Formal synthesis of 7-methoxymitosene and synthesis of its analog via a key PtCl2-catalyzed cycloisomerization

Article abstract of DOI:10.1021/ol301593w

A formal synthesis of 7-methoxymitosene is achieved via a key platinum-catalyzed cycloisomerization. The precursor for the Pt catalysis, a fully functionalized benzene intermediate, was prepared via a regioselective electrophilic bromination followed by a

Full text of DOI:10.1021/ol301593w

ORGANIC
LETTERS
2012
Vol. 14, No. 14
3736–3739
Formal Synthesis of 7-Methoxymitosene
and Synthesis of its Analog via a Key
PtCl2-Catalyzed Cycloisomerization
Lianzhu Liu, Yanzhao Wang, and Liming Zhang*
Department of Chemistry and Biochemistry, University of California, Santa Barbara,
California 93106, United States
zhang@chem.ucsb.edu
Received June 8, 2012
ABSTRACT
A formal synthesis of 7-methoxymitosene is achieved via a key platinum-catalyzed cycloisomerization. The precursor for the Pt catalysis, a fully
functionalized benzene intermediate, was prepared via a regioselective electrophilic bromination followed by a chemoselective Sonogashira
cross-coupling. It underwent the PtCl2-catalyzed cycloisomerization smoothly despite its hindered and highly electron-rich nature. Analogs of
7-methoxymitosene can be accessed in an expedient manner by following a similar synthetic sequence.
Mitomycins were isolated originally from Streptomyces
caespitosus in the 1950s1 and later from Streptomyces
verticillatus.2 They are members of a few aziridine-ring-
containing natural products3 and possess potent antibiotic
and antitumor activities (Figure 1). Mitomycin C is cur-
rently in clinical use and cross-links DNA upon in vivo
activation. The more stable aziridinomitosenes, different
from mitomycins by the formal loss of MeOH, possess
activities against tumor cells similar to mitomycin C.4
Among various analogs of these pharmacologically im-
portant mitosenes, 7-methoxymitosene, a compound lack-
ing the aziridine ring of 1, has shown to be effective against
Gram positive bacteria.5 Its total synthesis has been realized
by various creative approaches targeting the tricyclic pyrrolo-
[1,2-a]indole skeleton.6 In this manuscript, we describe a new
(1) (a) Hata, T.; Hoshi, T.; Kanamori, K.; Matsumae, A.; Sano, Y.;
Shima, T.; Sugawara, R. J. Antibiot. 1956, 9, 141–6. (b) Hata, T.;
Sugawara, R. J. Antibiot. 1956, 9, 147–51. (c) Wakaki, S.; Marumo,
H.; Tomioka, K.; Shimizu, G.; Kato, E.; Kamada, H.; Kudo, S.;
Fujimoto, Y. Antibiot. Chemother. 1958, 8, 228–40.
Figure 1. Mitomycins, aziridinomitosenes, and 7-metoxymitosene.
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Zbinovsky, V.; Monnikendam, P.; Adam, J.; Bohonos, N. J. Am. Chem.
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(5) Allen, G. R.; Poletto, J. F.; Weiss, M. J. J. Am. Chem. Soc. 1964,
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(3) Yudin, A. K. Aziridines and Epoxides in Organic Synthesis; Wiley:
Weinheim, Chichester, 2006.
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(b) Hodges, J. C.; Remers, W. A.; Bradner, W. T. J. Med. Chem. 1981,
24, 1184–1191. (c) Coates, R. M.; MacManus, P. A. J. Org. Chem. 1982,
47, 4822–4. (d) Luly, J. R.; Rapoport, H. J. Org. Chem. 1984, 49, 1671–
1672. (e) Asano, O.; Nakatsuka, S.; Goto, T. Heterocycles 1987, 26,
1207–10. (f) Wender, P. A.; Cooper, C. B. Tetrahedron Lett. 1987, 28,
6125–8. (g) Murphy, W. S.; O’Sullivan, P. J. Tetrahedron Lett. 1992, 33,
531–4. (h) Hirano, S.; Akai, R.; Shinoda, Y.; Nakatsuka, S.-i. Hetero-
cycles 1995, 41, 255–8.
(4) (a) Orlemans, E. O. M.; Verboom, W.; Scheltinga, M. W.;
Reinhoudt, D. N.; Lelieveld, P.; Fiebig, H. H.; Winterhalter, B. R.;
Double, J. A.; Bibby, M. C. J. Med. Chem. 1989, 32, 1612–20. (b)
Iyengar, B. S.; Remers, W. A.; Bradner, W. T. J. Med. Chem. 1986, 29,
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1991, 34, 1947–51. (d) Li, V.-S.; Choi, D.; Tang, M.-s.; Kohn, H. J. Am.
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r
10.1021/ol301593w
Published on Web 07/05/2012
2012 American Chemical Society

