activating enzyme E1.7 The conversion 5 f 6 proceeds
readily at room temperature through an unusual exo-[4 + 2]
Diels-Alder cycloaddition reaction that is followed by a
lactol-forming process within the initial cycloadduct.6 The
related epoxyquinol monomer 7 has been synthesized
recently and shown to undergo an analogous dimerization
process to give prehexacyclinol (8).8 In the absence of the
lactol-forming pathway, this last compound engages in an
acid-catalyzed intramolecular SN′ reaction to give (+)-
hexacyclinol (9), an antiproliferative agent originally isolated
from the fungal strain Panus rudis HK1 0254 by Gra¨fe and
co-workers.9,10 Since compound 9 also displays moderate
inhibitory activity against Plasmodium falciparum (IC50 2.49
µg/mL)9 it may serve as a lead for the development of new
antimalarial agents.
the relevant cross-coupling partner.17 The required haloxone
derivative is often generated from benzoquinone or protected
forms thereof18 while enzymatically mediated desymmetrization
or resolution processes19 have been used to obtain the required
substrates in enantiomerically pure form. As a consequence,
somewhat lengthy reaction sequences can be involved. Ac-
cordingly, we now report on the facile and chemoenzymatic
generation of several versatile epoxyquinol synthons from the
cis-1,2-dihydrocatechols 10-12, compounds that are readily
obtained in large quantity and enantiomerically pure form via
the enzymatic dihydroxylation of the corresponding haloben-
zene.20 The value of these synthons is highlighted through their
application to abbreviated total syntheses of (-)-bromoxone
(ent-1), (+)-epiepoformin (ent-2), (-)-harveynone (4), (+)-
panepophenanthrin (6), and (+)-hexacyclinol (9).
The key steps associated with the generation of the
epoxyquinol synthons from the starting materials 10-12 are
shown in Scheme 1. Thus, treatment of each of these
halodienes with N-bromosuccinimide and water in THF at
The densely functionalized cyclohexene frameworks as-
sociated with the epoxyquinol natural products together with
their diverse range of biological properties has prompted a
great deal of effort to establish economical syntheses.1,11-16
Much of this effort has relied upon the acquisition of protected
forms of bromoxone or its iodo analogue which are then
subjected to Heck, Sonogashira, Suzuki, or Stille reactions with
Scheme 1
(5) Nagata, T.; Ando, Y.; Hirota, A. Biosci. Biotechnol. Biochem. 1992,
56, 810.
(6) (a) Moses, J. E.; Comme´iras, L.; Baldwin, J. E.; Adlington, R. M.
Org. Lett. 2003, 5, 2987. (b) Lei, X.; Johnson, R. P.; Porco, J. A., Jr. Angew.
Chem. Int. Ed. 2003, 42, 3913. (c) Comme´iras, L.; Moses, J. E.; Adlington,
R. M.; Baldwin, J. E.; Cowley, A. R.; Baker, C. M.; Albrecht, B.; Grant,
G. H. Tetrahedron 2006, 62, 9892.
(7) Sekizawa, R.; Ikeno, S.; Nakamura, H.; Naganawa, H.; Matsui, S.;
Iinuma, H.; Takeuchi, T. J. Nat. Prod. 2002, 65, 1491.
(8) Porco, J. A., Jr.; Su, S.; Lei, X.; Bardhan, S.; Rychnovsky, S. D.
Angew. Chem., Int. Ed. 2006, 45, 5790.
(9) Schlegel, B.; Ha¨rtl, A.; Dahse, H.-M.; Gollmick, F. A.; Gra¨fe, U.;
Do¨rfelt, H.; Kappes, B. J. Antibiot. 2002, 55, 814
.
(10) The structure of (+)-hexacyclinol was originally misassigned and
then corrected using 13C chemical shift data predictions: Rychnovsky, S. D.
Org. Lett. 2006, 8, 2895
.
(11) Syntheses of bromoxone: (a) Gautier, E. C. L.; Lewis, N. J.;
McKillop, A.; Taylor, R. J. K. Tetrahedron Lett. 1994, 35, 8759 [(()-1].
(b) Johnson, C. R.; Miller, M. W. J. Org. Chem. 1995, 60, 6674 [(+)- and
(-)-1]. (c) Block, O.; Klein, G.; Altenbach, H.-J.; Brauer, D. J. J. Org.
