O-Quinone Methides via Oxone-Mediated Benzofuran Oxidative Dearomatization and Their Intramolecular Cycloaddition with Carbonyl Groups: An Expeditious Construction of the Central Tetracyclic Core of Integrastatins, Epicoccolide A, and Epicocconigrone A

Article abstract of DOI:10.1021/acs.orglett.5b03707

The intramolecular cycloaddition of o-quinone methides (o-QMs) with a carbonyl group has been envisaged and executed successfully in the context of constructing the complex and rare [6,6,6,6]-tetracyclic core found in the integrastatins, epicoccolide A, and epicocconigrone A. These transient o-QMs were generated easily from the oxidative dearomatization of the corresponding C2-(aryl)benzofuran by employing Oxone in acetone-water at rt. The subsequent cycloaddition with the carbonyl (or conjugated olefin) present on the C2-aryl group was spontaneous.

Full text of DOI:10.1021/acs.orglett.5b03707

Letter
pubs.acs.org/OrgLett
o‑Quinone Methides via Oxone-Mediated Benzofuran Oxidative
Dearomatization and Their Intramolecular Cycloaddition with
Carbonyl Groups: An Expeditious Construction of the Central
Tetracyclic Core of Integrastatins, Epicoccolide A, and
Epicocconigrone A
Atul A. More and Chepuri V. Ramana*
Division of Organic Chemistry, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
S
* Supporting Information
ABSTRACT: The intramolecular cycloaddition of o-quinone
methides (o-QMs) with a carbonyl group has been envisaged
and executed successfully in the context of constructing the
complex and rare [6,6,6,6]-tetracyclic core found in the
integrastatins, epicoccolide A, and epicocconigrone A. These
transient o-QMs were generated easily from the oxidative
dearomatization of the corresponding C2-(aryl)benzofuran by
employing Oxone in acetone−water at rt. The subsequent cycloaddition with the carbonyl (or conjugated olefin) present on the
C2-aryl group was spontaneous.
n 2002, Singh and co-workers from Merck laboratories
Ireported the isolation of integrastatins A and B from an
unnamed fungal source (ATCC74478) and from an endophytic
Ascochtya species (ATCC74477).1 Both compounds have been
identified as potent inhibitors for the strand-transfer reaction of
the recombinant HIV-1 integrase enzyme. Integrastatins are
characterized by an unprecedented [6,6,6,6]-tetracyclic skeleton
having a central [3.3.1]-bicyclic ketal core where the perimeter
is fused with two aromatic rings on both sides and pendant
methyl groups are present on the bridge-head carbon atoms. To
date, there are three approaches reported for assembling the
central tetracyclic skeleton of integrastatins.2−4 The Taylor
(2003)2 and Stoltz (2011)4 groups have executed the synthesis
of 1a as a model target. We documented a one-step assembly of
the central core by employing McMurry cross coupling of o-
phthaladehyde with o-hydroxy-benzaldehyde/acetophenones.3
Although a number of derivatives could be synthesized in
Figure 1. Structures of integrastatins and related natural products with
moderate yields, this method is limited to o-phthaladehyde, and
a rare [6,6,6,6]-tetracyclic core and the model target compound
thus only one of the pendant bridge-head methyl groups could
synthesized by the Taylor and Stoltz groups.2,4
be placed. Interestingly, in 2013, the Laatsch5 and Proksch
groups6 have independently reported the isolation of two
closely related congeners of integrastatins, namely epicoccolide
A and epicocconigrone A, respectively (Figure 1). The
epicocconigrone A inhibited 15 tyrosine kinases with IC50
values ranging from 0.07 to 9.00 μM and histone deacetylase
with IC50 = 9.8 μM, and epicoccolide A showed potential
antimicrobial and antifungal activity.
The promising HIV-integrase inhibition of integrastatins,
taken together with the diverse bioactivities by the newly added
members of this rare family, has led us to revisit their synthesis.
In this paper, we document a simple approach for the synthesis
of the tetracyclic core of these natural products by employing a
novel benzofuran oxidative dearomatization cascade.
