J. Org. Chem. 2001, 66, 5937-5939
5937 Scheme 1a
Investigation of Elimination Reactions of 7-Oxabicyclo[2.2.1]heptane-2-carboxylates Kyoo-Hyun Chung,*,† Hyung Goo Lee,† In-Young Choi,† and Jong-Ryoo Choi‡ Department of Chemistry, Inha University, Inchon 402-751, Korea, and LG Biotech./LG Chem. 104-1 Moongi, Yusung, Taejon 305-380, Korea
a
Key: (a) (i) 4, (ii) H2/Pd; (b) base.
Table 1. Epimerization in the Elimination Reaction
[email protected] Received April 16, 2001
A base-induced elimination of 7-oxabicyclo[2.2.1]heptane-2-carboxylates has been a useful synthetic transformation to prepare highly functionalized cyclohexenols.1 Some cyclohexenols were important intermediates in the synthesis of several natural products such as shikimic acid and podophyllotoxin.1,2 The cyclohexenols can be easily prepared by Diels-Alder reaction of furans with some appropriate dienophiles, followed by the treatment of the resulting 7-oxabicycloheptanes with a base (Scheme 1). The electron-withdrawing group (EWG) was CO2R′, CN, or SO2R′; LHMDS or LDA was usually employed.1,2 However, NaOMe or KO-t-Bu gave a better result when the EWG was CHO or C(O)R′.1c,2e,2g In addition to the bridged C-O bond, the C-N bond is also cleaved when the oxygen is replaced by NC(O)R′.2d,3 A two-step mechanism was proposed; carbanion formation followed by the bond cleavage. The reaction was quite stereoselective and little epimerization was observed.1,2 In this paper, we describe epimerization, substituent effects, and limitations in this elimination reaction. Three stereoisomers of dimethyl 7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylate1a were treated with LHMDS or KHMDS to examine the epimerization. As shown in Table 1, the epimerization hardly took place with diendo-1 (entries 1 and 2) but did with di-exo-1 in some cases (entries 5 and 6). The higher the reaction temperature, the more readily the epimerization proceeded. The potassium enolate tended to epimerize more readily than the lithium enolate. By treatment with DBU, di-endo-1 was isomerized to give exo,endo-1, while di-exo-1 was not. Under the cleavage conditions, the isomerization of di-exo-1 or di-endo-1 to exo,endo-1 was negligible. Therefore, compound 2, the thermodynamically more stable trans isomer, was formed †
Department of Chemistry, Inha University. LG Biotech./LG Chem. (1) (a) Brion, F. Tetrahedron Lett. 1982, 5299-5302. (b) Guildford, A, J.; Turner, R. W. J. Chem. Soc., Chem. Commun. 1983, 466-467. (c) Keay, B. A.; Razapaksa, D.; Rodrigo, R. Can. J. Chem. 1984, 62, 1093-1098. (2) (a) Royen, L. A. V.; Mijingheer, R.; Clercq, P. J. D. Tetrahedron Lett. 1983, 3145-3148. (b) Campbell, M. M.; Kaye, A. D.; Sainsburry, M.; Yavarzadeh, R. Tetrahedron 1984, 40, 2461-2470. (c) Koreda, M.; Jung, K.-Y.; Ichita, J. J. Chem. Soc., Perkin Trans. 1 1989, 21292131. (d) Campbell, M. M.; Mahon, M. F.; Sainsburry, M.; Searle, P. A. Tetrahedron Lett. 1981, 951954. (e) Gustafsson, J.; Sterner, O. J. Org. Chem. 1994, 59, 3994-3997. (f) Couche, E.; Deschatrettes, R.; Poumellec, K.; Bortolussi, M.; Mandville, G.; Bloch, R. Synlett 1999, 87-89. (g) Berkowitz, D, B.; Choi, S.; Maeng, J.-H. J. Org. Chem. 2000, 65, 847-860. (3) Kozikowski, A. P.; Kuniak, M. P. J. Org. Chem. 1978, 43, 20832048. ‡
entry
reagent
base
T (°C)
2:3
yield (%)
1 2 3 4 5 6 7 8
di-endo-1 di-endo-1 di-exo-1 di-exo-1 di-exo-1 di-exo-1 exo,endo-1 exo,endo-1
LHMDS KHMDS LHMDS KHMDS LHMDS KHMDS LHMDS KHMDS
-78 0 -78 -78 -20 -20 -78 0
99:1 99:1 1:99 1:99 40:60 69:31 16:84 75:25
85 80 83 78 83 79 83 78
Table 2. Some Substituent Effects in the Elimination Reaction
entry
R
base
yield (%)
1 2 3 4
CH2OCH3 (4a) CH2OCH3 (4a) TBDMS (4b) TBDMS (4b)
LHMDS LDA LHMDS LDA
80 67
