Hg(II) Reagent-Controlled Stereoselective Synthesis of 2,5-cis- and 2,5-trans-Polyhydroxylated Pyrrolidines

Abstract

Stereoselectivity in the intramolecular amidomercuration reaction of 11, which could form 2,5-cis- and 2,5-trans-polyhydroxylated pyrrolidines, was found to be dependent on the nature of the Hg(II) salts used as well as on the stereochemistry and protection state of the hydroxyl group at the allylic carbon. Thus, the amidomercuration reaction of 11 with Hg(CF₃CO₂)₂ led to the predominant formation of the 2,5-cis-polyhydroxylated pyrrolidine 16, while use of Hg(CF₃SO₃)₂ generated the corresponding 2,5-trans isomer 17. Isomers 16 and 17 were further elaborated to stereoselectively synthesize 2,5-dideoxy 2,5-imino-d-altritol and 2,5-dideoxy 2,5-imino-d-galactitol (for 20 and 21), which are known to be potent d-galactosidase inhibitors.

Key words

carbohydrate - glycosidase inhibitor - polyhydroxylated pyrrolidine - regioselective asymmetric aminohydroxylation reaction - intramolecular amidomercuration reaction

References

• 1a Iminosugars as Glycosidase Inhibitors. Nojirimycin and Beyond   Stutz AE. Wiley-VCH; Weinheim Germany: 1999. 
• 1b Martin OR. In Carbohydrate Mimics. Concepts and Methods   Chapleur Y. Wiley-VCH; Weinheim Germany: 1998. 
• 1c Asano N. Nash RJ. Molyneux RJ. Fleet GWJ. Tetrahedron: Asymmetry  2000,  11:  1645 
• 2a Izquierdo I. Plaza MT. Franco F. Tetrahedron: Asymmetry  2004,  15:  1465 
• 2b Cordona F. Faggi E. Liguori F. Cacciarini M. Goti A. Tetrahedron Lett.  2003,  44:  2315 
• 2c Izquierdo I. Plaza MT. Franco F. Tetrahedron: Asymmetry  2002,  13:  1581 
• 2d Gallos JK. Sarli VC. Stathakis CI. Koftis TV. Nachmia VR. Coutouli-Argyropoulou E. Tetrahedron  2002,  58:  9351 
• 2e Behr J.-B. Erard A. Guillerm G. Eur. J. Org. Chem.  2002,  1256 
• 2f Denmark SE. Cottell JJ. J. Org. Chem.  2001,  66:  4276 
• 2g White JD. Hrnciar P. J. Org. Chem.  2000,  65:  9129 
• 2h Romero A. Wong C.-H. J. Org. Chem.  2000,  65:  8264 
• 2i Yoda H. Katoh H. Takabe K. Tetrahedron Lett.  2000,  41:  7661 
• 2j Pearson WH. Hines JV. J. Org. Chem.  2000,  65:  5785 
• 2k Denmark SE. Hurd AR. J. Org. Chem.  2000,  65:  2875 
• 2l Denmark SE. Herbert B. J. Org. Chem.  2000,  65:  2887 
• 3a Han H. Cho CW. Janda KD. Chem.-Eur. J.  1999,  5:  1565 
• 3b Singh OV. Han H. Tetrahedron Lett.  2003,  44:  2387 
• 3c Singh OV. Han H. Tetrahedron Lett.  2003,  44:  5289 
• For a review, see
• 4a Robin S. Rousseau G. Tetrahedron  1998,  54:  13681 
• 4b Khalaf JF. Datta A. J. Org. Chem.  2004,  69:  387 
• 4c Enierga G. Espiritu M. Perlmutter P. Pham N. Rose M. Sjoberg S. Thienthong N. Wong K. Tetrahedron: Asymmetry  2001,  12:  597 
• 4d Takahata H. Bandoh H. Momose T. Tetrahedron: Asymmetry  1991,  2:  351 
• 4e Takahata H. Banba Y. Tajima M. Momose T. J. Org. Chem.  1991,  56:  240 
• 4f Takahata H. Takehara H. Ohkubo N. Momose T. Tetrahedron: Asymmetry  1990,  1:  561 
• 4g Tamaru Y. Hojo M. Yoshida Z. J. Org. Chem.  1988,  53:  5731 
• 4h Tokuda M. Yamada Y. Suginome H. Chem. Lett.  1988,  17:  1289 
• 4i Kinsman R. Lathbury D. Vernon P. Gallagher T. J. Chem. Soc., Chem. Commun.  1987,  243 
• 4j Harding KE. Marman TH. J. Org. Chem.  1984,  49:  2838 
• 4k Harding KE. Burks SR. J. Org. Chem.  1984,  49:  40 
• 4l Harding KE. Burks SR. J. Org. Chem.  1981,  46:  3920 
• 5 Singh S. Chikkanna D. Singh OV. Han H. Synlett  2003,  1279 
• 7 Takaku H. Kamaike K. Tsuchiya H. J. Org. Chem.  1984,  49:  51 
• 8 Burk MJ. Allen JG. J. Org. Chem.  1997,  62:  7054 
• 9a Mitsunobu O. Synthesis  1981,  1 
• 9b Hughes DL. Org. React.  1992,  42:  335 
• 10a Wang Y.-F. Takaoka Y. Wong C.-H. Angew. Chem., Int. Ed. Engl.  1994,  33:  1242 
• 10b Fechter MH. Stutz AE. Carbohydr. Res.  1999,  319:  55 
• 11 Hayes P. Suthers BD. Kitching W. Tetrahedron Lett.  2000,  41:  6175 
• 12 Fukuyama T. Laird AA. Hotchkiss LM. Tetrahedron Lett.  1985,  26:  6291 

