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J. Org. Chem. 2000, 65, 4058-4069
Stereoselective Synthetic Approaches to Highly Substituted Cyclopentanes via Electrophilic Additions to Mono-, Di-, and Trisubstituted Cyclopentenes Matthew A. Clark, Bradley K. Goering, Jun Li, and Bruce Ganem* Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell University, Ithaca, New York 14853-1301 Received January 25, 2000
Electrophilic additions to allylically substituted alkenes are of broad synthetic utility. The control of stereoselectivity in such reactions has attracted considerable interest. However, the effect of allylic and homoallylic substituents in cyclopentenyl systems has not been investigated systematically. Studies on a series of mono, di-, and trisubstituted cyclopentenes are reported in which transvicinal-additions favor a syn-selective approach of electrophiles to the cyclopentene system. The formal addition of HOBr, HOCl, CH3SCl, and dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF)/NaN3 with a variety of cyclopentene substrates has been carried out, and the effects of various allylic substituents on these selectivities have been examined. Additions of HOBr, HOCl, and DMTSF to highly functionalized substrates proceed predictably with syn selectivity, giving predominantly or exclusively one product. Methanesulfenyl chloride additions are less predictable, but can be tuned by suitable alteration of solvent and substrate. Results have proven useful in total syntheses of (+)-trehazolin and (+)-allosamidin. Introduction The promising biological activity of several new cyclopentane-containing natural products has generated considerable interest in their total synthesis. The polyhydroxylated cyclopentane rings in allosamidin 1 (Figure 1), trehazolin 2, the keruffarides and crasserides 3, and mannostatins A and B (4 and 5, respectively) are thought to mimic the structure of carbohydrates. As a result, many of these substances inhibit glycoside-processing enzymes, and total syntheses of several have been reported.1-4 In previous synthetic studies reported by our laboratory, penta- and hexasubstituted cyclopentane units were constructed in a two-stage process (Scheme 1). Stage 1 involved the well-precedented heterocycloaddition of a monosubstituted cyclopentadiene like 6, which, upon reduction of the intermediate bicyclic adduct 7, afforded 3,4,5-trisubstituted cyclopentenes such as 8. Stage 2 of the process involved a vicinal functionalization of the bisallylically substituted alkene group in 8 to introduce two (1) Allosamidin: (a) Kassab, D.; Ganem, B. J. Org. Chem. 1999, 64, 1782-1783. (b) Goering, B. K.; Ganem, B. Tetrahedron Lett. 1994, 35, 6997-7000. (c) Trost, B. M.; Van Vranken, D. L. J. Am. Chem. Soc. 1990, 112, 1261-1263. (d) Griffith, D. A.; Danishefsky, S. J. J. Am. Chem. Soc. 1991, 113, 5863-5864. (e) Takahashi, S.; Terayama, H.; Kuzuhara, H. Tetrahedron Lett. 1992, 33, 7565-7568. (2) Trehazolin: (a) Goering, B. K.; Li. J.; Ganem, B. Tetrahedron Lett. 1995, 36, 8905-8908. (b) Li, J.; Lang, F. R.; Ganem, B. J. Org. Chem. 1998, 63, 3403-3410. (c) Ogawa, S.; Uchida, C. Chem. Lett. 1993, 173-176. (d) Kobayashi, Y.; Miyazaki, H.; Shiozaki, M. J. Org. Chem. 1994, 59, 813-822. (e) Ledford, B. E.; Carreira, E. M. J. Am. Chem. Soc. 1994, 117, 11811-11812. (3) Mannostatins (a) King, S. B.; Ganem, B. J. Am. Chem. Soc. 1991, 113, 5089-5090. (b) King, S. B.; Ganem, B. J. Am. Chem. Soc. 1994, 116, 562-570. (c) Knapp, S.; Phar, T. G. M. J. Org. Chem. 1991, 56, 4096-4097. (d) Trost, B. M.; Van Vranken, D. L. J. Am. Chem. Soc. 1991, 113, 6317-6318. (e) Ogawa, S.; Kimura, H.; Uchida, C.; Ohashi, T. J. Chem. Soc., Perkin Trans. 1 1995, 1695-1705. (f) Ling, R.; Mariano, P. S. J. Org. Chem. 1998, 63, 6072-6076. (4) For a recent review, see (g) Berecibar, A.; Grandjean, C.; Siriwardena, A. Chem. Rev. 1999, 99, 779-844.