by bond cleavage followed by epimerization of the resulting cis isomer 3 in the reaction of di-exo-1 with base. The epimerization did not take place at -78 °C, but did at higher temperature. And also the potassium enolate tended to epimerize more readily at higher temperature. When exo,endo-1 reacted with LHMDS at -78 °C, the cis isomer 3 was formed as a major product, indicating that the exo hydrogen was abstracted more readily than the endo one (Table 1, entry 7).4 When KHMDS was employed, the trans-isomer 2 was major, resulting from epimerization as well as abstraction of the endo hydrogen in the enolate formation (Table 1, entry 8). The effect of the substituent R in Scheme 1 was not reported previously in this reaction. When R was an alkyl group or a protected amine, the ring opening reaction took place.1b,2f As shown in Table 2, the rearrangement of methoxymethyl ether 4a or TBDMS ether 4b did not proceed with LHMDS, but did with LDA. When ether 4b was treated with LHMDS and quenched with D2O at 0 °C, no deuterium was incorporated. The hydrogen at the C2 position was not abstracted under the reaction conditions. As the bulkiness of the substituent increases, a less (4) Yang, W.; Koreeda, M. J. Org. Chem. 1992, 57, 3836-3839.
10.1021/jo010394s CCC: $20.00 © 2001 American Chemical Society Published on Web 07/27/2001
5938
J. Org. Chem., Vol. 66, No. 17, 2001
hindered base is needed. In some cases, the choice of base is critical. Although the enolate was formed, the rearrangement did not take place in some cases. endo-Lactone 6 failed to give the ring-opening product upon treatment with a variety of bases. The reason was explained by geometric constraints.2g
To examine the stereoelectronic effect of the enolate, exo-lactone 7 was prepared by a known procedure.5 A PM3 calculation reveals that the lone pair at C2 in 6 is expected to be nearly orthogonal to the bridged C-O bond, but the one in 7 is nearly antiperiplanar to the bond, as shown in Figure 1. The orbital geometry should favor ring opening, when the enolate is formed from lactone 7. Indeed, the cleavage reaction was quite stereoselective and gave hydroxy lactone 8 in 85% yield (Scheme 2). Therefore, the proper geometry of the carbanion is important in the elimination reaction.
Notes
enolate was not participating in developing double-bond character at the bridgehead.1c The carbanion was too stable to induce C-O bond cleavage.
In conclusion, a base-induced elimination reaction of 7-oxabicyclo[2.2.1]heptane-2-carboxylates proceeds in two steps: enolate formation followed by ring opening. The reaction leads to a highly functionalized cyclohexenol. The reaction was quite stereoselective and epimerization was not observed at lower temperatures. When both exo and endo hydrogens were present, the exo hydrogen was abstracted more readily than the endo. However, the reaction did not take place when the enolate was stable or nearly orthogonal to the bridged C-O bond. Experimental Section
Figure 1. Newman projection viewed from C2 to C1 in PM3 MO optimized structure of enolates a and b, formed from 6 and 7.
Scheme 2
Evans reported that imide 9 did not give the ringopening product in contrast to the corresponding ester.6 When the alkylation of keto ester 10 was conducted in the presence of NaH, the C-O bond cleavage did not take place, either.7 The reason may not be the geometric constraint of the corresponding enolate. Upon treatment with a variety of bases, neither anhydride 115b,8 nor nitro ester 129 gave the ring-opening product. The deprotonation of nitro ester 12 was confirmed by trapping the enolate with D2O. pKa’s of compound 11 and 2-nitro-7oxabicyclo[2.2.1]heptane were estimated to be 8.8 and 25.1 lower than that of 7 by a PM3 calculation.10 Due to the resonance stability of the corresponding anion, the (5) (a) Bloch, R.; Guibe-Jampel, E.; Girard, C. Tetrahedron Lett. 1985, 4087-4090. (b) Agur, D. J.; East, M. B. Tetrahedron 1993, 49, 5683-5765. (6) Evans, P. A.; Barnes, D. M. Tetrahedron Lett. 1997, 57-58. (7) Rainier J. D.; Xu, Q. Org. Lett. 1999, 1, 27-29. (8) Lee, M. W.; Herndon, W. C. J. Org. Chem. 1978, 43, 518. (9) Itoh, K.; Kitoh, K.; Sera, A. Heterocycles 1999, 51, 243-248. (10) The relative pKa was calculated by the following equation where R′H is compound 7 and RH is 11 or 2-nitro-7-oxabicyclo[2.2.1]heptane: RH′ + R′Q a RQ + R′H, ∆pKa ) ∆∆G°/2.303RT.
