A brief and convergent synthetic route to defucogilvocarcin M chromophore: The formal synthesis of WS-5995 A and C

Article abstract of DOI:10.1021/jo0512960

Densely substituted styryl sulfone 20 is shown to undergo double annulation with phthalide 21 to give, in one-pot operation and in excellent yield, the benzonaphthopyranone scaffold 22 of gilvocarcins.

Full text of DOI:10.1021/jo0512960

naturally occurring quinonoids (e.g., 4 and angelmicin
A Brief and Convergent Synthetic Route to
Defucogilvocarcin M Chromophore: The
Formal Synthesis of WS-5995 A and C
B5) could be more challenging than anticipated (Figure
1).
We report herein an efficient and new synthesis of
benzonaphthopyranone chromophore of the gilvocarcin
family.
Asit Patra, Pallab Pahari, Sutapa Ray, and
Dipakranjan Mal*
Recently, we reported that the Hauser-Kraus annu-
lation could be maneuvered for direct entry to the
pentacyclic ring system (7) of chrymutasin (Scheme 1).6
The ester group in the peri-position of partially de-
aromatized naphthalene derivative 6 served as a handle
for in situ fabrication of the lactone ring following the
first annulation. Recognizing the utility of such a strategy
for the synthesis of gilvocarcin chromophores, we decided
to investigate the reactivity of styryl sulfones toward
Hauser-Kraus donors, because aryl sulfone moieties are
both electron-withdrawing and easily removable by re-
ductive procedures or base-induced elimination reac-
tions.7
Department of Chemistry, Indian Institute of Technology,
Kharagpur 721 302, India
dmal@chem.iitkgp.ernet.in
Received June 24, 2005
As a background study, we initially examined reactiv-
ity of styryl sulfone 10 toward Hauser-Kraus annulation
(Scheme 2). The ester group ortho to the vinyl sulfone
group in 10 was expected to undergo in situ lactone
formation giving tetracyclic sulfone 15. Accordingly,
styryl sulfone 10, prepared8 from methyl anthranilate
through Heck reaction of its diazonium salt with phenyl
vinyl sulfone, was submitted to reaction with isobenzo-
furanone 8 in the presence of freshly prepared lithium
tert-butoxide at -60 °C. After 2 h at room temperature,
the reaction was quenched with a solution of ammonium
chloride. Chromatographic purification of the crude
product yielded three products as summarized in Scheme
2. Although we anticipated formation of the sulfone-
containing tetracyclic compound 15, all three products
11, 13,9 and 16 were devoid of the phenylsulfonyl group.
The desulfonylation possibly occurred after the initial
Hauser-Kraus annulation and lactone ring formation.
The structure of the major product (i.e., 11; 68%) was
established by its conversion to methyl ester 12, which
is known in the literature.9 It may be noted that the
benzonaphthopyranone skeleton represented by structure
1610 is found in many natural products, namely WS-5995
A. The reaction of isobenzofuranone 911 with 10 similarly
proceeded with a product profile similar to that of 8. Since
arylnaphthoquinones of the type 11 are convertible to
benzonaphthopyranones (see 13) through reduction fol-
lowed by acid-catalyzed lactonization,9 we were encour-
aged to examine the reactivity of styryl sulfone 20, which
would give the required substitution pattern of gilvo-
carcins.
Densely substituted styryl sulfone 20 is shown to undergo
double annulation with phthalide 21 to give, in one-pot
operation and in excellent yield, the benzonaphthopyranone
scaffold 22 of gilvocarcins.
The gilvocarcin family of polyketide natural products
has stimulated considerable interest by virtue of their
challenging structures and potent antitumor activities.1,2
Since 1987, several research groups have pioneered the
development of synthetic methodologies and total syn-
theses for this class of molecules.3 Despite the classic
solution to the synthesis of the gilvocarcins 1 by Suzuki
et al., the synthetic interest in these molecules remains
unabated.4 In fact, the presence of the amino group in
sugar moiety of ravidomycin (2) has necessitated a newer
synthesis of its chromophore (3).4a Moreover, the synthe-
sis of highly substituted arylnaphthoquinones present in
(1) For a review on gilvocarcin class antibiotics, see: Hua, D. H.;
Saha, S. Recl. Trav. Chim. Pays-Bas 1995, 114, 341-355.