Figure 1. Structures of some naturally occurring cyclopentitols.
additional substituents leading to 9. For many stage 2 additions, the factors affecting stereoselectivity are not well-understood. In the case of vicinal dihydroxylation, numerous reports of the osmylation of such cyclopentenes have appeared,5 although no clear stereochemical trend (5) See inter alia: (a) Hanselaer, R.; Samson, M.; Vandewalle, M. Tetrahedron 1978, 34, 2393-2397. (b) Trost, B. M.; Kuo, G.-H.; Benneche, T. J. Am. Chem. Soc. 1988, 110, 621-622. (c) Poli, G. Tetrahedron Lett. 1989, 30, 7385-7388. (d) Halterman, R. L.; McEvoy, M. A. J. Am. Chem. Soc. 1992, 114, 980-985. (e) Donohoe, T. J.; Garg, R.; Moore, P. R. Tetrahedron Lett. 1996, 37, 3407-3410. (f) Donohoe, T. J.; Moore, P. R.; Waring, M. J.; Newcombe, N. J. Tetrahedron Lett. 1997, 38, 5027-5030.
10.1021/jo000101f CCC: $19.00 © 2000 American Chemical Society Published on Web 06/06/2000
Electrophilic Additions to Substituted Cyclopentenes Scheme 1
J. Org. Chem., Vol. 65, No. 13, 2000 4059 Scheme 3
Scheme 2
has emerged.6 Electrophilic addition reactions to allylically substituted alkenes are of broad synthetic utility, and the control of stereoselectivity in such reactions has attracted considerable interest7,8 However, the effect of allylic and homoallylic substituents in cyclopentenyl systems has not been investigated systematically.9 Here we report studies on a series of mono, di-, and trisubstituted cyclopentenes in which we have observed a pattern of trans-vicinal-additions derived from the approach of electrophiles syn to allylic substituents on the cyclopentene system. The stereochemical outcome with a variety of substrates and the effect of various allylic substituents on these selectivities have been examined. Our results have proven useful in total syntheses of (+)-trehazolin2a,b and (+)-allosamidin1a
Scheme 4
Results HOX Additions. Prior to the present study, the stereoselectivity of HOBr addition to a substituted cyclopentene, formally achieved using NBS-H2O, has been examined in the case of 3-methylcyclopentene 10 (Scheme 2).10 Reaction of 10 with NBS in water was reported to give a mixture of bromohydrins 11 and 12, in ratios of 3:1 to 7:1. Encouraged by that finding, our laboratory subsequently examined the reaction of 2-cyclopentenol 13 (Scheme 3) with NBS in H2O which afforded bromodiols 16 and 17 (4:1 ratio) in 78% overall yield.11 Direct NMR monitoring of the addition in D2O confirmed that 13 was completely consumed, that no other products were formed, and that the 4:1 product ratio was unaffected by the workup and isolation. The minor product 17 arises by the expected trans-opening of anti-bromonium ion 15, (6) Goering, B. K.; Ph.D. Dissertation, Cornell University, 1995. (7) For studies on electrophilic additions, see: De La Mare, P. B. D.; Bolton, R. Electrophilic Additions to Unsaturated Systems; Elesevier: Amsterdam, 1982. Fahey, R. C. Top. Stereochem. 1968, 3, 237342. (8) Kahn, S. D.; Pau, C. F.; Chamberlin, A. R.; Hehre, W. J. J. Am. Chem. Soc. 1987, 109, 650-663. (9) For seminal work on the stereochemistry of additions to substituted cyclohexenes, see (a) Barili, P. L.; Bellucci, G.; Marioni, F.; Morelli, I.; Scartoni, V. J. Org. Chem. 1972, 37, 4353-4357. (b) Bellucci, G.; Berti, G.; Ingrosso, G.; Mastrorilli, E. Tetrahedron Lett. 1973, 39113914. (c) Bellucci, G.; Berti, G.; Bianchini, R.; Ingrosso, G.; Mastrorilli, E. Gazz. Chim. Ital. 1976, 106, 955-966. (d) Bellucci, G.; Bianchini, R.; Ingrosso, G.; Mastrorilli, E. Gazz. Chim. Ital. 1978, 108, 643-650. (10) Finnegan, R. A.; Wepplo, P. J. Tetrahedron 1972, 28, 42674271.
