First Asymmetric Cycloaddition of Carbonyl Ylides to Vinyl

First Asymmetric Cycloaddition of Carbonyl Ylides to Vinyl Sulfoxides and Furan-2(5H)-ones Jose´ L. Garcı´a Ruano,* Alberto Fraile, M. Rosario Martı´n,* and Alberto Nu´n˜ez Departamento de Quı´mica Orga´ nica, UniVersidad Auto´ noma de Madrid, Cantoblanco, 28049 Madrid, Spain [email protected]; [email protected] ReceiVed May 12, 2006

The Rh2(OAc)4-catalyzed reactions of o-(methoxycarbonyl)-R-diazoacetophenone with enantiomerically pure 5-ethoxy-3-p-tolylsulfinylfuran-2(5H)-ones 1a and 1b afford 4,10-epoxybenzo[4,5]cyclohepta[1,2c]furan-3,9-diones 6a and 6b, in good or moderate yields and in a completely regioselective way. The π-facial selectivity is complete for 1a, which only yields anti-6a adducts, and very high for 1b. The endo stereoisomers are favored with respect to the exo ones in both reactions. The sulfinyl group significantly increases the reactivity of the dipolarophile as it has been demonstrated by studying the behavior of 5-methoxyfuran-2(5H)-one (3).

Introduction The generation of carbonyl ylides from diazo compounds and their cycloaddition reactions has gained much attention due to their use in the construction of highly complex polycycles.1 The main contributions to the development of these reactions in their achiral version were due to Ibata’s2 and Padwa’s groups,3 by using copper or rhodium complexes. The first example of these reactions in their chiral version was provided by Hodgson and co-workers, who reported the enantioselective intramolecular cycloaddition of unsaturated R-diazo-β-ketoesters, catalyzed by [Rh(S-DOPS)4],4 which evolved with moderate ee (53%). * Corresponding author. (J.L.G.R.) Tel.: +34-91-497-4701 and fax: +3491-497-3966. (M.R.M.) Tel.: +34-91-497-4703 and fax: +34-91-497-3966.

(1) (a) McMills, M. C.; Wright, D. In Synthetic Applications of 1,3Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products; Padwa, A.; Pearson, W. H., Eds.; John Wiley: New York, 2003; Ch. 4, pp 253-314. (b) Metha, G.; Muthusamy, S. Tetrahedron 2002, 58, 9477-9504. (c) Hodgson, D. M.; Le Strat, F.; Avery, T. D.; Donohue, A. C.; Bru¨ckl, T. J. Org. Chem. 2004, 69, 8796-8803. (2) (a) Suga, H.; Ishida, H.; Ibata, T. Tetrahedron Lett. 1998, 39, 31653166. (b) Suga, H.; Ito, K.; Inoue, H.; Ishida, H.; Ibata, T. Bull. Chem. Soc. Jpn. 2001, 74, 1115-1121. (3) (a) Padwa, A.; Fryxell, G. E.; Zhi, L. J. Am. Chem. Soc. 1990, 112, 3100-3109. (b) Padwa, A.; Weingarten, M. D. Chem. ReV. 1996, 96, 223269 and references therein. (c) Padwa, A.; Boonsombt, J.; Rashatasakhon, P.; Willis, J. Org. Lett. 2005, 7, 3725-3727. (4) Hodgson, D. M.; Stupple, P. A.; Jonstone, C. Tetrahedron Lett. 1997, 38, 6471-6472.

