LETTER
Synthesis of a 6-Iodo Isocoumarin Building Block for the Rubromycin Family
2737
Wadsworth–Emmons reaction of 3 with phosphonate 410 In summary, we reported a robust protocol for the prepa-
resulting in a 35:65 mixture of diastereoisomers (82% ration of a 6-iodo isocoumarin building block very
yield), (Z)-5 being the major product.11
suitable for rubromycin syntheses. The feasibility of
palladium-catalyzed couplings on the base-sensitive lac-
tone 7 was demonstrated, paving the way for our future
projects.
The acid-promoted intramolecular condensation of ortho-
carboxyl benzyl ketones or enol ether derivatives12 is a
key step in many isocoumarin syntheses. In the case of 5,
however, harsh conditions were required to achieve lac-
tone formation. Since the condensation under acidic con-
ditions may result in concomitant cleavage of the methyl
ester at C-3, various mixtures of acids and methanol were
applied. Finally, isocoumarin 6 was readily obtained
when 5 was refluxed in a 1:1 mixture of methanol and
concentrated aqueous HBr. The product 6 precipitated
from the mixture in 55–68% yield. The solid was very
poorly soluble and required no purification except wash-
ing and drying. We are confident that this method of con-
verting aldehyde 3 into isocoumarin 6 is convenient for
large-scale preparation. As subsequent step, isocoumarin
derivative 6 was converted into the benzyl ether 7 (81%
yield) previous to its use in coupling reactions.
Acknowledgment
The authors thank the Fonds der Chemischen Industrie and
Schering AG for financial support of this research. We thank Mr. X.
Luan for preliminary investigations in this area and Dr. R. Zimmer
for his assistance during preparation of this manuscript.
References
(1) (a) Brockmann, H.; Lenk, W.; Schwantje, G.; Zeeck, A.
Tetrahedron Lett. 1966, 3525. (b) Brockmann, H.; Lenk,
W.; Schwantje, G.; Zeeck, A. Chem. Ber. 1969, 102, 126.
(c) Brockmann, H.; Zeeck, A. Chem. Ber. 1970, 103, 1709.
(2) g-Rubromycin was isolated from Streptomyces collinus and
showed antibiotic activity against various bacteria strains.
(3) (a) Qin, D.; Ren, R. X.; Siu, T.; Zheng, C.; Danishefsky, S.
J. Angew. Chem. Int. Ed. 2001, 40, 4709; Angew. Chem.
2001, 113, 4845. (b) Siu, T.; Qin, D.; Danishefsky, S. J.
Angew. Chem. Int. Ed. 2001, 40, 4713; Angew. Chem. 2001,
113, 4849.
(4) Syntheses of isocoumarin fragments: (a) Trash, T. P.;
Welton, T. D.; Behar, V. Tetrahedron Lett. 2000, 41, 29.
(b) Waters, S. P.; Kozlowski, M. C. Tetrahedron Lett. 2001,
42, 3567.
(5) Gopinath, R.; Haque, S. J.; Patel, B. K. J. Org. Chem. 2002,
67, 5842.
(6) For related directed ortho-metallations of aromatic acetals,
see: (a) Plaumann, H. P.; Keay, B. A.; Rodrigo, R.
Tetrahedron Lett. 1979, 4921. (b) Winkle, M. R.; Ronald,
R. C. J. Org. Chem. 1982, 47, 2101. (c) Napolitano, E.;
Giannone, E.; Fiaschi, R.; Marsili, A. J. Org. Chem. 1983,
48, 3653. (d) Li, C.; Lobkovsky, E.; Porco, J. A. Jr. J. Am.
Chem. Soc. 2000, 122, 10484.
According to our strategy, isocoumarin 7 should be in-
serted into rubromycin syntheses by means of palladium-
catalyzed coupling reactions with appropriately function-
alized naphthoquinone moieties. To prove this concept,
base-labile lactone 7 was employed in first Sonogashira13
and Heck14 reactions. The Sonogashira couplings were
carried out under standard conditions15 in DMF
(Scheme 2). Both phenylacetylene derivative 8 and 3-
methoxypropyne derivative 9 were cleanly obtained in
high yields (84% and 91%).
MeO
O
MeO
O
BnO
I
BnO
a
O
O
CO2Me
CO2Me
R
7
(7) Procedure for the Carboxylation 1 → 2: n-BuLi (1.86 mL,
2.50 M in hexanes, 4.65 mmol) was added at 0 °C to a
solution of 1.26 g (3.88 mmol) of 1 in 25 mL of dry
cyclohexane. The mixture was stirred at r.t. for 3 h, recooled
to 0 °C and 1.00 mL (12.9 mmol) of methyl chloroformate
were added. Stirring was continued overnight and the
reaction was allowed to warm up to r.t. After quenching with
10 mL of sat. aq Na2CO3, the layers were separated and the
aqueous layer was extracted with 3 × 10 mL of Et2O. The
combined organic layers were concentrated in vacuo and the
residue was dissolved in 25 mL of THF. Then, 37% HCl (aq,
4 mL), 0.70 g (12.0 mmol) KF and 5 mL of H2O were added
and the mixture was stirred at r.t. until TLC indicated
complete conversion (6–24 h). The mixture was washed with
20 mL of brine. The layers were separated and the aqueous
layer was extracted with 3 × 20 mL of CH2Cl2. The
combined organic layers were dried over MgSO4, filtered
and evaporated. Column chromatography (silica gel,
EtOAc–hexane = 1:1) provided 0.47 g (58%) 2 as reddish
solid. Analytical data for methyl 6-formyl-3-hydroxy-2-
methoxybenzoate (2): mp 102–104 °C. 1H NMR (500 MHz,
CDCl3): d = 3.90 (s, 3 H, OMe), 3.98 (s, 3 H, CO2Me), 6.45
(br s, 1 H, OH), 7.11, 7.55 (2 d, J = 8.4 Hz, 2 × 1 H, 4-H, 5-
H), 9.79 (s, 1 H, CHO) ppm. 13C NMR (126 MHz, CDCl3):
d = 53.0 (q, CO2Me), 62.5 (q, OMe), 116.6, 129.9 (2 d, Ar),
127.0, 127.6, 144.4, 154.4 (4 s, Ar), 166.9 (s, CO), 189.0 (d,
84%
91%
8: R = Ph
9: R = CH2OMe
Scheme 2 Reagents and conditions: a) R-C≡CH, Pd(OAc)2, PPh3,
CuI, Et3N, DMF, r.t., 8 h.
Heck reactions of 7 with tert-butyl acrylate and 3-buten-
2-one proceeded smoothly, the latter being performed
under Jeffery’s mild conditions.16 The a,b-unsaturated
carbonyl compounds 10 and 1117 were isolated in 71%
and 91% yield, respectively (Scheme 3).
MeO
O
MeO
O
BnO
I
BnO
a,b
O
O
R
CO2Me
CO2Me
O
7
71%
91%
10: R = OtBu
11: R = CH3
Scheme
3
Reagents and conditions: a) tert-Butyl acrylate,
Pd(OAc)2, PPh3, LiCl, Et3N, DMF, 85 °C, 8 h; b) 3-buten-2-one,
Pd(OAc)2, n-Bu4NCl, NaHCO3, DMF, r.t., 72 h.
Synlett 2004, No. 15, 2736–2738 © Thieme Stuttgart · New York