and its meso-structure was readily established by NMR. The major product 16 can be seen to arise from the synbromonium ion 14 by a similar mechanism.1b As an additional test of the method, 3-azidocyclopentene12 18 (Scheme 4) was exposed to NBS in H2O (with DMSO as a cosolvent to improve solubility), affording a mixture of two products (3:1 ratio) in 91% yield. The (11) Ratios were obtained by integration of 1H NMR spectra of mixtures. Typically, one or more pairs of peaks were sufficiently wellresolved to obtain accurate integration values with (10% precision. Most reported yields are unoptimized. Because of the water-solubility and/or volatility of many low-molecular weight target compounds, the ratios of products, whenever appropriate, were measured using NMR for in situ reaction monitoring and the results compared with the ratios of isolated products. (12) Chmielowiec, U.; Uzarewicz, I.; Uzarewicz, A. Pol. J. Chem. 1990, 64, 613-619.
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J. Org. Chem., Vol. 65, No. 13, 2000 Scheme 5
major and minor products were assigned structures 19 and 20, respectively, on the basis of the following transformations. The product mixture was treated with K2CO3 in methanol to furnish two epoxyazides, 21 and 22. Peracid epoxidation of 18 also afforded 21 and 22 in a 1.3:1 ratio, and the two compounds were readily separated by chromatography. The structure of the major isomer was established as the trans-epoxyazide 21 by its reaction with NaN3, which afforded the meso-hydroxydiazide 23. The structure of the minor cis-epoxyazide 22 was confirmed by reduction of the azide and acetylation of the resulting amine to afford cis-epoxyacetamide 24, which was spectroscopically indistinguishable from an authentic sample prepared according to a literature method.13 Thus, the addition of HOBr to 18 proceeded predominantly via the syn-bromonium ion to afford 19 as the major addition product. The formal addition of HOBr to several more highly substituted cyclopentenes also favored products arising from an initial syn-bromonium ion (Scheme 5). Reaction of cis-cyclopentene-1,4-diol 2514 with NBS in H2O gave bromotriol 26 as the only product in 44% yield. That 26 was the only product formed was confirmed by 1H NMR monitoring of a parallel reaction performed in DMSO-d6 and D2O, which indicated 4:1, 31 mg, 0.16 mmol) in MeOH (1.5 mL) was treated with 10% palladium on carbon (40 mg) and stirred under 1 atm H2 for 2 h. The catalyst was removed by filtration through Celite, and solvent was removed in vacuo to afford impure amine 54 (21 mg, 80%) as a colorless oil. To a solution of 54 in CH2Cl2 (1.5 mL) were added triethylamine (22 µL, 0.16 mmol) and 4-bromophenyl isocyanate (95 mg, 0.48 mmol). After stirring 20 h, the resulting white precipitate was filtered through Celite and the filtrate evaporated. The resulting residue was chromatographed (SiO2, 4:1 hexanes:EtOAc) to afford 58 as a white solid (32 mg, 38%). mp 199-200 °C; Rf 0.33 (4:1 hexanes: EtOAc); 1H NMR (300 MHz, CDCl ) δ 11.74 (s,1 H), 7.43 (m, 6 H), 6.99 3 (m, 2 H), 5.10 (m, 1 H), 4.93 (d, 1 H, J ) 7.5 Hz), 3.31 (m, 1 H), 2.4-1.8 (m, 4 H), 2.17 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 149.7, 137.2, 132.2, 132.17, 125.4, 121.5, 118.5, 117.6, 116.7, 86.3, 59.9, 51.5, 32.1, 28.8, 15.3; IR (neat) 2977, 1668, 1699, 1592, 1487, 1384, 1307, 1236 cm-1; FDMS m/z 525 (M+, 100%) Crystals of 58 suitable for crystallographic analysis were obtained by recrystallization