An approach to aminonaphthoquinone ansamycins using a modified Danishefsky diene

Article abstract of DOI:10.1021/ol203437a

A robust and scalable synthesis of a novel, cyano-substituted Danishefsky-type diene and its use in the Diels-Alder reaction with various dienophiles is reported. The diene allows for the rapid construction of highly substituted aminonaphthoquinones that occur in numerous ansamycin antibiotics.

Full text of DOI:10.1021/ol203437a

ORGANIC
LETTERS
2012
Vol. 14, No. 4
1070–1073
An Approach to Aminonaphthoquinone
Ansamycins Using a Modified
Danishefsky Diene
Christian A. Kuttruff, Simon Geiger, Mesut Cakmak, Peter Mayer, and Dirk Trauner*
€
Department of Chemistry and Pharmacology, Ludwig-Maximilians-Universitat
Mu€nchen and Center for Integrated Protein Science, 81377 Munich, Germany
dirk.trauner@lmu.de
Received December 23, 2011
ABSTRACT
A robust and scalable synthesis of a novel, cyano-substituted Danishefsky-type diene and its use in the DielsꢀAlder reaction with various
dienophiles is reported. The diene allows for the rapid construction of highly substituted aminonaphthoquinones that occur in numerous
ansamycin antibiotics.
Ansamycins are an important class of natural products
that show potent antibacterial and antiviral activities. In
addition to members of the family that have long been
known, such as rifamycin or naphthomycin A (1a),1
several new aminonaphthoquinone ansamycins with intri-
guing structures have recently been reported, including
naphthomycin K (1b),2 ansalactam (2),3 and divergolides
C (3a) and D (3b).4 Asdepicted in Figure 1, these molecules
possess structurally diverse ansa chains of varying lengths
that are mounted to a shared naphthoquinone core (depicted
in blue) through an acyl linkage in position 5 and an amide in
position 2 (naphthoquinone nomenclature). Several mem-
bers have additional CꢀC bonds between the aromatic core
and the ansa chain, which is remarkable from both a
synthetic and biosynthetic point of view.
aminonaphthoquinone core (Scheme 1). We reasoned that
due to steric compression, attachment of an ansa chain to
the arene would be a challenge. This led us to consider
cyano naphthalene 4 as a key intermediate, which in turn
could be traced back to cyano-substituted Danishefsky
diene 5 and substituted aminoquinone 6 via DielsꢀAlder
reaction.
The original Danishefsky diene5 has been widely used in
organic synthesis along with several variations, which have
been developed to improve its reactivity and synthetic
scope.6 These include alterations of the electron-donating
substituents in positions 1 and 3, as well as the intro-
duction of further substituents in positions 2 and 4 (diene
nomenclature) that are not lost following cycloaddition.7
However, tothebestof ourknowledge, there islittle, ifany,
Our interest in the total synthesis of these natural prod-
ucts prompted us to devise a unified approach to their
(5) Danishefsky, S.; Kitahara, T. J. Am. Chem. Soc. 1974, 96, 7807–
7808.
(6) (a) Danishefsky, S. Acc. Chem. Res. 1981, 14, 400–406. (b)
Herczegh, P.; Kovacs, I.; Erdoesi, G.; Varga, T.; Agocs, A.; Szilagyi,
L.; Sztaricskai, F.; Berecibar, A.; Lukacs, G.; Olesker, A. Pure Appl.
Chem. 1997, 69, 519–524. (c) Han, G.; LaPorte, M. G.; Folmer, J. J.;
Werner, K. M.; Weinreb, S. M. J. Org. Chem. 2000, 65, 6293–6306.
(7) (a) Yu, Z.; Liu, X.; Dong, Z.; Xie, M.; Feng, X. Angew. Chem.,
Int. Ed. 2008, 47, 1308–1311. (b) Kozmin, S. A.; Rawal, V. H. J. Org.
Chem. 1997, 62, 5252–5253. (c) Amii, H.; Kobayashi, T.; Terasawa, H.;
Uneyama, K. Org. Lett. 2001, 3, 3103–3105.
(1) Keller-Schierlein, W.; Meyer, M.; Cellai, L.; Cerrini, S.; Lamba,
D.; Segre, A.; Fedeli, W.; Brufani, M. J. Antibiot. 1984, 37, 1357–1361.
(2) Lu, C.; Shen, Y. J. Antibiot. 2007, 60, 649–653.
(3) Wilson, M. C.; Nam, S.-J.; Gulder, T. A. M.; Kauffman, C. A.;
Jensen, P. R.; Fenical, W.; Moore, B. S. J. Am. Chem. Soc. 2011, 133,
1971–1977.
(4) Ding, L.; Maier, A.; Fiebig, H.-H.; Goerls, H.; Lin, W.-H.;
Peschel, G.; Hertweck, C. Angew. Chem., Int. Ed. 2011, 50, 1630–1634.
r
10.1021/ol203437a
Published on Web 02/01/2012
2012 American Chemical Society

