Cascade assembly of the benz[a]anthraquinone ring system common to the angucycline antibiotics

Article abstract of DOI:10.1016/j.tetlet.2011.12.126

A benz[a]anthraquinone ring system, common to a group of angucycline antibiotics, has been prepared by a unique cascade of reactions. The reaction sequence was initiated by a Suzuki-Miyaura cross-coupling between a bromoquinone and vinyl boronic anhydride

Full text of DOI:10.1016/j.tetlet.2011.12.126

Tetrahedron Letters 53 (2012) 1345–1346
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Cascade assembly of the benz[a]anthraquinone ring system common
to the angucycline antibiotics
⇑
Aleksandra Baranczak, Gary A. Sulikowski
Department of Chemistry, Institute of Chemical Biology, Vanderbilt University, Nashville, TN 77842-3012, USA
Department of Biochemistry, Institute of Chemical Biology, Vanderbilt University, Nashville, TN 77842-3012, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A benz[a]anthraquinone ring system, common to a group of angucycline antibiotics, has been prepared
by a unique cascade of reactions. The reaction sequence was initiated by a Suzuki–Miyaura cross-
coupling between a bromoquinone and vinyl boronic anhydride. The reaction product is proposed to
Received 9 December 2011
Revised 19 December 2011
Accepted 30 December 2011
Available online 12 January 2012
undergo a 6
p-electron cyclization triggered by reductive activation of the quinone. The reaction process
is proposed to be autocatalytic.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Cascade reaction
Quinone
Electrocyclization
Suzuki–Miyaura coupling
Reductive activation
The structural feature common to the angucycline antibiotics is
a benz[a]anthraquinone aglycone that varies in oxidation state
within the AB ring sub-structure (Fig. 1).1 Since the identification
of tetrangangomycin in 1965 a large number of angucycline
metabolites have been identified with associated biological activity
ranging from antitumor to antifungal. These discoveries have stim-
ulated interest in the total synthesis of this sub-class of aromatic
polyketide natural products.2 The Diels–Alder and Hauser type
annulations have figured prominently among synthetic strategies
leading to the chemical synthesis of a variety of angucyclinones.
Moore3a–c and others3d–f have employed a cascade of pericyclic
reactions starting from benzocyclobutenes to construct the central
quinone (C ring) in order to complete benzoanthraquinone ring
assembly (1z2, Scheme 1). In the course of studies on aromatic
polyketides unrelated to the angucyclines we have uncovered a
new route to access the angucyline ring system by apparent rear-
rangement of vinyl quinone 4 to construct the corner B ring. The
synthesis of quinone 4 required access to uniquely functionalized
protected hydroquinone 3. Herein, we detail the results of this ser-
endipitous discovery and a brief discussion of mechanistic implica-
tions of the key rearrangement.
as a phase-transfer reagent.5 At this point we required a bromo-
tin exchange resulting in desymmetrization of dibromide 7. The re-
quired metalation relied upon an initial lithium-halogen exchange
HO
O
O
O
O
C
O
A
OH
D
B
OH
O
OH
O
OH
O
ochromycinone
tetrangulol
tetrangomycin
Figure 1. Select angucycline antibiotics.
O
A
O
C
B
D
ref 3
OR
O
1
2
O
Our synthetic studies started from dibromonaphthazarin 6 pre-
pared by the Brazzard annulation reaction (Scheme 2).4 Reduction
of quinone 6 to the corresponding dihydroquinone was followed
by immediate phenol protection with MOMCl using Adogen 464
O
OP
C
O
O
C
A
M
X
B
D
OP
3
O
5
O
4
⇑
Corresponding author.
E-mail address: gary.a.sulikowski@vanderbilt.edu (G.A. Sulikowski).
Scheme 1. Pericyclic reactions leading to benz[a]anthraquinone core.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.126

