Synthesis of 4-Acetylisocoumarin: First Total Syntheses of AGI-7 and Sescandelin Sanghee Kim,* ,†,‡ Gao-jun Fan, †,‡ Jaekwang Lee, † Jung Joon Lee, § and Deukjoon Kim ‡ Natural Products Research Institute, Seoul National University, 28 Yungun, Jongro, Seoul 110-460, Korea, College of Pharmacy, Seoul National University, San 56-1, Shilim, Kwanak, Seoul 151-742, Korea, and Korea Research Institute of Bioscience and Biotechnology P.O. Box 115, Yusong, Taejon 305-600, Korea pennkim@snu.ac.kr Received August 3, 2001 Abstract: A practical synthetic route to 4-acetylisocou- marins and the first total synthesis of AGI-7 (5) and sescandelin (4) are described. The readily available homo- phthalate 8 was transformed to the vinylogous amide ester 13 in high overall yield. Upon treatment of 13 with refluxing aqueous formic acid, the desired 4-acetylisocoumarin (5) and its regioisomer 3-methyl-4-formylisocoumarin (17) were produced in a 3:1 ratio. After separation of the desired product (5) from the unwanted minor isomer, the enanti- oselective reduction of AGI-7 by borane in the presence of Corey’s (S)-oxazaborolidine reagent afforded (+)-sescandelin (4) with a 93% ee. Among the naturally occurring isocoumarin deriva- tives, 4-substituted isocoumarins with no substituent at the 3-position are very rare, 1 and only a few synthetic methods for construction of the skeleton have been developed. 2-5 Ray 3 synthesized 4-methylisocoumarin by cyclization of acetonyl benzoate in sulfuric acid, and Usgaonkar 4 reported the synthesis of 4-carboxyisocou- marin from homophthalic acid with DMF-POCl 3 . 4-Ace- tylisocoumarins have been prepared from 4-carboxyiso- coumarins by addition of magnesium malonate to the corresponding acid chloride followed by hydrolysis in poor to modest overall yields. 5 Some representative 4-substituted 3-nonsubstituted natural isocoumarins are oospoglycol (1), 6 oosponol (2), 7 4-acetyl-6,8-dihydroxy-5-methylisocoumarin (3), 8 and (-)- sescandelin (4) 1,9 as shown in Figure 1. It has been reported that these isocoumarin compounds possess various interesting bioactivities including root-promoting activity and antibiotic activities against plant cells, bacteria, and plant-pathogenic fungi. 7,9,10 In the screening of anti-angiogenic substances inhibit- ing differentiation of endothelial cells to a capillary-like structure on Matrigel, one of us isolated a new compound, 6,8-dihydroxy-4-acetylisocoumarin, which was named AGI-7 (5), along with sescandelin (4) from an unidentified fungal strain by bioassay-guided fractionation and isola- tion. 11 To further investigate the biochemical and phar- maceutical effects of sescandelin and AGI-7, especially in growth and proliferation of new blood vessels, we needed to synthesize these isocoumarins in large quanti- ties. Herein, we report a practical and high-yielding synthetic route to 4-acetylisocoumarins and the first total syntheses of AGI-7 (5) and sescandelin (4). The synthesis began from known homophthalate 8 12 (Scheme 1), which was synthesized as described previ- ously. 12b Diels-Alder reaction of diene 6 and allenedi- carboxylate 7, followed by aromatization with Et 3 NH + F - , provided 8 in 69% yield. Protection of the phenol 8 as its dibenzyl ether 9 and basic hydrolysis of diester provided homophthalic acid 10 in 81% yield. A facile two-step transformation of homophthalic acid 10 to ketone 11 was conducted by employing literature procedure. 13 Reaction of 10 with acetic anhydride/pyridine followed by hydroly- sis with aqueous sodium hydroxide gave ketone 11 in 76% yield. The 1 H NMR spectrum of 11 at room temperature showed two extremely broad singlets (δ 4.1-3.9 for the ArCH 2 COCH 3 protons and δ 2.4-2.2 for the ArCH 2 - COCH 3 protons). In contrast, that of methyl ester of 11 showed sharp singlets at δ 3.64 and 2.08. Two broad signals of 11 appeared at further downfield compare to the corresponding signals of methyl ester of 11. This * To whom correspondence should be addressed. Phone: +82-2-740- 8913. Fax: +82-2-762-8322 † Natural Products Research Institute. ‡ College of Pharmacy. § Korea Research Institute of Bioscience and Biotechnology. (1) Kimura, Y.; Nakadoi, M.; Shimada, A.; Nakajima, H.; Hamasaki, T. Biosci. Biotechnol. Biochem. 1994, 58, 1525. (2) For recent review on the synthesis of isocoumarins, see: Na- politano, E. Org. Prep. Proced. Int. 1997, 29, 633. (3) Arora, P. K.; Ray, S. J. Indian Chem. Soc. 1985, LXII, 383. (4) (a) Belgaonkar, V. H.; Usgaonkar, R. N. J. Chem. Soc., Perkin Trans. 1 1977, 702. (b) Belgaonkar, V. H.; Usgaonkar, R. N. Chem. Ind. (London) 1976, 954. (5) (a) Kimura, M.; Waki, I.; Deguchi, Y.; Amemiya, K.; Maeda, T. Chem. Pharm. Bull. 1983, 31, 1277. (b) Kokubo, M.; Kimura, M.; Japan patent 8035, 1967; Chem. Abstr. 1967, 67, 116818k. (6) Nitta, K.; Yamamoto, Y.; Yamamoto, I.; Yamatodani, S. Agric. Biol. Chem. 1963, 27, 822. (7) (a) Nozawa, K.; Yamada, M.; Tsuda, Y.; Kawai, K.; Nakaima, S. Chem. Pharm. Bull. 1981, 29, 2689. (b) Nitta, K.; Imai, J.; Yamamoto, I.; Yamamoto, Y. Agric. Biol. Chem. 1963, 27, 817. (c) Nakajima, S.; Kawai, K.; Yamada, S. Phytochemistry 1976, 15, 327. (8) Aldrige, D. C.; Grove, J. F.; Turner, W. B. J. Chem. Soc. C 1966, 126. (9) Kimura, Y.; Nakajima, H.; and Hamasaki, T. Agric. Biol. Chem. 1990, 54, 2477. (10) Kovacs, M.; Sonnenbichler, J. Liebigs Ann. Chem. 1997, 211. (11) Lee, J. H.; Park, Y. J.; Kim, H. S.; Hong, Y. S.; Kim, K.-W.; Lee, J. J. J. Antibiot. 2001, 54, 463. (12) (a) Singh, S.; Singh, I. Indian J. Chem. 1985, 24B, 568. (b) Roush, W. R.; Murphy, M. J. Org. Chem. 1992, 57, 6622. (13) Hauser, F. M.; Rhee, R. P. J. Org. Chem. 1977, 42, 4155. Figure 1. 4-Substituted 3-nonsubstituted natural isocou- marins. 3127 J. Org. Chem. 2002, 67, 3127-3130 10.1021/jo010789b CCC: $22.00 © 2002 American Chemical Society Published on Web 03/29/2002