(2) For isolation and structure determination of the gilvocarcins-
ravidomycin class of antibiotics, see: (a) Gilvocarcin
V and M:
Takahashi, K.; Yoshida, M.; Tomita, F.; Shirahata, K. J. Antibiot. 1981,
34, 271-275. Hirayama, N.; Takahashi, K.; Shirahata, K.; Ohashi, Y.;
Sasada, Y. Bull. Chem. Soc. Jpn. 1981, 54, 1338-1342. (b) Ravido-
mycin: Findlay, J. A.; Liu, J.-S.; Radics, L.; Rakhit, S. Can. J. Chem.
1981, 59, 3018-3020. (c) Defucogilvocarcin V and M: Misra, R.; Tritch,
H. R., III; Pandey, R. C. J. Antibiot. 1985, 38, 1280-1283.
(3) For the synthesis of defucogilvacarcins, see: (a) Patten, A. D.;
Nguyen, N. H.; Danishefsky, S. J. J. Org. Chem. 1988, 53, 1003-1007.
(b) McGee, L. R.; Confalone, P. N. J. Org. Chem. 1988, 53, 3695-3701.
(c) Jung, M. E.; Jung, Y. H. Tetrahedron Lett. 1988, 29, 2517-2520.
(d) McKenzie, T. C.; Hassen, W.; Macdonald, S. J. F. Tetrahedron Lett.
1987, 28, 5435-2436. (e) Hart, D. J.; Merriman, G. H.; Young, D. G.
J. Tetrahedron 1996, 52, 14437-14458. (f) Deshpande, P. P.; Martin,
O. R. Tetrahedron Lett. 1990, 31, 6313-6316. (g) James, C. A.;
Snieckus, V. Tetrahedron Lett. 1997, 38, 8149-8152.
(4) For total synthesis of ravidomycin, see: (a) Futagami, S.; Ohashi,
Y.; Imura, K.; Hosoya, T.; Ohmori, K.; Matsumoto, T.; Suzuki, K.
Tetrahedron Lett. 2000, 41, 1063-1067. For total synthesis of gilvo-
carcins M and V, see: (b) Matsumoto, T.; Hosoya, T.; Suzuki, K. J.
Am. Chem. Soc. 1992, 114, 3568-3570. (c) Hosoya, T.; Takashiro, E.;
Matsumoto, T.; Suzuki, K. J. Am. Chem. Soc. 1994, 116, 1004-1015.
(d) Takemura, I.; Imura, K.; Matsumoto, T.; Suzuki, K. Org. Lett. 2004,
6, 2503-2505.
(5) Narayan, S.; Roush, W. R. Org. Lett. 2004, 6, 3789-3792.
(6) Mal, D.; Patra, A.; Roy, H. Tetrahedron Lett. 2004, 45, 7895-
7898.
(7) Simpkins, N. S. Sulphones in Organic Synthesis; Pergamon
Press: Oxford, 1993.
(8) Sengupta, S.; Sadhukhan, S. K.; Singh, R. S. Ind. J. Chem. 2001,
40B, 997-999.
(9) Harigaya, Y.; Suzuki, T.; Onda, M. Chem. Pharm. Bull. 1979,
27, 2636-2641.
(10) Qabaja, G.; Jones, G. B. J. Org. Chem. 2000, 65, 7187-7194.
(11) Ghorai, S. K.; Roy, H. N.; Bandopadhyay, M.; Mal, D. J. Chem.
Res., Synop. 1999, 686-687.
10.1021/jo0512960 CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/27/2005
J. Org. Chem. 2005, 70, 9017-9020
9017

SCHEME 3. Preparation of Styryl Sulfone 20
SCHEME 4. Preparation of Defucogilvocarcin
Derivative 23
FIGURE 1. Gilvocarcin and WS-5995 antibiotics.
