Studies toward the synthesis of the epoxykinamycin FL-120B′: Discovery of a decarbonylative photocyclization

Article abstract of DOI:10.1021/ol3010563

Photo-Friedel-Crafts acylation of a naphthoquinone was attempted in an effort to access a diazobenzofluorenone en route to the epoxykinamycin natural product FL-120B′. Photoirradiation of the naphthoquinone substrate which resulted in the unexpected formation of a tetracyclic naphthofuran via a decarbonylative photocyclization process is described.

Full text of DOI:10.1021/ol3010563

ORGANIC
LETTERS
2012
Vol. 14, No. 10
2646–2649
Studies toward the Synthesis of the
Epoxykinamycin FL-120B0: Discovery of a
Decarbonylative Photocyclization
Stephen S. Scully and John A. Porco Jr.*
Department of Chemistry and Center for Chemical Methodology and Library
Development (CMLD), Boston University, Boston, Massachusetts 02215,
United States
porco@bu.edu
Received April 22, 2012
ABSTRACT
Photo-FriedelꢀCrafts acylation of a naphthoquinone was attempted in an effort to access a diazobenzofluorenone en route to the epoxykinamycin
natural product FL-120B0. Photoirradiation of the naphthoquinone substrate which resulted in the unexpected formation of a tetracyclic
naphthofuran via a decarbonylative photocyclization process is described.
Kinamycin C (1)1 and the epoxykinamycin FL-120B0
(2)2 belong to the family of diazobenzofluorene natural
products which possess broad antibacterial and antitumor
activities (Figure 1). The unique diazo functionality and its
involvement in the diazobenzofluorenes’ ability to damage
DNA have made this class of molecules attractive targets
for synthetic organic chemists.3 In 2006 and 2011, our
laboratory reportedthe total syntheses of kinamycin C and
FL-120B0, respectively.4 Our approach to 1 and 2 involved
elaboration of a benzofluorenone intermediate 3 which
was accessed from a trifluoroacetic anhydride (TFAA)-
mediated intramolecular FriedelꢀCrafts cyclization of
carboxylic acid precursor 4. During our studies toward
the synthesis of FL-120B0, an alternative cyclization in-
volving intramolecular photoacylation of an aldehyde
substrate containing a naphthoquinone chromophore
was also explored. In the present study, we describe our
efforts to implement the intramolecular photo-Friedelꢀ
Crafts acylation which resulted in the serendipitous
discovery5 of a novel decarbonylative photocyclization to
form naphthofurans.6
Historically, intermolecular photo-FriedelꢀCrafts acy-
lations of quinones and aldehydes have been demonstrated
to yield acylated hydroquinones.7 For example, photoir-
radiation of 1,4-napthoquinone 5 in the presence of pro-
pionaldehyde 6 provided the acylated hydroquinone 7
(Scheme 1).7i This reaction serves as an environmentally
(5) For a recent example of serendipitous reaction discovery in
studies toward diazobenzofluorene natural products, see: Baranczak,
A.; Sulikowski, G. A. Org. Lett. 2012, 14, 1027–1029.
(6) For an alternative synthesis of naphthofurans via [2 þ 2] photo-
cycloaddition/rearrangement, see: Liu, H.-J.; Chan, W. H. Can. J.
Chem. 1980, 58, 2196–2198.
(1) (a) Ito, S.; Matsuya, T.; Omura, S.; Otani, M.; Nakagawa, A.
J. Antibiot. 1970, 23, 315–317. (b) Hata, T.; Omura, S.; Iwai, Y.;
Nakagawa, A.; Otani, M. J. Antibiot. 1971, 24, 353–359. (c) Omura,
S.; Nakagawa, A.; Yamada, H.; Hata, T.; Furusaki, A. Chem. Pharm.
Bull. 1973, 21, 931–940.
(2) (a) Lin, H. C.; Chang, S. C.; Wang, N. L.; Chang, L. R.
J. Antibiot. 1994, 47, 675–680. (b) Young, J.-J.; Ho, S. N.; Ju, W. M.;
Chang, L. R. J. Antibiot. 1994, 47, 681–687.
(3) For a recent review including synthetic and mechanism-of-action
studies of diazobenzofluorene natural products, see: Herzon, S. B.;
Woo, C. M. Nat. Prod. Rep. 2012, 29, 87–118.
(4) (a) Lei, X.; Porco, J. A., Jr. J. Am. Chem. Soc. 2006, 128, 14790–
14791. (b) Scully, S. S.; Porco, J. A., Jr. Angew. Chem., Int. Ed. 2011, 50,
9722–9726.
(7) For select examples, see: (a) Klinger, H.; Kolvenbach, W. Chem.
Ber. 1898, 31, 1214. (b) Bruce, J. M.; Cutts, E. J. Chem. Soc. C 1966, 449–
458. (c) Maruyama, K.; Miyagi, Y. Bull. Chem. Soc. Jpn. 1974, 47, 1303–
1304. (d) Kraus, G. A.; Kirihara, M. J. Org. Chem. 1992, 57, 3256–3257.
(e) Kraus, G. A.; Liu, P. Tetrahedron Lett. 1994, 35, 7723–7726. (f)
€
Schiel, C.; Oelgemoller, M.; Mattay, J. Synthesis 2001, 1275–1279. (g)
€
Schiel, C.; Oelgemoller, M.; Ortner, J.; Mattay, J. Green Chem. 2001, 3,
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224–228. (h) Waske, P. A.; Mattay, J.; Oelgemoller, M. Tetrahedron
Lett. 2006, 47, 1329–1332. (i) Friedrichs, F.; Murphy, B.; Nayrat, D.;
€
Ahner, T.; Funke, M.; Ryan, M.; Lex, J.; Mattay, J.; Oelgemoller, M.
Synlett 2008, 3137–3140. (j) Benites, J.; Rios, D.; Dıaz, P.; Valderrama,
J. A. Tetrahedron Lett. 2011, 52, 609–611.
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10.1021/ol3010563
Published on Web 05/09/2012
2012 American Chemical Society