Chem. 2000, 65, 716 [(+)-1]. (d) Tachihara, T.; Kitahara, T. Tetrahedron
2003, 59, 1773 [(+)-1]. (e) Barros, M. T.; Matias, P. M.; Maycock, C. D.;
Ventura, M. R. Org. Lett. 2003, 5, 4321 [(+)-1].
(12) Syntheses of epiepoformin: (a) Kamikubo, T.; Ogasawara, K.
Tetrahedron Lett. 1995, 36, 1685 [(+)-2]. (b) Barros, M. T.; Maycock, C. D.;
Ventura, M. R. Chem.sEur. J. 2000, 6, 3991 [(+)-2]. (c) Shimizu, H.;
Okamura, H.; Yamashita, N.; Iwagawa, T.; Nakatani, M. Tetrahedron Lett.
2001, 42, 8649 [(+)-2]. (d) See ref 11d [(+)-2]. (e) Carren˜o, M. C.; Merino,
´
E.; Ribagorda, M.; Somoza, A.; Urbano, A. Chem.sEur. J. 2007, 13, 1064
[(+)-2].
(13) Syntheses of epiepoxydon: (a) Ichihara, A.; Kimura, R.; Oda, K.;
Sakamura, S. Tetrahedron Lett. 1976, 17, 4741 [(()-3]. (b) Kamikubo, T.;
Hiroya, K.; Ogasawara, K. Tetrahedron Lett. 1996, 37, 499 [(+)-3]. (c)
See ref 11d [(+)-3]. (d) Mehta, G.; Islam, K. Tetrahedron Lett. 2004, 45,
7683 [(+)-3].
(14) Syntheses of harveynone: (a) Graham, A. E.; McKerrecher, D.;
Davies, D. H.; Taylor, R. J. K. Tetrahedron Lett. 1996, 37, 7445 [(()-4].
(b) Miller, M. W.; Johnson, C. R. J. Org. Chem. 1997, 62, 1582 [(+)- and
(-)-4]. (c) Kamikubo, T.; Ogasawara, K. Heterocycles 1998, 47, 69 [(+)-
and (-)-4]. (d) See ref 12b [(+)-4]. (e) Li, J.; Park, S.; Miller, R. L.; Lee,
D. Org. Lett. 2009, 11, 571 [(-)-4].
(15) Syntheses of panepophenanthrin: (a) See ref 6a and 6c [(()-6 and
(+)-6, respectively. (b) See ref 6b [(+)-6]. (c) Mehta, G.; Ramesh, S. S.
Tetrahedron Lett. 2004, 45, 1985 [(+)-6]. (d) See ref 13d [(-)-6]. (e)
Matsuzawa, M.; Kakeya, H.; Yamaguchi, J.; Shoji, M.; Onose, R.; Osada,
H.; Hayashi, Y. Chem. Asian J. 2006, 1, 845 [(+)-6].
(16) Syntheses of hexacyclinol: (a) See ref 8 [(+)-9]. (b) Mehta, G.;
Roy, S. Tetrahedron Lett. 2008, 49, 1458 [ (+)-9].
(17) See refs 12b, 14a,b, 15a,b,e, and 16a,b for examples of the use of
these types of cross-coupling processes.
(18) See refs 11a-c, 12a,e, 13b,d, 14a,b, 15c and 16b for examples of
this type of approach.
(19) See refs 11b-d, 12a, 13b,d, 14b, 15a,c, and 16b for examples of
this type of approach.
(20) Compounds 10-12 can be obtained from Questor, Queen’s
University of Belfast, Northern Ireland. Questor Centre Contact Page: http://
questor.qub.ac.uk/newsite/contact.htm (accessed July 21, 2009). For reviews
on methods for generating cis-1,2-dihydrocatechols by microbial dihy-
droxylation of the corresponding aromatics, as well as the synthetic
applications of these metabolites, see: (a) Hudlicky, T.; Gonzalez, D.;
Gibson, D. T. Aldrichim. Acta 1999, 32, 35. (b) Banwell, M. G.; Edwards,
A. J.; Harfoot, G. J.; Jolliffe, K. A.; McLeod, M. D.; McRae, K. J.; Stewart,
S. G.; Vo¨gtle, M. Pure Appl. Chem. 2003, 75, 223. (c) Johnson, R. A. Org.
React. 2004, 63, 117. (d) Hudlicky, T.; Reed, J. W. Synlett 2009, 685.
Org. Lett., Vol. 11, No. 19, 2009
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