A strong-base induced 4+2 cycloaddition of homophthalic anhydrides with enolizable enones: a direct and efficient synthesis ofperi-hydroxy aromatic compounds

摘要

A strong-base induced 4+2 cycloaddition of homophthalic anhydrides with enolizable enones: a direct and efficient synthesis of peri-hydroxy aromatic compounds Namakkal G. Ramesh, Kiyosei Iio, Akiko Okajima, Shuji Akai and Yasuyuki Kita* Graduate School of Pharmaceutical Sciences, Osaka University, 1-6, Yamada-oka, Suita, Osaka 565-0871, Japan. E-mail: kita@phs.osaka-u.ac.jp Received (in Cambridge, UK) 11th September 1998, Accepted 28th October 1998 A direct and efficient synthesis of peri-hydroxy aromatic compounds via a strong-base induced 4+2 cycloaddition of homophthalic anhydrides with a-phenylsulfinyl enolizable enones has been accomplished.In the past two decades, considerable effort has been devoted to the synthesis of biologically important polycyclic peri-hydroxy aromatic compounds which include anthracyclines,1 fredericamycin A,2 granaticin,3 bostrycin,4 olivin5 and other polycyclic antibiotics. Among the methods known for the construction of the key peri-hydroxy aromatic frameworks,6 the strong-base induced 4+2 cycloaddition reaction of homophthalic anhydrides to dienophiles7 continues to dominate, due to the generality and efficiency of the reaction as well as ready accessibility of the starting materials.An added advantage is the direct synthesis of peri-hydroxy compounds in a single step. The applicability of this methodology has already been realized in the total synthesis of a variety of natural products such as anthracyclines,1i,8 galtamycinone9 and dynemicin A.10 However, all these examples utilize non-enolizable dienophiles such as quinone-type compounds or a,b-unsaturated esters.7b On the other hand, the strong-base induced reaction of homophthalic anhydride with enolizable enones such as cyclohex-2-en-1-one or its b-substituted derivatives did not give any of the cycloaddition products7b although in some cases the expected product was obtained in low yield.11 This is probably due to extensive enolization under the basic reaction condition, which might in turn retard the cycloaddition step.Since the discovery of this reaction by us in 1982,7a we have been engaged in developing its variants and utilizing this methodology for the synthesis of natural compounds. We have now extended this reaction to enolizable enones. We reasoned that the aforesaid problem could be readily overcome by the introduction of a suitable functional group at the a-position of the enone moiety which should be electron deficient in order to increase dienophilicity and should also behave as a leaving group, to provide directly the peri-hydroxy aromatic compounds.A number of functional groups such as Br, SPh, S(O)Ph, SO2Ph were considered and among them, the sulfinyl group, which fulfils the above-mentioned criteria, was found to be the substituent of choice. Here we report an efficient, strong-base induced 4+2 cycloaddition of various homophthalic anhydrides with a-sulfinyl substituted enones providing directly the peri-hydroxy aromatic compounds in moderate to good yields.The homophthalic anhydrides 1andash;d were prepared according to the reported method.7 The strong-base induced reaction of homophthalic anhydride 1a with 2-phenylsulfinylcyclopent- 2-en-1-one 2a was investigated in detail in order to optimize the reaction conditions. Similar to our earlier work,7d we have found that NaH is more suitable than other bases (ButOK, LDA etc.).As can be seen from Table 1, among the various sets of reaction conditions tried, use of 1.1 equiv. of NaH in refluxing dioxane was adjudged the best, affording after acylation the peri-hydroxy compound as its acetate 3a in good yield. In a typical experiment, to a slurry of NaH