A General Iridium-Catalyzed Reductive Dienamine Synthesis Allows a Five-Step Synthesis of Catharanthine via the Elusive Dehydrosecodine

Article abstract of DOI:10.1021/jacs.1c04980

A new reductive strategy for the stereo- and regioselective synthesis of functionalized isoquinuclidines has been developed. Pivoting on the chemoselective iridium(I)-catalyzed reductive activation of β,γ-unsaturated δ-lactams, the efficiently produced reactive dienamine intermediates readily undergo [4 + 2] cycloaddition reactions with a wide range of dienophiles, resulting in the formation of bridged bicyclic amine products. This new synthetic approach was extended to aliphatic starting materials, resulting in the efficient formation of cyclohexenamine products, and readily applied as the key step in the shortest (five-step) total synthesis of vinca alkaloid catharanthine to date, proceeding via its elusive biosynthetic precursor, dehydrosecodine.

Full text of DOI:10.1021/jacs.1c04980

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A General Iridium-Catalyzed Reductive Dienamine Synthesis Allows
a Five-Step Synthesis of Catharanthine via the Elusive
Dehydrosecodine
Pablo Gabriel,⊥ Yaseen A. Almehmadi,⊥ Zeng Rong Wong, and Darren J. Dixon*
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ABSTRACT: A new reductive strategy for the stereo- and regioselective synthesis of functionalized isoquinuclidines has been
developed. Pivoting on the chemoselective iridium(I)-catalyzed reductive activation of β,γ-unsaturated δ-lactams, the efficiently
produced reactive dienamine intermediates readily undergo [4 + 2] cycloaddition reactions with a wide range of dienophiles,
resulting in the formation of bridged bicyclic amine products. This new synthetic approach was extended to aliphatic starting
materials, resulting in the efficient formation of cyclohexenamine products, and readily applied as the key step in the shortest (five-
step) total synthesis of vinca alkaloid catharanthine to date, proceeding via its elusive biosynthetic precursor, dehydrosecodine.
aturated and semisaturated nitrogen-containing hetero-
activation of α,β-unsaturated imines 10 (Scheme 1d2)9 as well
Scycles are prevalent structures in bioactive natural products as via multistep cascade reactions involving proline-catalyzed
and pharmaceutical compounds,1 and accordingly, new
Mannich cyclization followed by oxidation and reduction
(Scheme 1d3).10 Notwithstanding these elegant reports, only
strategic approaches for their efficient and selective synthesis
specific substitution patterns are currently accessible,7−10 and a
are important. In parallel, Diels−Alder reactions have been
general strategy for the controlled synthesis of electron-rich
1,2-dihydropyridines currently remains elusive.
for nearly a centuryone of the most powerful tools for the
construction of cyclic and polycyclic products, allowing the
disconnection of six-membered rings to a four-electron diene
component and a two-electron dienophile.2,3 In the normal
electron demand Diels−Alder reaction, electron-rich dienes
locked in the reactive s-cis conformation are exceptionally
reactive. As such, 1,2-dihydropyridines 1 are a class of
compounds particularly poised for cycloaddition reactions,
producing the 2-azabicyclo[2.2.2]octane ring system 2, also
called isoquinuclidine (Scheme 1a).4 This bridged nitrogen-
containing bicycle is a familiar structural feature in a range of
alkaloid natural products, for instance, catharanthine (3),
cononusine (4), and caldaphinidine D (5) (Scheme 1b).5
Additionally, isoquinuclidines have been used as intermediates
toward octahydroisoquinolines in drugs and natural products,
such as pseudotabersonine (6) and oseltamivir (7) (Scheme
1c).6
Because of the important role of these compounds, and the
challenges associated with their generation, we recognized that
a mild and general reductive functionalization approach to
access 1,2-dihydropyridines using readily available lactam
starting materials could be of high synthetic value. Mechanistic
studies from our group on the iridium-catalyzed reductive
nitro-Mannich reaction revealed that tertiary lactams have a
strong propensity to form enamines from the silylated
hemiaminal intermediates via their corresponding iminium
species.11a−f Aware of this, and the tolerance of alkene moieties
to the reductive activation conditions,11g−v we reasoned that in
the presence of suitably placed β,γ-unsaturation in the lactam
ring of 15 (Scheme 1e), the 1,2-dihydropyridine species would
likely arise from iminium ion 17 via silylated hemiaminal 16.
Reactive conjugated dienamine intermediates such as 18 are
primed for downstream cycloaddition reactions with various
dienophiles, and granting new access to them via a reductive
manifold would provide a wealth of opportunities in both
library generation, and natural product synthesis alike; herein
we wish to report our findings.
