Catalytic Asymmetric [4+2]-Cycloadditions Using Tropolones: Developments, Scope, Transformations, and Bioactivity

Article abstract of DOI:10.1002/anie.201808221

An organocatalyzed asymmetric [4+2]-cycloaddition between tropolones and electron-deficient dienophiles is presented. Complex and biologically interesting dihydrohomobarrelenone scaffolds are formed through a Diels–Alder reaction utilizing bifunctional Br?nsted-base catalysis, affording the corresponding bridged bicyclic cycloadducts in up to quantitative yields with good enantio- (up to 92 % ee) and diastereoselectivity (up to >20:1 d.r.). The synthetic value of the obtained products is explored by downstream transformations, including photoisomerizations, and their biological relevancy by in vivo testing in MCF-7 cancer cells.

Full text of DOI:10.1002/anie.201808221

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Accepted Article
Title: Catalytic Asymmetric [4+2]-Cycloadditions Using Tropolones:
Developments, Scope, Transformations and Bioactivity
Authors: Karl Anker Jørgensen, Niels Hammer, Jeremy David
Erickson, Vibeke Henriette Lauridsen, Joakim Bøgelund
Jacobseb, Bente Kring Hansen, Kristian Mark Jacobsen, and
Thomas Bjørnskov Poulsen
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201808221
Angew. Chem. 10.1002/ange.201808221
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10.1002/anie.201808221
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Catalytic Asymmetric [4+2]-Cycloadditions Using Tropolones:
Developments, Scope, Transformations and Bioactivity
Niels Hammer, Jeremy D. Erickson, Vibeke H. Lauridsen, Joakim B. Jakobsen, Bente K. Hansen,
Kristian M. Jacobsen, Thomas B. Poulsen, and Karl Anker Jørgensen*
Abstract: An organocatalyzed asymmetric [4+2]-cycloaddition
between tropolones and electron-deficient dienophiles is presented.
Complex and biologically interesting dihydrohomobarrelenone
stereoselectivity unaddressed (Figure 1c).[6] Asymmetric Diels-
Alder reactions involving unactivated compounds with dienols
such as 3-hydroxy-2-pyrones and pyridones have successfully
been promoted by HOMO-activation via bifunctional Brønsted-
base catalysis.[7] By simultaneous deprotonation and hydrogen-
bond activation of an electron-deficient dienophile, asymmetric
cycloadditions can be carried out under mild conditions. Hence,
we set out to develop a synthetic strategy that would include
enantioselective modification of simple tropolones without altering
the α-hydroxy-ketone chelating motif. Based on these previous
examples of base-mediated Diels-Alder reactions, we envisioned
that a bifunctional Brønsted base could facilitate HOMO-
activation of tropolone, enhancing the reactivity towards a large
variety of hydrogen-bond activated electron-deficient dienophiles
(Figure 1d). In addition to containing the acyloin moiety, the
resulting products would include an α,β-unsaturated ketone,
which is a common motif in bioactive small-molecules that acts
through targeted covalent inhibition.[8]
scaffolds are formed through
a Diels-Alder reaction utilizing
bifunctional Brønsted-base catalysis, affording the corresponding
bridged bicyclic cycloadducts in up to quantitative yields with good
enantio- (up to 92% ee) and diastereoselectivity (up to >20:1 d.r.). The
synthetic value of the obtained products are explored by downstream
transformations, including photoisomerizations, and biological
relevancy by in-vivo testing in MCF-7 cancer cells.
Tropolones are a class of aromatic compounds exhibiting diverse
and well-documented bioactivity such as antibacterial, antifungal,
and anticancer activity, often attributed to its bi-chelating ability
(Figure 1a).[1] Owing to their natural abundance and unique
properties, both synthetic and natural tropolones have received
significant attention in order to identify possible lead compounds.
However, given the multitude of reported biological targets,
simple tropolones are criticized as unspecific, rendering them as
suboptimal drug candidates. Despite this, complex chemical
modifications of tropolones are scarcely reported in literature and
most existing derivatizations concern only the addition of simple
substituents such as alkyl or aromatic groups to the tropolone
scaffold.[2]
Attention to the biological activity of more complex tropolonic
derivatives, such as cycloadducts, has been sparse,[2d,3]
regardless of the potential to combine the chelating acyloin
functionality with increased steric effects and new moieties, such
as covalently modifying groups. The introduction of
stereochemistry is known to influence selectivity and potency
towards biological targets; two such tropolonic examples are the
natural alkaloid colchicine, used in the treatment of gout, and the
potent genotoxin goupiolone B (Figure 1b).[4] Thus, there is an
unmet need for research regarding the further chiral
functionalisation of tropolones.
