Synthesis of Enantiopure 5-Substituted 2,3-Methanopyrrolidines by Cyclization of Enantiopure α-Branched α-N-Homoallylamino Nitriles

Abstract

The preparation of 5-substituted 2,3-methanopyrrolidines by the stereoselective cyclization of zincated α-amino nitriles derived from enantiopure α-branched homoallylamines has been investigated. The formation of trans adducts in excellent diastereoselectivities (up to >98:2) and good yields (up to 71%) is observed. The absolute configuration and enantiomeric excess are dependent on the nitrogen protecting group.

Key words

cyclization - zinc - carbenoids - stereoselective synthesis - bicyclic compounds

• References and Notes

• 1a Switzer FL, Van Halbeek H, Holt EM, Stammer CH. Tetrahedron 1989; 45: 6091
• 1b Hanessian S, Reinhold U, Gentile G. Angew. Chem., Int. Ed. Engl. 1997; 36: 1881
• 1c Hanessian S, Reinhold U, Saulnier M, Claridge S. Bioorg. Med. Chem. Lett. 1998; 8: 2123
• 1d Magnin DR, Robl JA, Sulsky RB, Augeri DJ, Huang Y, Simpkins LM, Taunk P, Betebenner DA, Robertson JG, Abboa-Offei B, Wang A, Cap M, Xing L, Tao L, Sitkoff DF, Malley MF, Gougoutas JZ, Khanna A, Huang Q, Han S.-P, Parker RA, Hamann LG. J. Med. Chem. 2004; 47: 2587
• 1e Mykhailiuk PK, Afonin S, Palamarchuk GV, Shishkin OV, Ulrich AS, Komarov IV. Angew. Chem. Int. Ed. 2008; 47: 5765
• 2 Saxagliptin, a dipeptide-containing a 2,3-methano-pyrrolidine subunit is currently marketed for treatment of type 2 diabetes: Augeri DJ, Robl JA, Betebenner DA, Magnin DR, Khanna A, Robertson JG, Wang A, Simpkins LM, Taunk P, Huang Q, Han S.-P, Abboa-Offei B, Cap M, Xin L, Tao L, Tozzo E, Welzel GE, Egan DM, Marcinkeviciene J, Chang SY, Biller SA, Kirby MS, Parker RA, Hamann LG. J. Med. Chem. 2005; 48: 5025
• 3a Recent examples: Larquetoux L, Kowalska JA, Six Y. Eur. J. Org. Chem. 2004; 3517
• 3b Larquetoux L, Ouhamou N, Chiaroni A, Six Y. Eur. J. Org. Chem. 2005; 4654
• 3c Madelaine C, Six Y, Buriez O. Angew. Chem. Int. Ed. 2007; 46: 8046
• 3d Madelaine C, Ouhamou N, Chiaroni A, Vedrenne E, Grimaud L, Six Y. Tetrahedron 2008; 64: 8878
• 3e Madelaine C, Buriez O, Crousse B, Florent I, Grellier P, Retailleau P, Six Y. Org. Biomol. Chem. 2010; 8: 5591
• 4a Couty S, Meyer C, Cossy J. Angew. Chem. Int. Ed. 2006; 45: 6726
• 4b Couty S, Meyer C, Cossy J. Tetrahedron 2009; 65: 1809
• 4c Madelaine C, Buzas AK, Kowalska-Six JA, Six Y, Crousse B. Tetrahedron Lett. 2009; 50: 5367
• 5 Hercouet A, Bessières B, Le Corre M. Tetrahedron: Asymmetry 1996; 7: 1267
• 6 Simpkins LM, Bolton S, Pi Z, Sutton JC, Kwon C, Zhao G, Magnin DR, Augeri DJ, Gungor T, Rotella DP, Sun Z, Liu Y, Slusarchyk WS, Marcinkeviciene J, Robertson JG, Wang A, Robl JA, Atwal KS, Zahler RL, Parker RA, Kirby MS, Hamann LG. Bioorg. Med. Chem. Lett. 2007; 17: 6476
• 7 Ouizem S, Cheramy S, Botuha C, Chemla F, Ferreira F, Perez-Luna A. Chem. Eur. J. 2010; 16: 12668
• 8a Enders D, Reinhold U. Tetrahedron: Asymmetry 1997; 8: 1895
• 8b Bloch R. Chem. Rev. 1998; 98: 1407
• 8c Yus M, Gonzalez-Gomez JC, Foubelo F. Chem. Rev. 2011; 111: 7774
• 9 Wolan A, Soueidan M, Chiaroni A, Retailleau P, Py S, Six Y. Tetrahedron Lett. 2011; 52: 2501
• 10a Morton D, Stockman RA. Tetrahedron 2006; 62: 8869
• 10b Lin G.-Q, Xu M.-H, Zhong Y.-W, Sun X.-W. Acc. Chem. Res. 2008; 41: 831
• 10c Ferreira F, Botuha C, Chemla F, Pérez-Luna A. Chem. Soc. Rev. 2009; 38: 1162
• 10d Robak MT, Herbage MA, Ellman JA. Chem. Rev. 2010; 110: 3600
• 11a Rech JC, Yato M, Duckett D, Ember B, LoGrasso PV, Bergman RG, Ellman JA. J. Am. Chem. Soc. 2007; 129: 490
• 11b Yendapally R, Lee RE. Bioorg. Med. Chem. Lett. 2008; 18: 1607
