Stereoselective cascade double-annulations provide diversely ring-fused tetracyclic benzopyrones

Article abstract of DOI:10.1021/ol3028412

A cascade double-annulation strategy employing diverse pairs of zwitterions with 3-formylchromones is presented that provides stereoselective access to complex tetracyclic benzopyrones. Different zwitterions incorporated different rings that include aza-, oxa-, and carbocycles fused to a common benzopyrone scaffold and in the process created three contiguous chiral centers including an all-carbon-quaternary center with high efficiency and excellent stereoselectivity.

Full text of DOI:10.1021/ol3028412

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Stereoselective Cascade
Double-Annulations Provide Diversely
Ring-Fused Tetracyclic Benzopyrones
Baburaj Baskar,† Kathrin Wittstein,†,‡ Muthukumar G. Sankar,† Vivek Khedkar,†
§
Markus Schurmann, and Kamal Kumar*
,†,‡
€
Abteilung Chemische Biologie, Max-Planck-Institut fu€r Molekulare Physiologie,
€
Otto-Hahn-Strasse 11, 44227 Dortmund, Germany, Fakultat Chemie, Chemische
Biologie, Technische Universitat Dortmund, Otto-Hahn-Strasse 6, 44221 Dortmund,
€
€
Germany, and Fakultat Chemie, Anorganische Chemie, Technische Universitat
Dortmund, Otto-Hahn-Strasse 6, 44221 Dortmund, Germany
€
kamal.kumar@mpi-dortmund.mpg.de
Received October 16, 2012
ABSTRACT
A cascade double-annulation strategy employing diverse pairs of zwitterions with 3-formylchromones is presented that provides stereoselective
access to complex tetracyclic benzopyrones. Different zwitterions incorporated different rings that include aza-, oxa-, and carbocycles fused to a
common benzopyrone scaffold and in the process created three contiguous chiral centers including an all-carbon-quaternary center with high
efficiency and excellent stereoselectivity.
Building focused compound collections based on privi-
leged scaffolds of natural product and/or drugs is an
important goal in chemical biology1 and drug discovery2
research. Chemical transformations that further build up
novel ring systems on privileged scaffolds might enrich the
scanty supply of new chemical entities and are therefore
highly desired.3 In particular, concise and stereoselective
synthetic routes to complex natural product based poly-
cyclic compounds rich in sp3 character, i.e., decorated with
more than one chiral center, remain a formidable challenge
in organic syntheses.4 The benzopyrone or chroman-4-one
scaffold is one of the privileged ring systems that exists in
the molecular frameworks of numerous natural products
that display a range of different biological activities (Figure 1).5
However, efficient and stereoselective synthetic access to
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Biomol. Chem. 2011, 9, 2680–2684. (b) Wittstein, K.; Garcia, A. B.;
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H.; Khedkar, V.; Duckert, H.; Schumann, M.; Oppel, I. M.; Kumar, K.
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† Max-Planck-Institut f€ur Molekulare Physiologie.
§
€
Anorganische Chemie, Technische Universitat Dortmund.
‡
€
Chemische Biologie, Technische Universitat Dortmund.
(1) (a) Paterson, I.; Anderson, E. A. Science 2005, 310, 451–453.
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Rev. 2012, 41, 4444–4456 and references cited therein. (b) Terstappen,
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r
10.1021/ol3028412
XXXX American Chemical Society

