key step.

Full text of DOI:10.1021/ol0361251

ORGANIC
LETTERS
2004
Vol. 6, No. 1
87-89
First Diastereoselective Chiral Synthesis
of (−)-Securinine
Toshio Honda,* Hidenori Namiki, Kyosuke Kaneda, and Hirotake Mizutani
Faculty of Pharmaceutical Sciences, Hoshi UniVersity, Ebara 2-4-41, Shinagawa-ku,
Tokyo 142-8501, Japan
honda@hoshi.ac.jp
Received October 30, 2003
ABSTRACT
A diastereoselective total synthesis of securinine in optically pure form was achieved by employing ring-closing metathesis of the corresponding
dienyne compound as a key step.
Naturally occurring Securinega alkaloids, such as securinine
1, virosecurinine 2, allosecurinine 3, and viroallosecurinine
4, with their wide range of structural and stereochemical
features, continue to provide challenging synthetic targets,1
since these alkaloids exhibit attractive biological activities.
Securinine 1, embodying the basic structural features of
this class of alkaloids, was first isolated from Securinega
suffruticasa in 1956.2 Its structure (Figure 1) was determined
This alkaloid has been clinically used in Russia as a CNS
stimulating drug,5 acting as a stereospecific antagonist at the
GABA binding site of the GABAA-receptor complex.6 Since
it would appear to be a fairly rigid molecule with a well-
defined geometry, this alkaloid might aid in understanding
the shape of the GABAA receptor site.6
Due to its interesting biological activities, a number of
total and formal syntheses have appeared7 for racemic
securinine including the first total synthesis by Horii et al.8
However, no asymmetric synthesis has so far been achieved.9
(3) (a) Saito, S.; Kotera, K.; Shigematsu, N.; Ide, A.; Sugimoto, N.; Horii,
Z.; Hanaoka, M.; Yamawaki, Y.; Tamura, Y. Tetrahedron 1963, 19, 2085-
2099. (b) Horii, Z.; Ikeda, M.; Sugimito, N.; Tamura, Y.; Saito, S.; Kotera,
K. Tetrahedron 1963, 19, 2101-2110. (c) Sakoda, I.; Maruyama, M.; Tsuji,
J.; Yoshii, E. Tetrahedron Lett. 1962, 1199-1206. (d) Parello, J.; Melera,
A.; Goutarel, R. Bull. Soc. Chim. Fr. 1963, 898-910. (e) Chen, S.-F.; Hsieh,
C.-H.; Liang, H.-T. Yaoxue Xuebao 1963, 10, 225-236. (f) Nakano, T.;
Yang, T. H.; Terao, S. Tetrahedron 1963, 19, 609-619. (g) Nakano, T.;
Yang, T. H.; Terao, S. J. Org. Chem. 1963, 28, 2619-2621.
(4) Imado, S.; Shiro, M.; Horii, Z. Chem. Pharm. Bull. 1965, 13, 643-
651.
Figure 1.
(5) Russian Pharmacopeia, 10th ed.; Ministry of Health of the USSR:
Moscow, 1968; pp 612-614.
by chemical and spectroscopic studies in 1963,3 and later
verified by X-ray crystallography in 1965.4 It contains an
indolizidine skeleton that forms part of an azabicyclo[3.2.1]-
octane system fused onto an R,â-unsaturated γ-lactone ring.
(6) Beutler, I. A.; Karbon, E. W.; Brubaker, A. N.; Malik, R.; Curtis, D.
R.; Enna, S. J. Brain Res. 1985, 330, 135-140.
(7) Liras, S.; Davoren, J. E.; Bordner, J. Org. Lett. 2001, 3, 703-706
and references therein.
(8) Horii, Z.; Hanaoka, M.; Yamawaki, Y.; Tamura, Y.; Saito, S.;
Shigematsu, N.; Kotera, K.; Yoshikawa, H.; Sato, Y.; Nakai, H.; Sugimoto,
N. Tetrahedron 1967, 23, 1165-1174.
(1) Snieckus, V. The Alkaloids; Manske, R. H. F., Ed.; Academic Press:
New York, 1973; Vol. 14, pp 425-503 and references therein.
(2) Murav’eva, V. I.; Ban’kovskii, A. I. Dokl. Acad. Nauk SSSR 1956,
110, 998-1000.
(9) Recent approach to asymmetric synthesis of securinega alkaloids,
see: (a) Wanner, K. Th. Eur. J. Pharm. Sci. 1994, 2, 62-64. (b) Kammler,
R.; Polborn, K.; Wanner, K. Th. Tetrahedron 2003, 59, 3359-3368 and
references therein.