A possible biosynthetic pathway to form a [3.3.1] ring system
and epicoccolide B was proposed by Laatsch’s group and
parallels our disconnection of integrastatins.6 They proposed a
benzoin path comprising the dimerization of flavipin (o-
phthalaldehyde derivative) for the biogenesis of epicoccolide A
Received: December 30, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03707
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Letter
and epicocconigrone A. Interestingly, the epicoccolide B having
a simple benzofuran core has been assumed from the initial
benzoin product of the flavipin following a sequence of
reduction, acetalization, and dehydration. We wondered
whether this forward reaction cascade leading to 2-arylbenzo-
furan can be a backward retrosynthetic transform to disconnect
the [3.3.1]-tetracyclic heterocyclic skeleton, in other words, the
oxidation of a benzofuran to o-QM and its subsequent
intramolecular cycloaddition with a suitably positioned carbon-
yl group leading to the key tetracyclic skeleton.7−9 In this
regard, a report from the Adam’s group on generation of o-QM
from benzofuran via dimethyldioxirane (DMDO)-mediated
oxidative dearomatization, and its [4 + 2]−hetero-Diels−Alder
reaction with olefins (Figure 2b), is inspirational.10,11
Scheme 1. Synthesis of Benzofuran 2a and Its Oxidative
Dearomatization Cascade
provided 2a in 76% overall yield (Scheme 1). Having the model
substrate 2a with excellent yield, the stage was set for the
realization of the proposed hypothesis. The oxidation of
benzofurans reported by Adam’s group,10 in general, employed
the anhydrous DMDO at −78 °C. Considering recent
developments on the use of Oxone−acetone as a practical
alternative in DMDO-mediated oxidations, a careful screening
of the various alterations employing Oxone have been
examined.13 To this end, it has been realized that when
acetone alone is employed as the solvent along with water, the
oxidation of the benzofuran 2a can be successfully accom-
plished employing 2 equiv of Oxone at rt, and gratifyingly, the
intended cyclization was found to be realized with the
formation of the 1a in very good yields (89%) (Scheme 1).14
With the reaction conditions for the synthesis of complex
[3.3.1] tetracyclic heterocyclic skeleton present in integrastatins
in hand, we then examined the substrate scope of this reaction.
As shown in Table 1, various benzofuran substrates that have
been accessed by using Pd chemistry (see the SI for complete
details) have been found to undergo this oxidative trans-
formation leading to the corresponding tetracyclic bridged
bicyclic ketals in good to excellent yields without any
interference from the nature of the substituents present on
both aromatic rings.
Figure 2. (a) Structure of epiococcolide B, a biogenetic partner
isolated along with epicocconigrone A and epicoccolide A; (b) Adam’s
benzofuran oxidative dearomatization and [4 + 2]-cycloaddition; (c)
proposed disconnection of central core of the [6,6,6,6]-tetracyclic
system featuring a intramolecular [4 + 2]-cycloaddition of o-QM with
a carbonyl group.
In general, the o-QM intermediates are electrophilic in nature
and prefer cycloaddition with electron-rich olefins and undergo
conjugate additions with the nucleophiles.15 The current
successful cycloaddition with carbonyls is interesting. Next, in
order to examine the involvement of o-QM, as Adam’s group
had suggested,10 and also to examine the compatibility of
conjugated olefins, the α,β-unsaturated compound 3a has been
prepared from the corresponding aldehyde 2b and subjected to
the current reaction conditions.16 As indicated in Scheme 2, the
tandem o-QM generation and subsequent [4 + 2]−cyclo-
addition reaction proceeded smoothly and provided the
tetrahydronaphthalene framework 4a resulting with the
retention of the initial E-configuration of the olefin. The
scope of this o-QM/[4 + 2]-cycloaddition was examined
employing substrates 3b−f, and the corresponding tetrahy-
dronaphthalenes 4b−f were obtained in moderate to good
yields (Scheme 2). It is to be noted that the resulting
tetrahydronaphthalene framework is abundant in many natural
products such as podophyllotoxin, a famous anticancer natural
drug lead.17
In the forward sense, the synthesis of compound 1a, a model
target representing the central ketal core of integrastatins and
synthesized by the Taylor and Stoltz groups, has been planned.
