A R T I C L E S
Nicolaou et al.
Scheme 7. Model Studies en Route to BE-10988 (21)a
Scheme 5. Total Synthesis of Epoxyquinomycin B (20)a
a Reagents and conditions: (a) 15 (1.0 equiv), 16 (1.0 equiv), Et3N (1.1
equiv), CH2Cl2, 25 °C, 20 min, 100%; (b) DMP (3.0 equiv), H2O (2.0 equiv),
CH2Cl2, 25 °C, 3 h, 43%; (c) H2O2 (30% solution in H2O, 3.0 equiv), K2CO3
(1.0 equiv), THF, 25 °C, 30 min, 95%; (d) HF‚py (5.0 equiv), THF, 10
min, 95%.
a Reagents and conditions: (a) DMP (4.0 equiv), H2O (2.0 equiv),
CH2Cl2, 25 °C, 12 h, 36% for 25b.
of DNA.10 Because proliferating tumor cells exhibit much higher
levels of topoisomerase-II, selective inhibition of this critical
enzyme represents a unique opportunity for the design and
discovery of new antitumor agents.11 To date, two elegant total
syntheses of 21 have been reported, one from Moody and
Swann12 and the other from the Shizuri camp.13
Scheme 6. Retrosynthetic Analysis of BE-10988 (21)
The molecular structure of BE-10988 (21) contains a novel
thiazole-substituted indole-quinone and as such provides a
unique forum to test the utility of the tandem DMP oxidation.
Retrosynthetically, and as depicted in Scheme 6, we discon-
nected the molecule using an indole formylation. Condensation
with cysteine to implement the thiazole ring and a late-stage
DMP oxidation would then provide the natural product after
removal of protecting groups. Model studies were first per-
formed as shown in Scheme 7 to probe the viability of the
aforementioned strategy. Although the unprotected indole 24a
did not lead to the desired indolequinone 24b, N-protected indole
25a led smoothly to indolequinone 25b in 36% yield. Encourag-
ingly, the bromothiazole 23 was inert to the conditions used
for DMP-mediated p-quinone construction.
Armed with the confidence provided by these experiments,
we set forth toward the total synthesis, as summarized in Scheme
8. Thus, the known indole 2614 was converted to its N-benzoyl
derivative (25a) followed by formylation with POCl3/DMF (22,
100% overall). Condensation with cysteine methyl ester fol-
lowed by oxidation of the resulting thiazoline led to the thiazole
27 (37% overall, 85% conversion). DMP-mediated oxidation
of 27 led to the indole-quinone 28 (67% yield) which, after
treatment with ammonia in MeOH, led to synthetic BE-10988
(21). Synthetic 21 exhibited identical spectroscopic properties
to those reported for natural 21.10 Our total synthesis of BE-
10988 (21) represents the shortest and most efficient (24%
isolated yield overall, 54% yield based on recovered starting
material) route to this important antitumor compound.
and readily available starting materials and proceeding in 38%
overall yield (see Scheme 5). Thus, the aniline 15 was combined
with the carboxylic acid chloride 16 in the presence of
triethylamine to furnish the amide 17 in quantitative yield.
Treatment of 17 with DMP in CH2Cl2 then gave the quinone
18 in 43% yield after directly loading the reaction mixture onto
a pad of silica gel for high-speed purification. Regioselective
epoxidation of 18 with hydrogen peroxide in the presence of
K2CO3 in aqueous THF was accompanied by concomitant
acetate cleavage to give, after desilylation with HF‚py, epoxy-
quinomycin B (20) (via 19), whose spectral data were found to
be identical to those reported for the natural product.
As a second target for total synthesis in this program, we
identified the interesting metabolite BE-10988 (21, Scheme 6).
Isolated from the culture broth of a strain of Actinomycetes,
BE-10988 represents a promising topoisomerase-II inhibitor.10
Type-II topoisomerases are essential enzymes implicated in
DNA replication, recombination, transcription, and repair by
virtue of their ability to modulate the 3-dimensional structure
The total syntheses of epoxyquinomycin B (20) and BE-
10988 (21) serve to illustrate the advantage of the DMP-
(10) Oka, H.; Yoshinari, T.; Murai, T.; Kuwamura, K.; Satoh, F.; Funaishi, K.;
Okura, A.; Suda, H.; Okanishi, M.; Shizuri, Y. J. Antibiot. 1991, 44, 486.
(11) Ross, W. E. Biochem. Pharmacol. 1985, 34, 4191.
(12) Moody, C. J.; Swann, E. Tetrahedron Lett. 1993, 34, 1987.
(13) Suda, H.; Ohkubo, M.; Matsunaga, K.; Yamamura, S.; Shimomoto, W.;
Kimura, N.; Shizuri, Y. Tetrahedron Lett. 1993, 34, 3797.
(14) Prepared from 4-nitroindole by N-methylation followed by reduction of
the nitro group. See: Forbes, I. T.; Jones, G. E.; Murphy, O. E.; Holland,
V.; Baxter, G. S. J. Med. Chem. 1995, 38, 855.
(9) Matsumoto, N.; Ariga, A.; To-E, S.; Nakamura, H.; Agata, N.; Hirano,
S.-I.; Inoue, J.-I.; Umezawa, K. Bioorg. Med. Chem. Lett. 2000, 10, 865.
Block, O.; Klein, G.; Altenbach, H.-J.; Brauer, D. J. J. Org. Chem. 2000,
65, 716. Wipf, P.; Coish, P. D. G. J. Org. Chem. 1999, 64, 5053. Alcaraz,
L.; Macdonald, G.; Ragot, J.; Lewis, N. J.; Taylor, R. J. K. Tetrahedron
1999, 55, 3707. For the first total synthesis, see: Matsumoto, N.; Iinuma,
H.; Sawa, T.; Takeuchi, T. Bioorg. Med. Chem. Lett. 1998, 8, 2945.
9
2224 J. AM. CHEM. SOC. VOL. 124, NO. 10, 2002