Although these results have been improved up to 90% ee,5 the complete control of the stereoselectivity has not been achieved yet. Enantioselective tandem processes consisting of carbonyl ylide formation-intermolecular cycloaddition have been reported by Suga,6 Hashimoto,7 Hodgson,8 and Doyle.9 However, as is indicated by Padwa10 and Hodgson,8b the asymmetric induction of these reactions is usually low,11 providing tetrahydrofuranes with low or moderate ee values, which precludes the preparation of optically pure samples by using these (5) Hodgson, D. M.; Labande, A. H.; Pierard, F. Labande, A. H.; Expo´sito, M. A. J. Org. Chem. 2003, 68, 6153-6159. (6) Suga, H.; Inoue, K.; Ionue, I.; Kakehi, A.; Shiro, M. J. Org. Chem. 2005, 70, 47-56. (7) (a) Kitagaki, S.; Anada, M.; Kataoka, O.; Matsuno, K.; Umeda, C.; Watanabe, N.; Hashimoto, S. J. Am. Chem. Soc. 1999, 121, 1417-1418. (b) Kitagaki, S.; Yasugahira, M.; Anada, M.; Nakajima, M.; Hashimoto, S. Tetrahedron Lett. 2000, 41, 5931-5935. (8) (a) Hodgson, D. M.; Glen, R.; Redgrave, A. J. Tetrahedron Lett. 2002, 43, 3927-3930. (b) Hodgson, D. M.; Glen, R.; Grant, G. H.; Redgrave, A. J. J. Org. Chem. 2003, 68, 581-586. (c) Hodgson, D. M.; Labande, A. H.; Glen, R.; Redgrave, A. J. Tetrahedron: Asymmetry 2003, 14, 9211-924. (d) Hodgson, D. M.; Le Strat, F.; Avery, T. D.; Donohue, A. C.; Bruckl, T. J. Org. Chem. 2004, 69, 8796-8803. (9) Doyle, M. P.; Forbes, D. C. Chem. ReV. 1998, 98, 911-935. (10) (a) Padwa, A. J. Organomet. Chem. 2005, 690, 5533-5540. (b) Padwa, A. HelV. Chim. Acta 2005, 88, 1357-1374. (11) Some exceptions to this general behavior have been reported. Thus, Hashimoto achieved ee values up to 92% by using diazo ketones with DMAD as the dipolarophile (see ref 7a). 10.1021/jo060990s CCC: $33.50 © 2006 American Chemical Society

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J. Org. Chem. 2006, 71, 6536-6541

Published on Web 07/13/2006

Asymmetric Cycloaddition of Carbonyl Ylides SCHEME 1.