in dry dioxane was added a solution of homophtahlic anhydride 1a in dioxane. The resulting slurry was stirred at room temperature for 30 min and then for 20 min each at 80 deg;C and 120 deg;C (bath temperature).Enone 2a was then added and the reaction mixture was stirred for 20 min., cooled, quenched with aq. NH4Cl and extracted with EtOAc. The crude reaction mixture, after evaporation of the solvent, was treated with Ac2O and pyridine and left overnight at room temperature. Column chromatography afforded the peri-hydroxy aromatic compound as its acetate 3a. Subsequently, all the reactions were performed using the same conditions, except for the final reaction time.This base catalyzed 4+2 cycloaddition reaction was found to be general for a range of substituted homophthalic anhydrides 1andash;d as well as with different sulfinyl substituted enones 2andash;e, including that having an acetal functional group, affording the respective products in moderate to good yields (Table 2). Noteworthy is the success of the reaction with acyclic enone 2e, which is a rewarding result given the report that no reaction was observed between homophthalic anhydride and methyl but- 2-enoate.11a It is highly relevant that the reactions of homophthalic anhydrides 1a and 1b with cyclohex-2-en-1-one and cyclopent-2-en-1-one were not successful.The reactions under identical conditions resulted only in complex mixtures and no useful product could be isolated, indicating the possibility of a base-induced enolization in these cases. Thus, it is clearly evident that the sulfinyl group present at the a-position of the enone moiety plays an important role in directing the course of the reaction.Furthermore, the highlight of the reaction is the rapid syn-elimination of the phenylsulfinyl moiety under the reaction conditions, a unique characteristic of this functional group,7d providing directly the peri-hydroxy aromatic compounds in a single step. The advantages of the sulfinyl group are emphasized by the fact that the strong-base induced reaction of homophthalic anhydride with 2-bromocyclohex-2-en-1-one was not successful.Reaction of 1a with 2-bromocyclohex-2-en- 1-one, under identical conditions for 7 h, afforded after acylation acetate 3e in only 7 yield with the recovery of a large amount of unreacted bromocyclohexenone. Use of an additional equivalent of base (2.2 equiv.) in order to bring about the trans-elimination of HBr from a possible non-aromatized cycloadduct, did not lead to any significant improvement in the yield. The reaction afforded, after 3 h, the acetate 3e in only 10 yield.Table 1 Reaction of homophthalic anhydride 1a with the enone 2a in the presence of NaH under various conditions Entry Solvent T/deg;C Time Yield of 3aa () 1 THF room temp. 25 h 20 2 THF reflux 15 min 41 3 1,2-diethoxyethane reflux 20 min 45 4 1,4-dioxane reflux 20 min 62 a Isolated yields after column chromatography Chem. Commun., 1998, 2741ndash;2742 2741O O O R3 O S Ondash; Ph R3 AcO O R1 R2 R1 R2 2andash;e 3andash;n (ii) Ac2O, pyridine, room temp., overnight + + (i) NaH, dioxane 120 oC (bath temp.) R4 R5 R5 R4 1andash;d The generality and efficiency of the reaction, ready availability of the starting materials coupled with the unique activating as well as leaving ability of the sulfinyl group renders this method an attractive one for the synthesis of peri-hydroxy aromatic compounds using enolizable enones.The application of this methodology for the synthesis of natural products is in progress and will be reported in a forthcoming paper.This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture, Japan (08245101) and Special Coordination funds of the Science and Technology Agency of Japanese Govrnment. We are grateful to the Japan Society for the Promotion of Science for a postdoctoral fellowship to