Productive Syntheses of Privileged Scaffolds Inspired by the Recognition of a Diels–Alder Pattern Common to Three Classes of Natural Products

Article abstract of DOI:10.1002/chem.202002372

Identification of a common Diels–Alder pattern in three classes of bioactive natural products led us to study the synthesis and cycloaddition of a new class of cyclic dienes readily available from β,γ-unsaturated lactams. A practical and readily scalable route to the parent p-methoxybenzyl-protected 6- and 7-membered β,γ-unsaturated lactams was developed. These were readily transformed into the corresponding O-silylated dienes, which were reacted with dimethyl and diethyl fumarate to yield stereoselectively highly functionalized bicyclic adducts. These exhibited unexpected and versatile transformations upon acid hydrolysis depending on the nature of the dienophile substituents and the acid catalyst. All reactions have been performed on multigram quantities. These transformations provide a convenient, economical, and easily scalable pathway for the rapid construction of functionally and stereochemically dense privileged scaffolds for the construction of libraries of natural products-inspired molecules of pharmacological relevance.

Full text of DOI:10.1002/chem.202002372

Accepted Article
Accepted Article
Title: Productive Syntheses of Privileged Scaffolds Inspired by the
Recognition of a Diels-Alder Pattern Common to three Classes of
Natural Products
Authors: Eduard BADARAU, Harsha Vardhan Reddy, Aurore Loudet,
Charles Simon, Laurent Trembleau, Stijn Claerhout, Etienne
Pair, Stephane Massip, Philippe Breton, Brigitte Lesur, Solo
Goldstein, Jean-Marie Fourquez, Jean-Michel Henlin, and
Leon Ghosez
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To be cited as: Chem. Eur. J. 10.1002/chem.202002372
Link to VoR: https://doi.org/10.1002/chem.202002372
01/2020

10.1002/chem.202002372
Chemistry - A European Journal
COMMUNICATION
Productive Syntheses of Privileged Scaffolds Inspired by the
Recognition of a Diels-Alder Pattern Common to three Classes of
Natural Products
Eduard Badarau,[a,b] ‡ K. Harsha Vardhan Reddy,[a] ‡ Aurore Loudet,[a] ‡ Charles Simon,[a] ‡ Laurent
Trembleau,[c,d] Stijn Claerhout,[a] Etienne Pair,[a] Stéphane Massip,[a] Philippe Breton,[e] Brigitte
Lesur,[e] Solo Goldstein,[e] Jean-Marie Fourquez,[e] Jean Michel Henlin,[e] and Léon Ghosez,[a,c]
*
[a] Dr. E. Badarau, Dr. K. H. V. Reddy, Dr. A. Loudet, Dr. C. Simon,
Dr. S. Claerhout, Dr. E. Pair, S. Massip and Prof. L. Ghosez*
Université de Bordeaux, IECB, CNRS UMR 5248
CBMN, 2, rue Robert Escarpit, 33607 Pessac (France).
*E-mail: l.ghosez@iecb.u-bordeaux.fr ; leon.ghosez@uclouvain.be
[b] Dr. E. Badarau
Université de Bordeaux, Bordeaux INP, CNRS UMR 5248
CBMN, Allée Geoffroy Saint Hilaire, Bat B14,
33600 Pessac, France
[c] Pr. L. Ghosez and Dr. L. Trembleau
UCLouvain, Place Louis Pasteur 1,
1348 Louvain-la-Neuve, Belgium
[d] Dr. L. Trembleau ,
Chemistry, G95, School of Natural and Computing Sciences
University of Aberdeen, Meston Walk
Aberdeen, AB24 3UE, United Kingdom
[e] Dr. P. Breton, Dr. B. Lesur, Dr. S. Goldstein, Dr. J.-M. Fourquez, Dr. J.-M. Henlin
Institut de Recherche Servier
125, chemin de Ronde, 78290 Croissy Sur Seine, France
‡These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of the document.
Abstract: Identification of a common Diels-Alder pattern in three
classes of bioactive natural products led us to study the synthesis and
cycloaddition of a new class of cyclic dienes readily available from
훽, 훾-unsaturated lactams. A practical and readily scalable route to the
parent PMB-protected 6- and 7-membered 훽, 훾-unsaturated lactams
was developed. These were readily transformed into the
corresponding O-silylated dienes which were reacted with dimethyl-
and diethyl fumarate to yield stereoselectively highly functionalized
bicyclic adducts. These exhibited unexpected and versatile
transformations upon acid hydrolysis depending on the nature of the
dienophile substituents and the acid catalyst. All reactions have been
performed on multigram quantities. These transformations provide a
convenient, economical, and easily scalable pathway for the rapid
construction of functionally and stereochemically dense privileged
scaffolds for the construction of libraries of natural products-inspired
molecules of pharmacological relevance.
libraries of biologically relevant chemotypes.[1a,2] These scaffolds
should (1) retain some of the biologically relevant structural
features of the natural product, (2) be accessible in multigram
amounts by short and productive sequence of reactions.
