Total synthesis of 7′-desmethylkealiiquinone

Article abstract of DOI:10.1021/ol300704w

The total synthesis of an analogue of the marine alkaloid kealiiquinone has been completed through application of an intramolecular Diels-Alder reaction of an imidazole-containing enyne. Oxidative aromatization of the lactone adduct and N-methylation faci

Full text of DOI:10.1021/ol300704w

ORGANIC
LETTERS
Total Synthesis of 70-Desmethylkealiiquinone
2012
Vol. 14, No. 9
2274–2277
Heather M. Lima, Rasapalli Sivappa, Muhammed Yousufuddin, and Carl J. Lovely*
Department of Chemistry and Biochemistry, The University of Texas at Arlington,
Arlington, Texas 76019, United States
lovely@uta.edu
Received March 20, 2012
ABSTRACT
The total synthesis of an analogue of the marine alkaloid kealiiquinone has been completed through application of an intramolecular DielsꢀAlder
reaction of an imidazole-containing enyne. Oxidative aromatization of the lactone adduct and N-methylation facilitates C2-oxidation via the
imidazolium salt. Conversion of the lactone to the phthalaldehyde derivative and then to the dihydroxybenzoquinone was achieved via a reaction
with glyoxal in the presence of KCN. Esterification of the vinylogous diacid and deprotection provided 70-desmethylkealiiquinone.
Marine sponges have produced and continue to
provide a large number of architecturally unique and
biologically active natural products.1,2 These natural
products have provided a fertile testing ground for the
development and refinement of new synthetic methods
and strategies.1 Our group has been particularly inter-
ested in the development of synthetic approaches
to the growing number of imidazole-containing nat-
ural products from marine sponges.3,4 Sponges of the
Leucetta and Clathrina genus produce a remark-
able number of diverse secondary metabolites in which
an imidazole is a characteristic structural motif.5
Recently, our attention has been directed to two
structurally related imidazonaphthoquinone natural
products, kealiiquinone (1)6 and its 2-amino congener
(2-amino-2-deoxykealiiquinone (2)),7 which were iso-
lated by the Clardy and Schmitz groups, respectively,
from two Leucetta sponges (Figure 1). Although these
compounds were not reported to possess exceptional
biological activity, they are cytotoxic. An isomer of 18
has been shown to exhibit fairly potent anticancer activity
which based on its profile is thought to be mediated through
a novel mode of action. More recently, several naturally
occurring analogues of kealiiquinone, kealiinines AꢀC
(3ꢀ5), have been reported and have been suggested as
possible biosynthetic precursors to 1 and 2.9
Figure 1. Structures of the kealiinine family of alkaloids.
(1) Morris, J. C.; Phillips, A. J. Nat. Prod. Rep. 2011, 28, 269.
(2) Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.;
Prinsep, M. R. Nat. Prod. Rep. 2011, 28, 196.
(3) Jin, Z. Nat. Prod. Rep. 2011, 28, 1143.
(4) For a summary of some of our efforts, see:Du, H.; He, Y.;
Sivappa, R.; Lovely, C. J. Synlett 2006, 965.
(5) Koswatta, P. B.; Lovely, C. J. Nat. Prod. Rep. 2011, 28, 511.
(6) Akee, R.; Carroll, T. R.; Yoshida, W. Y.; Scheuer, P. J.; Stout,
T. J.; Clardy, J. J. Org. Chem. 1990, 55, 1944.
(7) Fu, X.; Schmitz, F. J.; Tanner, R. S.; Kelly-Borges, M. J. Nat.
Prod. 1998, 61, 384.
(8) Nakamura, S.; Tsuno, N.; Yamashita, M.; Kawasaki, I.; Ohta, S.;
Ohishi, Y. J. Chem. Soc., Perkin Trans. 1 2001, 429.
(9) Hassan, W.; Edrada, R. A.; Ebel, R.; Wray, V.; Berg, A.; van
Soest, R. W. M.; Wiryowidagdo, S.; Proksch, P. J. Nat. Prod. 2004, 67,
817.
(10) (a) Kawasaki, I.; Taguchi, N.; Yamamoto, T.; Yamashita, M.;
Ohta, S. Tetrahedron Lett. 1995, 36, 8251. (b) Kawasaki, I.; Taguchi, N.;
Yamashita, M.; Ohta, S. Chem. Pharm. Bull. 1997, 45, 1393.
r
10.1021/ol300704w
Published on Web 04/24/2012
2012 American Chemical Society

