Investigating Biogenetic Hypotheses of the Securinega Alkaloids: Enantioselective Total Syntheses of Secu'amamine E/ent-Virosine A and Bubbialine

Article abstract of DOI:10.1021/acs.orglett.6b03716

The synthesis of the Securinega alkaloid secu'amamine E (ent-virosine A) has been accomplished for the first time in 12 steps and 8.5% overall yield. In addition, bubbialine has been prepared and characterized. These two alkaloids and bubbialidine, all featuring an azabicyclo[2.2.2]octane core, were rearranged to their azabicyclo[3.2.1]octane congeners, a framework found in many Securinega alkaloids. These experiments suggest that azabicyclo[2.2.2]octane derivatives could serve as intermediates in the biosynthesis of the rearranged azabicyclo[3.2.1]octane products.

Full text of DOI:10.1021/acs.orglett.6b03716

Letter
pubs.acs.org/OrgLett
Investigating Biogenetic Hypotheses of the Securinega Alkaloids:
Enantioselective Total Syntheses of Secu’amamine E/ent-Virosine A
and Bubbialine
Robin Wehlauch,†,‡ Simone M. Grendelmeier,† Hideki Miyatake-Ondozabal,‡,§ Alexander H. Sandtorv,‡,∥
Manuel Scherer,†,‡ and Karl Gademann*,†
†Department of Chemistry, University of Zurich, 8057 Zurich, Switzerland
‡Department of Chemistry, University of Basel, 4056 Basel, Switzerland
S
* Supporting Information
ABSTRACT: The synthesis of the Securinega alkaloid
secu’amamine E (ent-virosine A) has been accomplished for
the first time in 12 steps and 8.5% overall yield. In addition,
bubbialine has been prepared and characterized. These two
alkaloids and bubbialidine, all featuring an azabicyclo[2.2.2]-
octane core, were rearranged to their azabicyclo[3.2.1]octane
congeners, a framework found in many Securinega alkaloids.
These experiments suggest that azabicyclo[2.2.2]octane derivatives could serve as intermediates in the biosynthesis of the
rearranged azabicyclo[3.2.1]octane products.
been obtained from a natural source, in contrast to securinol A
he Securinega alkaloids consist of a group of more than 60
Tknown secondary metabolites isolated from plants of (6) and viroallosecurinine (7).9
The biosynthetic origin of both the A ring and the C/D
several genera of the Phyllanthaceae family, including
Securinega, Phyllanthus, Flueggea, and others.1 Some of these
plants have been used in traditional folk medicines across Asia,
Africa, and Amazonia, and subsequently, several compounds of
the family were shown to exhibit antimalarial, antibacterial,
antitumor, and central nerve system activities.1,2 Among the
Securinega alkaloids, securinine constitutes the most abundant
and best-studied representative featuring the securinane
skeleton (Scheme 1A), and the group includes a series of
isomeric neosecurinane-type and two lower homologues of
norsecurinane- and neonorsecurinane-type, respectively (see
Scheme 1A for an overview). Structurally, these compounds
can be divided into groups featuring either azabicyclo[2.2.2]- or
azabicyclo[3.2.1]octane BC ring systems with a fused
pyrrolidine or piperidine ring. Their interesting biological
activities combined with the bridged tetracyclic core structure
triggered numerous synthetic efforts toward Securinega
alkaloids.1,2c,3,4
Secu’amamine E (1) was isolated along with two new
congeners from Securinega suffruticosa var. amamiensis by
Ohsaki et al. in 20095 and constitutes a member of the
neosecurinane series. The enantiomer ent-1 has also been
isolated as virosine A from Flueggea virosa,6 although this
relationship was not revealed in the subsequent publication.5
The lower homologue of 1, bubbialidine (2), the synthesis of
which we have reported recently,7 belongs to the neonorsecur-
inane family and was isolated along with the isomeric
bubbialine (3).8 While allosecurinine (4) is a natural epimer
of securinine, neither enantiomer of allonorsecurinine (5) has
system has been investigated over decades10 and can be traced
back to lysine and tyrosine catabolites, which merge to the
postulated tricyclic intermediate 8 (Scheme 1B). The origin of
the B/C bicyclic ring system, however, received much less
attention and, therefore, remains an interesting subject for
scientific investigation. The general biosynthetic pathway
formulated in the 1970s suggested that intermediate 8 can
either react via reduction and 1,6-addition to the azabicyclo-
[2.2.2]octane system to form e.g. 1 or via reduction and
amination to the azabicyclo[3.2.1]octane system to directly
afford 4.10 An alternative biogenetic hypothesis suggests that
compounds featuring the azabicyclo[2.2.2]octane ring system 1
could be intermediates, of which the azabicyclo[3.2.1]octane
compounds of type 4 would result through subsequent
rearrangement involving an aziridinium ion such as 9, which
has already been postulated by Horii et al. in the 1960s.11 This
hypothesis has, to the best of our knowledge, first been
suggested by Magnus et al. in 1993,12 but later received little
attention,4g and recent review articles do not mention this
mechanistic possibility.