SCHEME 1. Strategy for Chrymutasins6
SCHEME 2. Annulation with Styryl Sulfone 10
sulfone 20 for about 1 h. Subsequently, the reaction
mixture was allowed to return to room temperature
under ambient conditions during a period of 1 h. After
quenching (aqueous NH4Cl) and routine workup, we
isolated a crystalline yellow solid as the sole product 22
in 93-98% yields, which was further purified by recrys-
tallization. Unlike the products (i.e., 11, 13, and 16 from
styryl sulfone 10), compound 22 retained the phenyl
sulfone group. In stark contrast to the fact that Hauser-
Kraus annulation always provides 1,4-dihydroxynaph-
thalene derivatives,12 the compound 22 exists in the keto
form. The structure of 22 was confirmed by its X-ray
crystallographic analysis as well as NMR data (Figure
2).
To arrive at the gilvocarcin nucleus, it was necessary
to remove the PhSO2 group in compound 22. Of the many
methods available for desulfonylation,13 we chose to
employ Bu3SnCl/NaCNBH3, considering the susceptibil-
ity of the lactone present in 22 to base-catalyzed ring
opening. When compound 22 was subjected to reductive
desulfonylation14 with the above reagent, the product 23,
The preparation of sulfone 20 was achieved by extend-
ing Heck reaction8 to the diazonium salt of amine 19,
which was, in turn, synthesized in four steps from
commercially available amine 17 (Scheme 3) by a modi-
fication of the sequence3d developed by McKenzie et al.
Though the amine group in 19 was flanked by two ortho
substituents, in situ Heck coupling of its diazonium salt
with phenyl vinyl sulfone in the presence of a catalytic
amount of Pd(OAc)2 smoothly provided the desired styryl
sulfone 20 in 88% yield. The structure of styryl sulfone
20 was established by analysis of NMR data.
Results of the annulation study of sulfone 20 with
isobenzofuranone 21 are presented in Scheme 4. The
anion of cyanophthalide 21, generated at -60 °C by
reaction with lithium tert-butoxide, was treated with
9018 J. Org. Chem., Vol. 70, No. 22, 2005

was concentrated. Generally, a bright yellow solid appeared,
which was filtered and washed with 1:1 mixture (20 mL) of
diethyl ether and petroleum ether. Otherwise, the residue was
diluted with ethyl acetate (50 mL), and the layers were sepa-
rated. The aqueous layer was extracted with ethyl acetate (3 ×
25 mL). The combined extracts were washed with brine and H2O,
dried (Na2SO4), and concentrated. The crude product was
purified by column chromatography on silica gel or by recrys-
tallization. This procedure was adopted for the preparation of
compounds 11 and 22.
2-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)benzoic Acid
(11): Yellow solid. mp 193-195 °C; 1H NMR (500 MHz, CDCl3)
δ 8.12 (d, J ) 7.4 Hz, 2H), 8.08 (dd, J ) 7.4 Hz, 1.3 Hz, 1H),
7.89-7.71 (m, 2H), 7.67 (dt, J ) 7.5 Hz, 1.2 Hz, 1H), 7.56 (dt, J
) 7.5 Hz, 1.2 Hz, 1H), 7.36 (d, J ) 7.5 Hz, 1H), 6.91 (s, 1H); 13
C
NMR (125 MHz, CDCl3) δ 185.3, 184.1, 169.6, 151.8, 136.1, 134.1,
134.0, 133.7, 133.7, 132.6, 132.5, 131.2, 130.5, 129.9, 129.3, 127.2,
126.3. MS EI (70 eV), m/z: 293 (100%), 278 (M+), 262, 248, 233,
222, 206, 176, 162. Anal. Calcd for C17H10O4: C, 73.38; H, 3.62.
Found: C, 73.31; H, 3.37.
FIGURE 2. ORTEP plot of X-ray crystal structure of 22.
an isomer of gilvocarcin M, was obtained in 94% yield.
