Total synthesis of BE-23254, a chlorinated angucycline antibiotic

Article abstract of DOI:10.1016/j.tetlet.2005.06.062

The first synthesis of BE-23254, an unusual angucycline antibiotic, is reported. It involves regioselective condensation of naphthalenone 4 and chlorine-containing isobenzofuranone 16 as the key step.

Full text of DOI:10.1016/j.tetlet.2005.06.062

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5483–5486
Total synthesis of BE-23254, a chlorinated angucycline antibiotic
Satyajit Dey and Dipakranjan Mal*
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
Received 15 April 2005; revised 9 June 2005; accepted 14 June 2005
Abstract—The first synthesis of BE-23254, an unusual angucycline antibiotic, is reported. It involves regioselective condensation of
naphthalenone 4 and chlorine-containing isobenzofuranone 16 as the key step.
Ó 2005 Elsevier Ltd. All rights reserved.
The angucycline antibiotics are a large group of natu-
rally occurring quinone metabolites from microbial
sources.1,2 They exhibit a wide range of biological activ-
ities, which include antibiotic and antiviral activities,
enzyme inhibitory effects, vincristine cytotoxicity
potentiating activity and antigastrin activity. Although
all the members share a benz[a]anthraquinone frame-
work of decaketide origin, the structural diversity
among the members is very broad. They occur in a large
variety of oxidation states. The main differences are
observed in the aromaticity of the A and B rings, in
the location of the hydroxyl groups and the O-glycosidic
linkages. BE-23254 (1), an antitumour agent was iso-
lated from Streptomyces sp. A 23254.3 It was reported
to exhibit activity against the human colon cancer
DLD-1 (IC50 0.75 lg mlÀ1). Structurally, it is unique
amongst all presently known angucyclines and angucyc-
linones in that it bears a chlorine atom at C-9. The
methyl group at C-3, which is present in almost all other
angucyclines, is absent in BE-23254. Additionally, a car-
boxy group is present at C-2. These unusual structural
features prompted us to undertake the total synthesis
of this molecule.
densation. We report herein the first total synthesis of
BE-23254 (1) using the Hauser–Kraus annulation of a
partially dearomatized naphthalene derivative.
Previously, we have reported that 4a-methoxy-5,6,7,8-
tetrahydronaphthalen-2(4aH)-one can be regiospecifi-
cally annulated withbenzoisofuranones to give 6-hydr-
oxy-1,2,3,4-tetrahydrobenz[a]anthracene-7,12-diones in
excellent yields.5a,b This finding has been successfully
applied to the total synthesis of brasiliquinones, in
which the A-rings are non-aromatic.5c It was felt that
sucha strategy would also be very suitable for accessing
BE-23254 and its analogues, in which the A-ring is
aromatic. Accordingly, we planned to synthesize 1 via
aromatization of 2, obtainable by reaction of isobenzof-
uranone 3 withnaphthalenone 4 (Scheme 1).
For the synthesis of 4, commercially available 6-meth-
oxytetralone 5 was chosen as the starting material. Fol-
lowing the literature6 sequence, it was converted to
tetrahydronaphthalene-2-carboxylic acid 6 in 43% over-
all yield (Scheme 2). Reaction of this product with HBr
in acetic acid under standard conditions proceeded to
give phenolic acid 7a,7 which was selectively protected8
as methyl ester 7b, upon treatment withDBU and
iodomethane. The crucial dearomatization of 7b to
naphthalenone 4 was regioselectively performed in
65% yield by reaction withphenyliodonium diacetate
(1.2 equiv) in methanol. The stereostructure of the com-
pound 4 could not be ascertained by analysis of the cou-
pling constants due to difficulty in assigning the signals.
Several strategies have been reported for the synthesis of
this structurally diverse group of natural products.4
These include Diels–Alder methodology, Michael-type
cyclization, Hauser–Kraus annulation, Friedel–Crafts
reaction, free radical annulation, [2+2+2] cycloaddition,
nucleophilic addition, cyclobutenone rearrangement,
benzyne cycloaddition and biomimetic polyketide con-
We then focused our attention to the synthesis of CD
synthon 3. Since the phenolic ester 89 was easily accessi-
ble, we briefly studied its direct chlorination with
selected chlorinating agents to obtain chloro compound
Keywords: Angucycline; Phthalide annulation; BE-23254; Chlorination.
