Synlett 2010(14): 2136-2140  
DOI: 10.1055/s-0030-1258527
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Protecting-Group-Free Route to Hydroxylated Pyrrolidine and Piperidine Derivatives through Cu(I)-Catalyzed Intramolecular Hydroamination of Alkenes

Hirohisa Ohmiya, Mika Yoshida, Masaya Sawamura*
Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan
Fax: +81(11)7063749; e-Mail: sawamura@sci.hokudai.ac.jp;
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Publikationsverlauf

Received 22 April 2010
Publikationsdatum:
28. Juli 2010 (online)

Abstract

An efficient approach to hydroxylated pyrrolidine and piperidine derivatives through the intramolecular hydroamination catalyzed by a Cu(I)-Xantphos system is described. The transformation allows for the short synthesis of N-alkylated aza-sugars without a protection-deprotection event of the hydroxy groups.

    References and Notes

  • For reviews:
  • 1a Iminosugars as Glycosidase Inhibitors - Nojirimycin and Beyond   Stütz AE. Wiley-VCH; Weinheim: 1999. 
  • 1b Asano N. Nash RJ. Molyneux RJ. Fleet GW. Tetrahedron: Asymmetry  2000,  11:  1645 
  • 1c Lillelund VH. Jensen HH. Liang X. Bols M. Chem. Rev.  2002,  102:  515 
  • 1d Pearson MSM. Mathe-Allainmat M. Fargeas V. Lebreton J. Eur. J. Org. Chem.  2005,  2159 
  • For reviews on the hydroamination of alkenes and alkynes, see:
  • 2a Müller TE. Beller M. Chem. Rev.  1998,  98:  675 
  • 2b Müller TE. Hultzsch KC. Yus M. Foubelo F. Tada M. Chem. Rev.  2008,  108:  3795 
  • For late transition-metal-catalyzed intramolecular hydroaminations of amino alkenes bearing a protecting-group-free hydroxy group, see: Rh:
  • 3a Liu Z. Hartwig JF. J. Am. Chem. Soc.  2008,  130:  1570 
  • Pt:
  • 3b Han X. Widenhoefer RA. Angew. Chem Int. Ed.  2006,  45:  1747 
  • Pd:
  • 3c Michael FE. Cochran BM. J. Am. Chem. Soc.  2006,  128:  4246 
  • For intramolecular amidomercurations of amidoalkenes bearing a protecting-group-free free hydroxy group, see:
  • 4a Singh S. Chikkanna D. Singh OV. Han H. Synlett  2003,  1279 
  • 4b Chikkanna D. Han H. Synlett  2004,  2311 ; see also ref. 2
  • 5 Ohmiya H. Moriya T. Sawamura M. Org. Lett.  2009,  11:  2145 
  • For reviews on the protecting-group-free synthesis, see:
  • 6a Hoffmann RW. Synthesis  2006,  3531 
  • 6b Young IS. Baran PS. Nature Chem.  2009,  1:  193 
  • 7 For a synthesis of hydroxypyrrolidines without protecting groups, see: Dangerfield EM. Timmer MSM. Stocker BL. Org. Lett.  2009,  11:  535 
  • 9 The relative stereochemistry of 2bb was assigned according to the literature. See: Andrés JM. Pedrosa R. Pérez-Encabo A. Eur. J. Org. Chem.  2007,  1803 
  • 10 The ee of (2R,3S)-4 (95% ee) was determined by chiral HPLC analysis of the p-nitrobenzoate derivative. See: Jäger V. Hümmer W. Stahl U. Gracza T. Synthesis  1991,  769 
  • 11 The ee value of (2S,3R)-6 (99% ee) was determined by the Mosher’s NMR spectroscopic method. See: Crimmins MT. Powell MT. J. Am. Chem. Soc.  2003,  125:  7592 
  • 12 The epoxides 8 were prepared according to the reported procedure. The ee of 8 has not been determined in our hand. See: Takano S. Iwabuchi Y. Ogasawara K. J. Am. Chem. Soc.  1991,  113:  2786 
8