Addition of Carbonyl Ylide 2 to Furanone 3

procedures. Furthermore, it should be noted that the degree of asymmetric induction in these intermolecular cycloadditions is very sensitive to the substitution pattern of the dipole and dipolarophile.8b Consequently, the search of new and efficient methods giving access to these adducts in their optically pure form is nowadays an unsolved problem that deserves further investigation. In this context, the use of chiral auxiliaries could be a good solution because even if the control of the stereoselectivity is not complete, the separation of the resulting diastereoisomers would provide optically pure samples. Surprisingly, the cycloaddition of carbonyl ylides to dipolarophiles bearing chiral auxiliaries has never been reported. The sulfinyl group has been widely and successfully used as a chiral auxiliary in Diels-Alder reactions.12 By contrast, vinyl sulfoxides have been used as dipolarophiles only occasionally.13 Several years ago, we initiated a program to explore the usefulness of vinyl sulfoxides in asymmetric 1,3-dipolar reactions. Their behavior in reactions with diazoalkanes,14 nitrile oxides,15 nitrones,16 and azomethine ylides17 has evidenced a strong influence of the sulfinyl group on the course of these reactions, significantly enhancing the dipolarophilic reactivity of the double bonds and playing a very important role in the control of the π-facial and endo/exo selectivities. Sulfinyl furanones have been used as dipolarophiles in many of our studies14a-d,15a-b,16,17c due to the interest in the resulting highly functionalized adducts. Additionally, the reported behavior of furanones with no sulfinyl group as dienophiles and dipolarophiles allowed us to make the pertinent comparisons. However, to our knowledge, the reactions of carbonyl ylides with vinyl sulfoxides or furanones have never been reported. Therefore, we decided to study the reactions of sulfinyl furanones 1a and (12) Cid, B.; Garcı´a Ruano, J. L. In Topics in Current Chemistry; Page, P. C. B., Ed.; Springer: New York, 1999; pp 1-126. (13) With nitrones: (a) Louis, C.; Hootele´, C. Tetrahedron: Asymmetry 1997, 8, 109-131 and references therein. (b) Aggarwal, V. K.; Roseblade, S.; Barrell, J. K.; Alexander, K. Org. Lett. 2002, 4, 1227-1229. With nitrile oxides: (c) Bravo, P.; Bruche´, L.; Crucianelli, M.; Farina, A.; Meille, S. V.; Merli, A.; Seresini, P. J. Chem. Res., Synop. 1996, 348-349. (14) (a) Garcı´a Ruano, J. L.; Fraile, A.; Martı´n, M. R. Tetrahedron: Asymmetry 1996, 7, 1943-1950. (b) Garcı´a Ruano, J. L.; Fraile, A.; Gonza´lez, G.; Martı´n, M. R.; Clemente, F. R.; Gordillo, R. J. Org. Chem. 2003, 68, 6522-6534. (c) Garcı´a Ruano, J. L.; Peromingo, M. T.; Alonso, M.; Fraile, A.; Martı´n, M. R.; Tito, A. J. Org. Chem. 2005, 70, 89428947. (d) Garcı´a Ruano, J. L.; Bercial, F.; Gonza´lez, G.; Martı´n, A. M.; Martı´n, M. R. Tetrahedron: Asymmetry 2002, 13, 1993-2002. (e) Garcı´a Ruano, J. L.; Alonso, S.; Blanco, D.; Martı´n Castro, A. M.; Martı´n, M. R.; Rodrı´guez, J. Org. Lett. 2001, 3, 3173-3176. (15) (a) Garcı´a Ruano, J. L.; Fraile, A.; Martı´n, M. R. Tetrahedron 1999, 55, 14491-14500. (b) Garcı´a Ruano, J. L.; Fajardo, C.; Martı´n, M. R. Tetrahedron 2005, 61, 4363-4371. (16) (a) Garcı´a Ruano, J. L.; Fraile, A.; Martı´n Castro, A. M.; Martı´n, M. R. J. Org. Chem. 2005, 70, 8825-8834. (b) Garcı´a Ruano, J. L.; Andres, J. I.; Fraile, A.; Martı´n Castro, A. M.; Martı´n, M. R. Tetrahedron Lett. 2004, 45, 4653-4656. (17) (a) Garcı´a Ruano, J. L.; Tito, A.; Peromingo, M. T. J. Org. Chem. 2003, 68, 10013-10019. (b) Garcı´a Ruano, J. L.; Tito, A.; Peromingo, M. T. J. Org. Chem. 2002, 67, 981-987. (c) Garcı´a Ruano, J. L.; Fraile, A.; Martı´n, M. R. 19th International Symposium on the Organic Chemistry of Sulfur 2000; Book of Abstracts, p 52.