*
Corresponding author. Tel.: +91 3222 283318; fax: +91 3222
282252; e-mail: dmal@chem.iitkgp.ernet.in
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.062

5484
S. Dey, D. Mal / Tetrahedron Letters 46 (2005) 5483–5486
COOMe
COOH
COOMe
2
1
O
3
X
O
C
MeO
A
O
D
B
9
Cl
Cl
Cl
O
OMe
OMe O
OH
O
OH
O
OH
2
4
1
3
Scheme 1. Retrosynthesis of BE-23254 (1).
COOR
COOMe
COOH
O
MeO
a
b
c
OH
OMe
O
OMe
a:R = H
7
4
6
5
b:R = CH3
Scheme 2. Reagents and conditions: (a) (i) NaBH4, MeOH, rt, 96%; (ii) POCl3, DMF, 100 °C, 72%; (iii) Ag2O, EtOH–H2O, rt, 81%; (iv) H2, 10%
Pd–C, EtOH, rt, 91%; (b) (i) HBr, AcOH, reflux, 81%; (ii) DBU (2 equiv), CH3CN, CH3I (1 equiv), rt, 96%; (c) PhI(OAc)2 (1.2 equiv), MeOH, 0 °C–
rt, 65%.
Table 1. Product distribution of chlorination of phenol 8
Reagents and conditions
% Yield of 9
% Yield of 10
% Yield of 11
Cl2 (1.2 equiv), AcOH, rta
—
—
—
53
74
65
47
—
—
SO2Cl2 (1.5 equiv), 100 °C, 3 h—
Cl2 (1.2 equiv), AcOH, rtb
21
NCS (1.1 equiv), CCl4, reflux, 4–5 h11
NaOCl (1.1 equiv), AcOH, reflux, 4–5 hTrace
NCS (1.1 equiv), AcOH, reflux, 4–5 hTrace
15
49
35
—
a A Cl2/AcOH solution was added dropwise to the solution of phenol 8 in AcOH.
b Phenol 8 was added to a solution of Cl2 in AcOH.
9. It may be noted that methods for selective chlorina-
tion of substituted phenols are rare in the literature.10
The phenolic ester 8 was prepared in two steps from
ethyl acetoacetate and crotonaldehyde according to the
published procedure,9 and then subjected to chlorina-
tion under different conditions. The results of the chlori-
nations are presented in Table 1. As anticipated, the
chlorination was not regioselective. The majority of
the experiments failed to provide the desired chloro
derivative 9. Determination of the structures of the
monochlorinated products 9 and 10 was based on
NOE experiments (Scheme 3).
by treatment withDBU (3 equiv) at room temperature
afforded, after work-up, phenol ester 9 in 41% yield.
Subsequent conversion of 9 into 14 was achieved in
two steps. Protection of the phenolic OH with dimethyl
sulfate in the presence of K2CO3 gave 13, which was
subjected to benzylic bromination withNBS (2 equiv)
to produce dibromo derivative 14. This was then hydro-
lyzed witha refluxing mixture of AcOH–HCl–water to
give phthalaldehydic acid 15. Two key synthons 16
and 17 were, respectively, prepared according to the
general procedures developed for the preparation of
cyanophthalides and phenylsulfonylphthalides. Reac-
tion of phthaladehydic acid with KCN in the presence
of concd HCl furnished the cyanophthalide 16 in 83%
yield.12 Its structure was established by analysis of the
spectral data. Similarly, the corresponding phthalide
sulfone 17 was prepared in 70% yield according to our
Finally, the problem of preparing the monochlorophe-
nol 9 was solved via chlorination of cyclohexenone
12,11 the immediate precursor of phenol 8 (Scheme 4).
Treatment of 12 with2 equiv of SO 2Cl2 in CCl4 followed
Cl
Cl
CH3
CH3
CH3
CH3
a
Cl
COOEt
COOEt
Cl
COOEt
COOEt
OH
OH
OH
OH
10
11
8
9
Scheme 3. Reagents and conditions: (a) see Table 1.

S. Dey, D. Mal / Tetrahedron Letters 46 (2005) 5483–5486
5485
X
X
CH3
X
b
CH3
a
d
O
Cl
COOEt
Cl
COOEt
Cl
COOEt
O
e
OH
OMe
OMe
15
16
17
O
12
13: X = H
14: X = Br
9
X = OH
X = CN
c
f
X = SO2Ph
Scheme 4. Reagents and conditions: (a) (i) SO2Cl2 (2 equiv), CCl4, 78 °C; (ii) DBU (3 equiv), C6H6, rt, 41%; (b) K2CO3, Me2SO4, acetone, 55–56 °C,
68%; (c) NBS (2 equiv), (BzO)2, CCl4, 78 °C, 67%; (d) AcOH–HCl–water, 100 °C, 72%; (e) KCN, HCl, 0 °C–rt, 83%; (f) PhSO2OH, BF3ÆEt2O,
CH2Cl2, rt, 70%.
