Diastereoselective Synthesis of Racemic 3,4-cis and 3,4-trans Isomers of Isoxazolidine-4,5-diols and their Derivatives

Abstract

A new synthetic approach to racemic 3,4-cis- and 3,4-trans-isoxazoldine-4,5-diols and their derivatives is presented. Dihydroxylation reactions of 3-substituted 2,3-dihydroisoxazoles with K₂OsO₄·2H₂O in the presence of NMO in acetone–water proceeded from the less hindered side and provided the major 3,4-trans-isoxazolidine-4,5-diols in moderate to good yields. 3,4-cis-5-Methoxyisoxazolidin-4-ol was prepared diastereoselectively from the mixture of 3,4-cis- and 3,4-trans-4-bromo-5-hydroxyisoxazolidines using base-promoted intramolecular cyclization in anhydrous methanol. Representative derivatives of 3,4-cis- and 3,4-trans-5-cyano­isoxazolidin-4-ols are also presented as potentially useful building blocks for the synthesis of various C5-substituted isoxazolidines.

Key words

dihydroxylation - diols - elimination - 2,3-dihydroisoxazoles - isoxazolidines

• References and Notes

• 1a Calderwood DJ, Johnston DN, Munschauer R, Rafferty P. Bioorg. Med. Chem. Lett. 2002; 1683
• 1b Guile SD, Bantick JR, Cooper ME, Donald DK, Eyssade C, Ingall AH, Lewis RJ, Martin BP, Mohammed RT, Potter TJ, Reynolds RH, St-Gallay SA, Wright AD. J. Med. Chem. 2007; 50: 254
• 2a Dicken CM, DeShong P. J. Org. Chem. 1982; 47: 2047
• 2b DeShong P, Dicken CM, Leginus JM, Whittle RR. J. Am. Chem. Soc. 1984; 106: 5598
• 2c DeShong P, Li W, Kennington JW. Jr, Ammon HL. J. Org. Chem. 1991; 56: 1364
• 2d Burdisso M, Gandolfi R, Grünanger P. J. Org. Chem. 1990; 55: 3427
• 2e Xu Z, Johannes CW, Salman SS, Hoveyda AH. J. Am. Chem. Soc. 1996; 118: 10926
• 2f Xu Z, Johannes CW, La DS, Hofilena GE, Hoveyda AH. Tetrahedron 1997; 53: 16377
• 2g Xu Z, Johannes CW, Houri AF, La DS, Cogan DA, Hofilena GE, Hoveyda AH. J. Am. Chem. Soc. 1997; 119: 10302
• 3a Carboni B, Ollivault M, Le Bouguenec F, Carrié R, Jazouli M. Tetrahedron Lett. 1997; 38: 6665
• 3b Davies CD, Marsden SP, Stokes ES. E. Tetrahedron Lett. 2000; 41: 4229
• 3c Righi P, Marotta E, Rosini G. Chem. Eur. J. 1998; 4: 2501
• 3d Ishikawa T, Kudo T, Shigemori K, Saito S. J. Am. Chem. Soc. 2000; 122: 7633
• 3e Kudo T, Ishikawa T, Shimizu Y, Saito S. Org. Lett. 2003; 5: 3875
• 4a Lombardo M, Rispoli G, Licciulli S, Trombini C, Dhavale DD. Tetrahedron Lett. 2005; 46: 3789
• 4b Ishikawa T, Nagai K, Senzaki M, Tatsukawa A, Saito S. Tetrahedron 1998; 54: 2433
• 4c Jurczak M, Socha D, Chmielewski M. Tetrahedron 1996; 52: 1411