The benzofuran 2a has been identified as the model substrate
for the proposed oxidative skeletal reorganization. Interestingly,
the only report available on the existence of 2a has been
documented by Taylor’s group as a side product resulting from
an unwarranted intramolecular rearrangement of a penultimate
compound while synthesizing 1a.2 Otherwise, the synthesis of
this selected model substrate 2a has not been reported. This
warranted the necessity to develop enabling chemistry. Our
initial experiments in this regard have been focused on the
preparation of 2a by employing the Pd-catalyzed direct
coupling that has been documented by Doucet’s group
employing simple aryl halides.12 As shown in Scheme 1, the
coupling of 3-methylbenzofuran with 2-bromoacetopheone
under the prescribed conditions was sluggish, and the requisite
2a was obtained in moderate yields. However, when 2-
bromobenzaldehye was employed as a coupling partner, the
corresponding product 2b was obtained in excellent yields
(95%). The Grignard reaction of 2b with methylmagensium
bromide, followed by the oxidation of the intermediate alcohol,
Coming to the course of the reaction, the product formation
takes place via the formation of an o-QM followed by
cycloaddition with a suitably disposed carbonyl or olefin
B
DOI: 10.1021/acs.orglett.5b03707
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Letter
Table 1. Scope of the Oxone-Mediated Benzofuran
Oxidative Dearomatization and o-QM Cycloaddition with
Carbonyl Groups
Scheme 2. Scope of the Conjugated Olefins as the
Dienophiles in Oxone-Mediated Benzofuran Oxidative
Dearomatization and o-QM Cycloaddition Cascade
This cascade process comprises the Oxone-mediated oxidation
of the benzofuran ring leading to the transient o-QM and its
subsequent intramolecular [4 + 2]-cycloaddition with alde-
hydes, ketones, and olefins. This cascade process is simple to
execute by employing Oxone at rt in aqueous acetone and will
have potential implications in the chemical synthesis of natural
products containing chroman as well as tetrahydronaphthalene
frameworks. Further studies aimed at the total syntheses of
integrastatins A/B, epicoccolide A, and epicocconigrone A are
currently in progress and will be reported in due course.
functional group. The facile cycloaddition with conjugated
olefins and the exclusive formation of products resulting in the
retention of the initial olefin configuration is suggestive of a
concerted process. To examine the possibility of any alternative
stepwise processes, the reaction of 2a was carried out
employing H218O under similar conditions. A nominal 18O
labeling was noticed in the resulting product 1a. This
experiment clearly ruled out the an alternative path involving
the possible participation of the external water as a nucleophile
adding to the o-QM followed by intramolecular acetaliza-
tion.7b,18 Thus, these 18O-labeling experiments and the
reactions with olefin are indicative of the concerted nature of
the current cycloaddition process and clearly suggested the
involvement of an o-QM intermediate. Moreover, the
compatibility of the aryl aldehyde group under these conditions
is really interesting and revealed that the benzofuran oxidation
is preferred over the oxidation of the aldehyde unit despite the
fact that the reacting heterocyclic olefin is fully substituted.19 In
addition, the successful cyclization with both the substrates,
especially in the presence of acetone as solvent, is remarkable,
thus revealing complete dominance of the intramolecular
cyclization over the intermolecular one with acetone.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03707.
Full experimental procedures, characterization data, and
NMR/mass spectra of all new compounds (PDF)
Crystallographic data for compound 1a (CIF)
Crystallographic data for compound 1b (CIF)
Crystallographic data for compound 1e (CIF)
Crystallographic data for compound 1l (CIF)
Crystallographic data for compound 4a (CIF)
Crystallographic data for compound 4e (CIF)
In conclusion, a simple approach for the construction of the
rare [6,6,6,6]-tetracyclic core present in the integrastatins,
epicoccolide A, and epicocconigrone A has been developed
featuring a novel benzofuran oxidative dearomatization cascade.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: vr.chepuri@ncl.res.in.
C
DOI: 10.1021/acs.orglett.5b03707
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Organic Letters
Letter
(10) (a) Adam, W.; Hadjiarapoglou, L.; Peters, K.; Sauter, M. J. Am.
Chem. Soc. 1993, 115, 8603−8608. (b) Adam, W.; Peters, K.; Sauter,
M. Synthesis 1994, 1994, 111−119. (c) Adam, W.; Sauter, M.
Tetrahedron 1994, 50, 11441−11446.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(11) For recent reviews on phenol dearomatization cascades in
■
́
complex syntheses, see: (b) Quideau, S.; Pouysegu, L.; Deffieux, D.