A
A
A
O
O
O
O
X
MeO
b
a
O
Y
Y
Y
O
O
Z
B
Z
B
Z
20 A = H
4 A = COOMe
21 Y = Z = A= H, B = OH
22 Y = Z = A= H, B = OH
19 Y = Z = H, X = CN
16 Y = Cl, Z = OMe, X = CN
23
Y = Cl, Z = OMe,
Y = Cl, Z = OMe,
24
A= COOMe, B = OH
A = COOMe, B = OH
c
Y = Cl, Z = OH,
25
A = COOMe, B = OH
Scheme 5. Reagents and conditions: (a) LiOtBu, THF, À60 to 0 °C, 71%; (b) DDQ, benzene, reflux, 49%; (c) AlCl3, CH2Cl2, rt, 78%.
procedure by reacting the acid 1513 withphenylsulfinic
acid in the presence of BF3Æetherate.14
In summary, we have completed the first regioselective
total synthesis of BE-23254, an unusual angucycline
antibiotic. In the process, we have introduced a new
approachfor the preparation of ortho-chlorinated phe-
nols based on chlorinative aromatization of a cyclohex-
enone derivative. Further study on the synthesis of
bromo and fluoro analogues of BE-23254 is in progress.
Before examining the proposed annulation (Scheme 1),
we studied the aromatization of the model compound
21, which was prepared from 19 and 20 by our published
procedure.5a Treatment of 21 withDDQ (6 equiv) in
refluxing benzene effected aromatization of the A ring
to give compound 2215 in 67% yield. NMR analysis of
an interrupted reaction mixture showed the formation
of an inseparable mixture of didehydro intermediates
along withthe desired product 22 (Scheme 5).
Acknowledgements
The authors wish to thank CSIR and DST, New Delhi
for financial support of this work.
Since the reactivity of the naphthalenone 4 towards
phthalide annulation was unknown, we attempted to
annulate it with phthalide sulfone 17.5a Reaction of
phthalide sulfone 17 with naphthalenone 4 in the pres-
ence of lithium tert-butoxide from À60 to 0 °C, followed
by stirring at room temperature and routine work-up
did not yield the expected annulated product 23. Naphth-
alenone 4 could be recovered from the reaction in a
substantial yield, whereas phthalide sulfone 17 was
destroyed during the reaction. However, condensation
of cyanophthalide 16 with 4 in the presence of LiOtBu
at À60 °C provided tetrahydrobenz[a]anthraquinone 23
in 71% yield. Aromatization of the A-ring in 23 was
effected withDDQ in refluxing benzene to provide 24
in 49% yield, which was primarily characterized by exam-
ination of 1H NMR and mass spectral data.16 Demethyl-
ation of compound 24 was effected by treatment with
anhydrous AlCl3 in CH2Cl2 at room temperature to pro-
vide 25 in 78% yield. Base (NaOH) catalyzed hydrolysis
of 25 yielded the natural product 1 in 92% yield.17
References and notes
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Rep. 1992, 9, 103–137; (b) Krohn, K.; Rohr, J. Top. Curr.
Chem. 1997, 188, 127–195.
2. For newer angucyclines, see: (a) Uesato, S.; Tokunaga, T.;
Takeuchi, K. Bioorg. Med. Chem. Lett. 1998, 8, 1969–
1972; (b) Mendez, C.; Kunzel, E.; Lipata, F.; Lombo, F.;
Cotham, W.; Walla, M.; Bearden, D. W.; Brana, A. F.;
Salas, J. A.; Rohr, J. J. Nat. Prod. 2002, 65, 779–782; (c)
Taniguchi, M.; Nagai, K.; Watanabe, M.; Niimura, N.;
Suzuki, K.-I.; Tanaka, A. J. Antibiot. 2002, 55, 30–35; (d)
Martin, R.; Sterner, O.; Alvarez, M. A.; De Clercq, E.;
Bailey, J. E.; Minas, W. J. Antibiot. 2001, 54, 239–249; (e)
Abdelfattah, M.; Maskey, R. P.; Asolkar, R. N. J.
Antibiot. 2003, 56, 539–542; (f) Metsa-Ketela, M.; Palmu,
K.; Kunnari, T.; Ylihonko, K.; Mantsala, P. Antimicrob.