• 4d Amlaiky N, Leclerc G. Synthesis 1982; 426
• 4e Amlaiky N, Leclerc G, Carpy A. J. Org. Chem. 1982; 47: 517
• 4f Buchalska E, Plenkiewicz J. Synth. Commun. 2000; 30: 1467
• 4g Martin BP, Cooper ME, Donald DK, Guile SD. Tetrahedron Lett. 2006; 47: 7635
• 5 Fišera L. 1,3-Dipolar Cycloadditions of Sugar Derived Nitrones and their Utilization in the Synthesis. In Heterocycles from Carbohydrate Precursors . El Ashry ES. H. Springer; Berlin/Heidelberg: 2007: 287
• 6a Rehák J, Fišera L, Kožíšek J, Bellovičová L. Tetrahedron 2011; 67: 5762
• 6b Podolán G, Kleščíková L, Fišera L, Kožíšek J, Fronc M. Synlett 2011; 1668
• 6c Podolán G, Fišera L, Kožíšek J, Fronc M. Heterocycles 2012; 84: 683
• 7 Hýrošová E, Medvecký M, Fišera L, Hametner C, Fröhlich H, Marchetti M, Allmaier G. Tetrahedron 2008; 64: 3111
• 8 Fischer R, Lackovičová D, Fišera L. Synthesis 2012; 44: 3783
• 9a Forsman JJ, Wärnå J, Murzin DY, Leino R. Carbohydr. Res. 2009; 344: 1102
• 9b Forsman JJ, Wärnå J, Murzin DY, Leino R. Eur. J. Org. Chem. 2009; 5666
• 10 Typical Experimental Procedure for (±)-4,5-cis/4,5-trans-2-Benzyl-3-phenylisoxazolidine-4,5-diol (7a,b): 2,3-Dihydroisoxazole 2 (300 mg, 1.26 mmol) was dissolved in acetone–H₂O (6 mL, 3:1), the solution was cooled to 10 °C and aq NMO (0.52 mL, 2.52 mmol, 50%, w/w) was added followed by K₂OsO₄·2H₂O (4.6 mg, 0.012 mmol). The mixture was vigorously stirred at this temperature for 1.5 h. When starting 2,3-dihydroisoxazole had disappeared (TLC, hexanes–EtOAc, 67:33), the mixture was diluted with H₂O and repeatedly extracted with CH₂Cl₂. The combined organic layers were dried with Na₂SO₄, filtered and the solvent was evaporated in vacuo (bath temperature bellow 35 °C). Epimeric isoxazolidine-4,5-diols 7a,b were purified by column chromatography (silica gel, hexanes–EtOAc, 50:50). Yield: 84% (287 mg, 1.06 mmol); colorless oil. ¹H NMR (600 MHz, CDCl₃): δ = 3.30 (br s, 2 H, 4-OH_a,b), 3.59 (d, J = 7.0 Hz, 1 H, H-3_b), 3.71 (d, J = 14.1 Hz, 1 H, NCH₂Ph_b), 3.81 (d, J = 8.2 Hz, 1 H, H-3_a), 3.94 (d, J = 14.1 Hz, 1 H, NCH₂Ph_a), 3.96 (d, J = 14.1 Hz, 1 H, NCH₂Ph_b), 4.02 (d, J = 14.1 Hz, 1 H, NCH₂Ph_a), 4.16–4.19 (m, 1 H, H-4_a), 4.30 (dd, J = 1.8, 7.0 Hz, 1 H, H-4_b), 4.70 (br s, 2 H, 5-OH_a,b), 5.15 (d, J = 1.8 Hz, 1 H, H-5_b), 5.19–5.22 (m, 1 H, H-5_a), 7.17–7.43 (m, 20 H, Ph). ¹³C NMR (150.8 MHz, CDCl₃): δ = 59.8, 62.9, 73.6, 78.3, 80.7, 88.7, 94.3, 101.3, 127.3 (2 × C), 127.8, 128.1 (2 × C), 128.2 (2 × C), 128.3, 128.7, 128.9, 129.0, 129.1, 136.4, 136.6, 137.0, 137.4.