10.1021/ol0361251 CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/09/2003

Recently, we became involved in the synthesis of this
alkaloid, and successfully accomplished a formal synthesis
where an intramolecular Diels-Alder cycloaddition was
exploited as a key reaction.10
afforded the δ-lactonic compound 10 instead of the desired
compound, where a ruthenium carbene complex generated
from the terminal alkene in the butenyl group reacted with
alkyne prior to the olefin in the R,â-unsaturated ester.
As part of our continuing effort to synthesize and study
the biological activity of compounds related to important
CNS stimulating drugs, we aimed at developing a new and
improved general strategy for obtaining securinine and its
relatives in optically active form.
Scheme 2 a
In our retrosynthetic scheme, (+)-pipecolinic acid was
chosen as the starting material; its chirality would be trans-
ferred to the quaternary carbon center of (-)-securinine as
shown in Scheme 1. For forming the conjugated diene system
Scheme 1. Retrosynthetic Analysis
a Reaction conditions: (a) 3-butenylmagnesium bromide, THF,
0 °C; (b) n-BuLi, CeCl3, trimethylsilylacetylene, THF -78 °C; (c)
TBAF, THF, rt; (d) acryloyl chloride, EtMgBr, THF -78 °C; (e)
catalyst A, CH2Cl2, rt.
Thus, we focused our attention on the introduction of a
less reactive alkene moiety into 5. Treatment of 5 with 3(Z)-
hexenylmagnesium bromide gave ketone 11, which, on
alkynylation with lithium trimethylsilylacetylide in the pres-
ence of a stoichiometric amount of cerium(III) chloride as
described above, provided tertiary alcohol 12 as the sole
product via the Felkin-Anh model. By way of contrast, the
addition of lithium trimethylsilylacetylide to amine 13,
derived from ketone 11 by acid treatment, afforded the
chelation-controlled product 14,14 as expected.
It is noteworthy that the construction of the desired
stereochemistry at the quaternary carbon center for both
securine and viroallosecurinine can easily be achieved from
the same starting material depending on the substituents on
the piperidine nitrogen.
Two RCM strategies were investigated for obtaining
securinine. In the first we investigated the RCM of the R,â-
unsaturated ester 17, derived from 15 by acylation with
acryloyl chloride. For this, catalyst A was employed.
However, none of the desired product could be isolated under
a range of reaction conditions, presumably due to the
presence of a less reactive conjugated ester function. We,
therefore, turned our attention to employing a more reactive
allyl ether as the precursor for RCM.
we intended to exploit a tandem ring-closing metathesis
(RCM) of a dienyne system as a key reaction,11 and allylic
oxidation and ring closure would complete the sequence.
Thus, the optically active thioester 512 was treated with
3-butenylmagnesium bromide to give ketone 6, which, on
treatment with lithium trimethylsilylacetylide in the presence
of cerium(III) chloride, gave tertiary alcohol 7 as the sole
product. The observed stereoselectivity was rationalized by
assuming that the addition of the lithium reagent to 6 would
proceed via the Felkin-Anh model. After deprotection of
the silyl group with tetrabutylammonium fluoride, the
resulting alkyne 8 was further transformed into ester 9 by
acylation with acryloyl chloride. Attempted RCM of ester 9
with the highly active ruthenium catalyst (A),13 however,
Although difficulties were initially encountered in the
O-allylation of 15,15 we did eventually find that the reaction
of 15 with allyl trichloroacetimidate16 afforded the desired
allyl ether 16 in fairly good yield. The diastereomeric
(10) Honda, T.; Namiki, H.; Kudoh, M.; Watanabe, N.; Nagase, H.;
Mizutani, H. Tetrahedron Lett. 2000, 41, 5927-5930.
(11) For reviews on enyne metathesis, see: Poulsen, C. S.; Madsen, R.
Synthesis 2003, 1-18. For other reviews on metathesis, see: (a) Grubbs,
R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446-452. (b)
Schrock, R. R. Tetrahedron 1999, 55, 8141-8153. (c) Fu¨rstner, A. Angew.
Chem., Int. Ed. 2000, 39, 3012-3043. (d) Trunka, T. M.; Grubbs, R. H.
Acc. Chem. Res. 2001, 34, 18-29. (e) Hoveyda, A. H.; Schrock, R. R.
Chem. Eur. J. 2001, 7, 945-950.