Comparison of the NMR data with those of the litera-
ture15 authenticated the structure of the product. The
synthesis of 23 could be regarded as the formal total
synthesis of WS-5995 A and C (4b) antibiotics, which
have been previously synthesized10 from the methyl ether
derivative 24.
In summary, condensation of an appropriately substi-
tuted styryl sulfone with a phthalide has provided a
regiospecific convergent synthesis of benzo[d]naphtho-
[1,2-b]pyran-6-one nucleus of gilvocarcin antibiotics. This
route has resulted in a brief and efficient synthesis of
benzonaphthopyranone 23, an established late-stage
intermediate to WS-5995 A and C antibiotics. We believe
that this work should be applicable to other polycyclic
aromatic natural products, namely phenanthroviridins,
jadomycin A, kinamycins, and C-glycosidic polyketides.16
2-Methoxy-4-methylpivalanilide (18). Trimethylacetyl chlo-
ride (2.50 g, 20.75 mmol) was added dropwise to a stirred
mixture of 2-amino-5-methylphenol (2.00 g, 16.26 mmol) and
aqueous NaHCO3 (1.65 g, 19.64 mmol, in 10 mL of H2O) in
dichloromethane (20 mL) at room temperature. Stirring was
continued for 25 min, and then the resulting reaction mixture
was diluted with water (50 mL) and extracted with dichlo-
romethane (3 × 25 mL). The combined organic extracts were
washed with brine, dried (Na2SO4), and concentrated to provide
2-hydroxy-4-methylpivalanilide. Methyl iodide (2.27 mL, 5.15 g,
36.27 mmol) was added to a solution of 2-hydroxy-4-methylpiv-
alanilide and K2CO3 (7.0 g, 50 mmol) in dry acetone (25 mL) at
0 °C, and stirring was continued for 3 h. After completion of the
reaction, inorganic salts were filtered and the filtrate was
concentrated. The residue was diluted with ether (100 mL) and
successively washed with water (2 × 20 mL) and brine (20 mL),
dried over Na2SO4, and concentrated to give an oil. The crude
liquid was further purified by column chromatography on silica
gel (10% ethyl acetate-petroleum ether) to provide 2-methoxy-
4-methylpivalanilide (18) (3.38 g, 94%). 1H NMR (200 MHz,
CDCl3) δ 8.25 (d, J ) 8.1 Hz, 1H), 8.06-8.00 (brs, 1H), 6.75 (d,
J ) 8.1 Hz, 1H), 6.68 (s, 1H), 3.87 (s, 3H), 2.31 (s, 3H), 1.31 (s,
9H); 13C NMR (50 MHz, CDCl3) δ 176.2, 147.8, 133.1, 125.2,
121.3, 119.3, 110.6, 55.7, 39.8, 27.6, 21.3.
Methyl 3-Methoxy-5-methylanthranilate (19). n-Butyl-
lithium (1.6 M in hexane, 6.2 mL, 9.92 mmol) was added over a
period of 5 min to a stirred solution of 2-methoxy-4-methylpiv-
alanilide (1 g, 4.52 mmol) in THF (12 mL) at room temperature
under dry N2 atmosphere. After an additional 30 min, the
solution was cooled to -78 °C (ethyl acetate/liquid N2 bath),
carbonated by passing dry CO2 through the reaction mixture,
and stirred continually for 2 h while maintaining an internal
temperature of -78 °C. The reaction mixture was warmed to
room temperature and was quenched with saturated NaHCO3
solution (40 mL). The mixture was extracted with ethyl acetate
(2 × 20 mL). The resulting aqueous layer was acidified with
dilute HCl. The aqueous solution was successively extracted with
ethyl acetate (3 × 40 mL), dried (Na2SO4), and concentrated.