This work was supported by the DBT (grant BT/PR7442/
MED/29/680/2012) and CSIR (under 12th FYP, CSC0108).
We thank R. G. Gonnade for crystal X-ray diffraction data.
A.A.M. thanks UGC for a fellowship.
Synlett 2008, 2008, 467−495. (c) Roche, S. P.; Porco, J. A. Angew.
Chem., Int. Ed. 2011, 50, 4068−4093. (d) Zhuo, C.-X.; Zhang, W.;
You, S.-L. Angew. Chem., Int. Ed. 2012, 51, 12662−12686. (e) Ding,
Q.; Ye, Y.; Fan, R. Synthesis 2013, 45, 1−16.
(12) Ionita, M.; Roger, J.; Doucet, H. ChemSusChem 2010, 3, 367−
376.
(13) For selected reviews on Oxone-mediated oxidations, see:
(a) Hussain, H.; Green, I. R.; Ahmed, I. Chem. Rev. 2013, 113, 3329−
3371. (b) Adam, W.; Zhao, C.-G.; Jakka, K. Organic Reactions; John
Wiley & Sons, Inc., 2004.
(14) (a) Murray, R. W.; Jeyaraman, R. J. Org. Chem. 1985, 50, 2847−
2853. (b) Phatake, R. S.; Ramana, C. V. Tetrahedron Lett. 2015, 56,
2183−2186.
(15) Wang, Z.; Sun, J. Synthesis 2015, 47, 3629−3644.
(16) Electron-deficient olefins are rarely employed as dienophiles in
o-QM [4 + 2]-cycloaddition reactions: Wojciechowski, K.;
Dolatowska, K. Tetrahedron 2005, 61, 8419−8422.
(17) (a) Ward, R. S. Nat. Prod. Rep. 1999, 16, 75−96. (b) Gordaliza,
M.; García, P. A.; Miguel del Corral, J. M.; Castro, M. A.; Gomez-
́
Zurita, M. A. Toxicon 2004, 44, 441−459. (c) Qian Liu, Y.; Yang, L.;
Tian, X. Curr. Bioact. Compd. 2007, 3, 37−66. (d) Wu, Y.; Zhao, J.;
Chen, J.; Pan, C.; Li, L.; Zhang, H. Org. Lett. 2009, 11, 597−600.
(18) Curci, R.; Fiorentino, M.; Troisi, L.; Edwards, J. O.; Pater, R. H.
J. Org. Chem. 1980, 45, 4758−4760.
(19) Aromatic aldehydes can be converted into their corresponding
acids/phenols when treated with Oxone in aqueous acetone; see:
Webb, K. S.; Ruszkay, S. J. Tetrahedron 1998, 54, 401−410.
REFERENCES
■
(1) Singh, S. B.; Zink, D. L.; Quamina, D. S.; Pelaez, F.; Teran, A.;
Felock, P.; Hazuda, D. J. Tetrahedron Lett. 2002, 43, 2351−2354.
(2) Foot, J. S.; Giblin, G. M. P.; Taylor, R. J. K. Org. Lett. 2003, 5,
4441−4444.
(3) Ramana, C. V.; Nageswara Reddy, C.; Gonnade, R. G. Chem.
Commun. 2008, 3151−3153.
(4) Tadross, P. M.; Bugga, P.; Stoltz, B. M. Org. Biomol. Chem. 2011,
9, 5354−5357.
(5) Talontsi, F. M.; Dittrich, B.; Schuffler, A.; Sun, H.; Laatsch, H.
̈
Eur. J. Org. Chem. 2013, 2013, 3174−3180.
(6) El Amrani, M.; Lai, D.; Debbab, A.; Aly, A. H.; Siems, K.; Seidel,
C.; Schnekenburger, M.; Gaigneaux, A.; Diederich, M.; Feger, D.; Lin,
W.; Proksch, P. J. Nat. Prod. 2014, 77, 49−56.
(7) In some instances, despite the presence of o-QM being
unintentional, the possibility of a [4 + 2]-cycloaddition of o-QMs
with a carbonyl group has been noticed and/or proposed to account
for the minor side products isolated. See: (a) Jones, D. W. J. Chem. Soc.
D 1971, 1130−1131. (b) Castonguay, A.; Brassard, P. Can. J. Chem.
1977, 55, 1324−1332.
