Chemical synthesis of aspidosperma alkaloids inspired by the reverse of the biosynthesis of the rhazinilam family of natural products

Article abstract of DOI:10.1002/anie.201204151

Pyrrole reduction: Iterative metal-catalyzed C-H functionalization reactions facilitated the preparation of a highly substituted pyrrole derivative. This derivative could be transformed into the pyrrole-containing secondary metabolite, rhazinilam, which could in turn be transformed through a reductive transannular cascade process into the structurally complex pyrrolidine-containing alkaloid natural product, aspidospermidine.

Full text of DOI:10.1002/anie.201204151

Angewandte
Chemie
DOI: 10.1002/anie.201204151
Natural Product Synthesis
Chemical Synthesis of Aspidosperma Alkaloids Inspired by the
Reverse of the Biosynthesis of the Rhazinilam Family of Natural
Products**
Lindsay McMurray, Elizabeth M. Beck, and Matthew J. Gaunt*
Pyrrole and pyrroldine heterocycles are ubiquitous structural
features in natural products. Nature’s biosynthetic machinery
often synthesizes the pyrrole functionality in these molecules
from a saturated pyrrolidine as part of its metabolic degra-
dation pathway.[1] Interestingly, the chemical synthesis of
substituted pyrroles is usually more straightforward in
comparison to that of the corresponding pyrrolidines; the
saturated hydrocarbon framework of pyrrolidine is relatively
unreactive,[2] usually requiring the presence of additional
functional groups to install a particular substituent, thus
rendering the synthesis of such compounds difficult in
comparison to their aromatic congeners. Therefore, the
transformation of a highly substituted pyrrole into an
architecturally complex pyrrolidine becomes an attractive
and potentially powerful strategy for total synthesis
(Figure 1A).[3,4]
Herein, we report the realization of this ideal through
a reductive transannular cascade strategy that transforms the
pyrrole-containing aromatic metabolite, rhazinilam (1a),
directly into aspidospermidine (2), a more complex pyrroli-
dine-containing natural product possessing a core molecular
architecture that is common to a large number of terpene–
indole alkaloids (Figure 1B).[5] This strategy exploits the
reactivity of the substituted pyrrole ring by triggering
a cascade reaction that results in a dramatic structural
rearrangement; pyrrole-containing metabolites are trans-
formed into pyrrolidine-containing natural products. Key to
have great potential in drug-discovery programs because the
structural diversification would generate a completely differ-
ent scaffold that may have biological properties that are
different from those of the parent pyrrole compound.[11]
Implementing total-synthesis strategies using multiple
À
metal-catalyzed C H bond functionalizations is still a signifi-
cant challenge.[12] Controlling which C H bond transforms
À
becomes more difficult as the complexity of the molecular
environment increase. Accordingly, we envisioned that
À
a metal-catalyzed C H arylation process at the C3 position
of a simple pyrrole derivative would give the central biaryl
motif, a position that is not normally reactive in conventional
pyrrole chemistry (Scheme 1A). Functionalization of the
À
C2 position was planned through a C H alkenylation process
that not only builds the all-carbon quaternary center, but also
installs the topological features that define the structure of the
natural product. Furthermore, commencing our synthesis
using 2-carbomethoxypyrrole derivative 5 could provide
a handle to control the site selectivity of the two metal-
À
catalyzed C H bond functionalizations on the heteroarene,
and also engage a divergent endgame that would deliver
rhazinilam (1a),[8] kopsiyunnanine C3 (1b)[13] and other
natural-product congeners.
We employed the first of our proposed metal-catalyzed
À
C H bond functionalization reactions to build the hetero-
biaryl fragment (Scheme 1B). While we had used this tactic in
our synthesis of rhazinicine,[12a] our divergent strategy for the
synthesis of rhazinilam and kopsiyunnanine C3 required us to
the implementation of this synthesis is the use of metal-
[6]
À
catalyzed C H bond functionalization to introduce the
start from a different pyrrole, 8. Pleasingly, application of the
I
À
desired substituents selectively and sequentially around the
pyrrole ring,[7] thereby allowing rapid assembly of the core
framework of rhazinilam.[8,9] The confluence of this concise
pyrrole functionalization tactic with the complexity-generat-
ing cascade delivers a powerful synthetic process capable of
converting planar heteroarenes into architecturally complex
alkaloid natural products.[10] Moreover, this approach could
Ir -catalyzed C H borylation methodology, developed by the
research groups of Smith and Maleczka[14a] and the research
groups of Hartwig, Miyaura, and Ishiyama,[14b,c] enabled
exploitation of the synergistic steric effects of the N-Boc
and 2-carbomethoxy groups and led to borylation of the
À
pyrrole at the C4 position—the only C H bond not adjacent
to any other substituent. Immediate addition of ortho-
iodonitrobenzene (6), catalytic Pd(OAc)2, S-Phos, and
K3PO4 in nBuOH to the reaction mixture facilitated
[*] L. McMurray, Dr. E. M. Beck, Prof. M. J. Gaunt
Department of Chemistry, University of Cambridge
Lensfield Road, Cambridge, CB21EW (UK)
E-mail: mjg32@cam.ac.uk
a Suzuki coupling reaction,[15] which completed the C H
À
arylation process, as well as removal of the Boc group, thus
affording the heterobiaryl compound 9 in 63% yield from 8.