Purification of the crude product by recrystallization from ethyl
acetate-petroleum ether gave a white crystalline solid. The
white solid compound was refluxed with 10 mL of 25% aqueous
HCl in methanol (5 mL) for 12 h. After cooling, the reaction
mixture was diluted with H2O (30 mL) and extracted with ethyl
acetate (3 × 25 mL), washed with brine, dried (Na2SO4), and
concentrated to afford a solid residue. The residue was dissolved
in dry methanol (12 mL), and SOCl2 (0.9 mL, 12 mmol) was
added dropwise at 0 °C for 10 min. After being stirred for 1 h at
0 °C, the resulting reaction mixture was heated at reflux for 2
h. MeOH was removed, and the residue was diluted with
aqueous NaHCO3 solution (45 mL). The resulting mixture was
extracted with ether (3 × 25 mL). The combined organic phases
were washed with water and brine and concentrated. The
residue on column chromatographic purification afforded 19 as
an oil in 62% yield (550 mg). 1H NMR (200 MHz, CDCl3) δ 7.27
Experimental Section
General Procedure for Annulation. To a stirred solution
of lithium tert-butoxide (9.84 mmol) in THF (40 mL) at -60 °C
(chloroform/liquid N2 bath) under an inert atmosphere was
added a solution of a phthalide (3.28 mmol) in THF (5 mL). The
resulting yellowish solution was stirred at -60 °C for 25 min,
after which a solution of a Michael acceptor (1.0-1.5 equiv
unless otherwise stated) in THF (5 mL) was added to it. The
cooling bath was removed after about 1 h at -60 °C, and the
reaction mixture was brought to room temperature over a period
of 1 h and further stirred for 2-6 h. The reaction was then
quenched with 10% NH4Cl (15 mL), and the resulting solution
(12) (a) Hassner, A.; Stumer, C. Organic Syntheses Based on Name
Reactions; Pergamon: Amsterdam, 2002; p 153. (b) Mitchell, A. S.;
Russell, R. A. Tetrahedron 1995, 51, 5207-5236. (c) Hauser, F. M.;
Rhee, R. P. J. Org. Chem. 1978, 43, 178-180. (d) Hauser, F. M.; Mal,
D. J. Am. Chem. Soc. 1984, 106, 1098-1104. (e) Kraus, G. A.; Sujimoto,
H. Tetrahedron Lett. 1978, 19, 2263-2266. (f) Freskos, J. N.; Morrow,
G. W.; Swenton, J. S. J. Org. Chem. 1985, 50, 805-810. (g) Brade, W.;
Vasella, A. Helv. Chim. Acta 1989, 72, 1649-1657. (h) Shair, M. D.;
Yoon, T. Y.; Mosny, K. K.; Chou, T. C.; Danishefsky, S. J. J. Am. Chem.
Soc. 1996, 118, 9509-9525. (i) Swenton, J. S.; Freskos, J. N.; Dalid-
owicz, P.; Kerns, M. L. J. Org. Chem. 1996, 61, 459-464. (j) Matsumoto,
T.; Yamaguchi, H.; Tanabe, M.; Yasui, Y.; Suzuki, K. Tetrahedron Lett.
2000, 41, 8393-8396. (k) Couladouros, E. A.; Strongilos, A. T.;
Papageorgiou, V. P.; Plyta, Z. F. Chem.-Eur. J. 2002, 8, 1795-1083.
(l) Hauser, F. M.; Liao, L.; Sun, Y. Org. Lett. 2002, 4, 2241-2243. (m)
Hauser, F. M.; Dorsch, W. A. Org. Lett. 2003, 5, 3753-3754.
(13) Na´jera, C.; Yus, M. Tetrahedron 1999, 55, 10547-10658.
(14) Giovannini, R.; Petrini, M. Synlett 1995, 973-974.
(15) Frutos, D. O.; Atienza, C.; Echavarren, A. M. Eur. J. Org. Chem.
2001, 163-171.
(16) (a) Matsumoto, T.; Yamaguchi, H.; Tanabe, M.; Yasui, Y.;
Suzuki, K. Tetrahedron Lett. 2000, 41, 8393-8395. (b) Tatuta, K.;
Ozeki, H.; Yamaguchi, M.; Tanaka, M.; Okui, T. Tetrahedron Lett.
1990, 31, 5495-5498.
