Natural product biosynthesis inspired concise and stereoselective synthesis of benzopyrones and related scaffolds

Article abstract of DOI:10.1021/ol200389p

A natural product biosynthesis-inspired strategy to explore biologically relevant chemical space is presented. A phosphine-catalyzed cascade and stereoselective annulation provides a common tricyclic benzopyrone intermediate that was efficiently transformed into diverse and related naturally occurring scaffolds

Full text of DOI:10.1021/ol200389p

ORGANIC
LETTERS
2011
Vol. 13, No. 8
1988–1991
Natural Product Biosynthesis Inspired
Concise and Stereoselective Synthesis of
Benzopyrones and Related Scaffolds
Baburaj Baskar, Pierre-Yves Dakas, and Kamal Kumar*
Max-Planck-Institut fu€r molekulare Physiologie, Otto-Hahn Strasse 11, 44227-
Dortmund, Germany
kamal.kumar@mpi-dortmund.mpg.de
Received February 11, 2011
ABSTRACT
A natural product biosynthesis-inspired strategy to explore biologically relevant chemical space is presented. A phosphine-catalyzed cascade
and stereoselective annulation provides a common tricyclic benzopyrone intermediate that was efficiently transformed into diverse and related
naturally occurring scaffolds.
Biological activity is a unique property for any molecule
to possess, a keyrequisite for various discovery programsin
academic and pharmaceutical laboratories, and a crucial
function at a molecular level in numerous life-sustaining
processes.1 Recent years have witnessed chemists’ endea-
vors targeting bioactive small molecules shaping up differ-
ent hypothesis, for instance Diversity Oriented Synthesis2
and Biology Oriented Synthesis.3 It would however be
enlightening to understand the way nature targets bioactive
regionsofvastchemicalspacewhilecreatingdiversenatural
products.4 Adapting similar strategies in compound library
syntheses might enrich them with desired and interesting
biological activities. In a prominent biosynthetic strategy,
primary metabolites or derivatives would build up the
intermediate scaffold, which is later transformed into di-
verse secondary metabolites, often retaining the molecular
framework of the intermediate.5 For instance, in indole
alkaloid biosynthesis,6 tryptamine is converted into a tem-
plate structure, Strictosidine, which is further transformed
into a variety of monoterpene indole alkaloids (Figure 1A).
(1) (a) Dobson, C. M. Nature 2004, 432, 824–828. (b) Lipinski, C.;
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46–58. (b) Galloway, W. R. J. D.; Isidro-Llobet, A.; Spring, D. R. Nat.
Commun. 2010, 1, 1–13 and references therein.
Figure 1. (A and B) Biosynthetic strategies leading to diverse
secondary metabolites.
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Chem., Int. Ed. 2011, 50, accepted. (b) Wilk, W.; Zimmermann, T. J.;
Kaiser, M.; Waldmann, H. Biol. Chem. 2010, 391, 491–497. (c) Bon,
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Similarly, in the Gibberellin biosynthesis pathway,
geranylgeranyl diphosphate (GGDP) is cyclized to form
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r
10.1021/ol200389p
Published on Web 03/18/2011
2011 American Chemical Society