Scheme 2. Proposed Intramolecular Photo-FriedelꢀCrafts
Acylation
Figure 1. Synthetic approaches to kinamycin C and FL-120B0.
friendly alternative to the classical FriedelꢀCrafts acyla-
tion. In this regard, Mattay and co-workers performed this
photoacylation on a 500 g scale using a solar-chemical
reactor.7f,g One mechanism accounting for formation of 7
involves abstraction of the acyl hydrogen by photoexcited
naphthoquinone 8 to give semiquinone 9 and acyl radical
10. Subsequent carbonꢀcarbon bond formation via an
Naphthoquinone substrate 11 was obtained in six steps
from epoxyketone 15,4a an intermediate in our synthesis
of kinamycin C (Scheme 3). Acetylation of 15 followed
by reduction (LiEt3BH) provided syn-epoxyalcohol 16
(5:1 dr)11 which was protected as Boc-carbonate 17. Desi-
lylation and oxidation with Dess-Martin periodinane
(DMP)12 afforded aldehyde 18. Oxidative dealkylation with
ceric ammonium nitrate (CAN) provided 11 as our desired
substrate for intramolecular photo-FriedelꢀCrafts acyla-
tion studies.
Scheme 1. Intermolecular Photo-FriedelꢀCrafts Acylation7i
Photoirradation of 11 in a Rayonet reactor (315ꢀ
400 nm) gave full conversion to a product that could not be
identified as the expected benzofluorenone 12 (Scheme 4).
In addition, lactone 19 was not observed. Photochemical
studies on a substrate closely resembling 11 by Echavarren
and co-workers led to observation of a lactone byproduct
in their synthetic efforts toward prekinamycin.13 Analysis
of 13C NMR and mass spectra suggested formation of a
decarbonylated product which was tentatively assigned as
naphthofuran 20. However, a supporting correlation be-
tween the C(4)-proton and C(16)-carbon was not revealed
in the HMBC spectrum given that they are four bonds
removed and connected through a heteroatom.
To support the structural assignment for 20, the de-
carbonylative photocyclization was performed on the sim-
plified naphthoquinone 21 which provided naphthofuran
22 (Scheme 5). In addition to 22, a nondecarbonylated
byproduct arising from putative allylic hydrogen abstrac-
tion was formed.11 Fortunately, an X-ray crystal structure
of 22 was obtained, confirming the predicted carbon and
oxygen connectivities which can be directly correlated to
the more complex naphthofuran 20. The yield for forma-
tion of 22 was calculated to be 61% using nitromethane
(CH3NO2) as internal standard. However, purification by
silica gel chromatography resulted in a lower isolated yield
in-cage coupling8 of 9 and 10 provides the observed acyl
hydroquinone 7.9 On this mechanistic basis, we hypothe-
sized that photoirradiation of naphthoquinone 11 may
provide benzofluorenone 12 as a useful intermediate for
our synthesis of FL-120B0 (Scheme 2). This photo-Friedelꢀ
Crafts cyclization would require diradical 13 to undergo
intramolecular hydrogen abstraction through a seven-
membered10 cyclic transition state, in which the resulting
biradical species 14 would further cyclize to 12.
(8) (a) Maruyama, K.; Miyagi, Y. Bull. Chem. Soc. Jpn. 1974, 47,
1303–1304. (b) Maruyama, K.; Sakurai, H.; Otsuki, T. Bull. Chem. Soc.
Jpn. 1977, 50, 2777–2779. (c) Maruyama, K.; Takuwa, A.; Matsukiyo,
S.; Sogo, O. J. Chem. Soc., Perkin Trans. 1 1980, 1414–1419.
(11) See Supporting Information for complete experimental details.
(12) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156.
(b) Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.
(13) De Frutos, O.; Atienza, C.; Echavarren, A. M. Eur. J. Org.
Chem. 2001, 163–171.
(9) For an extensive discussion on the mechanism of the intermole-
€
cular photo-FriedelꢀCrafts acylation, see: Oelgemoller, M.; Schiel, C.;
€
Frohlich, R.; Mattay, J. Eur. J. Org. Chem. 2002, 2465–2474.
(10) Pappas, S. P.; Alexander, J. E.; Zehr, R. D., Jr. J. Am. Chem.
Soc. 1970, 92, 6927–6931.
Org. Lett., Vol. 14, No. 10, 2012
2647