N. G. R. Notes and references 1 (a) R. H. Thompson, Naturally Occurring Quinones, Academic Press, New York, 1971; (b) F. Arcamone, Topics in Antibiotics Chemistry, ed.P. G. Sammes, Halstead Press, New York, 1978, vol.2; (c) S. T. Crooke and S. D. Reich, Anthracyclines: Current Status and New Developments, Academic Press, New York, 1980; (d) F. Arcamone, Med. Res. Rev., 1984, 4, 153; (e) P. T. Gallagher, Contemp. Org. Synth., 1996, 3, 433; (f) S. Terashima, J. Synth. Org. Chem. Jpn., 1982, 40, 20; (g) M. J. Broadhurst, C. H. Hassall and G. J. Thomas, Chem. Ind. (London), 1985, 106; (h) K. Krohn, Angew. Chem., Int. Ed. Engl., 1986, 25, 790; (i) Y.Tamura and Y. Kita, J. Synth. Org. Chem. Jpn., 1988, 46, 205; (j) K. Krohn, Tetrahedron, 1990, 46, 291. 2 D. L. Boger, O. Huuml;ter, K. Mbiya and M. Zhang, J. Am. Chem. Soc., 1995, 117, 11839 and references cited therein. 3 K. Nomura, K. Okazaki, K. Hori and E. Yoshii, J. Am. Chem. Soc., 1987, 109, 3402. 4 D. S. Larsen and R. J. Stoodley, Tetrahedron, 1990, 46, 4711 and references cited therein. 5 W. R. Rousch, M. R. Michaelides, D. F. Tai, B. M. Lesur, W. K. M.Chong and D. J. Harris, J. Am. Chem. Soc., 1989, 111, 2984 and references cited therein. 6 N. J. Broom and P. G. Sammes, J. Chem. Soc., Chem. Commun., 1978, 162; G. A. Kraus and H. Sugimoto, Tetrahedron Lett., 1978, 2263; F. M. Hauser and R. P. Rhee, J. Org. Chem., 1979, 101, 178; J. H. Dodd and S. M. Weinreb, Tetrahedron Lett., 1979, 3593; J.-P. Gesson, J.-C. Jacquesy and B. Renoux, Tetrahedron, 1984, 40, 4743; G. A. Kraus and B. S. Fulton, Tetrahedron, 1984, 40, 4777; K.A. Parker and E. L. Tallman, Tetrahedron, 1984, 40, 4781; D. L. Boger and I. C. Jacobson, J. Org. Chem., 1991, 56, 2115. 7 (a) Y. Tamura, A. Wada, M. Sasho, K. Fukunaga, H. Maeda and Y. Kita, J. Org. Chem., 1982, 47, 4376; (b)Y. Tamura, M. Sasho, K. Nakagawa, T. Tsugoshi and Y. Kita, J. Org. Chem., 1984, 49, 473; (c) Y. Tamura, M. Sasho, S. Akai, H. Kishimoto, J. Sekihachi and Y. Kita, Chem. Pharm. Bull., 1987, 35, 1405; (d)Y. Kita, K. Iio, A. Okajima, Y. Takeda, K. Kawaguchi, B.A. Whelan and S. Akai, Synlett, 1998, 292 and references cited therein. 8 F. Matsuda, M. Kawasaki, M. Ohsaki, K. Yamada and S. Terashima Tetrahedron, 1988, 44, 5745; J.-F. Lavallee, R. Rej, M. Courchesne, D. Nguyen and G. Attardo, Tetrahedron Lett., 1993, 34, 3519; M. Kirihara and Y. Kita, Heterocycles, 1997, 46, 705. 9 T. Matsumoto, H. Yamaguchi and K. Suzuki, Synlett, 1996, 433. 10 M. D. Shair, T. Y. Yoon, K. K. Mosny, T. C. Chou and S. J. Danishefsky, J. Am. Chem. Soc., 1996, 118, 9509. 11 (a) Y. S. Rho, S. H. Park, Y. J. Kwon, J. H. Yoo and I. H. Cho, Bull. Korean Chem. Soc., 1996, 17, 944; (b) D. Mal, N. K. Hazra, K. V. S. N. Murthy and G. Majumdar, Synlett, 1995, 1239; (c) A. P. Marchand, P. Annapurna, W. H. Watson and A. Nagl, J. Chem. Soc., Chem. Commun., 1989, 281. Communication 8/07095D Table 2 NaH induced 4+2 cycloaddition reaction of various homophthalic anhydrides 1 with different sulfinyl substituted enones 2 in refluxing dioxane Homophthalic anhydride Dienophile Product Entry 1 R1 R2 2 R3 R4 R5 t/min 3 Yield ()a 1 1a H H 2a ndash;CH2ndash; H 20 3a 62 2 1b H SPh 2a ndash;CH2ndash; H 20 3b 58 3 1c H OMe 2a ndash;CH2ndash; H 20 3c 59 4 1d OBn H 2a ndash;CH2ndash; H 20 3d 56 5 1a H H 2b ndash;(CH2)2ndash; H 20 3e 70 6 1b H SPh 2b ndash;(CH2)2ndash; H 20 3f 58 7 1c H OMe 2b ndash;(CH2)2ndash; H 20 3g 62 8 1a H H 2c ndash;(CH2)3ndash; H 20 3h 60 9 1b H SPh 2c ndash;(CH2)3ndash; H 20 3i 52 10 1a H H 2d ndash;(CH2)2ndash; (CH2)2Xb 20 3j 63 11 1b H SPh 2d ndash;(CH2)2ndash; (CH2)2Xb 20 3k 57 12 1a H H 2ec Ph H H 90 3l 49 13 1b H SPh 2ec Ph H H 180 3m 48 14 1c H OMe 2ec Ph H H 210 3n 41 a Isolated yields after column chromatography. b X = 1,3-dioxan-2-yl. c E: Z = ca. 6 : 1 mixture. 2742 Chem. Commun., 1998, 2741ndash;2742