To date, one synthesis of kealiiquinone (1) has been
described in the literature by Ohta and co-workers10 and
involves the sequential metalation and electrophilic trap-
ping of a 2-thio-substituted imidazole. Subsequent Friedelꢀ
Crafts alkylation and adjustment of the oxidation state
around the oxygenated benzimidazole provides 1. Our
approach to this system involves a different and comple-
mentary strategy centered on de novo quinone assembly and
intramolecular DielsꢀAlder reaction of a 4-vinylimidazole
derivative, chemistry which we have extensively investigated
in our laboratories.11,12
This strategy, which is depicted retrosynthetically in
Figure 2, involves the late-stage introduction of the
C2 imidazole functionality, thereby potentially allowing
access to both 1 and 2 from an advanced and com-
mon intermediate. The precursor imidazonaphthoquinone
would be obtained by an interesting and rarely used
annulation reaction for incorporation of the dihydroxy-
quinone moiety involving a masked glyoxal equivalent.13
The requisite phthalaldehyde precursor 6 would be ob-
tained from lactone 7, which in turn would be constructed
through the DielsꢀAlder oxidation sequence involving the
enyne 8.
DCC-mediated esterification of the 4-vinylimidazole 9 and
the arylpropiolic acid derivative 10 (Scheme 1). The viny-
limidazole can be obtained in three steps from urocanic
acid by methods previously described by us in excellent
yield.11 The enyne undergoes a smooth DielsꢀAlder reac-
tion leading to the formation of the dihydrobenzimidazole
11 in 89% yield. Subjection of the cycloadduct to oxida-
tion by treatment with MnO2 provided the benzimida-
zole 7 in 95% yield.14 Benzimidazole 7 was nicely crystal-
line, and so the structure of the oxidized cycloadduct
was confirmed through an X-ray structure determination
(Scheme 1).
Scheme 1. Assembly of the Benzimidazole Framework and
X-ray Structure of Compound 7
Figure 2. Retrosynthetic analysis of kealiiquinones 1 and 2.
In a forward sense, our synthesis began with the con-
struction of the enyne 8 which was obtained from the
Our choice of the benzyl-protected 4-vinylimidazole was
guided by experience with vinylimidazoles which indicated
that the 4-isomers are better substrates in DielsꢀAlder
reactions, and we have developed a number of efficient
methods for construction of such derivatives.11 As a result,
our approach required an “isomerization” step in order to
properly position the N1-methyl group. It proved quite
convenient to accomplish this tactic with 7. Specifically, it
was found that treatment of 7 with methyl iodide provided
the imidazolium salt 12. Catalytic hydrogenation led to
efficient debenzylation, leaving the methyl group in the
(11) (a) He, Y.; Krishnamoorthy, P.; Lima, H. M.; Chen, Y.; Wu, H.;
Sivappa, R.; Dias, H. V. R.; Lovely, C. J. Org. Biomol. Chem. 2011, 9,
2685. (b) Sivappa, R.; Mukherjee, S.; Lovely, C. J. Org. Biomol. Chem.
2009, 7, 3215. (c) Sivappa, R.; Hernandez, N. M.; He, Y.; Lovely, C. J.
Org. Lett. 2007, 9, 3861. (d) Lovely, C. J.; Du, H.; Sivappa, R.; Bhandari,
M. K.; He, Y.; Dias, H. V. R. J. Org. Chem. 2007, 72, 3741. (e) Lovely,
C. J.; Du, H.; He, Y.; Dias, H. V. R. Org. Lett. 2004, 6, 735. (f) He, Y.;
Chen, Y.; Wu, H.; Lovely, C. J. Org. Lett. 2003, 5, 3623. (g) Lovely, C. J.;
Du, H.; Dias, H. V. R. Heterocycles 2003, 60, 1. (h) Lovely, C. J.; Du, H.;
Dias, H. V. R. Org. Lett. 2001, 3, 1319.
(12) For other reports of the DielsꢀAlder reactions of vinylimida-
zoles, see: (a) Walters, M. A.; Lee, M. D. Tetrahedron Lett. 1994, 35,
8307. (b) Deghati, P. Y. F.; Wanner, M. J.; Koomen, G.-J. Tetrahedron
Lett. 1998, 39, 4561. (c) Poeverlein, C.; Breckle, G.; Lindel, T. Org. Lett.
2006, 8, 819. (d) Cotterill, L. J.; Harrington, R. W.; Clegg, W.; Hall, M. J.
J. Org, Chem. 2010, 75, 4604.
(13) Venuti, M. C. Synthesis 1982, 61.
(14) Fatiadi, A. J. Synthesis 1976, 133.
Org. Lett., Vol. 14, No. 9, 2012
2275

