Synthetic studies directed toward dideoxy lomaiviticinone lead to unexpected 1,2-oxazepine and isoxazole formation

Article abstract of DOI:10.1021/ol203390w

In the course of studies directed toward the synthesis of dideoxy lomaiviticinone, 3-(nitromethyl)cyclohexenones 2a (X = H) and 2b (X = I) were prepared. The corresponding enolates were reacted with naphthazarin (1) and unexpectedly afforded 1,2-oxazepine

Full text of DOI:10.1021/ol203390w

ORGANIC
LETTERS
2012
Vol. 14, No. 4
1027–1029
Synthetic Studies Directed toward
Dideoxy Lomaiviticinone Lead to
Unexpected 1,2-Oxazepine and Isoxazole
Formation
Aleksandra Baranczak and Gary A. Sulikowski*
Departments of Chemistry and Biochemistry, Vanderbilt University, Vanderbilt Institute
of Chemical Biology, Nashville, Tennessee 37235, United States
gary.a.sulikowski@vanderbilt.edu
Received December 19, 2011
ABSTRACT
In the course of studies directed toward the synthesis of dideoxy lomaiviticinone, 3-(nitromethyl)cyclohexenones 2a (X = H) and 2b (X = I) were
prepared. The corresponding enolates were reacted with naphthazarin (1) and unexpectedly afforded 1,2-oxazepine 3 and isoxazole 4,
respectively. Rationale for their formation is proposed.
The diazofluorene antitumor antibiotics lomaiviticins
A and B1 have attracted considerable attention from the
synthetic community due to their molecular complexity,
potent cell cytotoxicity, and scarcity in nature.2,3 Lomai-
viticinone, the aglycone common to lomaiviticin A and B,
was recently prepared by an 11-step synthesis reported
by Herzon and co-workers.4 As expected lomaivitici-
none prepared by this route was isolated as a rigid
polycyclic ring system formed by closure of the C3/C30
tertiary alcohols onto the neighboring C1/C10 keto groups
(Figure 1). In anticipation of DNA cleavage studies, and
simplified synthetic obstacles, we considered it advanta-
geous to access C3/C30 dideoxy lomaiviticinone, an agly-
cone with free rotation about the C2ꢀC20 carbonꢀcarbon
bond as found in lomaiviticin A, the more abundant and
studied of the two dimeric diazofluorene natural products.
(1) He, H.; Ding, W.; Bernan, V.; Richardson, A.; Ireland, C.;
Greenstein, M.; Ellestad, G.; Carter, G. J. Am. Chem. Soc. 2001, 123,
5362–5363.
(2) For a comprehensive review of the lomaiviticins and kinamycins,
see: Herzon, S. B.; Woo, C. M. Nat. Prod. Rep. 2012, 29, 87–118.
(3) Synthetic studies: (a) Nicolaou, K. C.; Denton, R. M.; Lenzen,
A.; Edmonds, D. J.; Li, A.; Milburn, R. R.; Harrison, S. T. Angew.
Chem., Int. Ed. 2006, 45, 2076–2081. (b) Krygowski, E. S.; Murphy-
Benenato, K.; Shair, M. D. Angew. Chem., Int. Ed. 2008, 47, 1680–1684.
(c) Zhang, W.; Baranczak, A.; Sulikowski, G. A. Org. Lett. 2008, 10,
1939–1941. (d) Nicolaou, K. C.; Nold, A. L.; Li, H. Angew. Chem., Int.
Ed. 2009, 48, 5860–5863. (e) Gholap, S. L.; Woo, C. M.; Ravikumar,
P. C.; Herzon, S. B. Org. Lett. 2009, 11, 4322–4325. (f) Lee, H. G.; Ahn,
J. Y.; Lee, A. S.; Shair, M. D. Chem.;Eur. J. 2010, 16, 13058–13062. (g)
Morris, W. J.; Shair, M. D. Org. Lett. 2008, 11, 9–12. (h) Morris, W. J.;
Shair, M. D. Tetrahedron Lett. 2010, 51, 4310–4312.
Figure 1. Structure of lomaiviticin A, lomaiviticinone, and dide-
oxy lomaiviticinone.
In 2008 we reported on the synthesis of the C2-
symmetric core of dideoxy lomaiviticinone (3) starting
from (ꢀ)-quinic acid.3c We planned to advance bis-enone
3 to dideoxy lomaiviticinone starting with conversion of
3 to nitromethylcyclohexenone 2 (X = H or halogen),
(4) (a) Herzon, S. B.; Lu, L.; Woo, C. M.; Gholap, S. L. J. Am. Chem.
Soc. 2011, 133, 7260–7263. (b) Herzon, S. B. Synlett 2011, 2105–2114.
r
10.1021/ol203390w
2012 American Chemical Society
Published on Web 02/06/2012