1b18 with the carbonyl ylide 2. We report herein the results of these reactions, which provide optically pure 4,10-epoxy[4,5]cyclohepta[1,2-c]furan-3,9-diones with suitable substituents to be transformed into new highly functionalized polycyclic condensated systems with a benzoheptane moiety. To determine the role of the sulfinyl group in the course of 1,3-dipolar cycloadditions of carbonyl ylides, it was necessary to compare the results obtained from furanones 1 with those obtained in the reaction of 2 with the racemic 5-methoxyfuran-2(5H)-one (3),19 bearing no sulfinyl group, which are also described in this paper. Results and Discussion Carbonyl ylide 2 was generated by Rh2(OAc)4-catalyzed decomposition of o-methoxycarbonyl-R-diazoacetophenone (4).20 The reaction of 4 (1 equiv) with racemic furanone 3 (3 equiv) in THF at room temperature afforded a 3:2 mixture of anti-5endo21 and anti-5-exo (Scheme 1), the former adduct being the major one. The isolated yield was rather low (ca. 17%), probably due to the competitive decomposition of the dipole by different routes under the experimental conditions. It is noteworthy that the anti adducts were the only ones obtained. The predominance of the endo approach mode should also be noticed. The stereoisomers were isolated by column chromatography of the mixture. Diastereomerically pure endo and exo adducts were obtained in 10 and 7% isolated yields, respectively. To find the optimum conditions providing the highest yield and endo selectivity, other metal catalysts and solvents were investigated. The use of dichloromethane, acetonitrile, or an ionic liquid (1n-butyl-3-methylimidazolium tetrafluoroborate)22 as the solvent did not improve the result obtained with THF. The reaction crude contained, almost exclusively, 1H-isochromene-1,4(3H)dione, which results from the hydrolysis of dipole 2. It is noteworthy that the use of CuCl 10 mol % in THF as the catalyst, instead of Rh2(OAc)4, did not increase the endo/exo ratio (60:40), in contrast to the results reported by Ibata.2a The reaction of o-methoxycarbonyl-R-diazoacetophenone (4) with enantiomerically pure sulfinyl furanone 1b in the presence catalytic amounts of Rh(II) acetate was investigated under different experimental conditions (solvent, 4/1b ratio, temper(18) Carretero, J. C.; Garcı´a Ruano, J. L.; Lorente, A.; Yuste, F. Tetrahedron: Asymmetry 1993, 2, 177-180. (19) Schenck, G. O. Liebigs Ann. 1953, 584, 156-176. (20) Hodgson, D.; Holt, G.; Wall, D. K. J. Chem. Soc. C 1970, 971973. (21) The syn or anti character of the adducts, which indicates the cis or trans relationship between H1 and H10a (Scheme 1), is related to the face of the dipolarophile that is attacked by the dipole, using as a reference the spatial arrangement of the alkoxy group. The endo or exo terms, indicative of the cis or trans arrangement exhibited by furanone and dihydroisocromone moieties at the tetrahydrofurane ring, are related to the endo and exo addition modes of the dipole, using the ester group at the furanone ring as a reference. (22) Ionic liquids as convenient recyclable media for generation of carbonyl ylides have been reported: Muthusamy, S.; Gnanaprakasam, B. Tetrahedron 2005, 61, 1309-1315.

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Garcı´a Ruano et al. TABLE 1. Cycloaddition of Carbonyl Ylide 2 to Furanone 1b

entry

4/1b

solvent

T (°C)

ratio anti-6b-endo/anti-6b-exo/syn-6b-exo (yield (%))

1 2 3 4 5 6

1:1 1:3 1:3 1:3 1:3 1:3

THF THF THF CH2Cl2 MeCN MeCN

rt rt 0 rt rt 0

complex mixture 41a(23):27(20):32(21) 61a:20:19 54b:28:18 58b:18:24 62a,c:17:21

a Determined by HPLC. b Determined by 1H NMR. c The conversion of 4 was not complete, and the proportion of adducts 6 in the reaction mixture was very low.