Scheme 3. Synthesis of Naphthoquinone 11
Scheme 5. Synthesis and X-ray Crystal Structure of 22a
a Yield determined by 1H NMR analysis using CH3NO2 as an internal
standard.
intermediate 23 (Scheme 6). A photoinduced hydride shift
for o-vinylbenzaldehydes has been demonstrated in several
studies14,15 and in some instances decarbonylation prod-
ucts have been reported.15 In this regard, decarbonylation
of the derived vinyl ketene 23 may provide β-acyl alkenyl
carbene intermediate 24. Isomerization of 24 to carbene 25
would provide a suitable orientation for naphthofuran
formation upon 6π-electrocyclization.16
Scheme 4. Unexpected Decarbonylative Photocyclization to 20
Scheme 6. Proposed Mechanism for Decarbonylative Photocy-
clization
To explore the reaction mechanism, deuterium-labeled
aldehyde 2611 was prepared to study the photocyclization
to naphthoquinone 27 and the possibility for deuterium
incorporation at the C(8)-position (Scheme 7).17 However,
photoirradiation of 26 in benzene-d6 provided 22 in which
27 or deuterium incorporation of the phenol was not
observed. The half-life of 27 may be relatively short in
(37%) of 22 which was consistent with the isolated yield
(34%) for 20.
A mechanism for the decarbonylative photocyclization
may involve a photochemical, concerted [1,5]-hydride shift
of the acyl hydrogen to the vinylic carbon to afford ketene
(14) (a) Kessar, S. V.; Mankotia, A. K. S.; Gujral, G. J. Chem. Soc.,
Chem. Commun. 1992, 840–841. (b) Kessar, S. V.; Kessar, A. K. S.;
Scaiano, J. C.; Barra, M.; Huben, J.; Gebicki, K. J. Am. Chem. Soc.
1996, 118, 4361–4365.
(15) (a) Schiess, P.; Suter, C. Helv. Chim. Acta 1971, 54, 2636. (b)
Wilson, R. M.; Patterson, W. S.; Austen, S. C.; Douglas, M. H.; Bauer,
J. A. K. J. Am. Chem. Soc. 1995, 117, 7820–7820. (c) Lu, S.; Wang, R.;
Yang, Y.; Li, Y.; Shi, Z.; Zhang, W.; Tu, Z. J. Org. Chem. 2011, 76,
5661–5669.
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Kumler, P. L.; Creed, D. J. Am. Chem. Soc. 1973, 95, 7402–7406. (b)
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183–191. (c) Mukherjee, A. K.; Margaretha, P.; Agosta, W. C. J. Org.
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(17) For analogous deuterium-labelling studies for [1,5]-hydride
shifts of o-vinylbenzaldehydes, see ref 15b.
2648
Org. Lett., Vol. 14, No. 10, 2012