• 11a Mitsunobu O, Kudo T, Nishida M, Tsuda N. Chem. Lett. 1980; 1613
• 11b Smith AB. III, Hale KJ, Rivero RA. Tetrahedron Lett. 1986; 27: 5813
• 11c Juteau H, Gareau Y, Labelle M. Tetrahedron Lett. 1997; 38: 1481
• 12a Chanet-Ray J, Vessière R, Zéroual A. Heterocycles 1987; 26: 101
• 12b Shirahase M, Kanemasa S, Hasegawa M. Tetrahedron Lett. 2004; 45: 4061
• 12c Shirahase M, Kanemasa S, Oderaotoshi Y. Org. Lett. 2004; 6: 675
• 12d Egart B, Lentz D, Czekelius C. J. Org. Chem. 2013; 78: 2490
• 13 Selected Data: (±)-4,5-cis/4,5-trans-Benzoic Acid 2-Benzyl-4-hydroxy-3-phenylisoxazolidin-5-yl Ester (9a,b): Yield: 72%; colorless oil. ¹H NMR (300 MHz, CDCl₃): δ = 2.69 (br s, 1 H, OH_a), 3.18 (br s, 1 H, OH_b), 3.81 (d, J = 7.0 Hz, 1 H, H-3_b), 3.90 (d, J = 14.7 Hz, 1 H, NCH₂Ph_b), 4.03 (d, J = 9.4 Hz, 1 H, H-3_a), 4.07 (d, J = 14.1 Hz, 1 H, NCH₂Ph_a), 4.13 (d, J = 15.2 Hz, 1 H, NCH₂Ph_b), 4.21 (d, J = 14.1 Hz, 1 H, NCH₂Ph_a), 4.53 (dd, J = 4.1, 9.4 Hz, 1 H, H-4_a), 4.60 (d, J = 7.0 Hz, 1 H, H-4_b), 6.18 (s, 1 H, H-5_b), 6.54 (d, J = 4.1 Hz, 1 H, H-5_a), 7.16–7.63 (m, 26 H, Ph), 7.99–8.05 (m, 4 H, Ph). ¹³C NMR (75.4 MHz, CDCl₃): δ = 59.5, 62.8, 71.4, 80.6, 88.6, 95.2, 103.2, 127.2, 127.5, 127.8, 127.9, 128.1, 128.2 (2 × C), 128.4 (2 × C), 128.5, 128.7, 128.8 (2 × C), 129.4, 129.5 (2 × C), 129.7, 129.8, 133.4, 133.5, 135.8, 136.1, 136.3, 136.5, 165.6, 166.7. (±)-3,4-cis-2-Benzyl-4-bromo-3-phenylisoxazolidin-5-ol (10a,b): Yield: 34%; yellowish foam. Major isomer: (±)-4,5-trans-10a: ¹H NMR (300 MHz, CDCl₃): δ = 3.54 (br s, 1 H, OH), 4.02 (d, J = 14.2 Hz, 1 H, NCH₂Ph), 4.23 (d, J = 14.2 Hz, 1 H, NCH₂Ph), 4.49 (d, J = 4.3 Hz, 1 H, H-4), 4.57 (d, J = 4.3 Hz, 1 H, H-3), 5.60 (s, 1 H, H-5), 7.28–7.49 (m, 10 H, Ph). ¹³C NMR (75.4 MHz, CDCl₃): δ = 59.4, 62.6, 69.7, 102.1, 127.5, 128.3 (2 × C), 128.4, 128.5, 129.1, 134.8, 136.6. (±)-3,4-trans-2-Benzyl-4-bromo-3-phenylisoxa-zolidin-5-ol (10c,d): Yield: 34%; colorless solid; mp 88–89 °C (recrystallized from hexanes, 10c/10d = 83:17). Major isomer: (±)-4,5-trans-10c: ¹H NMR (300 MHz, CDCl₃): δ = 3.46 (br s, 1 H, OH), 3.76 (d, J = 14.8 Hz, 1 H, NCH₂Ph), 3.96 (d, J = 8.0 Hz, 1 H, H-3), 4.03 (d, J = 14.8 Hz, 1 H, NCH₂Ph), 4.20 (dd, J = 1.8, 8.0 Hz, 1 H, H-4), 5.50 (d, J = 1.8 Hz, 1 H, H-5), 7.28–7.51 (m, 10 H, Ph). ¹³C NMR (75.4 MHz, CDCl₃): δ = 59.5, 59.9, 80.1, 102.1, 127.5, 128.0, 128.3, 128.8, 128.9, 129.1, 134.5, 136.4.
