Total syntheses of (±)-securinine and (±)-allosecurinine

Article abstract of DOI:10.1021/ol3020072

Total syntheses of (±)-securinine and (±)-allosecurinine that employ a tandem rhodium carbenoid-initiated Claisen/α-ketol rearrangement sequence as a key step are described.

Full text of DOI:10.1021/ol3020072

ORGANIC
LETTERS
2012
Vol. 14, No. 17
4531–4533
Total Syntheses of (()-Securinine and
(()- Allosecurinine
Jung-Hsuan Chen,† Samantha R. Levine,† Jonas F. Buergler,† Travis C. McMahon,†
Matthew R. Medeiros,‡ and John L. Wood*,†
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523,
United States, and Department of Chemistry, Yale University, New Haven,
Connecticut 06520, United States
john.l.wood@colostate.edu
Received July 19, 2012
ABSTRACT
Total syntheses of (()-securinine and (()-allosecurinine that employ a tandem rhodium carbenoid-initiated Claisen/R-ketol rearrangement
sequence as a key step are described.
Securinine (1)1 was first isolated in 1956 from the leaves
of the Securinega suffruticosa plant and was the first
member of the so-called Securinega alkaloids2 to be char-
acterized. In addition to securinine, its enantiomer virose-
curinine (2)3 and two diastereomers, allosecurinine (3)1c
and viroallosecurinine (4),4 have also been isolated.
Among other notable natural products in this family are
the pyrrolizidine congeners of securinine: norsecurinine
(5)5 and allonorsecruinine (6)6 (Figure 1).
have received considerable attention from the synthetic
community, resulting in several total syntheses.6,7 Our
interest in these molecules stemmed primarily from recent
reports of promising anticancer properties.8 Given the
increasing interest in both the securine and norsecurine
structural motifs, we set out to develop a unified synthetic
approach that would deliver both the pyrrolizidine natural
products (e.g., 5 and 6) as well as their indolizidine homo-
logues (e.g., 1À4) via application of a rhodium-catalyzed
OÀH insertion/Claisen rearrangement/1,2-allyl migration
method, which has been developed in our laboratories.9 In
previous studies, we established a viable route to the pyrro-
lizidine congeners and herein report the tactics required to
deliver (()-securinine (1) and (()-allosecurinine (3).10
Retrosynthetically the planned synthesis was seen as
delivering both (()-securinine (1) and (()-allosecurinine
(3) via the late-state introduction of the butenolide onto
hydroxy ketone 7, a substrate that was expected to derive
from oxidative ring closure of 8. Cyclohexene 8 would
arise from a ring-closing metathesis of diene 9, the allyla-
tion and intramolecular reductive amination product of
keto-ester 10. At this stage, the R-hydroxy-β-keto-ester
motif common to the products of our rhodium catalyzed
OÀH insertion/Claisen rearrangement/1,2-allyl migration
sequence is apparent, and thus 10, is seen as arising from
Because of their interesting compact structures and a
variety of biological activities, the Securinega alkaloids
† Colorado State University.
‡ Yale University.
(1) (a) Murav’eva, V. I.; Ban’kovskii, A. I. Dokl. Akad. Nauk SSSR
1956, 110, 998–1000. (b) Saito, S.; Kotera, K.; Sugimoto, N.; Horii, Z.;
Tamura, Y. Chem. Ind. 1962, 1652. (c) Satoda, I.; Murayama, M.; Tsuji,
J.; Yoshii, E. Tetrahedron Lett. 1962, 3, 1199–1206. (d) Saito, S.; Kotera,
K.; Shigematsu, N.; Ide, A.; Sugimoto, N.; Horii, Z.; Hanaoka, M.;
Yamawaki, Y.; Tamura, Y. Tetrahedron 1963, 19, 2085–2099.
(2) (a) Snieckus, V. The Securinega Alkaloids. In The Alkaloids;
Manske, R. H. F., Ed.; Academic Press: New York, 1973; Vol. 14, pp
425À506. (b) Weinreb, S. M. Nat. Prod. Rep. 2009, 26, 758–775.
(3) Nakano, T.; Yang, T. H.; Terao, S. Chem. Ind. 1962, 1651–1652.
(4) Saito, S.; Iwamoto, T.; Tanaka, T.; Matsumura, C.; Sugimoto,
N.; Horii, Z.; Tamura, Y. Chem. Ind. 1964, 1263–1264.
(5) Joshi, B. S.; Gawad, D. H.; Pelletier, S. W.; Kartha, G.; Bhandary,
K. J. Nat. Prod. 1986, 49, 614–620.
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r
10.1021/ol3020072
2012 American Chemical Society
Published on Web 08/22/2012