synthetic approach to this compound, where its tricyclic core
is constructed via a key PtCl2-catalyzed cycloisomerization
reaction; in addition, a designed structural analog, which
might possess interesting biological activities, is easily pre-
pared by following a similar synthetic route.
Scheme 2. Retrosynthetic Analysis of 7-Methoxymitosene
A few years ago we reported a platinum-catalyzed for-
mation of cyclic ketone-fused indoles from N-(2-alkynyl-
phenyl)lactams.7 For example, when the β-lactam 2 was the
substrate, the dihydropyrrolo[1,2-a]indolone 30 was formed as
the major product (Scheme 1). Mechanistically, the reaction
likely begins with an initial Pt-promoted cyclization of the
β-lactam nitrogen onto the CꢀC triple bond and then under-
goes heterolytic fragmentation of the amide bond; the acylium
intermediate A thus formed then cyclizes to either the 7- or
2-position of the indole moiety. In the case of the former, it
leads to the minor tricyclic product 3; in the case of the latter, a
Pt carbene is formed, which would promote a 1,2-alkyl
migration, eventually yielding 30. This rapid access to the
pyrrolo[1,2-a]indole skeleton provides us with an oppor-
tunity to study the synthesis of mitosenes and in parti-
cular 7-methoxymitosene, while testing the Pt catalysis
under more demanding scenarios.
Scheme 3. Preparation of the Precursor for Pt Catalysis
Scheme 1. Example of Pt-Catalyzed Formation of Pyrrolo[1,2-
a]indolones
Scheme 2 shows the retrosynthetic analysis of 7-methoxy-
mitosene. This mitosene could be accessed through oxida-
tion and other manipulations of dihydropyrrolo[1,2-a]indo-
lone 4, the precursor of which would be the fully substituted
benzene 5based on our Pt chemistry. The side product of type
3 should be avoided due to substitution at the 7-position of
the nascent indole ring. Elaboration of dihalogenated ben-
zene 6 to the sterically congested 5 would rely on regio- or
chemoselective sequential coupling reactions.
At the onset, 2,3,6-trimethoxytoluene (i.e., 7) was pre-
pared in an excellent yield from commercially available
1,2,4-trimethoxybenzene by following a known procedure
(Scheme 3).8 Treatment of 7 with excess Br2 results in
efficient double bromination, yielding dibromobenzene 9.
Attempts to achieve regioselective mono-cross-coupling of
9 with the parent β-lactam (i.e., 2-azetidinone) surprisingly
led to the double coupling product 10, and neither mono-
coupling product was observed at all even with azetidinone
as the limiting reagent, suggesting that the second coupling
was much faster than the first one. Alternatively, a mono-
Sonogashira reaction with 9 was not successful. To achieve
regiocontrol in the desired double couplings, we decided to
install two different halogens onto 7. Fortuitously, the tar-
geted ortho-bromoaryl iodide 11 could be prepared easily via
sequential bromination and iodination. Of note, the initial
(7) Li, G.; Huang, X.; Zhang, L. Angew. Chem., Int. Ed. 2008, 47,
346–349.
(8) Carreno, M. C.; Garcia, R. J. L.; Toledo, M. A.; Urbano, A.
Tetrahedron: Asymmetry 1997, 8, 913–921.
Org. Lett., Vol. 14, No. 14, 2012
3737