J. Org. Chem, Vol. 70, No. 22, 2005 9019

(d, J ) 1.7 Hz, 1H), 6.69 (d, J ) 1.7 Hz, 1H), 3.85 (s, 3H), 3.84
(s, 3H), 2.25 (s, 3H); 13C NMR (50 MHz, CDCl3) δ 168.6, 147.1,
139.2, 124.0, 121.6, 114.4, 109.9, 55.6, 51.3, 20.8.
11-Phenylsulfonyl-1,10-dimethoxy-8-methyl-11H-diben-
zo[c,h]chromene-6,12-dione (22): Yellow solid; mp 198-200
°C; IR (KBr) cm-1 1732 (s), 1684 (s), 1622, 1583, 1471, 1444,
1322 (s), 1292, 1265, 1232, 1176, 1132, 1112, 1051, 1016, 784,
Methyl 2-(2-Benzenesulfonylvinyl)-3-methoxy-5-meth-
ylbenzoate (20). A solution of NaNO2 (170 mg, 2.46 mmol) in
water (0.5 mL) was added dropwise to an ice-cold solution of 19
(390 mg, 2.00 mmol) in 40% aqueous HBF4 (1.2 mL). Stirring
was continued for 45 min at 0 °C, after which phenyl vinyl
sulfone (370 mg, 2.20 mmol) in MeOH (0.5 mL) and Pd(OAc)2
(10 mg, 0.043 mmol) were added to the above mixture. This was
then heated on water bath for 1 h. The resulting mixture was
cooled to room temperature and extracted with ethyl acetate (3
× 25 mL). The combined organic extracts were successively
washed with brine, dried (Na2SO4), and concentrated. The crude
product was purified by column chromatography using petro-
leum ether-ethyl acetate (4:1) to give 20 (610 mg, 88%) as a
white solid. mp 135-137 °C; IR (KBr) cm-1 1716, 1599, 1461,
1438, 1323, 1296, 1223, 1169, 1142, 1065, 984, 887; 1H NMR
(200 MHz, CDCl3) δ 8.09 (d, J ) 15.4 Hz, 1H), 7.97 (dd, J ) 7.4
Hz, 1.7 Hz, 2H), 7.61-7.46 (m, 3H), 7.22 (s, 1H), 7.15 (d, J )
15.4 Hz, 1H), 6.87 (s, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 2.38 (s, 3H).
13C NMR (50 MHz, CDCl3) δ 167.7, 158.9, 141.8, 141.1, 136.5,
133.5, 133.0, 130.9, 129.1, 127.6, 123.0, 118.0, 115.0, 55.8, 52.5,
21.6; MS ESI (70 eV): [M + H]+, 347.0782, [M - OCH3]+,
315.0530; Anal. Calcd for C18H18O5S: C, 62.41; H, 5.24. Found:
C, 62.32; H, 5.47.
1
730, 686; H NMR (200 MHz, CDCl3) δ 7.84 (s, 1H), 7.59-7.15
(m, 7H), 7.08 (s, 1H), 6.94-6.85 (m, 1H), 6.63 (s, 1H), 3.99 (s,
3H), 3.93 (s, 3H), 2.49 (s, 3H); 13C NMR (50 MHz, CDCl3) δ 186.7,
160.5, 159.3, 156.5, 146.2, 141.0, 136.9, 135.8, 134.2, 133.9, 129.1,
128.3, 122.3, 122.1, 118.5, 118.2, 115.9, 113.4, 105.6, 75.0, 56.2,
56.1, 21.7 (one predicted signal was not observed); HMRS ESI
(70 eV): for C26H21O7S [M + H]+ calcd 477.1008, found 477.1005.
Acknowledgment. This work was financially sup-
ported by DST, New Delhi. A.P., P.P., and S.R. grate-
fully acknowledge the receipt of their Research Fellow-
ships from CSIR, New Delhi.
Supporting Information Available: Experimental de-
tails and spectral data. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO0512960
9020 J. Org. Chem., Vol. 70, No. 22, 2005