In this study, we provide experimental evidence for the
second hypothesis by converting three different azabicyclo-
[2.2.2] natural products to the rearranged azabicyclo[3.2.1]
congeners. Along these lines, the first total syntheses of
secu’amamine E/ent-virosine A (1) and bubbialine (3) are
reported.
Received: December 13, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03716
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Scheme 1. General Structures and Biogenetic Hypotheses of
Scheme 2. Synthesis of Bicyclic Key Intermediate 7
Securinega Alkaloids
yielded α-hydroxy ketone 15. In addition, clean formation of
the product was also observed when a mixture of enone 13 and
oxaziridine 14 in THF at −78 °C was reacted with NaHMDS.
However, isolation and purification turned out to be difficult, as
enone 15 was not stable during flash column chromatography.
Moreover, N-benzylidenebenzenesulfonamide, the byproduct
formed from oxaziridine 14, displayed very similar retention
properties on silica as the hydroxy ketone 15. When instead
(+)-(8,8-dichlorocamphorylsulfonyl)oxaziridine was used to
generate a different byproduct, none of the desired product
15 was detected. The best results were obtained by washing the
organic fraction with aqueous NaHSO3, therefore removing
most of the imine and aldehyde contents, and followed by
filtration with apolar solvent to remove insoluble benzene-
sulfonamide. To setup the butenolide D ring, we applied an
efficient one-pot addition/Wittig reaction sequence using the
Bestmann ylide ((triphenylphosphoranylidene)ketene, 16).16
α-Hydroxy enone 15 was heated in benzene in the presence of
ketene 16 to give the bicyclic key intermediate 10 in 43% yield
over two steps as a mixture of diastereoisomers (3.3:1), which
was inconsequential and the isomers were not separated. While
lower temperatures only slowed the reaction, the addition of
triethylamine did not have any impact on yield.
The A ring was introduced using a one-pot procedure
́
reported by Busque, de March et al. producing the desired
Analogous to our earlier work,7 the key intermediate in our
synthesis of secu’amamine E (1) is TBDPS-protected
(+)-aquilegiolide (10), for which a shorter synthesis was
developed (Scheme 2). Ketal 11 was transformed into enone
12 in four steps and 37% overall yield following procedures
developed by Hayashi et al. during their total synthesis of
(+)-panepophenanthrin.13 To this goal, a proline-catalyzed
stereoselective α-addition of nitrosobenzene, a reduction of the
ketone using K-selectride followed by reductive N−O cleavage,
and finally an acid-catalyzed ketal hydrolysis with concomitant
elimination of water led to the desired γ-hydroxy enone 12.
The hydroxyl function was protected with a TBDPS group to
give fully protected enone 13 in 94% yield. For the subsequent
α-hydroxylation, we first investigated the use of Rubottom
oxidation conditions.14 While 1H NMR analyses indicated clean
formation of the corresponding silyl enol ethers using either
TMSCl or TESCl and NaHMDS, the subsequent reaction with
mCPBA led to decomposition of the substrate, and complex
mixtures were obtained. We then evaluated Davis’ oxaziridines
as oxidants and treatment of the preformed sodium enolate
with 3-phenyl-2-(phenylsulfonyl)oxaziridine (14)15 at −78 °C
product 17 in high yield and good selectivity (Scheme 3).17
Scheme 3. Enantioselective Synthesis of Secu’amamine E
B
DOI: 10.1021/acs.orglett.6b03716
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Since the reaction proceeds via silyl enol ether 18, both
diastereoisomers of intermediate 10 lead to the same product.
The two diastereoisomers generated could be separated by
silica column chromatography. The Boc protecting group was
then removed with ethereal HCl solution at elevated
temperature to give the desired hydrochloride in 97% yield.
When the salt was heated in a suspension of dipotassium
phosphate in DMF the desired tetracycle 19 was isolated in
varying yields. Applying more basic potassium carbonate in this
transformation afforded silyl ether 19 in a yield of 81%. Final
deprotection of the hydroxyl function by treatment with excess
HF·pyridine afforded secu’amamine E (1) in 98% yield. Thus,
the neosecurinane alkaloid 1 was synthesized in 12 steps in an
overall yield of 8.5%. All analytical data obtained from the
synthetic material were identical with those reported for the
authentic natural product. The optical rotation of −45.7° (c =
0.10, MeOH) of the synthetic alkaloid 1 matched the value of
−43.8° (c = 0.08, MeOH) reported by Ohsaki et al.5
Scheme 4. Dehydrative Rearrangement of Securinega
Alkaloids
In order to profile the ecotoxicity of this alkaloid, we tested
the synthetic material for toxicity against the freshwater
crustacean Thamnocephalus platyurus (beavertail fairy
shrimp).18 In an acute toxicity assay, five concentrations of
alkaloid 1 ranging from 1.23 to 100 μM were incubated with 10
animals for 24 h, each concentration in three separate
experiments. Each experiment was evaluated by visual
inspection of the animals before and after incubation. However,
no toxicity of alkaloid 1 could be observed in this concentration
range. In addition to secu’amamine E (1), we have obtained
bubbialidine (2) and bubbialine (3) following a previously
published route.7 In this context, bubbialine (3) was
characterized for the first time during this work.