Cycloadditions are useful synthetic tools in contemporary
organic chemistry with regards to obtaining molecular complexity
in a selective manner. Yet, the inherent aromatic character and
electron-deficient nature of tropolones renders them less reactive
in these methodologies, as demonstrated by previous reports
wherein harsh conditions such as high temperature or pressure is
needed.[5] This has been somewhat addressed by applying
triethylamine as base catalyst, however this still leaves
Figure 1. Tropolones and cycloadditions using tropolones.
We herein present the first organocatalytic strategy involving
HOMO-activation of tropolones (seven-membered cyclic trienes)
via bifunctional Brønsted-base catalysis. The synthetic value of
the obtained products is demonstrated by a selection of
transformations, including photoisomerizations into complex
[a] N. Hammer, Dr. J. D. Erickson, Dr. V. H. Lauridsen, J. B. Jakobsen, B.
K. Hansen, K. M. Jacobsen, Prof. Dr. T. B. Poulsen and Prof. Dr. K. A.
Jørgensen
Department of Chemistry, Aarhus University, 8000 Aarhus C
(Denmark)
E-mail:kaj@chem.au.dk
chiral norcaranes. Furthermore,
a selection of products
underwent preliminary experiments to probe their performance in
cellular systems.
Supporting information for this article is given via a link at the end of
the document.
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Investigations were initiated by exploring the reactivity
between tropolone 1a and N-methylmaleimide 2a, using the
bifunctional Brønsted-base quinine (Scheme 1). The
cycloaddition went to full conversion within 1 h to afford
Under identical conditions, maleimides substituted with ethyl-,
cyclohexyl-, or propargyl groups (2b-d) easily underwent the
cycloaddition affording 4b-d in quantitative yields with good to
moderate enantio- and diastereoselectivity. Interestingly, N-
tertbutylmaleimide 2e was not stereochemically compatible with
organocatalyst 3a, providing a racemic product. However,
switching to the cinchonine-derived thiourea catalyst 3b allowed
us to isolate cycloadduct 4e in a quantitative yield with a 2.3:1 d.r.
and 84/92% ee. Subsequently, we found that altering the
characteristics of the bifunctional catalyst further allowed a scope
of electron-deficient dienophiles to form cycloadducts in decent to
good enantiomeric excess.
cycloadducts
4a/4a’
(endo/exo)
with
a
promising
enantioselectivity, but low diastereomeric ratio. Intrigued by these
results, we commenced a screening of reaction conditions and
organocatalysts. We discovered that the reaction is very sensitive
to the structure of the catalyst, with relatively small changes
resulting in large differences in the enantiomeric excess of the
product (see SI). Furthermore, the reaction of 2-methoxytropone
under similar reaction conditions proceeds much slower and were
therefore not investigated further.
Table 1. Scope of the organocatalyzed [4+2]-cycloaddition.[a]
Scheme 1. Preliminary reaction between tropolone 1a and N-methylmaleimide
2a, using the bifunctional Brønsted-base quinine.
In the course of the screening, we observed that the
diastereomeric ratio was highly unpredictable and variable.
Despite indications of complete initial endo-selectivity, we
propose that the observed deterioration of the diastereomeric
ratio can be attributed to a subsequent step-wise acyloin
rearrangement resulting from the α-hydroxyketone motif at the
bridgehead (Scheme 2a).[6,9] Essentially, the rearrangement
forms the exo-isomer of the opposite enantiomer. It should be
noted, that for the adducts resulting from the Diels-Alder reaction
with substituted tropolones, such as β-thujaplicin, the isomerized
products are distinctly different, and essentially generates a
constitutional isomeric ratio (i.r.) (see SI and Scheme 2b). It was
observed, that the rearrangement was accelerated by the
presence of base, as well as elevated temperatures and exposure
to silica gel. As a result, small variances in work-up and
purification procedures strongly impact the observed isomeric
ratios of the isolated products. A solution to this problem is
presented later.
[a] All reactions were performed using 1 (0.1 mmol), 2 (0.3 mmol), and 3a (0.02
mmol) in 0.6 mL dry CHCl3. The reported yields are for both isomers. The ee,
d.r. and i.r. values (major/minor) were determined by 1H NMR and chiral-phase
UPC2 after FC. The absolute configuration was determined by X-ray
crystallographic analysis, see SI. [b] Organocatalyst 3b (0.02 mmol) was used.
[c] Organocatalyst 3c (0.02 mmol) was used.
Using Takemoto’s bifunctional catalyst 3c, maleimide 2f was
employed, providing dihydrohomobarrelenone 4f in 80% yield
with moderate diastereoselectivity and good enantioselectivity.