• 14 Nair V, Jeffery A. Tetrahedron Lett. 1995; 36: 3627
• 15 Typical Experimental Procedure for (±)-3,4-cis-4,5-trans-2-Benzyl-5-methoxy-3-phenylisoxazolidin-4-ol (11): A two-necked flask was flushed with argon and charged with a solution of the 4-bromoisoxazolidines 10a–d (425 mg, 1.28 mmol) in anhyd MeOH (25 mL). The mixture was cooled in an ice/water-bath (2–5 °C), solid potassium tert-butoxide (286 mg, 2.56 mmol) was added under a stream of argon and stirring was continued at r.t. for 12 h. When starting materials had been consumed (TLC; hexanes–EtOAc, 75:25), the resultant mixture was neutralized by adding HCl (1 M). The solvents were partially removed under reduced pressure, H₂O was added and the mixture was extracted twice with CH₂Cl₂. The combined organic layers were dried over Na₂SO₄, filtered and the solvent was evaporated in vacuo giving the crude isoxazolidin-4-ol 11 as a yellowish viscous oil, which was used directly in the next reaction. ¹H NMR (300 MHz, CDCl₃): δ = 3.46 (s, 3 H, OMe), 4.01 (d, J = 14.2 Hz, 1 H, NCH₂Ph), 4.12 (d, J = 14.1 Hz, 1 H, NCH₂Ph), 4.34, 4.37 (2 × d, J = 3.7 Hz, 2 H, H-3, H-4), 4.93 (s, 1 H, H-5), 7.29–7.51 (m, 10 H, Ph). ¹³C NMR (75.4 MHz, CDCl₃): δ = 54.9, 64.2, 71.9, 81.1, 107.5, 127.3, 128.1, 128.3 (2 × C), 128.7, 128.9, 133.9, 137.4.
• 16 Selected NMR Data: (±)-3,4-trans-4,5-trans-Benzoic Acid 2-Benzyl-5-cyano-3-phenylisoxazolidin-4-yl Ester (13a): ¹H NMR (300 MHz, CDCl₃): δ = 3.90 (d, J = 15.2 Hz, 1 H, NCH₂Ph), 4.02 (d, J = 5.3 Hz, 1 H, H-3), 4.18 (d, J = 15.2 Hz, 1 H, NCH₂Ph), 4.80 (d, J = 1.8 Hz, 1 H, H-5), 5.65 (dd, J = 1.8, 5.3 Hz, 1 H, H-4), 7.27–7.65 (m, 13 H, Ph), 8.01–8.05 (m, 2 H, Ph). ¹³C NMR (75.4 MHz, CDCl₃): δ = 58.7, 70.7, 75.3, 88.1, 116.6, 127.5, 128.2 (2 × C), 128.3, 128.4, 128.6, 129.2, 129.3, 129.9, 134.0, 134.6, 135.8, 165.7. (±)-3,4-cis-4,5-trans-2-Benzyl-3-phenyl-4-trimethylsilyl-oxyisoxazolidine-5-carbonitrile (14a): ¹H NMR (600 MHz, CDCl₃): δ = –0.19 (s, 9 H, SiMe₃), 3.69 (d, J = 6.5 Hz, 1 H, H-3), 3.70 (d, J = 15.3 Hz, 1 H, NCH₂Ph), 4.14 (d, J = 15.3 Hz, 1 H, NCH₂Ph), 4.68 (t, J = 6.5 Hz, 1 H, H-4), 5.07 (d, J = 7.0 Hz, 1 H, H-5), 7.24–7.44 (m, 10 H, Ph). ¹³C NMR (150.8 MHz, CDCl₃): δ = –0.7, 59.0, 72.6, 74.4, 76.3, 116.0, 127.3, 128.1, 128.2, 128.4, 128.5, 130.5, 133.1, 136.2.
• 17a Camiletti C, Dhavale DD, Gentilucci L, Trombini C. J. Chem. Soc., Perkin Trans. 1 1993; 3157
• 17b Tanaka K, Sugimoto Y, Okafuji Y, Tachikawa M, Mitsuhashi K. J. Heterocycl. Chem. 1989; 26: 381
• 17c Shimizu T, Ishizaki M, Nitada N. Chem. Pharm. Bull. 2002; 50: 908
• 17d Merino P, Tejero T, Unzurrunzaga FJ, Franco S, Chiacchio U, Saita MG, Iannazzo D, Piperno A, Romeo G. Tetrahedron: Asymmetry 2005; 16: 3865