Agents Chemother. 2003, 47, 1291–1296; (g) Stroech, K.;
Zeeck, A.; Antal, N.; Fiedler, H.-P. J. Antibiot. 2005, 58,
103–110.

5486
S. Dey, D. Mal / Tetrahedron Letters 46 (2005) 5483–5486
3. Okabe, T.; Ogino, H.; Suzuki, H.; Okuyama, A.; Suda, H.;
Jpn. Kokai Tokyo Koho, 92,316,492; Chem. Abstr. 1992,
118, 167614v.
pound 1: Mp 324–326 °C; 1H NMR (d5-pyridine,
200 MHz): d 10.9 (1H, s), 8.55 (1H, d, J = 8.3 Hz), 7.90–
7.81 (4H, m); HRMS m/z (ESI): calcd for C19H9O6Cl
(M+ÀH): 367.0009; found: 367.0026. Compound 4: Waxy
solid; IR mmax (KBr, cmÀ1): 1735, 1667, 1636, 1441, 1305,
1207, 1085, 987, 891; 1H NMR (CDCl3, 200 MHz): d 6.64
(1H, d, J = 10.1 Hz), 6.63 (1H, dd, J = 1.7, 10.1 Hz), 6.21
(1H, d, J = 1.7 Hz), 3.65 (3H, s), 3.02 (3H, s), 2.53–2.20
(5H, m), 1.60–1.41 (2H, m); 13C NMR (CDCl3, 50 MHz): d
185.76, 174.65, 160.49, 149.79, 131.32, 127.09, 72.75, 51.82,
51.66, 40.55, 37.46, 31.04, 29.91. Compound 9: Mp 55–
56 °C; IR mmax (KBr, cmÀ1) 3442, 1663, 1424, 1256, 1205,
4. For reviews on synthesis, see: (a) Carreno, M. C.; Urbano,
A. Synlett 2005, 1–25; (b) Rozek, T.; Bowie, J. H.; Pyke, S.
M.; Skelton, B. W.; White, A. H. J. Chem. Soc., Perkin
Trans. 1 2001, 1826–1830; (c) Matsuo, G.; Miki, Y.;
Nakata, M.; Matsumura, S.; Toshima, K. J. Org. Chem.
1999, 64, 7101–7106; (d) Krohn, K.; Sohrab, M. H.;
Florke, U. Tetrahedron: Asymmetry 2004, 15, 713–718; (e)
Motoyoshiya, J.; Masue, Y.; Iwayama, G.; Yoshioka, S.;
Nishii, Y.; Aoyama, H. Synthesis 2004, 2099–2102; (f)
Collet, S. C.; Remi, J. F.; Cariou, C.; Laib, S.; Guingant,
A. Y.; Vu, N. Q.; Dujardin, G. Tetrahedron Lett. 2004, 45,
4911–4915; (g) Kalogerakis, A.; Groth, U. Synlett 2003,
1886–1888; (h) Carreno, M. C.; Ribagorda, M.; Somoza,
A.; Urbano, A. Angew. Chem., Int. Ed. 2002, 41, 2755–
2757; (i) Lebrasseur, N.; Fan, G.-J.; Oxoby, M.; Looney,
M. A.; Quideau, S. Tetrahedron 2005, 61, 1551–1562.
5. (a) Mal, D.; Roy, H. N.; Hazra, N. K.; Adhikary, S.
Tetrahedron 1997, 53, 2177–2184; (b) Ghorai, S. K.; Roy,
H. N.; Bandopadhyay, M.; Mal, D. J. Chem. Res. (S)
1999, 30–31; (c) Mal, D.; Roy, H. N. J. Chem. Soc., Perkin
Trans. 1 1999, 3167–3171.
6. Reddy, P. N.; Rao, G. S. K. Indian J. Chem. 1981, 20B,
100–103.
7. Dauben, W. G.; Hiskey, C. F.; Markhart; Albert, H. J. J.
Am. Chem. Soc. 1951, 73, 1393–1400.
8. Mal, D. Synth. Commun. 1986, 16, 331–335.
9. Hauser, F. M.; Pogany, S. A. Synthesis 1980, 814–815.
10. (a) Gnaim, J. M.; Sheldon, R. A. Tetrahedron Lett. 2004,
45, 8471–8473; (b) Smith, J. R. L.; McKeer, L. C.; Taylor,
J. M. J. Chem. Soc., Perkin Trans. 2 1988, 385–391.
11. Soriano, D. S.; Lombardi, A. M.; Persichini, P. J.;
Nalewajek, D. J. Chem. Educ. 1988, 65, 637.
