Total synthesis of the Securinega alkaloid (-)-secu'amamine A

Article abstract of DOI:10.1021/ja802700z

The first enantioselective total synthesis of the rearranged Securinega alkaloid (-)-secu-amamine A is reported starting from D-proline as the source of absolute chirality. The synthesis requires 15 steps starting from D-proline-derived N-trityl aldehyde 11 and proceeds in approximately 9% overall yield. Key steps include a stereoselective conjugate addition of pyrrolidino enedione 19 to afford indolizidine 24 as the major product and cyclization/lactonization of diketoester 25 to produce tetracycle 26. In addition, ¹H NMR NOE studies and X-ray analysis on the synthetic alkaloid have established that the indolizidine moiety is trans-fused. Copyright

Full text of DOI:10.1021/ja802700z

Published on Web 05/21/2008
Total Synthesis of the Securinega Alkaloid (-)-Secu’amamine A
Peng Liu, Sungwoo Hong, and Steven M. Weinreb*
Department of Chemistry, The PennsylVania State UniVersity, UniVersity Park, PennsylVania 16802
Received April 17, 2008; E-mail: smw@chem.psu.edu
Scheme 1
The Securinega alkaloids are a family of approximately 25
tetracyclic compounds produced by several species of Securinega
and Phyllanthus plants.1 The most abundant Securinega alkaloid
is securinine (1), isolated from the leaves of Securinega suffruticosa.
Allosecurinine (4), which is the C2 epimer of 1, is also a common
alkaloid of this group. Some additional congeneric alkaloids are
(-)-norsecurinine (3) and phyllanthine (2). These alkaloids have a
wide range of biological activities.1b For example, securinine is a
GABA receptor antagonist,2a an antimalarial,2b and has antibacterial
activity.2c Some Securinega alkaloids have been sporadically used
in the clinic for diseases such as poliomyelitis, ALS, and chronic
aplastic anemia.1b
Scheme 2
In 2003, Ohsaki and co-workers isolated (-)-secu’amamine A
(5), a Securinega alkaloid having a new structural framework, from
the leaves and twigs of Securinega suffruticosa var. amamiensis.3
The constitution and relative stereochemistry of this compound were
determined primarily by NMR spectral analysis to be as depicted
in 5. The absolute configuration of the alkaloid was established
using the OMe-mandelate NMR method. Although the stereochem-
istry of the indolizidine moiety was not initially addressed, we have
determined that the trans-fused invertomer shown in 5 is thermo-
dynamically preferred (vide infra). Therefore, this metabolite has
an intriguing tetracyclic bridged ring system containing four
stereogenic centers, which differs in structure from all the other
Securinega alkaloids. Recently, Magnus and Padilla have proposed
that secu’amamine A is derived biogenetically from allosecurinine
(4) via oxidation at C3 followed by a rearrangement.4 In this
communication, we describe the first total synthesis of (-)-
secu’amamine A (5).
Our initial concept was to effect a multistep cascade cyclization
sequence of the pyrrolidino enedione substrate 6 to afford the
tetracyclic lactone 10 that possesses the complete secu’amamine
A skeleton (Scheme 1). The first step of this transformation is
conjugate addition of the amino group of 6 to the R,ꢀ-unsaturated
ketone moiety to afford intermediate indolizidine 7. Compound 7
would then undergo a ring flip and nitrogen inversion to conformer
8. Subsequent ketone enolization, followed by intramolecular aldol
condensation, would lead to keto hydroxy ester 9. Finally, this
compound would cyclize to tetracyclic γ-lactone 10. We speculated
that all of the steps from amino enone 6 to hydroxy ketone 9 would
be reversible under basic protic conditions, and that the final
lactonization to form tetracycle 10 might drive the overall process
and produce the desired stereochemistry at the four requisite centers
(C2, C3, C7, C9).
basis of the work of Chemla et al.,5 aldehyde 11 was combined
with known vinyl Grignard reagent 126 via a Felkin-Ahn addition
to produce amino alcohol 13 as a single stereoisomer having the
desired C2,3 configuration (Scheme 2). This alcohol was then
protected as the MOM ether 14. The silyl group of 14 was removed
with fluoride, and the labile N-trityl group was replaced with a more
stable Boc substituent to generate carbamate alcohol 15. Dess-Martin
oxidation of the primary alcohol functionality of 15 led to aldehyde
16, which without purification reacted with the anion derived from
known levulinate phosphonate 177 to yield (E)-enone 18. Although
a number of attempts were made to oxidatively cleave the exo-
methylene group of 18 to produce the N-Boc-protected precursor
to the enedione cyclization substrate 6, this transformation could
not be effected. Therefore, we elected to explore a modified strategy
using 18.
After some experimentation, it was discovered that exposure of
carbamate 18 to TFA in methylene chloride to remove the Boc
group, followed by careful neutralization of the amine salt at low
temperature using Hunig’s base, led to a mixture of indolizidines
23 and 24, with the desired latter stereoisomer being formed as the
major product with 5:1 selectivity in good combined yield (Scheme
3). The configuration and conformation of these compounds were
determined to be as shown by 2D NMR NOE analysis. Although
the cyclization products cannot be interconverted by exposure to
various bases in solution, it was found that, when the major isomer
24 is adsorbed onto dry basic alumina and allowed to remain at
room temperature overnight, it is transformed completely to the