precedence for Danishefsky-type dienes that bear electron-
withdrawing groups. We now report the synthesis of such a
diene, compound 5, as well as studies on its reactivity and
use toward the synthesis of ansamycin antibiotics.
Scheme 2. Synthesis of Diene 5
of 10 failed due to its high lability toward various workup
conditions. However, we found that deprotonation with
LDA and subsequent silylation with TBSOTf delivered
silyloxy diene 5 as a 4.5:1 mixture of (2Z)- and (2E)-
isomers in excellent overall yield. These isomers could be
separated (see Supporting Information) but were usually
employed as a mixture in subsequent reactions.
With multigram quantities of diene 5 in hand, we
investigated its utility in the synthesis of naphthoquinones.
DielsꢀAlder reaction of 5 with the known benzoquinone
derivative 119 gave intermediary product 12 as a mixture of
stereoisomers, which was not further characterized. Treat-
ment of this crude material with oven-dried silica gel in
Figure 1. Structurally intriguing ansamycin antibiotics contain-
ing an aminonaphthoquinone core.
Scheme 3. Synthesis of the Aminonaphthoquinone Core and
Subsequent Reduction and Protection
Scheme 1. Retrosynthetic Analysis of the Aminonaphthoqui-
none Core of Ansamycins with Suitable Functionalization
Our synthesis of 5 commenced with the bromination of
commercially available methyl methacrylate8 (7), followed
by nucleophilic substitution and elimination to introduce a
β-methoxy substituent (Scheme 2). Subsequent Claisen-
type condensation with deprotonated acetonitrile gave
ketonitrile10, which proved tobesurprisingly stable. Next,
conditions for its enolization and subsequent silylation
were screened. Attempts to synthesize the TMS enol ether
(8) Werle, S.; Fey, T.; Neudoerfl, J. M.; Schmalz, H.-G. Org. Lett.
2007, 9, 3555–3558.
Org. Lett., Vol. 14, No. 4, 2012
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Table 1. Results of DielsꢀAlder Reactions of Diene 5 (4.5:1 Mixture of Stereoisomers) with Different Dienophiles
ethyl acetate/hexanes resulted in desilylation and aromati-
zation to afford our key naphthoquionone 13 in 84% over-
all yield. Notably, only a single regioisomer was isolated.
To elaborate 13 into a more useful building block and
confirm its structure, the naphthoquinone was reduced to
the corresponding naphthohydroquinone using sodium
borohydride. In situ protection of the phenolic hydroxy
groups as methyl ethers then afforded hexasubstituted
naphthalene 14, the crystal structure of which is depicted
in Scheme 3. Analogous protection of the three hydroxy
groups as MOM ethers required reduction with hydrogen
in the presence of Adam’s catalyst, followed by treatment
aminobenzoquinone 1610 gave naphthoquinone 17,
presumably through air oxidation of the intermediary
cycloadduct.
To establish the synthetic scope of diene 5 in Dielsꢀ
Alder reactions, we investigated its reactivity with other
dienophiles (Table 1). Encouraged by our initial results, we
first examined various quinones as dienophiles. Reaction
of 5 with commercially available dichlorobenzoquinone
(18) and theknowndibromobenzoquinone (19)11 provided
naphthoquinones 20 and 21, respectively, in satisfactory
yields following aromatization (entries 1 and 2). When
benzoquinone itself (22) was used as the dienophile, simple
heating in toluene proved to be less effective than catalysis
using AlCl3 as a Lewis acid. Following aromatization,
these catalytic conditions gave naphthoquinone 23 in good
overall yield (entry 3). Reaction of 5 with nitrostyrene 24
afforded the desired cycloaddition product 25 as a single
diastereomer (entry 4). Heating of diene 5 with dimethyl
fumarate (26) over 14 days afforded cycloadduct 27 as a
single diastereomer, but in only 23% yield. Reaction of 5
with phenyl triazoline dione (28) gave cycloadduct 29,
€
with MOM chloride and Hunig’s base. This gave naphtha-
lene derivative 15, which was also characterized by X-ray
crystallography. It should be noted that the alkylations
required careful optimization to avoid N-methylation
while ensuring that all three hydroxy groups were
affected. Interestingly, the aromatization following
the cycloaddition did not require an “inbuilt oxidant”
in the form of a halogen substituent on the benzoqui-
none. Reaction of diene 5 with Moody’s Boc-protected
(10) Nawrat, C. C.; Lewis, W.; Moody, C. J. J. Org. Chem. 2011, 76,
7872–7881.
(11) Omura, K. Synthesis 1998, 8, 1145–1148.
(9) Kelly, T. R.; Echavarren, A.; Behforouz, M. J. Org. Chem. 1983,
48, 3849–3851.
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Org. Lett., Vol. 14, No. 4, 2012