To initiate the synthesis, ethyl acetate was lithiated and
added to δ-valerolactone (12). The resulting β-keto ester
was converted to the diazo compound with pABSA11 and
the primary alcohol activated as the tosylate to give inter-
mediate 11. At this point, we were ready to investigate the
rhodium-catalyzed OÀH insertion/Claisen rearrangement/
1,2-allyl migration sequence, and while we recognized that
utilizing an enantioenriched allylic alcohol would result in
an asymmetric synthesis,10 we opted to explore this reaction
with racemic allylic alcohol 13.12 To this end, a mixture of
diazoester 11 and allylic alcohol 13 was treated with Rh2-
(OOct)4, which induced the desired OÀH insertion/Claisen
rearrangement and furnished intermediate 14. Subsequent
Figure 1. Selected securinega alkaloids.
treatment of the reaction mixture with BF3 EtO2 promoted
3
a 1,2-allyl migration to furnish 15. Addition of NaN3 to the
derived tosylate (15) followed by azide reduction under
Staudinger conditions produced a primary amine, which
spontaneously condensed onto the nearby ketone to furnish
imine 16 as the only isolable product. Imine 16 was reduced
and Boc-protected to give 17, which when treated with
LiAlH4 undergoes ester reduction to furnish diols 18a and
18b (Scheme 2). At this point, the two diastereomers were
separated and advanced separately.13
diazoester 11, which would be prepared in three steps from
δ-valerolactone (12) (Scheme 1).
Scheme 1. Retrosynthetic Analysis of Securinine (1) and Allo-
securinine (3)
Scheme 2. Synthesis of Diols 18a and 18b
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advance the major isomer, diol 18a. To this end, 18a was
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Org. Lett., Vol. 14, No. 17, 2012

Scheme 3. Synthesis of (()-Allosecurinine (3)
Scheme 4. Synthesis of (()-Securinine (1)
converted to the corresponding aldehyde by treatment with
IBX14 and then exposed to allyl Grignard to provide 9a.
Diene 9a was treated with the HoveydaÀGrubbs II catalyst,15
which efficiently induced ring-closing metathesis and fur-
nishes cyclohexene 8a. Treatment of 8a with bromine gave
a dibromide, which when treated under Swern conditions
provided enone 19a. The Boc protecting group was removed,
and the resulting amine was treated with Cs2CO3 to give
indolizidine 7a.16 Completion of the synthesis was realized by
first coupling acid 20 to tertiary alcohol 7a followed by an
intramolecular HornerÀWadsworthÀEmmons olefination
to give (()-allosecurinine (3) (Scheme 3).
to the diastereomeric system. Boc-deprotection and
base-mediated ring closure then gave indolizidine 7b
which, upon acylation with acid 20, underwent HornerÀ
WadsworthÀEmmons olefination to give (()-securinine
(1) (Scheme 4).
In summary, we have completed the total syntheses of
(()-securinine and (()-allosecurinine via a route that
employs a highly efficient rhodium-catalyzed OÀH inser-
tion/Claisen rearrangement/1,2-allyl migration domino
process. Efforts to employ this chemistry to facilitate the
emerging biological investigations into this class of com-
pounds are underway.
Turning next to (()-securinine (1), we attempted to
apply the same reaction sequence to diol 18b; however,
oxidation of the primary alcohol of diol 18b under the
conditions we utilized for diol 18a (i.e., IBX) resulted in a
product mixture that contained a considerable amount of
an inseparable byproduct.17 In an effort to circumvent this
deleterious event, we turned to the Swern conditions,
which cleanly delivered the desired aldehyde. As before,
treatment with allyl Grignard provided the corresponding
secondary alcohol (9b), which upon ring-closing metath-
esis furnished cyclohexene 8b. Bromination followed by
oxidation to the enone (19b) proceeded in a fashion similar
Acknowledgment. H.C. thanks the National Science
Council, ROC (Taiwan), and J.F.B. thanks the Swiss
National Science Foundation (SNF) and the Novartis
Jubilee Foundation for financial support. J.L.W. thanks
Amgen and the NSF (CHE-1058292) for financial sup-
port. Dr. Chris Rithner, Don Heyse, and Don Dick of the
CSU central instrumentation facility are acknowledged for
their assistance with spectroscopic analyses.
Supporting Information Available. Experimental de-
1
tails and copies of H and 13C NMR for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(13) The relative stereochemistry of diols 18a and 18b was not
determined at the time of synthesis and instead was assigned after
proceeding to natural products 1 and 3 separately and comparing those
to literature data.
(14) For the employed IBX protocol, see: More, J. D.; Finney, N. S.
Org. Lett. 2002, 4, 3001–3003.
(15) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H.
(17) Although not characterized in a pure state, we believe the
undesired material to be oxidative cleavage product 21.
J. Am. Chem. Soc. 2000, 122, 8168–8179.
(16) The relative stereochemistry of bromides 19a and 19b was not
determined; however, as demonstrated by both Honda7k and
Figueredo,7n this stereochemistry is inconsequential as both diastereo-
mers can be advanced to the desired product.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 17, 2012
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