minor isomer 23. It seems reasonable that 24 arises from cyclization
The synthesis commenced with N-tritylpyrrolidine aldehyde 11,
which was prepared enantiomerically pure from D-proline.5 On the
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7562 J. AM. CHEM. SOC. 2008, 130, 7562–7563
10.1021/ja802700z CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3
Scheme 5
that, if the 1H NMR spectrum of 5 is run in deuteriobenzene, peaks
due to the protons at C2,6 are sufficiently dispersed to allow NOE
analysis, which clearly demonstrated that the indolizidine is trans-
fused. We have also been able to obtain an X-ray crystal structure
of synthetic 5 which supports these conclusions.
Scheme 4
In summary, we have devised a convergent enantioselective total
synthesis of the novel Securinega alkaloid secu’amamine A (5).
The synthesis requires 15 steps starting from D-proline-derived
aldehyde 11 and proceeds in approximately 9% overall yield. Key
steps include a stereoselective conjugate addition of amino enedione
19 to afford indolizidine 24 as the major product and cyclization
of diketoester 25 to produce tetracyclic γ-lactone 26.
of the free amine derived from carbamate 18 via conformation 19,
leading initially to the intermediate cis-indolizidine 20. This
compound can undergo conformational isomerization to 21, fol-
lowed by nitrogen lone pair inversion, to produce 24.
The isomeric cyclization product 23 could form directly via
amino enone conformation 22. Our rationale for the conjugate
addition to occur primarily via conformer 19 to afford 24 as the
major kinetic product is based upon the known conformational
preferences of acyclic allylic ethers.8 Thus, work by Gung and
others has shown that the allylic hydrogen in such systems prefers
to be eclipsed (in plane) with the double bond as is the case in
conformation 19. An in plane C-O bond, as in the alternative
conformer 22, is generally disfavored.
Acknowledgment. Dedicated to Professor Deukjoon Kim on
the occasion of his 60th birthday. We are grateful to the National
Science Foundation (CHE-0404792) for support of this research.
We also thank Dr. Hemant Yennawar (Penn State Small Molecule
X-RayCrystallographicFacility)forthecrystalstructuredeterminations.
Supporting Information Available: Experimental procedures for
preparation of new compounds and copies of NMR spectra, as well as
X-ray data for compounds 5 and 27. This material is available free of
charge via the Internet at http://pubs.acs.org.
References
To continue the synthesis, the major exo-methylene indolizidine
24 was first oxidatively cleaved to ketone 25 (Scheme 4). We were
pleased to find that exposure of this compound to sodium methoxide
in methanol at room temperature afforded the desired tetracyclic
lactone 26 in 75% yield along with a small amount of a polar
compound which we believe is epimeric hydroxy ester 28. Support
for this assignment is that treatment of 28 with NaOMe/MeOH
produces lactone 26 in high yield. The structure of γ-lactone 26
was confirmed by an X-ray crystal structure analysis of the methyl-
protected analogue 27, prepared via the same route used for the
MOM compound. Interesting features of the structure include a
trans-fused indolizidine and a boat cyclohexanone ring.
Completion of the synthesis involved first selectively converting
ketone 26 to the enol triflate 29,9 followed by palladium-mediated
reduction to alkene 30 (Scheme 5).10 The γ-lactone moiety of 30
could be stereoselectively selenated to produce 31, which upon
periodate oxidation underwent syn-elimination to give diene lactone
32.11 Finally, removal of the MOM protecting group with MeOH/
HCl yielded (-)-secu’amamine A (5) having proton and carbon
NMR spectra identical to those of authentic material.3,12 Moreover,
the observed optical rotation of synthetic 5 was in good accord
with that of the natural alkaloid, thereby confirming the original
assignment of absolute configuration. In addition, we have found
(1) For reviews, see: (a) Snieckus, V. The Securinega Alkaloids. In The
Alkaloids; Manske, R. H. F., Ed.; Academic Press: New York, 1975, Vol.
14, p 425. (b) Beutler, J. A.; Brubaker, A. N. Drugs Fut. 1987, 12, 957.
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J.-M.; Durant, F.; Wermuth, C.-G. J. Med. Chem. 1992, 35, 1969. (b)
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(3) (a) Ohsaki, A.; Ishiyama, H.; Yoneda, K.; Kobayashi, J. Tetrahedron Lett.
2003, 44, 3097. Some additional compounds named secu’amamines have
been isolated recently from the same plant, but these are structurally related
to securinine: (b) Ohsaki, A.; Kobayashi, Y.; Yoneda, K.; Kishida, A.;
Ishiyama, H. J. Nat. Prod. 2007, 70, 2003.
(4) Magnus, P.; Padilla, A. I. Org. Lett., 2006, 8, 3569; Org. Lett. 8, 5177
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(8) (a) Kahn, S. D.; Hehre, W. J. Tetrahedron Lett. 1985, 26, 3647. (b) Lessard,
J.; Saunders, J. K.; Viet, M. T. P. Tetrahedron Lett. 1982, 23, 2059. (c)
Gung, B. W.; Wolf, M. A.; Peat, A. J. Tetrahedron Lett. 1993, 34, 1417.
(d) Gung, B. W.; Wolf, M. A. J. Org. Chem. 1993, 58, 7038.
(9) McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1983, 24, 979.
(10) (a) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1984, 25, 4821. (b)
Mori, M.; Nakanishi, M.; Kajishima, D.; Sato, S. J. Am. Chem. Soc. 2003,
125, 9801.
(11) Reich, H. J.; Wollowitz, S. Org. React. 1993, 44, 1.
(12) We are grateful to Dr. Ayumi Ohsaki for providing copies of the 1H and
13C NMR spectra of natural (-)-secu’amamine A.
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