correct position affording 13 (Scheme 2). However, the
presence of aqueous base resulted in variable levels of
Scheme 4. Successful C2-Oxidation and X-ray Crystal Structure
of Compound 20
Scheme 2. Site-Selective Methylation and Oxidation-State
Adjustment
Scheme 3. Installation of Quinone and Attempted Elaboration
of C2
proved to be a more challenging undertaking than antici-
pated. Out of the initial set of common oxidants that
we evaluated, Swern conditions were found to be most
encouraging, but there were some reproducibility issues.
Therefore, we searched for Swern-like oxidations with
improved reliability. In the process of this search, we
came across the use of S-chlorosufinimines reported by
Mukaiyama and co-workers and found this procedure to
be the most reproducible, providing the dialdehyde 6 in
∼70% yield (Scheme 3).15 The phthalaldehyde 6 was then
reacted with the masked glyoxal derivative 16 to arrive at
the 2,3-dihydroxyquinone 17 in moderate but reproducible
yield.13 Treatment of 17 (effectively a vinylogous diacid)
(15) Matsuo, J.-i.; Iida, D.; Tatani, K.; Mukaiyama, T. Bull. Chem.
Soc. Jpn. 2002, 75, 223.
lactone hydrolysis during this reaction; thus, treatment
ofthe reduction product withacid prior topurification was
necessary to reproducibly provide 13 in good yields. The
lactone was then reduced to the corresponding diol 14 on
treatment with DIBAL-H.
With diol 14 in hand, we were in a position to introduce
the final ring, and to accomplish this, the diol required
oxidation to the dialdehyde. However, this transformation
(16) We have used this strategy extensively in various total syntheses;
see, for example: (a) Lima, H. M.; Garcia-Barboza, B. J.; Khatibi, N. N.;
Lovely, C. J. Tetrahedron Lett. 2011, 52, 5725. (b) Koswatta, P.; Lovely,
C. J. Chem. Commun. 2010, 46, 2148. (c) Koswatta, P.; Lovely, C. J.
Tetrahedron Lett. 2010, 51, 164. (d) Koswatta, P. B.; Lovely, C. J.
Tetrahedron Lett. 2009, 50, 4998. (e) Koswatta, P.; Sivappa, R.; Dias,
H. V. R.; Lovely, C. J. Synthesis 2009, 2970. (f) Bhandari, M. R.;
Sivappa, R.; Lovely, C. J. Org. Lett. 2009, 11, 1535. (g) Koswatta, P. B.;
Sivappa, R.; Dias, H. V. R.; Lovely, C. J. Org. Lett. 2008, 10, 5055.
(17) Lima, H. M.; Lovely, C. J. Org. Lett. 2011, 13, 5736.
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Org. Lett., Vol. 14, No. 9, 2012

DIBAL (confirmed by X-ray crystallography), and oxida-
tion to the dialdehyde 21 was performed as above with the
thioimidoylchloride.15 Subsequent treatment ofthe phtha-
laldehyde 21 with the glyoxal derivative 16 and KCN
provided the dihydroxy quinone 2213 which upon treat-
ment with TMS-diazomethane provided 3-benzyl kealii-
quinone 23 (Scheme 5). It is well recognized that the
removal of benzyl groups from amidescan be a challenging
proposition with many of the standard debenzylation
techniques failing to result in cleavage. We also found this
to be the case with imidazolone 23. We subsequently deter-
minedthatthe benzylmoiety could be removed upon treat-
ment with TfOH and heating (55 °C), but this also resulted
in the loss of the methyl group on the p-anisyl moiety.18
A number of attempts have been made to remethylate the
phenolic OH, but these have not been successful due to
either bismethylation or selective N-methylation.
Scheme 5
In summary, we have developed a convenient 10-step
synthesis of a close analogue of the Leucetta-derived
alkaloid kealiiquinone via an intramolecular DielsꢀAlder
reaction from the known vinylimidazole 9. Introduction of
the C2-oxo moiety was accomplished through a novel
hypochlorite-mediated oxidation. Incorporation of the
quinone fragment was accomplished through the use of a
masked glyoxal system. Efforts toimprove the efficiency of
the quinone forming step and to obtain the 2-deoxy-2-
amino congener 2 are underway.
with TMS-diazomethane led to esterification and forma-
tion of the dimethyl derivative 18. We have routinely
functionalized imidazoles and benzimidazoles via lithia-
tion and electrophilic trapping to incorporate either the
2-oxo or 2-amino group. Unfortunately, C2-metala-
tion of 18 with LDA and trapping with an appro-
priate electrophile (e.g., (PhCO2)2 or TsN3) was not
successful.16 Although we do not know the precise fate
of the imidazole-containing species, a brightly colored
and water-soluble material was produced, suggesting
some sort of electron-transfer process. Clearly, in order
to move this project forward we had to overcome this
roadblock. A general solution to functionalizing at the
C2-position of imidazoles has been reported recently
by our laboratory through the use of hypochlorite or
N-chloroamides with imidazolium salts. This leads to
the direct formation of 2-imidazolones and 2-imino-
imidazoles, respectively.17
Acknowledgment. This work was supported by the
Robert A. Welch Foundation (Y-1362) and in part by
the NIH (GM065503). The NSF (CHE-0234811 and
CHE-0840509) is thanked for partial funding of the pur-
chases of the NMR spectrometers used in this work.
Supporting Information Available. Detailed experimen-
tal procedures and copies of 1H and 13C NMR spectra for
all new compounds. X-ray data for compounds 7 and 20
(CIF). This material is available free of charge via the
Internet at http://pubs.acs.org. The authors declare no
competing financial interest.
Specifically, we found that treating a THF solution
of 12 with commercial bleach solutions provided the
2-benzimidazolone 19 in an excellent 75% yield (Scheme
4).17 Lactone reduction to the diol was accomplished with
(18) Rombouts, F.; Franken, D.; Martꢀınez-Lamenca, C.; Braeken, M.;
Zavattaro, C.; Chen, J.; Trabanco, A. A. Tetrahedron Lett. 2010, 51, 4815.
The authors declare no competing financial interest.
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