Nature provides a highly diversified library of complex biologically
relevant structures which have been fashioned by a long-term co-
evolution within biological communities.[1] The diversity and
complexity of NPs makes them able to target biological
macromolecules in a highly selective fashion. Nonetheless it
seldom happens that a given natural product will be perfectly
designed for interacting with the targets selected by
pharmacologists. Biologically active natural products should thus
rather be viewed as pharmacologically relevant templates for the
design of privileged scaffolds ( NPPS) allowing the production of
Scheme 1. A common Diels-Alder strategy to mesembrenone, ottelione A and
lycorine-inspired privileged scaffolds.
1
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They should be equipped by functional groups allowing the
generation of libraries of natural product analogs by simple and
high yield chemistry. We recently became interested in privileged
scaffolds derived from three classes of natural products (Scheme
1). Careful examination of these natural products and of the
proposed scaffolds led us to the identification of a common Diels-
Alder pattern.[3] This was particularly attractive since the
venerable Diels-Alder reaction is a unique tool for Diversity
Oriented Synthesis: it indeed leads to structurally and
stereochemically complex cyclic molecules from simple starting
material and with 100% atom economy.[4] We were also seduced
by the possibility of accessing to these diverse scaffolds by a
unified synthetic strategy involving a new class of cyclic nitrogen-
containing dienes and simple electrophilic dienophiles.
In this short communication we wish to demonstrate the
usefulness of these new nitrogen-containing dienes for the
synthesis of NP-inspired functionally and stereochemically rich
scaffolds. We will describe: (a) a highly practical and large scale
synthesis of two representatives of this new class of cyclic
nitrogen-containing dienes, (b) their reactions with dialkyl-
fumarates and N-methylmaleimide as representative dienophiles,
c) the unexpected versatility of the mode of cleavage of the
adducts which further extents the utility of the method.
The new nitrogen-containing dienes are cyclic analogs of alkenyl
ketene O,N-acetals.[5] It was expected that these cyclic derivatives
would be even more prone to undergo Diels-Alder reactions since
the conjugated double bonds are forced into a syn-configuration
and the interaction with the nitrogen lone pair should be enhanced
when N is endocyclic. It was also anticipated that the dienes could
be generated by silylation of the corresponding 훼, 훽 or 훽, 훾 −
unsaturated lactams. In light of our synthetic goals (large scale
syntheses of NP-inspired privileged scaffolds) we selected a
convergent synthetic route offering possibilities for diversification
(Scheme 2). PMB-protected allylic and homoallylic amines 1a
and 1b reacted with 3-butenoyl chloride to yield the dienyl amides
2a and 2b. Ring-closing metatheses of 2a in the presence of
bis(tricyclohexylphosphine)benzylidene ruthenium dichloride [6] in
toluene at 60°C yielded dihydropyridinone 3a. The metathesis
reaction with 2b was also successful, yielding 3b but it required a
more reactive catalyst. [7] This route proved to be very efficient. It
was readily applied to large scale syntheses of lactams 3a and 3b
by the industrial partner.
Scheme 2. A practical synthesis of dienes
found to rapidly decompose upon heating or in the presence of
water. It also decomposed on silica gel. Diene 5b was more stable
and could be heated at 80C for 24 h in benzene without
noticeable decomposition. If not used immediately, both dienes
5a,b were kept under inert atmosphere and stored in the
refrigerator. We then studied the cycloaddition of diene 5a to
dimethylfumarate (Scheme 3). In our first trials the reactants were
left overnight at room temperature. 1H- and 13C-NMR of the crude
product confirmed that it was a [4+2] cycloadduct 6 resulting from
The silylation of the lactams had to be performed before
deprotonation to avoid competitive C-silylation. Lactams 3a and
3b were thus reacted with trialkylsilyl triflate to yield quantitatively
the stable iminium salts 4a,b. The deprotonation step was more
complicated because the iminium salts and the newly formed
dienes 5a,b reacted with each other to give complex mixtures.
Eventually, we found that the dienes could be conveniently
prepared by adding a THF solution of LDA into the THF solution
of the iminium salt at -70°C. Evaporation of the solvent and of
diisopropylamine gave a high yield of crude dienes 5a,b. The
removal of all diisopropylamine generated from the deprotonation
by LDA was found to be critical for the reproducibility of the
following steps. Addition of acetonitrile to crude 5a,b followed by
extraction with pentane or hexane and evaporation was found to
generate dienes 5a,b of sufficient purity (by 1H-NMR) to be
directly used in the cycloaddition reactions. Crude diene 5a was
Scheme 3. Productive syntheses of scaffolds 8, 10a and 11a.