the presence of small amounts of water through ketoꢀenol
tautomerization. The latter hypothesis was disproved
upon failure to observe the reverse process, deuterium
incorporation at the C(8)-position after exchange of 22
with D2O. Furthermore, deuterium exchange was not
observed when 22 was photoirradiated in a 10% solution
of D2O in anhydrous benzene.18
Scheme 8. Alternative Mechanism for Decarbonylative Photo-
cyclization
Scheme 7. Deuterium-Labeling Studies
cyclohexenemoiety.21 This motif is found in natural products
(e.g. propolis-benzofuran B)22 in which application of this
photochemical methodology may prove beneficial for total
synthesis. Moreover, the methodology provides neutral con-
ditions to synthesize the benzofuran unit without using harsh
acidic or basic conditions that may compromise the integrity
of functionalized cyclohexenes. Further mechanistic studies
and applications of the decarbonylative photocyclization are
currently in progress and will be reported in due course.
An alternative mechanism accounting for the deuterium-
labeling studies may not involve direct transfer of deuter-
ium to the C(8)-carbon. For example, photoexcited qui-
none 28 may cyclize to form biradical 29 (Scheme 8).
Benzoquinones bearing an alkenyl moiety with a vinyl
hydrogen have been demonstrated to undergo photocycli-
zation to diradical intermediates, in which a subsequent
hydrogen shift yields benzofurans.19 Likewise, intramole-
cular abstraction of the deuterium in29would provide acyl
radical 30 which upon decarbonylation20 may afford furan
intermediate 31. Rearomatization with water would give
naphthofuran 22 without deuterium incorporation.
Acknowledgment. Financial support from the National
Institutes of Health (RO1 CA137270) is gratefully acknowl-
edged. We thank Dr. Jeffrey Bacon (Boston University) for
X-ray crystal structure analysis and Prof. Corey Stephenson
(Boston University) for helpful discussions.
Supporting Information Available. Experimental pro-
cedures, compound characterization data, and X-ray
crystallographic information files. This material is
available free of charge via the Internet at http://
pubs.acs.org.
The serendipitous discovery of the decarbonyl-
ative photocyclization represents a novel synthesis of
a benzofuran containing a highly substituted, fused
(18) For photoinduced deuterium incorporation of naphthyl deriva-
tives, see: Lukeman, M.; Veale, D.; Wan, P.; Munasinghe, V. R. N.;
Corrie, J. E. T. Can. J. Chem. 2004, 82, 240–253.
(19) (a) Iwamoto, H.; Takuwa, A.; Hamada, K.; Fujiwara, R.
J. Chem. Soc., Perkin Trans. 1 1999, 575–581. (b) Ogata, T.; Okamoto,
I.; Kotani, E.; Takeya, T. Tetrahedron 2004, 60, 3941–3948.
(20) For a review on the chemistry of acyl radicals, see: Chatgilialoglu,
C.; Crich, D.; Komatsu, M.; Ryu, I. Chem. Rev. 1999, 99, 1991–
2069.
(21) For the synthesis of benzofurans with fused cyclohexenes utiliz-
ing a Nazarov reaction, see: Phun, L. H.; Patil, D. V.; Cavitt, M. A.;
France, S. Org. Lett. 2011, 13, 1952–1955.
(22) Banskota, A. H.; Tezuka, Y.; Midorikawa, K.; Matsushige, K.;
Kadota, S. J. Nat. Prod. 2000, 63, 1277–1279.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 10, 2012
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