which has the opposite relative stereochemistry with re-
spect to the OMe and CN substituents compared to 25 and
27. This stereochemical outcome presumably reflects iso-
merization of the initial cycloadduct to the thermodyna-
mically more stable product via reversible cleavage of the
N,O-acetal. The structures of 21, 25, 27, and 29 were
confirmed by X-ray crystallography (Table 1 and Support-
ing Information). Attempted reactions of diene 5 with
tetracyanoethylene or maleic anhydride failed to give the
desired products despite extensive screening of conditions.
NOE correlation between olefinic proton d and the pro-
tons of the methyl group along with weak inter-
actions between olefinic proton b and protons e and f of
the TBS group. By contrast, no NOE could be observed
between protons b and d or between proton c and the
protecting group substituents. This strongly suggests that
(2Z)-5 mostly adopts an s-trans conformation and that
the requisite s-cis conformation is sparsely populated. We
assume that this effect is even more pronounced in the
(2E)-isomer of 5 and that this isomer is essentially un-
reactive in DielsꢀAlder cycloadditions, or it may isomer-
ize to its (2Z)-diastereomer under the reaction conditions.
In summary, we have reported the synthesis of a novel
Danishefsky-type diene, which allows for the rapid assem-
bly of substituted aminonaphthoquinones or other highly
functionalized small molecules. Related studies on Dielsꢀ
Alder dienes that bear substituents with opposing electro-
nic effects will be further pursued. Our ongoing attempts to
implement our synthetic strategy in the total synthesis of
ansamycin antibiotics will also be reported in due course.
Figure 2. Conformational analysis of diene 5.
Acknowledgment. We thank Dr. Rob Webster (Ludwig-
€
Maximilians-Universitat Munchen) for helpful discussions.
€
From these data, it is apparent that diene 5 exhibits
markedly reduced reactivity when compared to the parent
Danishefsky diene. This can be partially attributed to the
electronic effect of the cyano substituent but is probably
also due to the influence of the methyl substituent on the
preferred conformation of the diene. To undergo a [4 þ 2]
cycloaddition, 5must adopt an s-cis conformation (Figure 2).
NMR spectroscopy of pure (2Z)-5 demonstrated a strong
Supporting Information Available. Experimental pro-
cedures, spectroscopic and analytical data for com-
pounds 5ꢀ29, and X-ray data for compounds 14, 15,
21, 25, 27, and 29. This material is available free of charge
via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 4, 2012
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