The process required only one purification step and was
amenable to being conducted on multigram scale. In common
with our synthesis of rhazinicine,[12a] 11 was available in
3 steps from 10, in 79% overall yield (Scheme 1C). Reduc-
tion of carboxylic acid 11 with sodium borohydride, via the
mixed acylcarbonate, afforded the primary alcohol, which was
converted into iodide 12. Fragment union of 9 and 12
Homepage: http://www-gaunt.ch.cam.ac.uk/
[**] L.M. is grateful to the EPSRC and AstraZeneca for a Ph.D.
studentship, M.J.G. is grateful for funding from Phillip & Patricia
Brown through a Next Generation Fellowship and to unrestricted
funding from Novartis. We are grateful to the EPSRC Mass
Spectrometry Service at the University of Swansea.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204151.
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Figure 1. Synthesis blueprint.
proceeded smoothly through treatment of pyrrole 9 with NaH
in DMF before addition of iodide 12, thus forming the key
alkyl pyrrole 13 in 85% yield.
afford the desired product 14 in 60% yield (78% based on
recovered starting material). Notably, the use of oxygen as
À
a terminal oxidant reinforces the efficiency of this C H
With the entire acyclic backbone of rhazinilam in place,
the remaining steps focused on “zipping up” the linear system
13 to the natural products 1a and 1b. Construction of the all-
carbon quaternary center was initially planned through an
alkenylation process, through which we have introduced an
extremely sterically hindered structural feature of the rhazi-
nilam natural products from the readily assembled pyrrole 13.
Having installed the key architectural features of rhazi-
nilam, the remaining steps, comprising global hydrogenation,
cleavage of the TSE ester, and macrolactamization, pro-
ceeded smoothly to give methyl ester 15 in 70% yield over
three steps. The presence of the C2 ester group in 15 provided
an ideal handle to implement our divergent endgame strategy.
Saponification, followed by decarboxylation of the C2 ester
group, afforded rhazinilam (1a) in 68% yield; on the other
hand, DIBAL-H reduction of the same C2 ester group
delivered kopsiyunnanine C3 (1b), thus completing the first
total synthesis of this natural product (Scheme 1E). The
longest linear sequence in the divergent synthesis of both
rhazinilam and kopsiyunnanine C3 is 11 steps with 15% and
16% overall yields, respectively.
intramolecular PdII-catalyzed C H bond alkenylation
À
(Scheme 1D), a strategic disconnection similar to that
deployed in our rhazinicine synthesis. We first applied the
reaction conditions adapted from the rhazincine synthesis to
the transformation of compound 13, but disappointingly, even
with a stoichiometric amount of Pd(OTFA)2, a low yield of 14
was observed (Scheme 1D, entry 1). This reaction is thought
to proceed through electrophilic palladation of the pyrrole,
a pathway favored for electron-rich arenes. However, the
nucleophilicity of pyrrole 13 is relatively low owing to the
presence of the 2-carbomethoxy substituent and therefore
palladation may be suppressed, thus resulting in poor
reactivity.
While considering this problem, we reasoned that palla-
dation proceeding through concerted metalation–deprotona-
With an expedient method for the functionalization of
pyrroles established, we were then able to return to our initial
question: can these substituted pyrroles be converted directly
into architecturally more-complex pyrrolidines? We reasoned
that the inherent nucleophilicity of the pyrrole moiety could
be used to induce an alkylation reaction on the heteroarene at
a position bearing a substituent, a transformation that would
be followed by interception of the consequent pyrrolium ion
with a reducing agent, thus completing an alkylative–reduc-
tive dearomatization event (Figure 2). The resulting pyrroli-
dine would display a quaternary carbon center as part of the
intricate array of new stereogenic centers, installed directly
from the planar pyrrole.