All chemicals were reagent grade (Aldrich Chemical Co.) and were used as purchased without further purification. 1H and 13C NMR spectra were recorded at 200 and 50 MHz in CDCl3 unless otherwise noted. Column chromatographic purifications were performed using 70-230 mesh silica gel. General Procedure for the Elimination Reaction. A base (1-3 equiv) was added to a solution of a 7-oxabicyclo[2.2.1]heptane-2-carboxylate (30-40 mg) in THF (2 mL) at -78 °C. The reaction mixture was stirred at -78 to 0 °C for 1-2 h, quenched with saturated ammonium chloride solution, and then warmed to room temperature. The resulting solution was extracted with ether, and the combined organic extracts were washed with water, dried over MgSO4, and concentrated in vacuo to give the ring-opening product. Dimethyl trans-3-hydroxycyclohex-5-ene-1,2-dicarboxylate (2):1a 1H NMR δ 1.65-1.84 (m, 2H), 2.28-2.37 (m, 2H), 2.48 (s, 1H), 3.41-3.45 (m, 1H), 3.69 (s, 6H), 4.11-4.20 (m, 1H), 7.107.14 (m, 1H); 13C NMR δ 20.1, 24.7, 47.3, 49.4, 49.9, 65.8, 123.8, 138.8, 164.3, 170.6. Dimethyl cis-3-hydroxycyclohex-5-ene-1,2-dicarboxylate (3):1a 1H NMR δ 1.77-1.89 (m, 2H), 2.20-2.55 (m, 3H), 3.72 (s, 6H), 3.65-3.76 (m, 1H), 4.04-4.13 (m, 1H), 7.08-7.13 (m, 1H); 13C NMR δ 21.4, 24.2, 43.8, 49.4, 49.8, 64.9, 124.3, 139.1, 164.2, 170.2. Methyl 2,3-Di-endo-3-methoxymethoxymethyl-7-oxabicyclo[2.2.1]heptane-2-carboxylate (4a). Chloromethyl methyl ether (936 mg, 10.4 mmol) was added dropwise to a stirred solution of methyl 2,3-di-endo-3-hydroxymethyl-7-oxabicyclo[2.2.1]heptane-2-carboxylate (300 mg, 1.61 mmol)5b and N,N-diisopropylethylamine (1.6 g, 12.2 mmol) in CH2Cl2 (10 mL). The reaction mixture was stirred for 4 h at room temperature, diluted with water, and then extracted with EtOAc. The combined organic extracts were washed with water and brine solution, dried over MgSO4, and then concentrated in vacuo to give an oil. Purification by column chromatography on silica gel (hexane/EtOAc ) 2:1) gave 4a (343 mg, 95%): 1H NMR (CDCl3, 300 MHz) δ 1.53-1.87 (m, 4H), 2.41-2.53 (m, 1H), 2.53-2.63 (m, 1H), 3.29-3.51 (m, 2H), 3.37 (s, 3H), 3.72 (s, 3H), 4.46 (d, 1H, J ) 5.2 Hz), 4.63 (s, 2H), 4.72 (t, 1H, J ) 5.1 Hz); 13C NMR (CDCl3, 75 MHz) δ 26.5, 29.5, 46.7, 52.1, 52.3, 55.7, 69.9, 78.1, 79.9, 96.4, 172.6. Methyl 2,3-Di-endo-3-tert-butyldimethylsilyloxymethyl7-oxabicyclo[2.2.1]heptane-2-carboxylate (4b). A mixture of methyl 2,3-di-endo-3-hydroxymethyl-7-oxabicyclo[2.2.1]heptane-
