Efficient synthesis of the tetracyclic aminoquinone moiety of marmycin A

Article abstract of DOI:10.1021/ol9020496

An efficient four-step route to the tetracyclic aminoquinone moiety of marmycin A that proceeds in 41% overall yield from 5-nitronaphthoquinone and 5-methy 1-1-vinylcyclohexene will facilitate preparation of marmycin A analogues for biological evaluation.

Full text of DOI:10.1021/ol9020496

ORGANIC
LETTERS
2009
Vol. 11, No. 21
4926-4929
Efficient Synthesis of the Tetracyclic
Aminoquinone Moiety of Marmycin A
Nathan Maugel and Barry B. Snider*
Department of Chemistry MS 015, Brandeis UniVersity,
Waltham, Massachusetts 02454-9110
snider@brandei.edu
Received September 3, 2009
ABSTRACT
An efficient four-step route to the tetracyclic aminoquinone moiety of marmycin A that proceeds in 41% overall yield from 5-nitronaphthoquinone
and 5-methyl-1-vinylcyclohexene will facilitate preparation of marmycin A analogues for biological evaluation. The Diels-Alder reaction gave
exclusively the desired adduct that is favored by steric considerations rather than the regioisomeric adduct that is favored by electronic
considerations.
Fenical and co-workers recently isolated two cytotoxic
quinones of the angucycline family, marmycins A (1a) and
B (2), from a marine sediment-derived actinomycete related
to the genus Streptomyces (Scheme 1).1 The structures were
determined by spectroscopic analysis and X-ray crystal-
lography. C-Glycosidic linkages are quite common in an-
gucyclines,2 but the C- and N-glycosidic linkages resulting
in a hexacyclic skeleton are unique to the marmycins.
Marmycin A (1a) showed potent activity against 12 human
tumor cell lines with a mean IC50 value of 22 nM. The
combination of the novel skeleton and potent biological
activity of 1a prompted us to undertake its synthesis.
reported a ten-step synthesis of tetracyclic aminoquinone 3
and the InBr3-catalyzed condensation of 3 and 2b to afford
C-3′-desmethyl marmycin A (1c).4
Scheme 1. Retrosynthesis of Marmycin A
We envisioned that condensation of glycal 2a with
tetracyclic aminoquinone 3 would provide the acetate of 1a.
Yadav has extensively studied related condensations of
simple anilines with glycals such as 2b that contain hydrogen
on C-3 to form the tricyclic ABC ring system of the
marmycins with a hydrogen rather than a methyl group at
C-3′.3 While our work was in progress, Yao and Zhang
(1) Martin, G. D. A.; Tan, L. T.; Jensen, P. R.; Dimayuga, R. E.;
Fairchild, C. R.; Raventos-Suarez, C.; Fenical, W. J. Nat. Prod. 2007, 70,
1406–1409.
Our approach to tetracyclic aminoquinone 3 by the
Diels-Alder reaction of 5-nitronaphthoquinone (4)5 with
5-methyl-1-vinylcyclohexene (5)6 will form the complete
carbon skeleton in a single step. However, the regiochemistry
(2) (a) Rohr, J.; Thierike, R. Nat. Prod. Rep. 1992, 103–137. (b) Krohn,
K.; Rohr, J. Top. Curr. Chem. 1997, 188, 127–195. (c) Carren˜o, M. C.;
Urbano, A. Synlett 2005, 1–25.
10.1021/ol9020496 CCC: $40.75
Published on Web 10/05/2009
 2009 American Chemical Society