The increased reactivity of maleic anhydride 2g was managed by
lowering the temperature to -60 °C using catalyst 3a. This allowed
the desired product (4g) to be isolated in excellent yield albeit with
65% ee. Gratifyingly, the linear dienophile trans-1,2-
bis(phenylsulfonyl)ethylene 2h tolerated the reaction conditions
well, affording 4h as a single diastereomer with moderate yield
Scheme 2. The intramolecular acyloin rearrangement.
We proceeded by investigating the reaction scope, starting
with a selection of N-substituted maleimides 2a-e and tropolone
1a (Table 1). Using N-methylmaleimide 2a and 20 mol% of
cinchonine 3a, the reaction went to full conversion in 44 h at -
35 °C, affording dihydrohomobarrelenone 4a with a 10:1 crude d.r.
Following flash column chromatography, 4a was isolated in
quantitative yield as a mixture with 4a’ in 2:1 d.r. and 80/83% ee.
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and enantioselectivity. Alterations to the tropolone scaffold were
also tolerated, as shown in 4i-n.
To further investigate the synthetic application of the
unprotected adducts, the attention turned towards the challenge
of performing selective reductive transformations. The
dihydrohomobarrelenone scaffold features several reducible
moieties, such as two olefins and a maleimide, which complicates
selective hydride-based reductions. However, we decided to
focus on the α,β-unsaturated ketone, as the Luche reduction is
well-known for its 1,2-selectivity. Gratifyingly, a diastereomeric
mixture of 4a/4a’, procured from the large-scale synthesis,
underwent the reaction in a regioselective manner, obtaining the
desired 1,2-diol 6 in 93% yield with conserved diastereo- and
enantiopurity (Scheme 5).
To study the scalability of the catalytic strategy, the
cycloaddition between tropolone 1a and N-methylmaleimide 2a
was performed on a 12.3 mmol scale. After 62 h, cycloadduct 4a
was isolated in 93% yield, maintaining the enantioselectivity.
Notably, the crude diastereoselectivity was observed to be 16:1
(4a:4a’) however following flash chromatography, this was
inverted to 1:3.2 d.r. Finally, it should be noted that maleimides
substituted with aromatic moieties, such as phenyl and benzyl
groups reacted readily in the cycloaddition, although with
unsatisfactory enantioselectivities.
During the scope investigations, it was found that
crystallization of the cycloadducts occurred in a conglomerate
fashion, allowing for chiral resolution. To demonstrate, 2.14 mmol
of 4a/4a’ was recrystallised in ethyl acetate, and re-isolated in
73% yield with an improved 88/89% ee. This proved helpful with
regards to producing optically pure crystals for X-ray
crystallographic analysis.
We propose the reaction mechanism follows the trends of
asymmetric bifunctional-base catalysis. As such, the diene
undergoes HOMO-activation through deprotonation of the α-
hydroxy group while the dienophile is simultaneously directed and
activated by hydrogen bonds (Scheme 3).[7b,c,10] The Brønsted-
base activation is supported by the experiments performed with
2-methoxytropone.
Scheme 5. Regioselective Luche reduction.
Next, we investigated the possibility of performing
a
hydrogenation of the two olefins, which would afford a fully
saturated core structure. Using Pd/C hydrogenation at
atmospheric pressure gave 7 in a quantitative yield.
Scheme 6. Pd/C hydrogenation of the two olefins in cycloaddition product 4a’.
Based on preceding photochemical transformations, we
believed that the dihydrohomobarrelenones 4 would be eligible for
photoisomerizations forming complex polycyclic compounds.[5d,11]
The formed norcarane derivates would include fully substituted
chiral cyclopropanes, which are often considered challenging
synthetic targets.[12] To our delight, the photoisomerization
proceeded smoothly when subjecting a mixture of cycloadduct
4e:4e’ to light in CHCl3, yielding the tetracyclic norcarane 8 in 47%
yield, >20:1 d.r. and maintaining the enantiomeric excess
(Scheme 7a).
Scheme 3. Proposed reaction mechanism.
To address the acyloin rearrangement (Scheme 2), which
deteriorated the diastereomeric ratio of the isolated cycloadducts,
we envisioned modifying the hydroxyl-group in a one-pot
procedure to block the intramolecular proton shift and carbonyl re-
formation. Following the standard reaction conditions of the
cycloaddition, the crude mixture containing 4a was treated with
trimethylsilyl chloride and pyridine to cap the hydroxyl-group. Full
conversion into the corresponding TMS-protected cycloadduct 5a
was observed within 40 min and isolated in 96% yield, 18:1 d.r.
and 81% ee (Scheme 4). Similarly, the one-pot silylation strategy
was successfully employed on cycloadducts with good pre-
isolation diastereomeric ratios (4c,e to 5b,c), demonstrating the
practicability of the strategy.