2
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Table 1. Reaction conditions and yields from lactam 3a.
Table 1, entry e). We observed the stereoselective formation of
11a in 39% yield from lactam 3a contaminated by small amounts
of 8 and 10a. Compound 8 was crystalline. Compounds 10a and
11a yielded crystalline diacids 10b and 11b by basic hydrolysis
followed by acidification. The structure and stereochemistry of
10b, 11b were confirmed by X-ray diffraction analysis (ORTEP
diagrams in supplementary material).
The origin of 11a is still unclear. Ketene acetals and aminals are
known to react under mild conditions (even in the absence of an
acid catalyst) with electrophilic double bonds to give four-
membered ring[5,8]. Unfortunately we have no clear evidence of
the presence of 11a in the crude cycloaddition mixture before the
hydrolysis step. The formation of 11a could also result from the
cascade removal of TIPS group, cleavage of C-C bond, and an
intramolecular Michael addition to the resulted unsaturated
lactam. However, this alternative route is less probable because
it would involve a “forbidden” 4-endo-trigonal addition of a
carbanion to the unsaturated lactam.[9] Such cyclizations are
indeed very rare and usually take place under electrophilic
conditions.[10]
Entry
Cyclo-
hydrolysis
8
[%]
10a
[%]
11a
[%]
addition
a
b
0°C to rt
0°C to rt
HFaq(5%), THF,
0°C to rt, 18 h
52
33
-
-
-
KF, HCOOH, THF,
0°C to rt , 12 h
<10
c
d
e
0°C to rt
0°C to rt
60°C
Et3N then HF (10%) in MeOH,
0°C to rt, 12 h
4
-
32
26
5
-
Pyridine, HF.pyridine,
0°C to rt, 8 h
-
1.1 eq HF (10%), MeOH,
60°C, 12 h
9
39
Yields are calculated from the starting lactame 3a
an endo approach of the reactants. Adduct 6 was unstable on
silica gel. It was thus directly submitted to hydrolysis. It was
anticipated that the treatment of adduct 6 with HFaq would
hydrolyze the O,N-ketene acetal (C-N bond cleavage) to generate
7. That turned out to be the case but, under these conditions,
intermediate 7 was found to cyclize immediately to give the
interesting bicyclic lactam 8 in 52% optimized yield from lactam
3a (Table 1, entry a). Compound 8 was also the major product
when the reaction was run in KF/formic acid (entry b) but yields
(not optimized) were lower. We never observed compound 9
resulting from the reaction of the amine with the neighbouring
trans ester group. Thus, the amine group exclusively reacted with
the closer cis ester to yield 8. In the reaction of entry b, we had
observed small amounts of a new compound 10a. Interestingly,
10a became the major product when the reaction was run at
higher pH (entries c and d). Compound 10a had never been
detected in significant amount in the crude cycloadduct 6. Thus,
it could not result from a Michael addition of the terminal carbon
of diene 6 competing with the Diels-Alder cycloaddition. We
believe that 10a resulted from a retro-aldol type reaction (C-C
bond cleavage) of the primary endo-adduct 6 thus leading to the
formation of a single diastereoisomer. At this stage one can only
speculate about the structural factors responsible for this
chemical dichotomy. Hyperconjugative interactions between the
Si-O bond and either the C-N or a C-C bond could be the driving
force for the cleavage of these bonds. The observation of different
mode of fragmentation according to the pH of the reaction could
be the result of two different reacting conformations of the
protonated and non-protonated adduct (Scheme 4).
Thus, a single reaction of a representative of this class of highly
functionalized cyclic dienes was shown to efficiently produce
multigram quantities of three classes of scaffolds without
purification of intermediates. Yields were quite satisfactory: 52%
yield (around 85% per step) for 8, 32% (around 75% per step) for
10a and 39% (around 73% per step) for 11a.
Another illustration of the power of this strategy was found
in our studies of the more stable 7-membered diene 5b. It was
also used in the cycloaddition step without prior chromatography.
Preliminary studies also revealed that 5b was less reactive than
5a. Thus, the reaction with an activated dienophile such as N-
methyl maleimide required heating at 60°C in THF for several
hours (Scheme 5). At 60°C, contrary to our earlier observation for
the reaction of diene 5a with dimethylfumarate (Scheme 4), we
did not observe the formation of a [2+2] cycloadduct. The reaction
gave the expected [4+2] cycloadduct 12. It was stable enough to
be purified by mild work-up (Et3N/HFaq) to give 48% (from lactam
3b) pure Diels-Alder adduct 12. X-ray diffraction analysis showed
that adduct 12 also resulted from an endo cycloaddition.