We then focused on evaluating the feasibility of the
hypothesis outlined above, i.e. if the azabicyclo[2.2.2]octane
ring system 1 constitutes an intermediate en route to
azabicyclo[3.2.1]octane compounds of type 4. To test the
generality of the dehydrative rearrangement outlined above in
Scheme 1B, we treated synthetic samples of secu’amamine E
(1), bubbialidine (2), and bubbialine (3) with MsCl in the
presence of DMAP and Et3N. Alkaloids 1 and 2 reacted within
seconds at room temperature to give the rearranged alkaloids
allosecurinine (4) and (−)-allonorsecurinine ((−)-5), respec-
tively, in up to 93% yield (Scheme 4A and B). In contrast,
bubbialine (3) reacted to give the corresponding mesylate 20
under these conditions, which could be isolated and purified by
chromatography on silica gel (Scheme 4C). To effect the
rearrangement of the sulfonate 20, forcing conditions had to be
applied (100 °C, microwave, 6 h) and (+)-allonorsecurinine
((+)-5) was isolated in low yield and moderate purity. These
experimental observations can be explained by the mechanistic
rationale outlined in Scheme 4. Formation of the aziridinium
intermediate 9 or 21 is highly favored for alkaloids with an
antiperiplanar configuration of the amino and hydroxy groups
on the C ring, as the nitrogen is well aligned to donate electron
density into the σ* orbital of the exocyclic C−O bond. Thus,
the structure allows for rapid extrusion of the mesylate via such
a mechanism. However, when the groups are arranged in a
synperiplanar configuration, such as for 3, this orbital interaction
is less feasible and the mesylate has to leave in an SN1 fashion.
As a consequence of these mechanistic observations, we
speculate that neosecurinane- and neonorsecurinane-type
alkaloids possessing a [2.2.2]-bicyclic core serve as direct
biosynthetic intermediates of securinane- and norsecurinane-
type alkaloids with an unsaturated [3.2.1] core. Accordingly, the
biosynthesis of α,β,γ,δ-unsaturated Securinega alkaloids would
be extended by an additional intermediate featuring an OH
group and thus follow a linear pathway (Scheme 1B). Based on
́
the hypothesis by Busque, de March et al., intermediate 8 may
also be formulated as an alcohol instead of the ketone.17
Analogous to the transformation of 10 reported in Scheme 3,
the tricyclic amine might derive naturally from the bicyclic
lactones (+)-aquilegiolide and/or (+)-menisdaurilide via vinyl-
ogous Mannich reaction and thus already contain the hydroxy
group.
In summary, we have completed the first enantioselective
total synthesis of secu’amamine E (1) in 12 steps and 8.5%
overall yield. Key transformations are a butenolide formation
using the Bestmann ylide (16), a vinylogous Mannich reaction
to introduce the A ring, and an intramolecular aza-Michael
addition to form the B ring. Furthermore, three synthetic
natural products (1, 2, and 3) featuring an azabicyclo[2.2.2]-
octane core were rearranged to their azabicyclo[3.2.1]octane
congeners supporting a linear biogenetic hypothesis for
Securinega alkaloids. Thus, neo(nor)securinane-type alkaloids
with an antiperiplanar configuration on the C ring might serve
as natural precursors of the (nor)securinane-type alkaloids.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03716.
Detailed experimental procedures, analytical data, and
NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: karl.gademann@uzh.ch.
ORCID
Karl Gademann: 0000-0003-3053-0689
C
DOI: 10.1021/acs.orglett.6b03716
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Letter
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Present Addresses
§Bayer Pharma AG, Global Drug Discovery, Medicinal
Chemistry, 42096 Wuppertal, Germany.
∥Department of Chemistry, Portland State University, Portland,
OR 97201, USA.
(15) (a) Davis, F. A.; Lamendola, J., Jr.; Nadir, U.; Kluger, E. W.;
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Notes
The authors declare no competing financial interest.
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We gratefully acknowledge partial financial support by the
NCCR Molecular Systems Engineering, the Latsis Prize (to
K.G.), and the Novartis Early Career Award (to K.G.). Andrea
Meier (University of Basel) is gratefully acknowledged for
skillful technical assistance.
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