from CH2Cl2:hexanes. Addition of CH3SCl to cis-1,4-Diacetoxy-2-cyclopentene 59; Synthesis of 1-Methylthio-2-chloro-3,5-diacetoxycyclopentane 60. To a stirred solution of diacetate 59 (50 mg, 0.27 mmol) in CCl4 (0.5 mL) at 0 °C was added a 1.6 M solution of MeSCl in CCl4 (0.51 mL) dropwise. After stirring 8 h at room temperature, the solution was concentrated in vacuo and the resulting yellow oil was purified by flash chromatography (3:1 hexanes:EtOAc) to afford pure 60 (61 mg, 84%) as a clear oil: Rf ) 0.28 (3:1 hexanes: EtOAc); 1H NMR (300 MHz, CDCl3) δ 5.36 (m, 1 H), 5.13 (ddd, 1 H, J ) 10.0, 6.2, 4.9 Hz), 4.19 (dd, 1 H, J ) 10.0, 6.2 Hz), 3.10 (dd, 1 H, J ) 10.0, 5.2), 2.71 (ddd, 1 H, J ) 15.5, 8.9, 6.5 Hz), 2.22 (s, 3 H), 2.11 (s, 3 H) 2.10 (s, 3 H), 1.81 (ddd, 1 H, J ) 15.6, 4.8, 2.5 Hz); 13C NMR (75 MHz, CDCl3) δ 170.0, 169.7, 78.8, 72.4, 64.9, 56.9, 36.6, 21.0, 20.8, 15.8; IR (film) 2950, 2850, 1750, 1440, 1370, 1240, 1050 cm-1, FABMS m/z 267 (M + 1, 11%), 154 (100%). Saponification of 60; all-cis-1-Hydroxy-2-methylthio3,4-oxidocyclopentane 62. To a stirred solution of diacetate 60 (56 mg, 0.21 mmol) methanol (7 mL) at 0 °C was added K2CO3 (115 mg, 0.83 mmol) in one portion. The resulting heterogeneous mixture was stirred at room temperature for 4 h. The reaction was then cooled to 0 °C and quenched by the addition of NH4Cl (90 mg, 1.68 mmol) in H2O (5 mL). Acid (2 N HCl) was added dropwise to pH 7. The mixture was then concentrated in vacuo, and the remaining aqueous portion was
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J. Org. Chem., Vol. 65, No. 13, 2000
extracted with Et2O (5 × 10 mL). The combined Et2O layers were washed with brine (5 mL) and then dried over MgSO4. Filtration and concentration provided an oil. Purification by flash chromatography (3:1 EtOAc:hexanes) gave pure 62 (10 mg, 60%) as a clear oil: Rf 0.41 (3:1 EtOAc:hexanes); 1H NMR (300 MHz, CDCl3) 4.05 (m, 1H, 3.69 (s, 2H), 3.24 (d, 1H, J ) 5.7 Hz), 2.32 (d, 1H, J ) 15.2 Hz), 2.23 (s, 3H), 2.07 (dd, 1H, J ) 15.2, 5.9 Hz); 13C-NMR (75 MHz, CDCl3) 69.0, 58.9, 57.2, 53.4, 37.3, 14.8; IR (film) 3400, 2850, 1550, 1400, 1100, 1060 cm-1; FABMS m/z 147 (M + 1, 6%), 119 (100%). Addition of CH3SCl to cis-Cyclopentene-1,4-diol 25; Synthesis of 2-Chloro-3-methylthio-1,4-cyclopentanediols 63 and 64. To a solution of diol 25 (96 mg, 0.96 mmol) in CH2Cl2 (25 mL) at 0 °C was added MeSCl (103 mg, 1.2 mmol). After 3 h, the solution was evaporated, and the orange residue was chromatographed on SiO2 with 5:1 CH2Cl2:acetone to afford a colorless oil (150 mg, 81% yield): Rf 0.37 (9:1 CH2Cl2: MeOH). Diastereomers 63 and 64 (2:1 ratio) could be partially separated by the above chromatography procedure. For 63: 1H NMR (300 MHz, CDCl3) δ 4.26 (m, 2 H), 3.95 (m, 1 H), 3.12 (dd, 1 H, J ) 9.0 Hz, 4.3 Hz), 2.67 (bs, 2 H), 2.4-2.2 (m, 1 H), 2.20 (s, 3 H), 2.1-2.0 (m, 1 H); 13C NMR (75 MHz, CDCl3) δ 77.6, 73.8, 67.9, 60.4, 39.2, 15.2. For 64: 1H NMR (300 MHz, CDCl3) δ 4.25 (m, 1 H), 4.06 (m, 1 H), 3.94 (m, 1 H), 3.22 (m, 1 H), 2.4-2.1 (m, 2 H), 2.27 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 80.2, 71.1, 61.8, 39.2, 15.3; IR of mixture (neat) 3300, 2900, 1100 cm-1; EIMS m/z 185 (M+, 17%), 146 (M - HCl, 50%). A sample of diol 63 (25 mg, 0.13 mmol) in distilled pyridine (0.4 mL) at room temperature was acetylated by dropwise addition of Ac2O (82 mg, 0.80 mmol) and stirring of the resulting solution at room temperature for 4 h. The solvent was then removed in vacuo (