with the nitro group serving the purposes of methylene
activation and as a progenitor to the central diazo group
(Figure 2). Given the symmetry of quinone 1, annulation
between 1 and nitro activated cyclohexenone 2 could proceed
by one of two orders of bond formation (a versus b).
Herein we describe model studies in anticipation of Michael
addition of 2 to quinone 1 (bond b). Our investigations
started from cyclohexenone led us to discover novel oxida-
tive nitronate mediated [5 þ 2] and [3 þ 2] quinone
annulations.
Scheme 2. Base-Catalyzed Oxidative Addition of Nitrocyclo-
hexenone 6 to Quinone 1
The Michael oxidative addition of enolates to quinones
is oftentimes complicated by secondary reactions and
electron transfer mediated processes.9 Nonetheless, we
chose to explore the addition of the conjugate base of
3-(nitromethyl)cyclohexenone (6) to naphthazarin 110 un-
der oxidative conditions aimed to deliver adduct 9. After
screening a large number of reaction conditions including
varying pH and base we eventually isolated an adduct of
enone 6 and quinone 1 which, surprisingly, proved not to
be 9 but instead [5 þ 2] adduct 1,2-oxazepine 8, albeit
isolated in only 14% yield (Scheme 2). The structural
assignment of 8 was based on extensive NMR and high-
resolution mass spectral analysis. Presented in Scheme 3 is
a tentative mechanism for the formation of 8 starting with
the addition of 10 to quinone 1. Tautomerization accom-
panied by proton transfer results in conversion of 11 to
hydroquinone 12, poised for quinone methide formation
(13). Loss of a molecule of water then leads to nitroso 14,
equivalent to oxime anion 15 by electron delocalization.
Finally, cyclization followed by terminal oxidation ac-
counts for production of 1,2-oxazepine 8.
Figure 2. Synthetic strategy leading to dideoxy lomaiviticinone
by way of quinone annulation.
Our studies began with an efficient two-step conver-
sion of 2-cyclohexenone (4) to 3-(nitromethyl)cyclohexen-
one starting with the addition of the conjugate base of
(phenylthio)nitromethane to 4 (Scheme 1).5,6 The resulting
Michael adduct (5) was then oxidized with m-CPBA to the
corresponding sulfoxides and immediately heated in re-
fluxing benzene to provide 2-(nitromethyl)cyclohexenone
6. The R-carbon of enone 6 was then iodinated7 in antici-
pation of an intramolecular Heck reaction (bond a
formation) following formation of bond b (Figure 2).
Surprisingly, this proved to be the first example of using
(phenylthio)nitromethane to introduce a nitromethyl
group at the β-position of an enone. Historically,
(phenylthio)nitromethane has been used primarily in
carbonyl additions, alkylations, dipole additions, and
ring expansion reactions.6a,8
Scheme 3. Proposed Base-Catalyzed Oxidative Addition of 6 to
Quinone 1 Leading to 8
Scheme 1. Preparation 3-(Nitromethyl)cyclohexenones 6 and 7
(5) (a) Barrett, A.; Graboski, G.; Russell, M. J. Org. Chem. 1985, 50,
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C. B. W.; Wovkulich, P. M.; Uskokovic, M. R. Tetrahedron Lett. 1992,
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Scheme 4. Base Catalyzed Oxidative Addition of
Nitrocyclohexenone 7 to Quinone 1
Scheme 5. Proposed Base-Catalyzed Oxidative Addition of 7 to
Quinone 1 Leading to 16
Examination of the reaction pathway leading to unde-
sired quinone 8 (Scheme 3) suggested the desired carbonꢀ
carbon bond formation (bond b, Scheme 1) could be
directed by blocking the R-carbon of dienolate 10 by a
halogen atom (cf. 7, Scheme 5). In this case we anticipated
base-catalyzed addition of 7 to naphthazarin 1 under
oxidative conditions would afford adduct 19 appropriately
functionalized for an intramolecular Heck reaction as
demonstrated by Herzon’s group.4 In the event, our
plan was once again thwarted leading to a 46% yield
of isoxazole quinone 18 without 19 being observed
(Scheme 4). In this case the desired carbonꢀcarbon bond
formation (20 þ 1f21) was followed by undesired reor-
ganization of oxidation state (22f24) followed by oxida-
tive cyclization (24f18) (Scheme 5).
incompatibility is reduction of the nitro group to a pro-
tected amine. This possibility and other approaches to
dideoxylomaiviticinoneareunderinvestigationand will be
reported in due course.
Our failure to effect base-promoted annulation between
either cyclohexenone 6 or 7 and quinone 1 can be ascribed
to the incompatibility of the nitronate and hydroquinone
conjugated systems 12 and 21. A potential solution to this
Acknowledgment. This work was supported by the Na-
tional Institutes of Health (CA 059515).
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all 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.
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