of the proposed Diels-Alder reaction was of some concern.
Naphthoquinones with electron-withdrawing substituents on
C-5 react preferentially with nucleophiles, including the
nucleophilic end of a diene, at C-2, not C-3, which should
lead to the undesired regioisomer in the Diels-Alder reaction
(see Scheme 2).7 Nitroquinone 4 reacts with 1,1-dimethoxy-
Diels-Alder transition states provide a possible explanation
for this loss of selectivity.10 The formation of 6 is preferred
sterically by 0.34 kcal/mol in addition to the electronic
preference. However, the formation of 9 is preferred sterically
by 0.37 kcal/mol due to repulsion between the nitro and
methyl groups in the transition state that leads to the
electronically preferred adduct 8. Competing electronic and
steric preferences should result in reduced selectivity.
Calculations for the Diels-Alder reaction of 4 with 1-vi-
nylcyclohexene suggest that the transition state for the desired
adduct 11 is favored over that for the electronically preferred
adduct 10 by 1.02 kcal/mol due to steric repulsion between
the nitro group and cyclohexene ring (see Figure 1). We
therefore decided to investigate this route to aminoquinone 3.
Scheme 2
.
Diels-Alder Reactions of 4 with Unsymmetrical
Dienes
Figure 1. MMX calculated structure for the Diels-Alder reaction
leading to 11 with the arrow showing steric repulsion between the
nitro group and cyclohexene ring.
Addition of vinylmagnesium bromide to 3-methylcyclo-
hexanone (12) followed by dehydration of the resulting
tertiary allylic alcohol in 90:1 THF/H2SO4 for 72 h at 50 °C
afforded a 1.5:1 mixture of the desired diene 5 and 13 in
70% yield, which was used directly because previous studies
of Diels-Alder reactions with other naphthoquinones indi-
cated that the more hindered minor isomer 13 was much
less reactive than 5 (see Scheme 3).6 Nitration of naphtho-
quinone with sodium nitrate in sulfuric acid afforded 4 in
75% yield.5 Treating 4 with 2 equiv of the 1.5:1 mixture of
5 and 13 in EtOH for 12 h at 25 °C and 2 h at 40 °C afforded
a complex mixture of stereo- and regioisomeric Diels-Alder
adducts 14 and 15 that was oxidized to the quinone and
aromatic E ring prior to purification.
ethylene preferentially (2.7:1) at C-2.8 Oda studied the
Diels-Alder reactions of 4 with isoprene, which gave a 9.2:1
mixture favoring the expected major isomer 6.9 However,
with piperylene, the expected major isomer 8 was favored
by only 1.4:1. Molecular mechanics calculations of the
(3) (a) Yadav, J. S.; Reddy, B. V. S.; Rao, K. V.; Raj, K. S.; Prasad,
A. R.; Kumar, S. K.; Kunwar, A. C.; Jayaprakash, P.; Jagannath, B. Angew.
Chem., Int. Ed. 2003, 42, 5198–5201. (b) Yadav, J. S.; Reddy, B. V. S;
Parimala, G.; Raju, A. K. Tetrahedron Lett. 2004, 45, 1543–1546. (c) Yadav,
J. S.; Reddy, B. V. S.; Srinivas, M.; Padmavani, B. Tetrahedron 2004, 60,
3261–3266. (d) Yadav, J. S.; Reddy, B. V. S.; Padmavani, B. Synthesis
2004, 405–408. (e) Yadav, J. S.; Reddy, B. V. S.; Meraj, S.; Vishnumurthy,
P.; Narsimulu, K.; Kunwar, A. C. Synthesis 2006, 2923–2926. (f) Rafiee,
E.; Azad, A. Bioorg. Med. Chem. Lett. 2007, 17, 2756–2759. (g) Yadav,
J. S.; Subba Reddy, B. V.; Srinivas, M.; Divyavani, Ch.; Kunwarb, A. C.;
Madavi, Ch. Tetrahedron Lett. 2007, 48, 8301–8305. (h) Narasimhulu, M.;
Reddy, S. M.; Rajesh, K.; Suryakiran, N.; Ramesh, D.; Venkateswarlu, Y.
Heteroatom Chem. 2008, 19, 429–433.
Oda oxidized 6-9 to anthraquinones by aeration in ethanolic
potassium hydroxide or by heating in hexane containing
alumina.9 Stirring the mixture of 14 and 15 in 0.1 M KOH in
EtOH at 25 °C for 24 h in a tube sealed under air gave a 1:1
(7) (a) Rozeboom, M. D.; Tegmo-Larsson, I. M.; Houk, K. N. J. Org.
Chem. 1981, 46, 2338–2345. (b) Pyrek, J. St; Achmatowicz, O., Jr.;
Zamojski, A. Tetrahedron 1977, 33, 673–680.
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L.; Zhang, A. J. Org. Chem. 2009, 74, 6111–6119.
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Bull. Acad. Sci. USSR, Ser. Chem. 1984, 33, 2345-2348; IzV. Akad. SSSR,
Ser. Khim. 1984, 33 2261-2265..
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33, 1805–1816.
(9) Oda, N.; Kobayashi, K.; Ueda, T.; Ito, I. Chem. Pharm. Bull. 1978,
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Y.; Aoyama, H. Synthesis 2004, 2099–2102. (b) Krohn, K.; Sohrab, Md.
H.; Flo¨rke, U. Tetrahedron: Asymmetry 2004, 15, 713–718.
(10) PCMODEL version 8.0 from Serena Software was used. MMX
calculations were performed with transition state bond formation of 30%.
Org. Lett., Vol. 11, No. 21, 2009
4927