• 12 Daicel Chiralpak AD column [(4.6 mm × 250 mm, 5 μm); hexane–i-PrOH (95:5), flow rate = 1.0 mL min^–1, detection λ = 220 nm]: t _R [(1S,3S,5S)-6a] = 10.4 min; t _R [(1R,3R,5R)-6a] = 11.1 min. Racemic 6a was prepared from racemic 4a obtained by reaction of allylmagnesium bromide with (E)-N-benzylpropan-1-imine
• 13 Daicel Chiralpak AD column [(4.6 mm × 250 mm, 5 μm); hexane–i-PrOH (95:5), flow rate = 0.8 mL min^–1, detection λ = 220 nm]: t _R [(1S,3R,5S)-6b] = 13.9 min; t _R [(1R,3S,5R)-6b] = 15.0 min. Racemic 6b was prepared from racemic 4b obtained by reaction of allylmagnesium bromide with (E)-N-benzyl-2-methylpropan-1-imine
• 14 Daicel Chiralpak AD column [(4.6 mm × 250 mm, 5 μm); hexane–i-PrOH (98:2), flow rate = 0.4 mL min^–1, detection λ = 220 nm]: t _R [(2R,4S)-7] = 52.4 min; t _R [(2S,4R)-7] = 53.2 min. Racemic 7 was prepared from racemic 4b obtained by reaction of allylmagnesium bromide with (E)-N-benzyl-2-methylpropan-1-imine
• 15 Procedure for the Preparation of 5a–d (Table 2) and 11 – Preparation of 5b is Representative Diisopropylamine (0.17 mL, 1.2 mmol) was added at r.t. to n-BuLi (2.4 M in hexane, 0.50 mL, 1.2 mmol). Once the gummy mixture formed, dry THF (1.5 mL) was added, and the solution was cooled to –80 °C. A solution of α-amino nitrile (2b, 243 mg, 1 mmol) in dry THF (1.5 mL) was added dropwise. After 1 h of stirring at –80 °C, ZnBr₂ (1.0 M in dry THF, 4.0 mL, 4.0 mmol) was added at once, and the cooling bath was removed and replaced by a water bath. Once the temperature of the solution reached r.t., the bath was removed, and the mixture was stirred for 2 h. An aq solution of NH₄Cl–NH₃ (2:1; 10 mL) and ethanolamine (1 mL) were added. The biphasic mixture was stirred vigorously during 30 min before the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organics were washed with brine, dried over MgSO₄, filtered, and concentrated. Purification by flash chromatography over silica gel afforded 5b (144 mg, 67%). [α]_D ²⁰ +230.5 (c 1.89, CHCl₃). IR (neat): 3029, 2954, 1494, 1453, 1157, 733, 696 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.02 (dt, J = 8.1, 5.5 Hz, 1 H), 0.63–0.66 (m, 1 H), 0.91 (d, J = 7.0 Hz, 3 H), 0.96 (d, J = 6.8 Hz, 3 H), 1.25–1.35 (m, 1 H), 1.80–1.83 (m, 2 H), 1.90–1.94 (m, 1 H), 2.19–2.25 (m, 1 H), 2.55–2.58 (m, 1 H), 3.23 (d, J = 12.7 Hz, 1 H), 3.91 (d, J = 12.7 Hz, 1 H), 7.25–7.45 (m, 5 H). ¹³C NMR (100 MHz, CDCl₃): δ = 3.1, 13.5, 15.8, 20.5, 27.8, 28.2, 41.4, 57.0, 64.1, 126.8, 128.3, 129.1, 140.5. HRMS: m/z [M – H]⁺ calcd for C₁₅H₂₂N₁: 216.17468; found: 216.17453
• 16 Daicel Chiralpak AD column [(4.6 mm × 250 mm, 5 μm); hexane–i-PrOH = 98:2, flow rate = 0.8 mL min^–1, detection λ = 220 nm]: t _R [(2S,4S)-12] = 13.5 min; t _R [(2R,4R)-12] = 14.5 min. Racemic 12 was prepared from racemic 9 obtained by reaction of allylmagnesium bromide with (E)-N-benz-hydrylpropan-1-imine
• 17a Bégis G, Cladingboel DE, Motherwell WB. Chem. Commun. 2003; 2656
• 17b Bégis G, Cladingboel DE, Motherwell WB, Sheppard TD, Tocher DA. Synthesis 2005; 3186
• 17c Motherwell WB, Bégis G, Cladingboel DE, Jerome L, Sheppard TD. Tetrahedron 2007; 63: 6462
• 17d Bégis G, Cladingboel DE, Jerome L, Motherwell WB, Sheppard TD. Eur. J. Org. Chem. 2009; 1532
• 17e Jerome L, Sheppard TD, Aliev AE, Motherwell WB. Tetrahedron Lett. 2009; 50: 3709
• 18 Johnson BF, Marrero EL, Turley WA, Lindsay HA. Synlett 2007; 893
• 19 Linderman RJ, Anklekar TV. J. Org. Chem. 1992; 57: 5078
• 20 Beruben D, Marek I, Normant JF, Platzer N. J. Org. Chem. 1995; 60: 2488
• 21a Casey CP, Vollendorf NW, Haller KJ. J. Am. Chem. Soc. 1984; 106: 3754
• 21b Soderberg BC, Hegedus LS. Organometallics 1990; 9: 3113
• 21c Ogawa A, Takami N, Sekigushi M, Ryu I, Kambe N, Sonoda N. J. Am. Chem. Soc. 1992; 114: 8729
• 21d Barluenga J, Aznar F, Gutierrez I, Llorca-Baragano MA. Org. Lett. 2002; 4: 4273