ent-kaurene, which undergoes skeletal and functional
group transformations to at least 136 products with only
a few of them displaying biological activities (Figure 1B).7
In a research program targeting concise synthesis of
natural product-inspired8 focused compound collections
for chemical biology research, we devised a biosynthesis-
inspired synthesis strategy wherein a common intermedi-
ate scaffold would be efficiently transformed into diverse
naturally occurring ring systems. Here we present an
efficient and concise synthesis access tonaturally occurring
benzopyrone9 and related scaffolds employing easily ac-
cessible primary substrates.
(Figure 2). To this end, we explored a phosphine-catalyzed
[4 þ 2] annulation reaction of the zwitterion (4) (generated
by addition of phosphine11 to allene ester 3) with 4H-
chromen-4-one 1 (Scheme 1). Recently, Kwon et al. have
demonstrated the feasibility of the annulation of4 with1,1-
dicyanoolefins;12 however, further scope of this annulation
remains unexplored.13 The reaction of 4 with chromone 1,
to our disappointment, did not yield any desired product
even under forcing reaction conditions. We reasoned that
vinylogous ester 1 might not be sufficiently electron-defi-
cient to receive a nucleophilic attack of the zwitterion 4 at
the C-2 position. Gratifyingly, employing more electron-
deficient 3-formylchromone 2, we observed a cascade
reaction sequence of [4 þ 2] annulation of the zwitterion
4a (R3 = CO2Et) with 2 followed by deformylation to
provide the desired scaffold 8a in excellent yield (Table 1)
and with good diastereoselectivity (∼8:1).
Differently substituted chromones (2) yielded the cas-
cade annulation adducts 8aꢀe in moderate to very good
yields (Table 1) and with high diastereoselectivities (see
Supporting Information).
Scheme 1. Phosphine-Catalyzed Cascade Synthesis of Common
Benzopyrone Scaffold
Figure 2. Natural products embodying benzopyrone and related
frameworks and the common scaffold to access diverse natural
ring systems.
A structural analysis of the natural products embodying
diverse benzopyrone10 scaffolds led us to choose the
tricyclic cyclohexene-fused-chromone ring as the common
scaffold for further elaboration into natural ring systems
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Allene ester 3b also underwent the cascade annulation,
smoothly yielding adducts 8fꢀi supporting a phenyl sub-
stitution on cyclohexene ring of the tricyclic benzopyrones
in good yields and diastereoselectivities (for spectroscopic
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Org. Lett., Vol. 13, No. 8, 2011
1989

(dr = 10:1) access to tetracyclic benzopyrones 10aꢀd. To
the best of our knowledge, this is the first report of
employing allenic lactone in a phosphine catalyzed annu-
lation reaction.
Table 1. Phosphine Catalyzed Cascade Synthesis of Tricyclic
Benzopyrones 8
Scheme 2. Cascade Synthesis of Tetracyclic Benzopyrones
Efficient and stereoselective synthesis of the stereodeco-
rated common scaffold set the stage for their further
transformations into naturally occurring benzopyrone
and related scaffolds (Figure 2). It is notable that this
strategy offers great synthetic challenges and calls for
developments in devising stereoselective and high yielding
skeletal-transformations of multifunctionalized small mole-
cules. We chose xanthone ring systems as the first target
modification of common scaffold 8 (Scheme 3). Xanthone
ring systems are ubiquitous molecular architectures in a
variety of naturally occurring and synthetic compounds
possessing diverse and important biological activities.15
Therefore, there has been a continued interest in the
development of efficient synthetic methods for functiona-
lized xanthone rings.16
a Isolated yields.
Treating 8 with 2 equiv of DDQ under microwave
heating conditions at 220 °C for 10 min in 1,2-dichloro-
benzene provided the desired xanthones 11aꢀc in excellent
yields.17 The same method also yielded tetracylic
xanthones 12aꢀb in very high yields employing benzoy-
prones 10a and 10c, respectively (Scheme 3).
The stereodecoration on the common scaffold should be
passed on to higher order ring systems to achieve more
three-dimensional diversity and to incorporate further
complexity in the resulting molecules. To this end, we
targeted stereoselective epoxidation of the olefin present
in the substrates 8. We reasoned that the π-facial selectivity
in the epoxidations would be influenced by the spatially
arranged functional groups in 8 and could provide
benzopyrone epoxides supporting up to five stereogenic
centers. Such complex electrophiles would be interesting
details of representative molecules, see Supporting
Information).14
When allene 3c was employed in this cascade annulation
with 2, benzopyrones 8jꢀ8m were obtained as single diaster-
eoisomers in very good yields (Table 1). Overall, the cascade
annulation of zwitterions 4 with 3-formylchromones pro-
vided an efficient and concise route to the desired common
scaffolds embodying up to three stereogenic centers.
While we were planning further elaboration of the
common scaffold into higher order tetracyclic benzo-
pyrones,10d,h we realized that employing an exocyclic
allene ester in the cascade annulation-deformylation reac-
tion sequence with 2 could provide a straightforward
synthesis of tetracyclic benzopyrones. The exocyclic allenic
lactone 9 was thus synthesized by Wittig olefination of the
ketene with corresponding phosphorus ylide (see Support-
ing Information) and employed in the cascade annulation
reaction (Scheme 2). Pleasingly, the reaction went
smoothly providing efficient, direct, and diastereoselective
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(17) All our attempts to partially dehydrogenate 8 leading to cyclo-
hexadiene ring structure that exist in Nidulalin A failed and provided
only the xanthone ring; however a similar framework 16b was obtained
during reducitve olefination of common scaffold (Scheme 3).
(14) (a) Lee, Y. G.; Ishimaru, K.; Iwasaki, H.; Ohkata, K.; Akiba,
K. Y. J. Org. Chem. 1991, 56, 2058–2066. (b) Hintz, S.; Mattay, J.; van
Eldik, R.; Fu, W. F. Eur. J. Org. Chem. 1998, 1583–1596.
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Org. Lett., Vol. 13, No. 8, 2011