1
802; H NMR (CDCl3+CCl4, 200 MHz): d 11.97 (1H, s),
7.37 (1H, d, J = 8.2 Hz), 6.67 (1H, d, J = 8.2 Hz), 4.45 (2H,
q, J = 7.2 Hz), 2.52 (3H, s), 1.44 (3H, t, J = 7.2 Hz); 13C
NMR (CDCl3, 50 MHz): d 171.38, 158.15, 140.01, 133.96,
122.76, 119.88, 113.58, 62.15, 23.81, 14.08. Compound 16:
Mp 90–91 °C; IR mmax (KBr, cmÀ1) 1788, 1601, 1390, 1024,
768; 1H NMR (CDCl3+CCl4, 200 MHz): d 7.82 (1H, d,
J = 8.1 Hz), 7.31 (1H, d, J = 8.1 Hz), 6.97 (1H, s), 4.21 (3H,
s); 13C NMR (CDCl3, 50 MHz): d 163.80, 155.50, 141.62,
137.53, 130.26, 117.43, 116.61, 113.19, 64.56, 62.86; MS
m/z (EI): 223 (M+), 205, 194, 177, 167, 149. Compound 23:
Orange solid; mp 135–136 °C; IR mmax (KBr, cmÀ1): 3408,
1733, 1634, 1273, 1025, 763, 697; 1H NMR (CDCl3,
200 MHz): d 13.00 (1H, s), 7.99 (1H, d, J = 8.3 Hz), 7.82
(1H, d, J = 8.3 Hz), 7.06 (1H, s), 4.01 (3H, s), 3.74 (3H, s),
3.61 (1H, dd, J = 5.6, 18.6 Hz), 3.31 (1H, dd, J = 10.1,
18.6 Hz), 2.94–2.89 (2H, m), 2.80–2.68 (1H, m), 2.21–2.12
(1H, m), 2.03–1.90 (1H, m); 13C NMR (CDCl3, 50 MHz): d
187.79, 183.75, 175.37, 160.74, 156.07, 147.76, 136.53,
135.79, 135.24, 131.76, 129.87, 126.21, 124.52, 124.25,
116.39, 61.62, 51.92, 39.83,30.94, 29.89, 24.15; MS m/z
(EI): 400 (M+), 369, 340, 326, 322, 297, 284, 256, 236, 197.
Compound 24: Red solid; mp 234–235 °C; mmax (KBr,
cmÀ1) 3426, 1725, 1644, 1570, 1459, 1314, 1265, 1222, 1019,
12. Freskos, J. N.; Gary, W. M.; Swenton, J. S. J. Org. Chem.
1985, 50, 805–810.
1
760; H NMR (CDCl3, 200 MHz): d 12.42 (1H, s), 10.04
13. Napolitano, E.; Ramacciotti, A.; Morsani, M.; Fiaschi, R.
Gazz. Chim. Ital. 1991, 121, 257–259.
14. Murty, K. V. S. N.; Pal, R.; Datta, K.; Mal, D. Synth.
Commun. 1990, 20, 1705–1711.
(1H, s), 8.12 (1H, d, J = 8.4 Hz), 8.08 (1H, d, J = 8.6 Hz),
7.86 (1H, d, J = 8.4 Hz), 7.75 (1H, d, J = 8.6 Hz). 7.68 (1H,
s), 4.06 (3H, s), 4.01 (3H, s); HRMS m/z (ESI): calcd for
C21H13O6Cl (M++H): 397.0479; found: 397.0468. Com-
1
15. Valderrama, J. A.; Pessoa-Mahana, C. D.; Tapia, R. J.
Chem. Soc., Perkin Trans. 1 1994, 3521–3523.
pound 25: Red solid; mp 273–274 °C; H NMR (CDCl3,
200 MHz): d 12.34 (1H, s), 11.90 (1H, s), 10.15 (1H, s), 8.14
(1H, dd, J = 1.5, 8.7 Hz), 7.83 (2H, s), 7.76 (1H, d,
J = 8.7 Hz), 7.71 (1H, s), 4.02 (3H, s); HRMS m/z
(ESI): calcd for C20H11O6Cl (M+ÀH): 381.0166; found:
381.0150.
16. 13C NMR data could not be recorded due its poor
solubility in common deuterated organic solvents.
17. The compounds gave satisfactory elemental analyses,
EIMS and NMR data. Selected spectroscopic data: Com-