bromination was highly regioselective and efficient, yielding
the monobromide 8 in 96% yield. A subsequent chemoselec-
tive Sonogashira reaction of 11 followed by a Cu-catalyzed
CꢀN bond formation9 was delightfully uneventful, providing
the propargyl alocohol 13, the precursor for the key platinum
catalysis, in a combined 71% yield.
Treatment of the propargyl alcohol 13, however, led to a
messy reaction, and no desired product was detected (Scheme
4). We speculated that the free HO group might be the culprit;
consequently, it was capped by a benzyl group. Treatment of
the resulting benzyl ether 15 with PtCl2 (5 mol %) under an
oxygen atmosphere still did not afford the desired product;
however, to our delight, the anticipated pyrrolo[1,2-a]indole
skeleton was formed, as the tricyclic ketone 16 was isolated in
a 41% yield. Notably, 16 has no substitution at its indole
3-position. The apparent loss of the benzyloxymethyl group
during the reaction is rationalized in the same scheme.
Apparently, the platinum carbene 17 undergoes CꢀC bond
fragmentation preferentially over the desired Wagnerꢀ
Meerwein-type rearrangement.
Knowing that the platinum catalysis could work with
hindered substrates like 15, we chose to avoid the problematic
alkyl migration process and install the substituent at the indole
3-position at a later stage. The successful execution of this
approach is detailed in Scheme 5. Starting from dihalide 11,the
desired arylacetylene 21 was prepared via similar sequential
regiocontrolled cross-couplings and then a routine desilyla-
tion. The platinum catalysis, to our delight, occurred
smoothly, converting 21 into the dihydropyrrolo[1,2-a]-
indolone 16 in 87% yield. With the core structure set, the
penultimate structure, hydroxyquinone 24 was accessed via
the following sequence: first, a WolffꢀKishner reductive
deoxygenation, then a VilsmeierꢀHaack reaction to install
the formyl group, which was followed by an oxidation of the
p-dimethoxybenzene into a p-benzoquinone by nitrous acid,
and finally a reduction of the aldehyde and reoxidation of the
hydroquinone back to the desired quinone structure. Since the
conversion of 24 to 7-methoxymitosene has been achieved
previously,6c,f the synthesis of 24 constitutes a formal synthesis
of the mitosene.
Scheme 4. Initial Studies with PtCl2-Catalyzed Cycloisomerization:
Access to the Pyrroloindole Skeleton
Although the hydroxymethyl group in 24 could not be
secured directly via the Pt catalysis, other R groups might be
possible. This approach (i.e., from 5 to 4, R ¼ H, Scheme 2)
would offer a succinct preparative route to various mitosene
analogs with potential biological activities. To demonstrate
feasibility, we targeted the bisacetate 29 (Scheme 6). Its
1-acetoxy group can act as a leaving group en route to
generate a reactive alkylating moiety in a manner similar to
the case of the aziridine ring in aziridinomitosene,10 and its
9-acetoxyethyl group, though suspect in mimicking11 the car-
bamoyloxymethyl moiety in aziridinomitosenes/mitomycins
in the formation of the second alkylating site,12 can demon-
strate the feasibility of direct installation of functional groups
at the 9-position via the Pt catalysis. As shown in Scheme 6,
the synthesis of this designed structure commenced with the
Scheme 5. Synthesis of 7-Methoxymitosene
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Org. Lett., Vol. 14, No. 14, 2012

Scheme 6. Succinct Synthesis of an 1-Acetoxy-7-methoxymitosene Analog
same sequential chemoselective cross-coupling reactions as
In conclusion, we have successfully applied the platinum-
those in Scheme 5, but but-3-yn-1-yl benzyl ether was used as
the alkyne. Much to our delight, the platinum catalysis pro-
ceeded with excellent efficiency, delivering the dihydropyr-
rolo[1,2-a]indolone 27 with a 2-benzyloxyethyl substituted at
its 9-position in 89% yield. Sequential one-pot hydrogenative
debenzylation, ketone reduction, and double acetylation
readily converted 27 into bisacetate 28 in 67% overall yield,
which in turn was oxidized to the targeted molecule in 68%
yield. This short sequence constitutes a five-pot, seven-step
synthesis of the mitosene analog from the dihalide 11 in 27%
overall yield. Its biological activities will soon be studied.
catalyzed cycloisomerization, previously developed in
our laboratory, as a key step in a formal synthesis of
7-methoxymitosene. The reaction precursor, a fully func-
tionalized benzene intermediate, is prepared in a succinct
manner featuring two highly selective events: a regiose-
lective electrophilic bromination and a chemoselective
Sonogashira cross-coupling. The Pt catalysis proceeds
smoothly despite the hindered and highly electron-rich
nature of the substrate. An analog of 7-methoxymitosene
is prepared in an expedient manner by following a similar
synthetic sequence.
(9) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 7421–7428.
(10) Remers, W. A.; Schepman, C. S. J. Med. Chem. 1974, 17, 729–
732.
Acknowledgment. General financial support from
NIGMS (R01 GM084254) is greatly appreciated.
(11) Though we envisioned that a spirocyclopropane intermediate
substituted with an iminium moiety could be formed via the expulsion of
the acetoxy group by the indole ring, the related structures substituted
with an imine moiety were previously shown not to be susceptible toward
ring opening. For references, see: (a) Bajtos, B.; Pagenkopf, B. L. Eur. J.
Org. Chem. 2009, 1072–1077. (b) Brak, K.; Ellman, J. A. Org. Lett. 2010,
12, 2004–2007.
Supporting Information Available. Experimental pro-
cedures, NMR spectra, and compound characterization.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(12) Kraus, G. A.; Malpert, J. H. Synlett 1997, 1, 107–108.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 14, 2012
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