Notes 2-carboxylate (300 mg, 1.61 mmol), tert-butyldimethylsilyl chloride (267 mg, 1.77 mmol), TEA (195 mg, 1.93 mmol), and DMAP (65 mg, 0.53 mmol) in DMF (3 mL) was stirred for 5 h at room temperature. The reaction mixture was poured into water and extracted with EtOAc. The combined organic layer was washed with water and brine, dried over MgSO4, and then concentrated in vacuo to give an oil. Purification by column chromatography on silica gel (hexane/EtOAc ) 3:1) gave 4b (411 mg, 85%): 1H NMR δ 0.02 (s, 6H), 0.86 (s, 9H), 1.51-1.81 (m, 4H), 2.27-2.38 (m, 1H), 2.46-2.50 (m, 1H), 3.30-3.51 (m, 2H), 3.66 (s, 3H), 4.45 (d, 1H, J ) 4.8 Hz), 4.63-4.68 (m, 1H); 13C NMR δ -5.2, 18.4, 26.0, 26.3, 29.4, 49.3, 51.5, 52.0, 65.0, 77.9, 79.3, 172.6. Methyl trans-5-hydroxy-6-(methoxymethoxymethyl)cyclohex-1-enecarboxylate (5a): 1H NMR (CDCl3, 300 MHz) δ 1.71-1.93 (m, 2H), 2.18-2.49 (m, 2H), 3.11-3.24 (m, 1H), 3.36 (s, 3H), 3.55 (d, 1H, J ) 5.6 Hz), 3.68-3.82 (m, 2H), 3.73 (s, 3H), 3.91-4.01 (m, 1H), 4.61 (ABq, 2H, J ) 10.4, 6.5 Hz), 7.01 (t, 1H, J ) 3.6 Hz); 13C NMR (CDCl3, 75 MHz) δ 25.4, 26.5, 39.2, 52.1, 55.9, 67.7, 70.2, 96.8, 128.9, 142.3, 167.2. Anal. Calcd for C11H18O5: C, 57.38; H, 7.88. Found: C, 57.37; H, 7.97. Methyl trans-5-hydroxy-6-(t-butyldimethylsilyloxymethyl)cyclohex-1-enecarboxylate (5b): 1H NMR δ 0.11(d, 6H), 0.91(s, 9H), 1.71-1.96 (m, 2H), 2.26-2.43 (m, 2H), 3.123.19 (m, 1H), 3.75 (s, 3H), 3.79-4.04 (m, 3H), 4.49 (d, 1H), 7.04 (t, 1H, J ) 4.0 Hz); 13C NMR δ -8.2, -7.9, 15.6, 22.7, 23.3, 23.7, 37.7, 49.2, 61.3, 68.1, 125.9, 139.9, 164.4. Anal. Calcd for C8H10O3: C, 59.69; H, 9.39. Found: C, 60.00; H, 9.30 4-Hydroxy-3a,4,5,6-tetrahydro-3H-isobenzofuran-1one (8): 1H NMR δ 1.61-1.79 (m, 1H), 1.96-2.09 (m, 2H), 2.342.46 (m, 2H) 3.02-3.15 (m, 1H), 4.23-4.32 (m, 2H), 4.48 (t, 1H,
J. Org. Chem., Vol. 66, No. 17, 2001 5939 J ) 8.8 Hz), 6.86-6.91 (m, 1H); 13C NMR δ 18.4, 25.5, 38.6, 59.7, 65.3, 123.1, 133.7, 167.8; IR: 3438, 2923, 1740, 1681, 1420, 1229. Anal. Calcd for C8H10O3: C, 62.33; H, 6.54. Found: C, 62.30; H, 6.67. Deuterium Exchange of Methyl 2-exo,3-endo-3-Nitro-7oxabicyclo[2.2.1]heptane-2-carboxylate (12). To a solution of methyl 2-exo,3-endo-3-nitro-7-oxabicyclo[2.2.1]heptane-2-carboxylate (30 mg, 0.149 mmol)9 in THF (2 mL) was added 1.0 M LHMDS in THF (0.15 mL, 0.15 mmol) at -78 °C. The reaction mixture was stirred at -78 to 0 °C for 1 h and quenched with D2O, and then the reaction mixture was warmed to room temperature. The resulting solution was extracted with ether, and the combined organic extracts were washed with water, dried over MgSO4, and concentrated to give an oil. 1H NMR showed that the peak at 5.39 ppm completely disappeared. The proton at the C3 position was exchanged to deuterium, and the carbanion was formed next to the nitro group.
Acknowledgment. This work was supported by the Korea Science and Engineering Foundation (NO. 9703-01-01-5-L). We thank Professor B.-S. Lee of Inha University for a PM3 calculation. Supporting Information Available: 1H and 13C NMR spectra for compounds 2, 3, 4a,b, 5a,b, and 8 and 1H NMR spectra for compounds 12 and 12-d1. This material is available free of charge via the Internet at http://pubs.acs.org. JO010394S