Scheme 3
.
Diels-Alder Reaction to Form 17
Scheme 4. Synthesis of Aminoquinone 3
nitroquinone 19 in 71% yield (see Scheme 4).12 Although
only 2 equiv of DDQ are required stoichiometrically, the
reaction did not go to completion with 6 equiv, even after
heating for 30 min at 140 °C, suggesting that DDQ
decomposes at a rate competitive with the oxidation of 17.
Oxidation with DDQ at lower temperatures was less effec-
tive. The DDQ byproducts are very polar and easily removed
by flash chromatography. Reduction of the nitro group of
19 with aqueous sodium sulfide for 2 h at 95 °C provided
the desired fully aromatic tetracyclic aminoquinone 3 in 91%
yield.11 The structure of 3 was established by X-ray
crystallography. The spectral data are identical to those
reported by Yao and Zhang.4 This sequence provides
tetracyclic aminoquinone 3 in only 4 steps from naphtho-
quinone 4 in 41% overall yield.
Yao and Zhang reported that the reaction of 3 with 2b
was very sluggish with many catalysts but gave a 2:1 mixture
of 20 (56%) and 21 (28%) by reaction for 12 h at 25 °C
with 10% InBr3 in CH2Cl2. In our hands, this reaction with
InBr3 appeared to be exceedingly moisture sensitive. Reaction
with In(OTf)3 was less moisture sensitive; use of 10%
In(OTf)3 in CH2Cl2 for 12 h at 45 °C provided 20 (27%)
and 21 (14%).
Yadav proposed that these reactions proceed by a
Friedel-Crafts reaction (C-glycosylation) to give 22 followed
by an intramolecular hydroamination to form 20 and 21 (see
Scheme 5).3a,4 The formation of C-glycoside 22 is well
precedented.13 Although hydroaminations of unactivated
alkenes catalyzed by acid or lanthanum triflates have recently
been reported, they require temperatures between 135 and
160 °C.14 Therefore, the intramolecular hydroamination of
22 to give 20 and 21 is unlikely to take place at 25 °C. It
seems more likely that the first step involves loss of acetate
mixture of the desired nitroquinone 17 and the unexpected
aminoquinone 16 in low yield. The structure of amine 16 was
confirmed by reduction of 17 with aqueous Na2S at 95 °C for
3 h to give 16 in 98% yield.11 This suggested that both oxygen
and the nitro group could function as oxidants for the aroma-
tization of the E ring. Bubbling air into the reaction through a
dispersion tube decreased the formation of 16, giving a 10:1
mixture of 17and amine 16, but in only 24% yield from
naphthoquinone 4. A possible mechanism for the formation of
16 is presented below in Scheme 6.
Much better results were obtained by heating the mixture
of 14 and 15 in 90:10 hexane/benzene containing alumina
in a sealed tube under oxygen (∼0.7 equiv) for 2 h, followed
by replacing the oxygen and heating for an additional 2 h.
This gave a 9:1 mixture of the desired adduct 17 and adduct
18 (formed from the undesired diene 13) that contained only
2-4% of amine 16. Recrystallization from CHCl3 afforded
pure nitroquinone 17 in 63% overall yield from naphtho-
quinone 4. The oxidation was not complete and more amine
was formed if the reaction was heated for 4 h without
replacement of the oxygen after 2 h. The structure of 17
was established by X-ray crystal structure determination of
3 as described below. We were delighted to find that the
Diels-Alder reaction was very selective for the desired
product 17 that was expected on steric grounds rather than
the undesired regioisomer corresponding to 10 that was
expected on the basis of electronic considerations.
(11) Ghaieni, H.; Sharifi, M.; Fattollahy, M. Dyes Pigm. 2007, 72, 97–
100.
Oxidation of 17 with 10 equiv of DDQ in benzene at 140
°C in a microwave oven for 20 min provided fully aromatic
(12) Mal, D.; Dey, S. Tetrahedron 2006, 62, 9589–9602.
(13) Ferrier, R. J.; Zubkov, O. A. Org. React. 2003, 62, 569–736.
4928
Org. Lett., Vol. 11, No. 21, 2009