higher order polycyclic benzopyrones remains scarcely
reported in the literature.6
Scheme 1. Design of Cascade Annulation Strategy Providing
Diversely Ring-Fused and Complex Benzopyrones
Figure 1. Natural products embodying a common benzoyprone
scaffold fused to different ring systems.
Here, we present cascade double-annulations as stereo-
selective complexity generating transformations wherein
diverse pairs of zwitterions add in tandem to a common
substrate, 3-formylchromones to generate highly complex
tetracyclic benzopyrones decorated with two new rings
and three contiguous chiral centers including an all-
carbon-quaternary center.
We envisioned that a general synthetic access that keeps
the chroman-4-one scaffold intact and provides diverse ring
systems fused to this core structure would provide far greater
structural diversity in the focused compound collection. The
further unambiguously confirmed by single-crystal X-ray
analysis (Supporting Information).9 Increasing the amount
of DIAD and the phosphine (2.2 and 2.5 equiv, respectively)
enhanced the yield of 11a more than 2-fold (entry 1 in Table 1).
Differently substituted 3-formylchromones and diazodicarbox-
ylates (12) were employed in this cascade double-annulation
reaction that yielded benzopyrones 11aꢀj in moderate to very
good yields (Scheme 2 and Table 1). Excellent stereoselectiv-
ity (>99% de) was observed in this novel cascade double-
annulation that generates three contiguous chiral centers
with one of them an all-carbon quaternary center.
ꢀ
reported annulation of chalcones (1) with Huisgens zwitter-
ion 2 leading to pyrazolines (eq 1, Scheme 1)7 raised our
curiosity for a possible cascade double-annulation sequence
to access complex benzopyrones. We wondered how the
expected adduct 7 arising from a reaction of 3-formylchro-
mone 6 and 2 would react, if at all, to another nucleophilic
zwitterion (eq 2 and 3). Unlike the reaction of 2 with
chalcone 1 (eq 1) that consumes the ketone moiety in 5,
adduct 7 still keeps an R,β-unsaturated ketone for a further
annulation. A second zwitterion, for instance 2might under-
go sequential annulation as depicted in eq 1 to yield tetra-
cyclic benzopyrone 8 (eq 2, Scheme 1). However, a plausible
Scheme 2. Cascade Double Annulation of 3-Formylchromones
with Two Huisgen Zwitterions
ꢀ
SN2 addition of another zwitterion might lead to an inter-
mediate phenoxide 9that cyclizes to yield novel and complex
tetracyclic benzopyrone 10 (eq 3). We anticipated that the
latter cascade annulation might exploit different zwitterions8
as annulations partners and thus building differently ring-
fused and complex tetracyclic benzopyrones (eq 3, Scheme 1).
In order to ascertain the annulation potential of the
Isolation of the monoannulation adduct 7a suggested
the possibility of trapping this intermediate with another
zwitterion to afford diversely ring-fused and complex
benzopyrones. That implies the use of similar reaction
conditions that leads to intermediate 7. To incorporate a
carbocycle along with a heterocycle in the tetracyclic
benzopyrones, we resorted to [3 þ 2] annulation reaction
of allene ester (13) derived zwitterion 158d with intermediate
7(Scheme 4a). In the presence of phosphine, substrates 6, 12,
and 13 can undergo many possible and reported reactions.10
However, treating a mixture of phosphine and chromones
ꢀ
Huisgen’s zwitterion 2 on 3-formylchromone, an equimolar
THF solution of 3-formylchromone (6a) and triphenylpho-
sphine was treated with diisopropyl diazodicarboxylate
(DIAD) for 3 h at room temperature. Though the reaction
afforded the expected monoannulation adduct 7 in 26%
yield, to our surprise, bis-adduct 11a was also formed in
about 27% yield along with unreacted 3-formylchromone
(∼40%). The structure and stereochemistry of the tetracyclic
adduct 11a was established by 2D-NMR analysis and was
(9) (a) While this work was in progress, Papafilippou et al. reported a
reaction of 2 with 6 leading to chromeno[2,3-e]tetrazepines (ref 9b). In
our hands and under reported conditions, we did not observe formation
of tetrazepines. (b) Papafilippou, A.; Terzidis, M. A.; Stephanidou-
Stephanatou, J.; Tsoleridis, C. A. Tetrahedron Lett. 2011, 52, 1306–1309.
(10) (a) Kumar, K.; Kapoor, R.; Kapur, A.; Ishar, M. P. S. Org. Lett.
2000, 2, 2023–2025. (b) Nair, V.; Biju, A. T.; Mohanan, K.; Suresh, E.
Org. Lett. 2006, 8, 2213–2216.
(7) Nair, V.; Mathew, S. C.; Biju, A. T.; Suresh, E. Angew. Chem., Int.
Ed. 2007, 46, 2070–2073.
(8) (a) Nair, V.; Menon, R. S.; Sreekanth, A. R.; Abhilash, N.; Biju,
A. T. Acc. Chem. Res. 2006, 39, 520–530. (b) Nair, V.; Biju, A. T.;
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B
Org. Lett., Vol. XX, No. XX, XXXX