Scheme 7. Photoisomerization of 4a into tetracyclic norcarane 8.
Following the formation of the cyclopropane through a
diradical pathway, the intermediate features an electrophilic
ketene that undergoes nucleophilic attack by intramolecular
enolate addition, forming the tetracyclic norcarane 8 (Scheme 7b).
To explore this reaction further, we envisaged using the silylated
cycloadducts 5 in a complementary photochemical reaction. As
TMS-enolates are bulkier and have reduced nucleophilic
character compared to enolates, intramolecular cyclization is less
likely. If combined with a nucleophilic solvent like methanol, the
ketene should form a methyl ester, ultimately yielding a simpler
norcarane scaffold. Gratifyingly, irradiating a methanolic solution
of silylated adducts 5a,b, procured the desired products in
Scheme 4. One-pot silylation strategy.
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quantitative yields, with complete preservation of the diastereo-
and enantioselectivity (Scheme 8).
concentrations tested (Figure 2a), which suggest that the ,-
unsaturated ketone 4j’ (and 4d’) indeed is not a biologically
competent electrophile. In accordance with these observations,
4d was cytotoxic whereas 4j was not (Figure 2b).[13]
In conclusion, we have developed an asymmetric Brønsted-
base catalyzed [4+2]-cycloaddition between tropolones and
electron-deficient dienophiles to produce a broad selection of
chiral dihydrohomobarrelenones. The obtained products are
Scheme 8. Photoisomerization of 5a,b into norcaranes 9a,b.
successfully subjected to
transformations, such as
a
large variety of synthetic
selective reductions and
Small-molecules bearing Michael acceptors may be both
potent and selective modulators of biological macromolecules as
well as non-discriminant alkylators of mainly proteinogenic thiol
groups.[8] The aforementioned acyloin-rearrangement has unique
consequences for this type of reactivity within the cycloadducts 4
as the rearrangement interconverts two different ,-unsaturated
ketones. To investigate the thiol-reactivity of 4a/4a’, we first
attempted a hetero-Michael addition using thiophenol. Following
5 h of reaction time, the Michael adduct 10 was isolated in 50%
yield, >20:1 d.r. and with conservation of the enantiomeric excess
(Scheme 9). Gratifyingly, the absolute configuration of 10 was
obtained following X-ray crystallographic analysis, establishing
the preceding stereochemistry of the cycloadducts formed using
catalyst 3a.
photoisomerizations. The preliminary biological investigations
show that despite of their complex natural-product-looking
scaffold, tropolone-cycloadducts should be critically assessed for
potential non-specific interactions, however by judicious scaffold-
selection these liabilities can be strongly reduced or even
eliminated. Such compounds could be advantageously applied in
future biochemical or cell-based screens.
Scheme 9. Thiophenol Michael addition.
Interestingly, the outcome of the thiophenol-addition suggests
that the endo-product (4a) is markedly more reactive towards
thiols which explains formation of 10 in accordance with the
Curtin-Hammett principle. By comparison, cycloadducts derived
from hinokitiol (e.g. 4i/4i’ and 4j/4j’) also contain two Michael-
acceptor motifs formed reversibly via the acyloin rearrangement,
however the presumed reactive endo ,-unsaturated ketone
present in 4i/4j is blocked at the -carbon atom (Scheme 10).
Scheme 10. Michael acceptor properties of tropolone and hinokitiol derivatives.
To study how these fundamental stereochemical properties of
the cycloadducts impact their performance in a complex biological
system, we subjected live MCF-7 cancer cells to increasing
quantities of the optically active propargyl-derivatives 4d and 4j to
investigate their proteomic reactivity. Following cell lysis, click-
conjugation with FAM-azide was performed and covalent binding
Figure 2. a) In-gel fluorescence assay. b) Viability of MCF-7 cancer cells.
Acknowledgements
This work was made possible by financial support from Carlsberg
targets
was
detected
via
in-gel
fluorescence
measurementsThese experiments demonstrated that 4d is
promiscuous and labels a large number of cellular proteins, but –
Foundation Semper Ardens, Aarhus University and DNRF.
remarkably
– 4j was almost devoid of reactivity at the
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Keywords: Tropolone • Organocatalysis • Cycloaddition •
Bioactivity • Photoisomerization
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Text for Table of Contents
Niels Hammer, Jeremy D. Erickson,
Vibeke H. Lauridsen, Joakim B.
Jakobsen, Bente K. Hansen, Kristian M.
Jacobsen, Thomas B. Poulsen and K. A.
Jørgensen*
Page No. – Page No.
Catalytic Asymmetric [4+2]-
Cycloadditions Using Tropolones:
Developments, Scope,
Transformations and Bioactivity
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