ature, addition speed of 4 to furanone, and catalyst). The best results are collected in Table 1. The reaction of o-methoxycarbonyl-R-diazoacetophenone (4) with an equimolecular amount of sulfinyl furanone 1b in dichloromethane or tetrahydrofuran afforded a very complex mixture (entry 1, Table 1). This mixture consisted of three adducts 6b, such as those depicted in Table 1, along with other adducts resulting from the cycloaddition of dipole 2 to the ketone group of 6b adducts and 1H-isocromene1,4-dione. The isolation of adducts 6b as pure compounds was not possible from these mixtures. When the ratio of 1b/4 was increased up to 3 (entry 2, Table 1), the chromatographic isolation and purification of the three adducts 6b (65% combined isolated yield) could be performed, and only traces of the adducts containing two molecules of dipole were detected by 1H NMR of the reaction crude. The proportion of stereoisomer 6b depended on the solvent and the reaction temperature. Reactions in dichloromethane are less clean. Stereoselectivity is higher in acetonitrile (compare entries 2, 4, and 5 in Table 1); however, decomposition of 4 into 2 is lower in acetonitrile, which did not allow us to work at lower temperatures in such a solvent (see entry 6, Table 1). The reaction of 2 (1 equiv) with sulfinyl furanone 1a (3 equiv) at room temperature in THF provided a 76:24 mixture of only two anti adducts (entry 1, Table 2), the anti-6a-endo being the major one. They were isolated in 51% (exo) and 23% (endo) yields by column chromatography. Higher stereoselectivity (81: 19) was attained when the reaction was carried out at 0 °C. However, the use of acetonitrile or dichloromethane instead of THF did not show any substantial change in the stereochemical outcome. Desulfinylation of adducts 6 with aluminum amalgam gave complex mixtures because the ketone group at the adducts is more sensitive to the reagent than the C-S bond. However, we have found that hydrogenolysis of the C-S bond can be efficiently performed with activated zinc in a mixture of THF and saturated aqueous ammonium chloride solution at room temperature (Scheme 2).23 Under these mild conditions, the tolylsulfinyl group was completely removed with no competitive (23) Holton, R. A.; Crouse, D. J.; Williams, A. D.; Kennedy, R. M. J. Org. Chem. 1987, 52, 2317-2318.

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TABLE 2. Cycloaddition of Carbonyl Ylide 2 to Furanone 1a

entry

solvent

T (°C)

ratio anti-6a-endo/anti-6a-exo (yield (%))

1 2 3 4

THF THF CH2Cl2 MeCN

rt 0 rt rt

76a(51):24(23) 81a:19 68b:32 69a:31

a

Determined by HPLC. b Determined by 1H NMR.

process such as reduction, hydrolysis of the acetals, or racemization. The isolated yields of enantiomerically pure compounds 7 obtained in these reactions ranged between 70 and 80%. Compounds obtained from anti-6a-exo and anti-6b-exo have identical NMR spectra but opposite specific rotation since they are enantiomers.24 The same is true for compounds anti-7-endo resulting from anti-6a-endo and anti-6b-endo. The regio- and stereochemistry of adducts 6 were established from their NMR data, after unequivocal assignment of the acetalic and ether CH protons by HMQC.25 Thus, we assigned the anti stereochemistry to those adducts exhibiting J1,10a values smaller than 3 Hz (they are indicative of a trans relationship), whereas the compound with J1,10a 6.9 Hz was assigned as a syn adduct. The regiochemistry and the cis relationship of the protons at C-10 and C-10a of the anti-6-endo adducts and anti7-endo was unequivocally established from the large value observed for J10,10a (9-10 Hz).26 Further evidence for the regiochemistry of primary cycloadducts anti-6a,b-endo and syn(24) The ee values determined by HPLC (Chiracel OD, hexane/i-PrOH 90: 10, flow rate ) 1 mL/min) for both enantiomers of compounds anti7-endo and anti-7-exo were higher than 99.5%. (25) The acetalic carbon at C-1 appears at 101-107 ppm, whereas the chemical shift of C-10 in the R-position with respect to the carbonyl group was ranked at 79-85 ppm.

Asymmetric Cycloaddition of Carbonyl Ylides

FIGURE 1. π-Facial selectivity for additions of carbonyl ylide to 3-sulfinyl furanones 1. SCHEME 2.

Desulfinylation of Adducts 6

6b-exo is provided by the fact that desulfinylation products showed the proton at C-3a as a doublet. COSY and NOESY experiments with cycloadducts anti-6a,b-exo unequivocally revealed their regiochemistry. Thus, a strong NOE effect was observed between H-1 and H-10 of these compounds, whereas the COSY effect was not observed in anti-6a-exo, and it is very weak in anti-6b-exo. The comparison of the results obtained from compounds 1 and 3 allowed us to know the role of the sulfinyl group in the course of these reactions. The first point concerns the dipolarophilic reactivity of the double bonds toward dipole 2, which is strongly increased by the presence of the sulfinyl group. Thus, the yields obtained in reactions from 1 (>65%) are higher than those from 3 (