To date, because of their inherent instability, the selective
and efficient generation of electron-rich 1,2-dihydropyridines
has been challenging, and in most cases the presence of a
carbamoyl, or similar, electron-withdrawing group on the
nitrogen atom is required to make them sufficiently stable for
downstream manipulation, albeit at the expense of further
deprotection steps or functional group manipulation.7 Other
methods rely on the partial reduction of, or nucleophilic
addition to, pyridinium species (Scheme 1d1),8 but indirect
strategies are often required to circumvent the undesired or
imperfect regioselectivity in the borohydride-mediated reduc-
tion7b,c,f or nucleophilic addition. More recently, highly
substituted (and inherently more stable) 1,2-dihydropyridines
such as 12 have been generated via Rh-catalyzed C−H
1
We began our studies with a H NMR experiment to assess
the feasibility of formation of the desired dienamine from
Received: May 13, 2021
Published: July 13, 2021
© 2021 The Authors. Published by
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Scheme 1. (a) Diels−Alder Cycloadditions of 1,2-Dihydropyridines; (b) Isoquinuclidine-Containing Natural Products; (c)
Use of Isoquinuclidines in Synthesis; (d) Existing Methods (and Limitations) toward the Synthesis of 1,2-Dihydropyridines
and Downstream Isoquinuclidines; and (e) This Work
Figure 1. 1H NMR spectra of the reduction of lactam 15a to the dienamine 18a and downstream cycloaddition with N-phenylmaleimide. Reaction
performed in d8-toluene, in an NMR tube; 1,3,5-trimethoxybenzene (TMB) was used as internal standard.
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lactam precursors (Figure 1). We subjected the model N-
benzyl β,γ-unsaturated δ-lactam substrate 15a to standard
reduction conditions in d8-toluene (0.1 mol % of Vaska’s
complex and 2 equiv of TMDS),12 and very pleasingly, after 20
min, we observed a clean 1H NMR spectrum fully assignable to
dihydropyridine 18a.13 Because of the expected instability of
this intermediate, we chose to add in one portion the reactive
dienophile N-phenylmaleimide 21a directly to the reaction
mixture, and indeed the desired [4 + 2] cycloadduct 19a was
formed as the major reaction product (along with TMDS-
derived side-products) in 93% NMR yield and as the endo
diastereoisomer.
(19f) or alicyclic side-chains (19g−19l). Keeping 15g as the
parent lactam, we also explored the range of dienophiles that
could be successfully deployed in the cycloaddition step.
Pleasingly, the use of maleimide 21h as the dienophile resulted
in a smooth reaction, providing 19h in excellent 85% yield and
>95:5 dr, while oxazolidinone 21i reacted similarly, forming
19i in 90% yield and >95:5 dr. Methyl acrylate (21j), dimethyl
fumarate (21k), and acrylonitrile (21l) also led to the
formation of the respective cycloadducts 19j, 19k, and 19l,
albeit with imperfect diastereoselectivity (85:15, 91:9, and
64:36 dr, respectively).
Having successfully established a scope for the formation of
isoquinuclidines from unsaturated δ-lactams, we turned our
attention to acyclic systems. Simple β,γ-unsaturated amides are
indeed readily available from secondary amines via coupling
with 3-butenoic acid. Our hope was that our newly developed
methodology could be extended to the generation of acyclic
dienamine species that, in turn, could be valuable inter-
mediates for the formation of tertiary amine-appended
cyclohexene architectures, with potential control of up to
four newly formed stereocenters.16
Encouraged by these preliminary data, we began investigat-
ing the scope of this reaction by varying the substituents and
substitution patterns on the lactam substrate (Scheme 2).
Scheme 2. Scope of the Isoquinuclidine-Generating
Methodology
Although the reduction step required longer reaction times
than for cyclic systems (3 h, see Scheme 3), we were pleased to
find that but-3-enamides 22a−c did indeed form the desired
Scheme 3. Extension to Acyclic Dienamine Generation/[4 +
2] Cycloaddition Reactions
These substrates were accessible via α-functionalization of the
parent lactam (15b, 15d), already known in the literature (15c,
15e),14 or synthesized using a recently developed three-
component reaction (15f, 15g).15 We were pleased to find
that, when used in conjunction with N-phenylmaleimide (1.05
equiv) as the dienophile, the corresponding cycloadducts of
increasing complexity 19a−19g could be isolated in good to
excellent yields and with essentially complete diastereoselec-
tivity.