General Procedure for the Cu(I)-Catalyzed Hydroamination of Amino Alkene [Procedure A with CuO t -Bu-Xantphos (Scheme 1, Tables 1 and 2)] In a glove box, CuOt-Bu (0.06 mmol, 8.2 mg or 0.08 mmol, 10.9 mg) and Xantphos (0.06 mmol, 34.7 mg or 0.08 mmol, 46.3 mg) were placed in a screw vial. Anhydrous, degassed mixed solvent, MeOH-p-xylene (1:1, 0.4 mL) was added and stirred at r.t. for 10 min to give a pale yellow solution.
A solution of a hydroxylated amino alkene (0.4 mmol) in MeOH-p-xylene (1:1, 0.4 mL) was added. The vial was sealed with a screw cap and was removed from the glove box. The mixture was stirred and heated at 140 ˚C for 72 h. The reaction mixture was cooled to r.t. and concentrated. An internal standard (1,1,2,2-tetrachloroethane) was added to the residue. The yield of the product was determined by ¹H NMR. Purification by Kugelrohr distillation or preparative TLC (silica gel, MeOH) gave the desired product in a practically pure form.
General Procedure for the Cu(I)-Catalyzed Hydroamination of Amino Alkene [Procedure B with CuOAc-KO t -Bu-Xantphos (Tables 1 and 2)] In a glove box, CuOAc (0.06 mmol, 7.4 mg or 0.08 mmol, 9.8 mg), Xantphos (0.06 mmol, 34.7 mg or 0.08 mmol, 46.3 mg), and KOt-Bu (0.09 mmol, 12.3 mg or 0.12 mmol, 16.4 mg) were placed in a screw vial. Anhydrous, degassed mixed solvent, MeOH-p-xylene (1:1, 0.4 mL) was added and stirred at r.t. for 10 min to give a pale yellow solution. The following procedure is identical to that described above.

13

The isolated 2e was contaminated with unidentified materials. See experimental procedure in note 17.

14

1-Benzyl-3-hydroxy-2-methylpyrrolidine (2ac, 69:31 mixture of diastereomers) Viscous oil. ¹H NMR (300 MHz, CDCl3): δ (major isomer) = 1.22 (d, J = 6.3 Hz, 3 H), 1.66 (m, 1 H), 1.97-2.16 (m, 2 H), 2.30 (m, 1 H), 2.93 (ddd, J = 11.1, 8.4, 2.1 Hz, 1 H), 3.10 (d, J = 12.9 Hz, 1 H), 4.02 (d, J = 12.9 Hz, 1 H), 4.03 (m, 1 H), 7.23-7.35 (m, 5 H); δ (minor isomer) = 1.18 (d, J = 6.3 Hz, 3 H), 1.53 (m, 1 H), 1.97-2.16 (m, 2 H), 2.41 (m, 1 H), 2.79 (ddd, J = 11.4, 8.7, 2.4 Hz, 1 H), 3.29 (d, J = 12.9 Hz, 1 H), 3.89 (m, 1 H), 3.94 (d, J = 12.9 Hz, 1 H), 7.23-7.35 (m, 5 H). ¹³C NMR (75 MHz, CDCl3): δ = 12.84 16.25, 32.22, 32.84, 50.89, 51.24, 57.51, 57.77, 63.85, 67.26, 74.31, 78.22, 126.98, 127.01, 128.27 (2×), 128.98, 129.03, 138.99, 139.04. ESI-HRMS: m/z [M + H]+ calcd for C12H18ON: 192.1382; found: 192.1381.

15

(3 S ,4 R )-3,4-Dihydroxy-1,2-dimethylpyrrolidine (2ca, >20:1 mixture of diastereomers) Viscous oil. ¹H NMR (300 MHz, CDCl3): δ = 1.15 (d, J = 6.6 Hz, 3 H), 2.26 (s, 3 H), 2.31 (m, 1 H), 2.42 (dd, J = 11.0, 6.9 Hz, 1 H), 2.97 (dd, J = 11.0, 2.7 Hz, 1 H), 4.00 (dd, J = 6.3, 5.2 Hz, 1 H), 4.22 (ddd, J = 6.9, 6.3, 2.7 Hz, 1 H). ¹³C NMR (75 MHz, CDCl3): δ = 12.27, 39.84, 63.42, 65.02, 69.53, 73.37. HRMS-FAB: m/z [M + H]+ calcd for C6H13O2N: 131.0946; found: 132.1032. [α]D ²7 +37.0 (c 0.6, MeOH).