1346
A. Baranczak, G. A. Sulikowski / Tetrahedron Letters 53 (2012) 1345–1346
OMe O
OMe OMOM
Br
O
O
O
OMe O
O
O
O
O
Br
Br
1) Na2S2O4
+1e-
-1e-
+1e-
-1e-
2) MOMCl, i-Pr2NEt
55%
Br
OMe OMOM
OMe O
OMe O
6
7
18c
18b
18a
O
OMe OMOM
O
8 X = SnMe3; Y = Br
9 X = Y = SnMe3
10 X = Y = H
OMe OH
OMe O
n-BuLi-TMEDA
X
-2H+
-2e-
-1e- (18b)
-2e- (18c)
then Me3SnCl
-78 to 25 °C
80-85%
16
Y
11 X = Br;Y = H
OMe OMOM
OMe OH
OMe O
20
19
Scheme 2. Desymmetrization of dibromonaphthazarin.
Scheme 4. Proposed reaction pathway from 18 to 16.
either semiquinone 18b or two-electron reduction product 18c.9
Interestingly, many quinone containing natural products including
mitomycin, dynemycin, and anthracyclines utilize quinone reduc-
tive activation to trigger chemical transformations leading to reac-
tive intermediates poised to modify biomolecules such as DNA.10
When accompanied by subsequent oxidation rearrangement of
18b/18c leads to dihydroquinone 20 by way of quinone 19. Finally,
oxidation of 20 would account for the observed production of
angular quinone 16. The final oxidation of 20 could be achieved
by conversion of quinone 18a to dihydroquinone 18c. Overall,
the proposed reaction pathway shown in Scheme 4 is reductive
rendering the process autocatalytic.11
In conclusion, we have discovered a new synthetic route to ac-
cess the core tetracyclic structure common to members of the
angucycline group of antibiotics. Interestingly, this transformation
may take advantage of quinone reduction as a means of reaction
acceleration, and when combined with a final oxidation step con-
stitutes an autocatalytic process.
that under standard conditions provided a mixture of distannane 9
and proton quenched products 10 and 11. A solution to this unde-
sired reaction outcome was found in a publication by Yoshida and
co-workers6a who studied the mono lithium-halogen using 1,2-
dibromobenzene.6 Yoshida’s studies indicated a rapid quench with
stannyl chloride was critical to the success of the reaction. Indeed,
when addition of n-butyllithium to dibromide 7 was followed by
the addition of trimethylstannyl chloride after 50 s we were grati-
fied to isolate bromostannane 8 in a reproducible 80–85% yield.
Stille cross-coupling of bromostannane 8 with 2-iodocyclohex-
enone proceeded smoothly using reaction conditions reported by
Porco in his synthesis of (À)-kinamycin C (Scheme 3).7 Oxidation
of MOM protected dihydroquinone 13 with CAN in acetonitrile
led to bromoquinone 14 now activated to engage in a Suzuki–
Miyaura cross-coupling. In the event reaction of 14 with vinyl
boronic anhydride did not lead to the expected vinyl quinone but
unexpectedly angular quinone 16 (29%). When the coupling was
carried out with vinyl boronate 15 quinone 17 was produced in a
48% yield.
The cross-coupling of 14 with vinyl boronic anhydride likely
delivers vinyl quinone 18a, less clear is the pathway by which
18a proceeds to the observed product quinone 16. The most direct
Acknowledgments
This research was supported by the National Institutes of
Health (CA 059515) and the Vanderbilt Institute of Chemical Biol-
ogy. We also acknowledge Dr. Weidong Zhang for early studies on
the conversion of dibromide 7 to arylstannane 8.
pathway proceeds by the way of a 6p-electrocyclic ring closure to
19 followed by isomerization to hydroquinone 20 followed by oxi-
dation to 16. However, the pericyclic rearrangement of 18a–19
would likely be a high-energy transformation requiring a reaction
temperature significantly higher than observed.8 An alternate
explanation would be anion-accelerated process by the way of
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.12.126.
OMe OMOM
O
SnMe3
Pd2(DBA)3
I
References and notes
Ph3As, CuCl
MeCN, 70 °C
Br
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2. Carreno, M.; Urbano, A. Synlett 2005, 1–25.
OMe OMOM
92%
12
3. (a) Heileman, M.; Tiedemann, R.; Moore, H. J. Am. Chem. Soc. 1998, 120, 3801–
3802; (b) Tiedemann, R.; Heileman, M.; Moore, H.; Schaumann, E. J. Org. Chem.
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Suzuki, T.; Hamura, T.; Suzuki, K. Angew. Chem., Int. Ed. 2008, 47, 2248–2252; (f)
Mori, K.; Tanaka, Y.; Ohmori, K.; Suzuki, K. Chem. Lett. 2008, 37, 470–471.
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Am. Chem. Soc. 2007, 129, 3046–3048; (b) Saito, M.; Nitta, M.; Yoshioka, M.
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8
OMe OR
OMe O
CAN
MeCN
90%
O
O
Br
Br
OMe OMOM
OMe O
14
13 R = MOM
O
OMe O
PinB
OTBS
7. Lei, X.; Porco, J. A. J. Am. Chem. Soc. 2006, 128, 14790–14791.
8. (a) Faragher, R.; Gilchrist, T.; Southon, I. Tetrahedron Lett. 1979, 4113–4116; (b)
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Fleming, I., Paquette, L. A., Eds.; Pergamon Press: New York, 1991; Vol. 5, pp
699–750.
15
or
BO
R
3
OMe O
Pd(OAc)2, Ph3P, A g 2CO3
THF (aq), 75 °C
16 R = H, 29%
17 R = CH2OTBS, 48%
10. Wolkenberg, S.; Boger, D. Chem. Rev. 2002, 102, 2477–2495.
11. Pererson, D.; Fisher, J. Biochemistry 1986, 25, 4077–4084.
Scheme 3. Preparation of benz[a]anthraquinone.