Modification of the substitution on the nitrogen atom
showed that reactivity was not diminished when using linear
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dienamines 23a−c and the downstream cyclohexene structures
24a−f with complete diastereocontrol upon reaction with N-
phenylmaleimide or other dienophiles in good to excellent
yields. Moving away from simple but-3-enamides, indole
substrate 25a,b, where the β,γ-unsaturation is an integral part
of the heteroaromatic ring, also produced the desired
cycloadducts 26a,b. For ease of isolation, these were further
oxidized by addition of DDQ at the end of the reaction and
isolated as the aromatized β-carbolines 27a and 27b in 77%
and 89% yield, respectively. Finally, both amide functional
groups within succinamide 28 could be reduced to their
respective enamine intermediates, forming overall a symmetric
bisamino-diene species 29 that underwent cycloaddition to
furnish symmetric tetrasubstituted 30 as a single isomer.
Remarkably, during the course of this reaction, all six carbons
contained within the final cyclohexene product saw their
hybridization state change from sp3 to sp2 (or vice versa),
resulting in a relatively complex architecture arising in a single-
pot transformation from a simple building block.
Scheme 4. (a) Dehydrosecodine at the Center of the
Monoterpene Indole Alkaloid Biosynthesis; (b) A New
Total Synthesis of Catharanthine
To firmly establish this reductive dienamine generation
strategy in complex natural product total synthesis, we set our
sights on one of the most important yet elusive intermediates
in monoterpene indole alkaloid natural products chemistry,
dehydrosecodine (20). Since the pioneering studies of
Wenkert in 1962,17 Scott,18a and recently De Luca18b and
O’Connor,18c−e this functionally rich molecular entity has been
putatively identified as the common precursor to a wide variety
of skeletally varied Vinca, Iboga, and Aspidospema alkaloids.18f
Possessing a 1,2-dihydropyridine motif capable of meeting
either the electronic demands of a diene (normal electron
demand Diels−Alder cycloaddition toward catharanthine 3;
see Scheme 4a) or a dienophile (inverse electron demand
Diels−Alder cycloaddition toward tabersonine 31),19 dehy-
drosecodine (20) has remained elusive due to its high
reactivity and inherently redox-sensitive functionalities, in
particular 1,2-dihydropyridine and indole-2-acrylate.18e,20 Not
unsurprisingly, nature’s way has inspired the approaches of
many synthetic chemists over the years;21 in fact, more than
half of the total and formal syntheses of catharanthine
published to date have indeed relied on a Diels−Alder
approach to the isoquinuclidine core.21a−n Interestingly,
however, not one proceeded directly via dehydrosecodine.
This is partly due to the difficulty of accessing the 5-ethyl-
substituted 1,2-dihydropyridine motif (because of undesired
regioselectivity in the reduction of pyridinium ions; see
Scheme 1d), particularly in the presence of the sensitive/
reactive indole-2-acrylate fragment.20
Recognizing that our reductive strategy offers reliable
regiocontrol in 1,2-dihydropyridine synthesis, as well as
notable and well-documented chemoselectivity for the
reduction of the lactam carbonyl over other functional groups,
including alkenes, we set on a journey to access catharanthine
(3) via its elusive biosynthetic precursor dehydrosecodine
(20).
Our synthesis began with the formation of the α-substituted,
β,γ-unsaturated δ-lactam 35 in a two-step sequence from
commercially available starting materials (Scheme 4b). At high
temperatures, tryptamine (33) and dihydropyrone (34)
reacted to form the unsaturated lactam as a mixture of
constitutional isomers in 51% yield.22 Subsequent double
deprotonation of the mixture with 2 equiv of LDA and α-
alkylation with ethyl iodide resulted in the formation of desired
35 in 83% yield. After extensive investigations (see the
Supporting Information), and taking inspiration from
Stephenson’s photoredox-catalyzed C2-functionalization of
unprotected indoles,23 we were able to introduce a
phosphonoester group at the C2 position of indole 35,
resulting in isolation of 37 in 54% yield. The phosphonoester
37 could in turn be used to install the terminal methylene
group of 38 via the Rathke modification of the Horner−
Wadsworth−Emmons reaction by using paraformaldehyde, in
83% yield.24,25
Having established a four-step route to the precursor of
dehydrosecodine 20, the stage was set for the final reductive [4
+ 2] cycloaddition sequence. Pleasingly, upon submission of
38 to the newly developed reaction conditions, catharanthine
(3) was indeed produced, albeit in trace amounts as
determined by 1H NMR analysis of the crude reaction
mixture. Extensive optimization of the reductive activation
step led to an improved isolated yield (11%) of 3 when TMDS
was slowly added to a solution of precursor 38 and Vaska’s
complex, thus completing the fully biomimetic total synthesis
of the alkaloid and establishing the intermediacy of its evasive
and intriguing biosynthetic precursor, dehydrosecodine.
