TBAT-Mediated Nitrone Formation of ω-Mesyloxy-O-tert-butyldiphenylsilyl-oximes: Facile Synthesis of Cyclic Nitrones from Hemiacetals

Abstract

Chiral and cyclic nitrones were synthesized by TBAT-mediated desilylative cyclization of ω-mesyloxy-O-tert-butyldiphenylsilyloximes, readily prepared from sugar derivatives by a consecutive treatment with O-tert-butyldiphenylsilylhydroxyl­amine and with mesyl chloride. The method was applied to sequential nitrone formation and intramolecular cycloaddition.

Key words

carbohydrate-derived ω-mesyloxy-O-tert-butyldiphenylsilyloxime - TBAT - cyclization - nitrone - intramolecular cycloaddition

References

• For recent examples of syntheses of natural products and related compounds using chiral and cyclic nitrones, see:
• 1a Nagasawa K. Georgieva A. Koshino H. Nakata T. Kita T. Hashimoto Y. Org. Lett.  2002,  4:  177 
• 1b Watanabe H. Okue M. Kobayashi H. Kitahara T. Tetrahedron Lett.  2002,  43:  861 
• 1c Ooi H. Urushibata A. Esumi T. Iwabuchi Y. Hatakeyama S. Org. Lett.  2001,  3:  953 
• 1d Looper RE. Williams RM. Tetrahedron Lett.  2001,  42:  769 
• 1e Duff FJ. Vivien V. Wightman RH. Chem. Commun.  2000,  2127 
• 1f Cordero FM. Gensini M. Goti A. Brandi A. Org. Lett.  2000,  2:  2475 
• 1g Peer A. Vasella A. Helv. Chim. Acta  1999,  82:  1044 
• 1h Williams GM. Roughly SD. Davis JE. Holmes AB. J. Am. Chem. Soc.  1999,  121:  4900 
• 1i For recent examples using racemic cyclic nitrones, see: White JD. Blakemore PR. Korf EA. Yokochi AFT. Org. Lett.  2001,  3:  413 
• 1j Also see: Werner KM. de los Santos JM. Weinreb SM. J. Org. Chem.  1999,  64:  686 
• 2a Cicchi S. Marradi M. Goti A. Brandi A. Tetrahedron Lett.  2001,  42:  6503 
• 2b Goti A. Cicchi S. Cacciarini M. Cardona F. Fedi V. Brandi A. Eur. J. Org. Chem.  2000,  3633 
• 2c Goti A. De Sario F. Romani M. Tetrahedron Lett.  1994,  35:  6571 
• 2d Ballini R. Marcantoni E. Petrini M. J. Org. Chem.  1992,  57:  1316 
• 2e Tronchet JMJ. Zosimo-Landolfo G. Balkadjian M. Ricca A. Zsély M. Barbalat-Rey F. Cabrini D. Lichtle P. Geoffroy M. Tetrahedron Lett.  1991,  32:  4129 
• 3a Hall A. Meldrum KP. Therond PR. Wightman RH. Synlett  1997,  123 
• 3b Ishikawa T. Tajima Y. Fukui M. Saito S. Angew. Chem., Int. Ed. Engl.  1996,  35:  1863 
• 4 Cicchi S. Corsi M. Brandi A. Goti A. J. Org. Chem.  2002,  67:  1678 
• 5 A part of this work has been the subject of a preliminary report, see: Toyao A. Miyazaki I. Tamura O. Ishibashi H. 121st Annual Meeting of The Pharmaceutical Society of Japan; Sapporo: 2001. 
• 6 Ballou CE. J. Am. Chem. Soc.  1957,  79:  165 
• 7 Muri D. Bode JW. Carreira EM. Org. Lett.  2000,  2:  539 
• 10 Mita N. Tamura O. Ishibashi H. Sakamoto M. Org. Lett.  2002,  4:  1111 
• 11a Pilcher AS. Ammon HL. DeShong P. J. Am. Chem. Soc.  1995,  117:  5166 
• 11b Pilcher AS. DeShong P. J. Org. Chem.  1996,  61:  6901 
• 14 Matsuda M. Kobayashi T. Nagao S. Ohta T. Nozoe S. Heterocycles  1996,  43:  685 

8

When H₂NOTMS or H₂NOTBDMS was used, a mixture of the corresponding ω-hydroxy-O-silylated oxime and the desilylated oxime was obtained. Use of azeotropic removal of water instead of MgSO₄, again gave a similar mixture.

