addition, benanomicins A and B inhibit de novo infection
of human T-cells with HIV-1.4
While there has been strong interest in the total synthesis
of benzo[a]naphthacene natural products,5 there has been
only one total synthesis of the pradimicin/benanomicin
aglycone, which was performed by Suzuki et al.6
Our planned approach to the synthesis of the benzo[a]-
naphthacene quinone ring system conceptually parallels that
employed for synthesis of PD116740, in that the angular ring
system would be regiospecifically fabricated through use of
the ortho-quinone monoketal 2 in a condensation reaction
(Scheme 1).1 In this case, we would condense an ortho-
affords 1-hydroxy-2-carboxynaphthoates in high yield.8 The
corresponding reaction of 4 with the lithium enolate of
methyl acetate afforded the naphthoate 5 in 80% yield. The
resultant naphthol 5 was methylated with K2CO3 and
(CH3O)2SO2 to the methyl ether 6 (96%). Sequential hydro-
genolysis of 6 followed by oxidation of the resultant phenol
with PhI(OAc)2 in MeOH9 afforded the ortho-quinone ketal
2 (68% from 6).
Preparation of the ortho-phenylsulfinyl naphthoate 11 was
accomplished as shown in Scheme 3. Condensation of the
Scheme 3a
Scheme 1
a Reagents and conditions: (a) (i) LiOtBu, THF, methyl cro-
tonate; (ii) (CH3O)2SO2, K2CO3, acetone (88% for two steps). (b)
NBS, CCl4 (86%). (c) KOH, PhSH, MeOH (93%). (d) NaBO3‚4H2O,
AcOH (86%).
anion of the sulfone 7 with methyl crotonate afforded the
1,4-dihydroxynaphthoate intermediate, which proved to be
too reactive for isolation, readily undergoing air oxidation
to the quinone. To overcome this problem, the initially
formed naphthoate dianion was directly treated with
(CH3O)2SO2 in the same flask in which the condensation
was conducted. This protocol produced a regioisomeric
mixture of mono- and dimethylated products. The mixture
was isolated and subjected to additional methylation, afford-
ing the dimethyl ether 8 in 88% overall yield from 7.
Attempted free-radical bromination of the methyl group
in 8 with 1 equiv of NBS afforded a mixture of methyl and
ring brominated products, as well as unreacted starting
material. Bromination with 2 equiv cleanly afforded the
dibrominated product 9 in 86% yield. Since we expected to
phenylsulfinylmethyl naphthoate with 2. This condensation
reaction was previously developed and used by us for
regiospecific construction of naturally occurring polycyclic
aromatic systems.7
Preparation of the needed ortho-quinone monoketal 2
capitalized on our earlier development of a route to the
benzyl ether-protected isobenzopyranone 4 (Scheme 2).1 We
have previously shown that reaction of isobenzopyranones
with the lithium enolate of ethyl acetate regiospecifically
Scheme 2a
(4) Hoshino, H.; J. Seki, J.; Takeuchi, T. J. Antibiot. 1989, 42, 344.
(5) Hauser, F. M.; Caringal, Y. J. Org. Chem. 1990, 55, 555. Kelly, T.
R.; Xu, W.; Ma, Z.; Li, Q.; Bhushan, V. J. Am. Chem. Soc. 1993, 115,
5843. Kraus, G. A.; Zhao, G. J. Org. Chem. 1996, 61, 2770. Hirosawa, S.;
Nishizuka, T.; Kondo, S.; Ikeda, D. Chem. Lett. 1997, 305. Nishizuka, T.;
Hirosawa, S.; Kondo, S.; Ikeda, D. J. Antibiot. 1997, 50, 755.
(6) Kitamura, M.; Ohmori, K.; Kawase, T.; Suzuki, K. Angew. Chem.,
Int. Ed. 1999, 38, 1229.
(7) Hauser, F. M.; Rhee, R. J. Org. Chem. 1977, 42, 4155. Hauser, F.
M.; Rhee, R. J. Am. Chem. Soc. 1977, 99, 4533.
(8) Hauser, F. M.; Pogany, S. J. Heterocycl. Chem. 1978, 15, 1535.
(9) Mallik, U.K.; Mallik, A. K. Ind. J. Chem. 1991, 30B, 611.
a Reagents and conditions: (a) LDA/THF, CH3CO2CH3 (80%).
(b) (CH3O)2SO2, acetone, K2CO3 (96%). (c) H2/Pd-C, MeOH
(98%). (d) PhI(OAc)2, CH3OH (68%).
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Org. Lett., Vol. 4, No. 13, 2002