candidates in chemical biology investigations.18 While
mCPBA failed to convert the substrate 8a into the epoxide,
treatment of 8a with freshly prepared trifluoroperacetic
acid (see Supporting Information) at 0 °C provided the
epoxide 13a in 68% isolated yield as major product (dr =
9:1). Employing 8f supporting a phenyl substitution pro-
vided 13b with even better diastereoselectivity (>30:1). On
the contrary, 8j lacking any functional group on C10
(Scheme 3) provided 1:0.65 mixture of two inseparable
epoxides 13c, indicating the steric steering of epoxidations
favoring anti-epoxide formation.19
Scheme 3. Elaboration of Common Scaffold into Diverse
Natural Ring-Systemsa
Interestingly, while optimizing the epoxidation reaction
conditions, we observed that using catalytic tBuOK,
tBuOOH led to selective R-hydroxylation of 8f yielding
14a in good yield (Scheme 3). We assume that an epoxide
of the enol is initially formed from the least hindered face,
thatis, antito phenyl-group substitution which opens up to
generate R-hydroxyl group.20 8g and 8i also provided the
corresponding R-hydroxylated benzopyrones 14b and 14c
in moderate yields. Considering the occurrence of R-
hydroxylated benzopyrone scaffolds in many natural pro-
ducts (Figure 2), this methodology looks very promising
and its further potential in general organic synthesis is
being investigated.
a Reaction conditions: a) 8 or 10 (1.0 equiv.), DDQ (2.0 equiv), 1,2-
dichlorobenzene, microwave heating (125 w, 220 °C, 10 min.); b) 8 (1.0
equiv), UHP (1.2 equiv) in CH2Cl2, TFAA (1.0 equiv), 0 °C, 30 min.; c) 8
(1.0 equiv), NaBH4 (1.5 equiv), MeOH, 10 h, MeSO3H (∼ 20 mol %),
benzene, reflux, 12 h; d) 8 (1.0 equiv), KOtBu (0.6 equiv), tBuOOH (2.0
equiv), THF, 0 °C, 5 h; e) over silica gel (2ꢀ5 h).
In yet another ring elaboration of the common scaffold,
8 was transformed in a one-pot strategy into the dihydrox-
anthene framework (15) supporting the same stereode-
coration as in the common scaffold. Various natural
products, for instance, dipuuphetriol contain dihydrox-
anthene ring systems (Figure 2), and an efficient access to
suitably functionalized dihydroxanthenes is very desirable.
Thus, tricyclic benzopyrone 8f was reduced to a secondary
alcohol using NaBH4 and treatment of the crude reaction
product with methane sulfonic acid provided the desired
15a in good overall yield (Scheme 3). When 8e supporting
an ester group was employed in this ring-transformation,
we realized that initially formed 15b isomerizes to doubly
conjugated xanthene 16b during column chromatography
over silica gel.17 In the case of 8i, however, both isomeric
products 15c and 16c were found to exist as an inseparable
mixture (Scheme 3).
cascade annulation reaction was developed to provide a
stereochemically decorated common scaffold which was
successfully elaborated into diverse natural product based
benzopyrone and related ring systems. While this strategy
brings new synthetic challenges to transform a stereofunc-
tionalized common intermediate scaffold into diverse nat-
ural ring systems, the hope is that compound collections
with structural features of natural products will yield
interesting and useful small molecules for drug discovery
and in particular chemical biology research.
Acknowledgment. This researchwork was supported by
Max Planck Gesellschaft. We are grateful to Prof. Dr. H.
Waldmann (Max Planck Institute of Molecular Physiol-
ogy, Dortmund) for his constant support and
encouragement.
In summary, we have explored a natural product bio-
synthesis inspired strategy to access biologically relevant
chemical space.21 In this planning, a phosphine catalyzed
Supporting Information Available. Details of all experi-
mental procedures and spectroscopic data for new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
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