À
tion (CMD) C H bond cleavage would be more suited to the
electron-deficient pyrrole 13,[16] because this pathway is
À
facilitated by the acidity of the C H bond. We were, however,
À
conscious that the relatively acidic C H bond ortho to the
nitro group on the other arene might undergo competitive
palladation, or that the carbomethoxy substitutent would
potentially direct the reaction to the position adjacent to the
ester group. Pleasingly, we found that under reaction con-
ditions reported by Liꢀgault and Fagnou for the PdII-catalyzed
alkylation of pyrroles,[17] the desired intramolecular catalytic
À
C H alkenylation reaction to give 14 proceeded in a low but
encouraging 15% yield (Scheme 1D, entry 4). Only trace
byproducts were observed and the remaining mass balance
was starting material. Subsequent investigations of this intra-
molecular oxidative Heck reaction led to optimal reaction
conditions (Scheme 1D, entry 6) requiring treatment of 13
with 10 mol% Pd(OAc)2, 20 mol% NaOtBu, and 10 mol%
DMF in pivalic acid at 1108C under a balloon of oxygen to
Rhazinilam (1a) and aspidospermidine (2)[18] display
a number of congruent features including a common quater-
nary stereogenic center (C9), as well as pyrrole and pyrroli-
dine rings at the heart of their respective structures (Fig-
ure 1B). The crucial difference between the framework
connectivity of rhazinilam and aspidospermidine was the
À
presence or absence of a C C bond between the C12 and C4
2
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Figure 2. Propagation of structural complexity: pyrroles to pyrrolidines.
positions in the two natural products. Excited by the prospect
of transforming one class of natural product into a structurally
different natural product, we analyzed the three-dimensional
structure of rhazinilam and noted that the C12-amide
carbonyl group, a moderately electrophilic functionality, was
located in close proximity to the C4 position of the pyrrole
motif. Therefore, conversion of this C12 amide into a more
reactive iminium functionality would potentially trigger
a transannular nucleophilic attack of the pyrrole onto this
À
electrophilic species, thereby generating the C C bond
essential for the connectivity of aspidospermidine. Accord-
ingly, addition of a Boc group to the nitrogen atom of the C12
amide gave 16, which was reduction using LiBHEt3
(Scheme 2). Immediate treatment of the reaction mixture
with acetic anhydride and DMAP allowed in situ acylation,
thus furnishing the desired acetylated hemiaminal 16a, which
was directly treated with trifluoroacetic acid, thus generating
the desired iminium species 16b and initiating the planned
cascade reaction. Gratifyingly, this iminium intermediate
À
underwent C4 C12 transannular bond formation, forming
16c. After two hours, NaCNBH3 was added, stereoselectively
reducing the pyrrolium ion, as well as the enamine motif to
give 17. Treatment with trifluoroacetic acid afforded aspido-
spermidine (2), thus completing the synthesis of the natural
product in just three steps from rhazinilam (1b) in 47% yield.
The complexity-generating transannular cascade process
forms two new stereocenters and two new rings, which are
present in aspidospermidine, the core structure of which is
prevalent in the indole–terpene alkaloid family of natural
products. Furthermore, this remarkable transformation is the
reverse of a proposed biosynthesis that oxidatively degrades
the aspidosperma alkaloids to rhazinilam.[19]
The pyrrole and pyrrolidine heterocyclic motifs, present at
the heart of rhazinilam and aspidospermidine, impart the
conformational restrictions that most likely define the
structure and biological properties of these natural products.
Our bioinspired transformation, which converts a rapidly
assembled pyrrole into a complex pyrrolidine, therefore leads
to a dramatic change in the structural, functional, and physical
properties of the parent molecule and generates a completely
different natural product scaffold. It is this diversification that
we believe could have great potential in the search for
molecules with novel therapeutic properties.
Received: May 28, 2012
Published online: && &&, &&&&
Scheme 1. Divergent and modular synthesis of rhazinilam alkaloids.
Ac=acetyl, Boc=t-butoxycarbonyl, cod=1,5-cyclooctadiene,
DCE=dichloroethane, DIBAL-H=diisobutylaluminum hydride,
DMF=N,N-dimethylformamide, pin=pinacolate, Piv=pivalyl,
S-Phos=2-dicyclohexylphosphino-2’,6’-dimethoxybiphenyl,
TFA=trifluoroacetyl, TSE=trimethylsilylethyl.
À
Keywords: biomimetic synthesis · C H functionalization ·
.
domino reactions · natural products · reduction
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Scheme 2. Transformation of rhazinilam to aspidospermidine. DMAP=4-(dimethylamino)pyridine, TFA=trifluoroacetic acid.
À
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Communications
Natural Product Synthesis
L. McMurray, E. M. Beck,
M. J. Gaunt*
&&&& — &&&&
Chemical Synthesis of Aspidosperma
Alkaloids Inspired by the Reverse of the
Biosynthesis of the Rhazinilam Family of
Natural Products
Pyrrole reduction: Iterative metal-cata-
rhazinilam, which could in turn be trans-
À
lyzed C H functionalization reactions
formed through a reductive transannular
cascade process into the structurally
complex pyrrolidine-containing alkaloid
natural product, aspidospermidine.
facilitated the preparation of a highly
substituted pyrrole derivative. This deriv-
ative could be transformed into the
pyrrole-containing secondary metabolite,
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