Hydrolysis with 10% aqueous HF in THF yielded a tricyclic ketone
13 resulting from a C-N cleavage in adduct 12 followed by an
intramolecular Michael addition of the protected amine to the
unsaturated (activated) ketone. This new stereochemically-rich
scaffold 13 was obtained in 24% yield (4 steps, one-pot, 70%
yields per step). This can certainly be improved since we also
found some unreacted lactam 3b in the crude product.
Scheme 4. Possible explanation for the pH-dependent mode of cleavage of 7.
An unexpected product was obtained when the cycloaddition and
the HF catalyzed methanolysis were run at 60°C (Scheme 3,
Scheme 5. Cycloaddition of diene 5b with maleimide
3
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Both in situ generated TIPS and TBS-protected dienes 5b and 5c
also reacted with dimethyl or diethylfumarate to yield adducts 14a
and 14b (Scheme 6). The reactions were slower than with 6-diene
5a. The crude adduct 14 was hydrolyzed in HFaq/MeOH to the
octahydro-1-p-methoxybenzyl-6H-indol-6-one 16 in equilibrium
with its enol tautomer. We also isolated a small amount of a
product 15 which was shown to result from a C-C bond cleavage
in adduct 14a. Compound 15 was the only isolated product from
the treatment of 14a with a solution of LiF in methanol. Compound
16 was obtained in 47% yield from lactam 3b (83% per step, no
isolation of intermediates). This was an interesting scaffold
containing four stereogenic centers and four functional groups
which could generate diversity by simple chemistry. We were
particularly interested in the production of lycorine-derived
scaffolds which would require anchoring an additional aromatic
group at both the nitrogen atom and the activated neighboring
carbon atoms. We anticipated that this could be difficult: creating
a C-C bond at C-3 could be problematic since this carbon should
be less acidic than the carbon activated by the ketone and the
ester group. It would then be highly desirable to keep intact the
silylenol ether function which would activate carbon-3. This turned
out to be rather easy: the TIPS enol ether 17 was formed upon
cleavage of the ketene acetal in 14a using formic acid in methanol
instead of HF. However, TIPS enol ethers are known to be much
less reactive than most enol ethers. [10] Rewardingly, we were
also able to efficiently prepare the corresponding t-
butyldimethylsilyl-enol ether 18. Formolysis of adduct 14b in
dichloromethane did not cleave the TBS enol ether and gave the
desired product 18 in 55% yields from 3b (86% per step). The
PMB nitrogen-protecting group could be easily removed from 18
to yield a salt 19 which was sufficiently pure to be used in further
transformations. Both 18 and 19 are interesting privileged
scaffolds offering 4 sites for the construction of libraries of
lycorine-analogs.
Scheme 6. Cycloadditions of dienes 5b,c to dimethyl and diethylfumarate
We believe to have demonstrated that the combination of
biologically relevant structural informations gathered from natural
products with the recognition of a synthetically accessible pattern
and with some… imagination can be a powerful approach to the
production of privileged scaffolds from which libraries of
biologically interesting compounds could certainly be easily
produced. The recognition of a common Diels-Alder pattern in
three classes of natural products led to the design of new highly
functionalized dienes. These have been produced in multigram
quantities and directly used in model Diels-Alder reactions.
Interestingly we have shown that subtle differences in the
conditions of hydrolysis of the adducts drastically modified the
course of the reaction allowing to produce different scaffolds from
a single adduct. This strategy allowed to prepare functionally and
stereochemically rich scaffolds in multigram quantities and
without purification of intermediates. This communication reports
only a few representative examples of this natural product-
inspired synthetic strategy but we believe that these data would
be essential to allow other chemists to use this approach to
produce new biologically relevant scaffolds. We presently
continue unravelling the synthetic potential of this strategy and
studying some transformations of the scaffolds for the production
of libraries of therapeutically interesting compounds.
4
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[8]
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Acknowledgements
This work was generously supported by Institut Servier
(fellowships to EB, KHVR, AL, CS, SC, EP), the former Rhône-
Poulenc-Rorer (fellowship to LT) and IECB. We thank Frédéric
Rosu and Estelle Morvan for their experimental help (MS and
NMR).
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Conflict of interest
The authors declare no conflict of interest
Keywords: Cycloaddition • pattern recognition • natural products
• lactam • molecular diversity
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5
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Entry for the Table of Contents
Natural products-inspired chemistry: Identification of a common Diels-Alder pattern in three classes of bioactive natural products
led to the discovery of very productive syntheses of stereochemically rich and functionally dense scaffolds for the construction of
libraries of molecules of therapeutic interest.
6
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