Scheme 5. Mechanistic Considerations
Scheme 6. Oxidation to the Anthraquinone by the Nitro Group
from C-3 of 2b to give an allylic cation that reacts with the
amine to give 23. There is ample precedent for the formation
of compounds analogous to 23 from glycals and other
nucleophiles. The BF3·OEt2-catalyzed reaction of 2b with
NaN3 occurs initially at C-1, but the major product formed
after equilibration is the C-3 azide corresponding to 23.15a
Similarly, the SnCl4-catalyzed reaction of glycals with
aliphatic thiols occurs initially at C-1 but gives mainly
3-alkylthio glycals corresponding to 23 under equilibrium
conditions.15b Protonation of glycal 23 and an intramolecular
Friedel-Crafts reaction will then form 20 and 21. The
intramolecular Friedel-Crafts reaction of 23 appears to be
more likely for the cyclization step than the intramolecular
hydroamination of unactivated alkene 22.
There is limited precedent for a nitro group functioning
as an oxidant in the conversion of 14 to 16.16 A possible
mechanism involves enolization of 14 to give 24 followed
by addition of the enolate to the nitro group, which will give
25 after protonation and loss of water (see Scheme 6).
Deprotonation and elimination will convert 25 to nitroso-
quinone 26. Enolization of 26 followed by attack of the
enolate on the nitroso group will give 27 after protonation.
Deprotonation and elimination will give anthraquinone 28
at the hydroxylamine oxidation state which must then be
reduced to give 16.
In conclusion, we have developed an efficient four-step
route to aminoquinone 3 from naphthoquinone 4 that
proceeds in 41% overall yield. This will facilitate the
preparation of marmycin analogues for biological evaluation.
The Diels-Alder reaction of 4 and 5 gave exclusively the
desired Diels-Alder adduct 14 that is favored by steric
considerations rather than the adduct corresponding to 10
that is favored by electronic considerations.
Acknowledgment. We are grateful to the National Insti-
tutes of Health (GM-50151) for support of this work. We
thank the National Science Foundation for partial support
of this work through grant CHE-0521047 for the purchase
of a new X-ray diffractometer.
(14) (a) Anderson, L. L.; Arnold, J.; Bergman, R. G. J. Am. Chem. Soc.
2005, 127, 14542–14543. (b) Marcsekova´, K.; Doye, S. Synthesis 2007,
145–154. (c) Yin, P.; Loh, T.-P. Org. Lett. 2009, 11, 3791–3793.
(15) (a) Jaunzems, J.; Kashin, D.; Scho¨nberger, A.; Kirschning, A. Eur.
J. Org. Chem. 2004, 3435–3446. (b) Priebe, W.; Zamojski, A. Tetrahedron
1980, 36, 287–297.
Supporting Information Available: Complete experi-
mental procedures, copies of 1H and 13C NMR spectral data,
details of the structure determination of 3, and CIF file of 3.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(16) (a) Rosenblum, M. J. Am. Chem. Soc. 1960, 82, 3796–3798. (b)
Srinivasan, P. S.; Mahesh, R.; Venkateswara Rao, G.; Kalyanam, N. Synth.
Commun. 1996, 26, 2161–2164.
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