6

The compound I was prepared from the reaction of ethyl 4-bromocrotonate with p-methoxyphenol in the presence of K₂CO₃ and a catalytic amount of 18-crown-6 in MeCN at r.t. (yield: 80%).

13

Compound 14: [α]_D +20.0 (c 1.0, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 7.35-7.25 (5 H, m), 6.82-6.75 (4 H, m), 4.77-4.64 (1 H, m), 4.60-4.55 (2 H, m), 4.25 and 3.84 (1 H, br s), 4.20-4.02 (5 H, m), 3.75 (3 H, s), 2.30 and 2.11 (1 H, m,) 1.59 and 1.30 (1 H, t, J = 10.5 Hz), 1.44 and 1.40 (9 H, s). ¹³C NMR (125 MHz, CDCl₃): δ = 154.0, 153.9, 152.8, 137.4, 128.6, 128.2, 127.8, 115.9, 114.6, 81.3, 80.9, 73.4, 71.6, 65.4, 56.7, 55.6, 55.3, 30.3, 28.4, minor peaks due to rotational isomer(s): 81.0, 80.4, 73.7, 71.6, 70.8, 65.4, 64.1, 58.9, 54.6. Compound 16: [α]_D +50.0 (c 1.0, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 7.35-7.28 (5 H, m), 6.93 (2 H, d, J = 9.0 Hz), 6.83 (2 H, d, J = 9.0 Hz), 4.71 (1 H, d, J = 11.5 Hz), 4.67 (1 H, d, J = 11.5 Hz), 4.25-4.12 (6 H, m), 3.78-3.70 (1 H, m), 3.77 (3 H, s), 2.25 (1 H, dd, J = 11.5 and 6.0 Hz), 2.17 (1 H, dd, J = 11.5 and 4.5 Hz), 1.48 (9 H, s). ¹³C NMR (125 MHz, CDCl₃): δ = 155.1, 154.5, 151.9, 137.3, 128.5, 128.1, 127.9, 116.2, 114.7, 81.2, 77.1, 72.6, 70.9, 66.7, 60.1, 59.1, 55.7, 34.0, 28.5. Compound 17: [α]_D +19.0 (c 1.0, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 7.40-7.20 (5 H, m), 6.85-6.70 (4 H, m), 4.72 (1 H, d, J = 11.5 Hz), 4.51 (1 H, d, J = 11.5 Hz), 4.50-4.35 (2 H, m), 4.25-4.10 (3 H, m), 4.00 (1 H, br s), 3.71 (3 H, s), 1.91 (1 H, d, J = 12.0 Hz), 1.48 (1 H, d, J = 12.0 Hz), 1.32 (9 H, s). ¹³C NMR (75 MHz, CDCl₃): δ = 154.8, 154.1, 152.0, 137.3, 128.5, 128.0, 127.7, 116.8, 114.6, 81.6, 75.9, 75.8, 71.4, 65.5, 65.4, 58.3, 55.6, 35.0, 28.4.