Efforts to isolate byproducts in the final reaction, to
understand the low mass return, were unfruitful. Consequently,
the reaction was performed in deuterated solvent in an NMR
tube, in the hope of observing transient species.26 Upon slow
addition of TMDS to a solution of 38 and Vaska’s complex in
d8-toluene, catharanthine was immediately produced in 15%
NMR yield, alongside reduced species 40 (85% NMR yield, as
a mixture of isomers at the dihydropyridine), arising from the
apparent hydridic reduction of the indole-2-acrylate in
dehydrosecodine (20) (Scheme 5).27 Attempted purification
via flash column chromatography on silica gel failed to provide
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Authors
Scheme 5. NMR Studies Uncover a Reactive and Short-
Lived Species
Pablo Gabriel − Department of Chemistry, Chemistry
Research Laboratory, University of Oxford, Oxford OX1
3TA, United Kingdom; orcid.org/0000-0002-3462-5151
Yaseen A. Almehmadi − Department of Chemistry, Chemistry
Research Laboratory, University of Oxford, Oxford OX1
3TA, United Kingdom; Department of Chemistry, Rabigh
College of Science and Arts, King Abdulaziz University,
Jeddah 21589, Saudi Arabia; orcid.org/0000-0002-
9094-8393
Zeng Rong Wong − Department of Chemistry, Chemistry
Research Laboratory, University of Oxford, Oxford OX1
3TA, United Kingdom
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c04980
Author Contributions
⊥P.G. and Y.A.A. contributed equally to this work.
Notes
The authors declare no competing financial interest.
40,28 while 3 could be isolated in 11% yield. Interestingly, no
reaction product arising from the other intramolecular Diels−
Alder (IMDA) pathway (see 31, Scheme 4) was observed in
any of these experiments.
ACKNOWLEDGMENTS
■
P.G. is grateful to the EPSRC Centre for Doctoral Training in
Synthesis for Biology and Medicine (EP/L015838/1) for a
studentship, generously supported by AstraZeneca, Diamond
Light Source, Defence Science and Technology Laboratory,
Evotec, GlaxoSmithKline, Janssen, Novartis, Pfizer, Syngenta,
Takeda, UCB, and Vertex. Y.A.A. thanks King Abdulaziz
University (KAU) for a postgraduate scholarship. Z.R.W. is
grateful to the CN Yang Scholars Programme of Nanyang
Technological University for an undergraduate scholarship.
Further efforts to improve reaction efficiency by introducing
hydride scavengers did not change the ratio between
catharanthine and the undesired rearranged product, suggest-
ing an intramolecular hydride transfer, followed by protonation
and hydridic reduction of the resulting pyridinium species 39
to give 40.29 Although not completely unprecedented,30 this
dihydropyridine-triggered hydride reduction of the pendant
indole-2-acrylate suggests that any chemical synthesis of
dehydrosecodine will likely always suffer from this undesired
internal redox adjustment outside of the exquisitely controlled
environment offered by nature’s optimized enzymatic path-
ways.
In conclusion, an iridium(I)-catalyzed reductive activation of
β,γ-unsaturated δ-lactams and amides allows efficient and
controlled access to cyclic and acyclic dienamines, delivering
after [4 + 2] cycloadditiona range of bridged bicyclic and
cyclohexene-substituted amine products. This robust approach
proceeds with high stereocontrol, low catalyst loading, from
readily available starting materials, and has enabled a short and
protecting group-free total synthesis of catharanthine via its
biosynthetic precursor, dehydrosecodine. Further work to
uncover new reactivity of common functional groups through
reductive activation approaches is ongoing in our laboratory,
and the results will be disclosed in due course.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c04980.
■
sı
Experimental procedures and characterization data
(PDF)
AUTHOR INFORMATION
Corresponding Author
Darren J. Dixon − Department of Chemistry, Chemistry
Research Laboratory, University of Oxford, Oxford OX1
3TA, United Kingdom; orcid.org/0000-0003-2456-
5236; Email: darren.dixon@chem.ox.ac.uk
■
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(27) NMR yield based on the ratio of 3 and the two isomers of 40.
Structure of 40 partially assigned by in situ 2D NMR experiments; see
the Supporting Information for more information.
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