(6) with DIAD followed by addition of allene ester provided
the tetracyclic benzopyrones (14) in appreciable yields. The
cascade double annulation was completely diastereoselec-
tive and favored the γ-addition of zwitterion 15, thus
providing adducts 14 as single diastereoisomers (Scheme 3
and Table 1).
Scheme 4. Proposed Mechanism of the Cascade Double
Annulations
Scheme 3. Cascade Double Annulation of 3-Formylchromones
with Two Huisgen Zwitterions
Table 1. Cascade Synthesis of Diversely Ring-Fused Tetracyclic
Benzopyrones (11, 14, 26, and 27)
further diverse rings to the chorman-4-one scaffold. In
particular, annulations that are catalyzed by phosphines
could provide a dual-catalytic access to novel benzopyr-
ones. To this end, [4 þ 2] annulation of zwitterion 22
(generated by addition of phosphine to acetylene carbox-
ylates 21) with chromones 6 was employed as the first
catalytic annulation6d followed by catalytic [3 þ 2] annula-
tion of zwitterion 15 with the resulting intermediate 23.
Gratifyingly, the cascade annulations worked nicely albeit
with slightly higher loading of phosphine catalyst (0.6
equiv) and under a constant flow of argon to yield a 1:1
mixture of γ- and R-regioisomeric adducts 26 and 27,
respectively (Scheme 5 and Table 1).11 Interestingly, these
double-annulations too were completely stereoselective.
This cascade reaction sequence represents one of the few
known cases of stereoselective dual organocatalysis.12
entry
product
R1
R2
R3
yielda (%)
1
2
11a
H
H
iPr
65b
11b
Cl
Me
H
iPr
41b
3
11c
Br
Cl
Et
54b
4
11d
Me
H
Et
44b
5
11e
Me
H
iPr
43b
6
11f
H
Bn
53b
7
11g
Cl
H
iPr
39b
8
11h
iPr
H
H
iPr
51b
9
11i
H
Et
44b
10
11
12
13
14
15
16
17
18
19
20
11j
Me
iPr
H
H
Et
52b
14a
H
iPr
42c
14b
H
iPr
48c
14c
Me
Cl
H
iPr
46c
14d
H
iPr
55c
14e
Cl
Me
Me
H
iPr
40c
26a/27a
26b/27b
26c/27c
26d/27d
26e/27e
H
CO2Me
CO2Me
CO2Me
CO2Me
H
21/29d
40/23
32/42
32/38
20/20
OMe
H
H
H
iPr
iPr
Scheme 5. Dual-Catalyzed Cascade Synthesis of Tetracyclic
Benzopyrones
H
a Isolated yields. b Isolated yields after HPLC purification. c 10ꢀ15%
of 11 was formed and easily separable by column chromatography.
d 10% each of corresponding 6 and 23 were isolated.
Stereoselectivity in the cascade double-annulations as
depicted in Schemes 2 and 3 is plausibly dictated by steric
factors along with the preferred cis-ring fusions in the
ensuing adducts to avoid ring strain. Thus, SN20 addition
of the second zwitterion (15 or 2) to the common inter-
mediate 7 is followed by a conjugated addition of the
phenoxide (16 or 18, Scheme 4b) that happens from the
least hindered face (anti- to addition of zwitterion 2 or 15)
providing intermediates 17 or 19. Elimination of phosphine
oxide in 17 provided the adducts 11. The intermediate 19
undergoes a 1,2-H shift leading to 20 before the phosphine
leaves the catalytic cycle to yield the adduct 14 (Scheme 4b).
Successful double-annulations with two zwitterions en-
couraged us to explore zwitterions that could incorporate
(11) CCDC886337 (11a) and CCDC886338 (26c) contain the supple-
mentary crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(12) (a) Cai, L. C.; Zhang, B.; Wu, G. P.; Song, H. B.; He, Z. J. Chem.
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Duschek, A.; Kirsch, S. F. Angew. Chem., Int. Ed. 2008, 47, 5703–5705.
Org. Lett., Vol. XX, No. XX, XXXX
C

reactions with olefins.14 For this to be the case with the
intermediate 7, the reaction with 31 would yield two
diastereoisomers. However, the reaction cleanly yielded
the tetracyclic benzopyrone 32 as single diastereoisomer,
thus favoring the proposed SN20 addition of the zwitterion
to the intermediate 7, followed by a cascade annulation as
proposed in Scheme 4.
Scheme 6. (a) Attempted Cascade Double Annulation of Olefin
28 with 2 and of Adduct 29a with Allene-Derived Zwitterion and
(b) Annulation of Intermediate 7 with an Azide
In summary, we have disclosed a novel cascade double-
annulation approach as complexity generating transfor-
mations around privileged chromone scaffold. Different
rings that include aza-, oxa-, and carbocycles were effi-
ciently incorporated to the common benzopyrone scaffold
by different zwitterions, thus adding great structural di-
versity to a small sized compound collection. Overall, two
tandem annulations transformed the relatively flat sub-
strates (6) into highly sp3-enriched new chemical entities,
with high efficiency and excellent stereoselectivity. Easily
accessible substrates and milder reaction conditions make
the reactions amenable to compound collection synthesis.
With all possiblities to employ various zwitterionic and
nonzwitterionic annulation partners, weanticipate that the
double-annulation strategy would provide easy and effi-
cient access toward unprecedented and complex benzopyr-
ones that may find applications in various life science
disciplines.
To ascertain the proposed role of SN20 addition of
second zwitterion to the intermediate 7 in driving the
cascade annulations and determining the stereoselectivity
in tetracyclic benzopyrones, we designed some control
experiments. In the first case, 2-formyl-3-arylacrylates
(28), which resemble 3-formylchromone in terms of func-
tional group placement and in principle can undergo
double annulation reaction, were treated with 2.2 equiv
of Huisgen’s zwitterion 2. However, the reaction yielded
only monoannulation adducts 29.13 In a separate reaction
with allene-derived zwitterion 15, adduct 29a did not
provide the desired annulation adduct 30 (Scheme 6a).
This result manifests the inability of zwitterions 2 and 15
to undergo either conjugated addition or a concerted
cycloaddition with 29.8a,b In the second experiment, the inter-
mediate 7 (racemic) was treated with 2-azidobenzyl acetate
(31). Azides do undergo concerted [3 þ 2] cycloaddition
Acknowledgment. This research was supported in part by
funding from the Max-Planck-Gesellschaft and the European
Union Seventh Framework Programme under grant agree-
ment no. HEALTH-F2-2009-241498 (“EUROSPIN”
project). We thank Prof. H. Waldmann for his constant
support and encouragement.
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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The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX