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