16

(4 R ,5 S )-4,5-Dihydroxy-1,2-dimethylpiperidine (2d, 62:38 mixture of diastereomers) Viscous oil. ¹H NMR (300 MHz, CD3OD): δ (major isomer) = 1.10 (d, J = 6.3 Hz, 3 H), 1.54-1.67 (m, 2 H), 2.18-2.41 (m, 2 H), 2.19 (s, 3 H), 2.91 (dd, J = 12.6, 3.3 Hz, 1 H), 3.55 (m, 1 H), 3.77 (m, 1 H); δ (minor isomer) = 1.04 (d, J = 6.3 Hz, 3 H), 1.44 (ddd, J = 14.7, 11.8, 2.7 Hz, 1 H), 1.77 (dt, J = 14.7, 3.6 Hz, 1 H), 2.18-2.41 (m, 2 H), 2.27 (s, 3 H), 2.62 (dd, J = 10.8, 4.8 Hz, 1 H), 3.65 (m, 1 H), 3.90 (m, 1 H). ¹³C NMR (75 MHz, CD3OD): δ = 19.38, 20.25, 37.71, 40.50, 42.57, 43.15, 53.45, 57.39, 58.89, 61.80, 68.61, 69.61, 69.70, 70.95. ESI-HRMS: m/z [M + H]+ calcd for C7H15O2N: 145.1103; found: 146.1179. [α]D ²7 +19.8 (c 1.0, MeOH).

17

Procedure for the Synthesis of Trihydroxylated Piperidine 2e (Procedure C, Scheme 5)
In a glove box, CuOAc (0.04 mmol, 4.9 mg), Xantphos (0.04 mmol, 23.1 mg), and KOt-Bu (0.06 mmol, 8.2 mg) were placed in a screw vial. Anhydrous, degassed mixed solvent, MeOH-p-xylene (1:1, 0.2 mL) was added and stirred at r.t. for 10 min to give a pale yellow solution. A solution of 1e (0.2 mmol) in MeOH-p-xylene (1:1, 0.2 mL) was added. The vial was sealed with a screw cap, and was removed from the glove box. The mixture was stirred and heated at 140 ˚C for 72 h. The reaction mixture was cooled to r.t. and concentrated. The residue was dissolved in EtOAc (5 mL) and H2O (5 mL). The mixture was extracted with H2O (3 × 5 mL). The combined aqueous layers were evaporated under reduced pressure to give a pale yellow oil (25.5 mg). ¹H NMR analysis of the material using t-BuOH as an internal standard indicated that the yield and purity of 2e were 53% (17.7 mg) and 67%, respectively.

18

(3 R ,4 S ,5 S )-3,4,5-Trihydroxy-1,2-dimethylpiperidine (2e, 61:39 mixture of diastereomers) Oil. ¹H NMR (600 MHz, D2O): δ (major isomer) = 1.14 (d, J = 6.6 Hz, 3 H), 2.25 (m, 1 H), 2.28 (s, 3 H), 2.41 (m, 1 H), 2.66 (dd, J = 11.4, 4.8 Hz, 1 H), 3.26 (m, 1 H), 3.72 (m, 1 H), 4.02 (m, 1 H); δ (minor isomer) = 1.17 (d, J = 6.6 Hz, 3 H), 2.19 (s, 3 H), 2.25 (m, 1 H), 2.35 (d, J = 12.6 Hz, 1 H), 2.41 (m, 1 H), 2.96 (m, 1 H), 3.72 (m, 1 H), 3.97 (m, 1 H). ESI-HRMS: m/z [M + H]+ calcd for C7H16O3N: 162.11247; found: 162.11242.