(8) For recent reviews on o-QM synthesis and utility, see: (a) Van De
Water, R. W.; Pettus, T. R. R. Tetrahedron 2002, 58, 5367−5405.
(b) Jackson, S. K.; Wu, K.-L.; Pettus, T. R. R. Sequential Reactions
Initiated by Oxidative Dearomatization. Biomimicry or Artifact? In
Biomimetic Organic Synthesis; Nay, B., Poupon, E., Eds.; VCH:
Weinheim, 2011; Vol. 2, pp 723−749. (c) Pathak, T. P.; Sigman, M.
S. J. Org. Chem. 2011, 76, 9210−9215. (d) Willis, N. J.; Bray, C. D.
Chem. - Eur. J. 2012, 18, 9160−9173. (e) Bai, W.-J.; David, J. G.; Feng,
Z.-G.; Weaver, M. G.; Wu, K.-L.; Pettus, T. R. R. Acc. Chem. Res. 2014,
47, 3655−3664. (f) Singh, M. S.; Nagaraju, A.; Anand, N.; Chowdhury,
S. RSC Adv. 2014, 4, 55924−55959.
(9) For selected recent total syntheses employing o-QM synthons,
see: (a) Takao, K.-i.; Noguchi, S.; Sakamoto, S.; Kimura, M.; Yoshida,
K.; Tadano, K.-i. J. Am. Chem. Soc. 2015, 137, 15971−15977.
(b) Gervais, A.; Lazarski, K. E.; Porco, J. A. J. Org. Chem. 2015, 80,
9584−9591. (c) Zhao, N.; Ren, X.; Ren, J.; Lu, H.; Ma, S.; Gao, R.; Li,
̈
Y.; Xu, S.; Li, L.; Yu, S. Org. Lett. 2015, 17, 3118−3121. (d) Spence, J.
T. J.; George, J. H. Org. Lett. 2015, 17, 5970−5973. (e) Markwell-
Heys, A. W.; Kuan, K. K. W.; George, J. H. Org. Lett. 2015, 17, 4228−
4231. (f) Song, L.; Yao, H.; Tong, R. Org. Lett. 2014, 16, 3740−3743.
(g) Jepsen, T. H.; Thomas, S. B.; Lin, Y.; Stathakis, C. I.; de Miguel, I.;
Snyder, S. A. Angew. Chem., Int. Ed. 2014, 53, 6747−6751. (h) Spence,
J. T. J.; George, J. H. Org. Lett. 2013, 15, 3891−3893. (i) Li, L.; Liu, Y.;
Wang, Q. Eur. J. Org. Chem. 2013, 2013, 8014−8021. (j) Pepper, H.
P.; Kuan, K. K. W.; George, J. H. Org. Lett. 2012, 14, 1524−1527.
(k) Liao, D.; Li, H.; Lei, X. Org. Lett. 2012, 14, 18−21. (l) Green, J. C.;
Burnett, G. L.; Pettus, T. R. R. Pure Appl. Chem. 2012, 84, 1621−1631.
(m) Bai, W.-J.; Green, J. C.; Pettus, T. R. R. J. Org. Chem. 2012, 77,
379−387. (n) Wenderski, T. A.; Marsini, M. A.; Pettus, T. R. R. Org.
Lett. 2011, 13, 118−121. (o) Spence, J. T. J.; George, J. H. Org. Lett.
2011, 13, 5318−5321. (p) Kuttruff, C. A.; Zipse, H.; Trauner, D.
Angew. Chem., Int. Ed. 2011, 50, 1402−1405. (q) Green, J. C.;
́
Jimenez-Alonso, S.; Brown, E. R.; Pettus, T. R. R. Org. Lett. 2011, 13,
5500−5503. (r) Snaddon, T. N.; Buchgraber, P.; Schulthoff, S.; Wirtz,
C.; Mynott, R.; Furstner, A. Chem. - Eur. J. 2010, 16, 12133−12140.
̈
(s) Lawrence, A. L.; Adlington, R. M.; Baldwin, J. E.; Lee, V.; Kershaw,
J. A.; Thompson, A. L. Org. Lett. 2010, 12, 1676−1679. (t) George, J.
H.; Baldwin, J. E.; Adlington, R. M. Org. Lett. 2010, 12, 2394−2397.
D
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