(13) Grela, K.; Harutyunyan, S.; Michrewska, A. Angew. Chem., Int.
Ed. 2002, 41, 4039-4040.
(14) Tramontini, M. Synthesis 1982, 604-644.
(15) O-Allylation of 15 with allyl bromide under basic conditions
afforded the corresponding oxazolidinone arising from the reaction of tertiary
alcohol with a Boc group.
(12) Thai, D. L.; Sapko, M. T.; Reiter, C. T.; Bierer, D. E.; Perel, J. M.
J. Med. Chem. 1998, 41, 591-601.
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Org. Lett., Vol. 6, No. 1, 2004

bromide with potassium carbonate furnished (-)-securinine
1, mp 142-143 °C (n-hexane) (lit.18 mp 139-141 °C; lit.7
mp 143-144 °C). The spectroscopic data of 1 including
optical rotation {[R]D -1082 (c 1.0, CHCl3) {lit.2 [R]D -1106
(CHCl3)} were identical with those reported.3 Thus, we were
Scheme 3 a
Scheme 5 a
a Reaction conditions: (a) (Z)-3-hexenylmagnesium bromide,
THF, 0 °C; (b) n-BuLi, CeCl3, trimethylsilylacetylene, THF -78
°C; (c) TFA, CH2Cl2, 0 °C; (d) trimethylsilylacetylene, n-BuLi,
THF, -78 °C.
N-acetyl allyl ether 19 was also prepared from 14, via 18,
by employing the same procedure as above (Scheme 4).
Scheme 4 a
a Reaction conditions: (a) catalyst A, CH2Cl2, rt; (b) CrO3, 3,5-
dimethylpyrazole, CH2Cl2, -20 °C; (c) NBS, AIBN, CCl4, reflux;
(d) TFA, CH2Cl2, rt; (e) K2CO3, THF; (f) acryloyl chloride, EtMgBr,
THF -78 to 0 °C.
able to establish a facile synthetic route to the Securinega
alkaloids, and this is the first synthesis of optically pure
securinine.
The diastereomeric N-acetyl tertiary alcohol 1819 was also
converted into lactone 23, a potential intermediate for the
synthesis of viroallosecurinine, via the allyl ether 19 and the
diene 22, by adopting the same procedures as described
above.
In conclusion, we have completed a facile chiral synthesis
of (-)-securinine by using a tandem RCM reaction on a
dienyne derivative as a key step. This strategy should be
applicable to the synthesis of other Securinega alkaloids, and
this is currently under investigation.
a Reaction conditions: (a) TBAF, THF, 0 °C; (b) CH2dCH-
CH2OC(dNH)CCl3, TfOH, CH2Cl2, rt; (c) Ac2O, Et3N, CH2Cl2,
rt; (d) NaH, allyl bromide, THF-HMPA, rt.
The tandem RCM of 16 was again conducted with the
highly active ruthenium catalyst (A) in dichloromethane at
room temperature; it afforded the cyclized compound 20, in
74% yield. Thus, the stereoselective construction of the A,
C, and D rings of securinine was achieved in a relatively
short sequence.
To accomplish the total synthesis of securinine, diene 20
was oxidized at the allylic position with chromium tri-
oxide and 3,5-dimethylpyrazole at -20 °C to provide lac-
tone 21. Finally, allylic bromination of 21 with NBS and
AIBN,17 followed by removal of the protecting group with
TFA and subsequent cyclization of the resulting amino
Acknowledgment. This work was supported in part by
a grant from the Ministry of Education, Culture, Sports,
Science and Technology of Japan.
Supporting Information Available: Experimental details
and compound characterization. This material is available
free of charge via the Internet at http://pubs.acs.org.
(16) (a) Iversen, T.; Bundle, D. R. J. Chem. Soc., Chem. Commun. 1981,
1240-1241. (b) Wessel, H. P.; Iversen, T.; Bundle, D. R. J. Chem. Soc.,
Perkin Trans. 1 1985, 2247-2250.
(17) The stereochemistry of the bromide could not be determined at this
stage, unfortunately. However, the following cyclization of allylic bromide
would be assumed to proceed with both SN2 and SN1-like reaction
mechanisms. Thus, we used the crude material in the next reaction as
reported previously: see, refs 7 and 8.
OL0361251
(18) Krivut, B. A.; Perel’son, M. E. Khim.-Farm. Zh. 1967, 1, 44-46.
(19) To investigate RCM for the diastereomerical compound, a readily
accessible racemic N-acetyl compound 18 was employed.
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