9

In contrast, treatment of desilylated congener of 2a with mesyl chloride (1 equiv) and Et₃N (2 equiv) gave an inseparable complex mixture.

12

The reaction required a prolonged reaction time without MS 4Å.

13

Typical procedure. Preparation of 4a from 1a: A mixture of 1a (500 mg, 3.12 mmol) and MgSO₄ (1.5 g) in toluene (5 mL) was heated at reflux for 5 min. To this mixture were added successively H₂NOTBDPS (2.54 g, 9.36 mmol) and PPTS (39.0 mg, 0.156 mmol) at the same temperature. After further heating for 15 min, MgSO₄ was filtered off, and the filtrate was washed successively with an aqueous saturated solution of NaHCO₃ and brine, dried (MgSO₄), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (2:1) to give 2a. Compound 2a was dissolved in CH₂Cl₂ (8 mL). Mesyl chloride (0.73 mL, 9.26 mmol) and Et₃N (0.60 mL, 9.27 mmol) were added to the stirred solution at 0 °C. After stirring for 15 min, water was added to the mixture, and the whole was extracted with CHCl₃. The organic phase was washed with brine, dried (MgSO₄), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (3:1) to afford a 65:35 mixture of (E)-3a and (Z)-3a (1.51 g, 98% from 1a). (E)-3a: ¹H NMR (500 MHz, CDCl₃) δ 1.09 (9 H, s), 1.36 (3 H, s), 1.53 (3 H, s), 2.97 (3 H, s), 4.16 (1 H, dd, J = 6.8, 11.2 Hz), 4.20 (1 H, dd, J = 4.5, 11.2 Hz), 4.46 (1 H, br dt, J = 4.5, 6.8 Hz), 4.79 (1 H, br t, J = 7.3 Hz), 7.39-7.41 (5 H, m), 7.64-7.69 (6 H, m). (Z)-3a: 1.11 (9 H, s), 1.31 (3 H, s), 1.49 (3 H, s), 2.86 (3 H, s), 4.08 (1 H, dd, J = 5.5, 11.0 Hz), 4.27 (1 H, dd, J = 2.8, 11.0 Hz), 4.76 (1 H, br dt, J = 2.8, 7.3 Hz), 5.44 (1 H, br dd, J = 3.7, 7.3 Hz), 7.19 (1 H, d, J = 3.7 Hz), 7.36-7.43 (5 H, m), 7.61-7.68 (5 H, m). To a boiling suspension of 3a obtained above (603 mg, 1.23 mmol) and MS 4A (powder, 2.5 g) in THF (50 mL) was added a solution of TBAT (682 mg, 1.23 mmol) in THF (3 mL), and the mixture was further heated at the same temperature for 7 min. After cooling, MS 4A was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with EtOAc-MeOH (1:0 to 8:1) to give 4a (135 mg, 70%), mp 110-112 °C (diisopropyl ether), [α]_D ²⁶ -26.3 (c 0.50, CH₂Cl₂) [lit. [4] mp 110-111 °C, [α]_D ²⁰ -28.0 (c 0.46, CH₂Cl₂)]. ¹H NMR (500 MHz, CDCl₃) δ 1.38 (3 H, s), 1.47 (3 H, s), 4.05 (1 H, br d, J = 15.1 Hz), 4.14 (1 H, br dd, J = 4.4, 15.1 Hz), 4.92 (1 H, br t, J = 6.4 Hz), 5.31 (1 H, br d, J = 5.9 Hz), 6.89 (1 H, br s); ¹³C NMR (125 MHz, CDCl₃) δ 25.6, 27.1, 67.9, 73.5, 79.8, 112.1, 132.5. The ¹H NMR spectral data are identical with those previously reported. [4]