Asymmetric Organocatalytic Domino Reactions of γ-Nitroketones and Enals

Abstract

Chiral substituted cyclohexene carbaldehydes are readily synthesized in excellent enantiomeric excesses from simple nitro­ketone and enal precursors. The domino Michael addition-aldol condensation reaction catalyzed by a chiral secondary amine involves tandem iminium-enamine activation.

Key words

Michael additions - aldol reactions - asymmetric synthesis - domino reactions - organocatalysis

References and Notes

• For reviews concerning organcatalysis, see:
• 1a Dalko PI. Moisan L. Angew. Chem. Int. Ed.  2004,  43:  5238 ; Angew. Chem. 2004, 39, 5248
• 1b Berkessel A. Gröger H. Asymmetric Organocatalysis   Wiley-VCH; Weinheim: 2005. 
• 1c Seayad J. List B. Org. Biomol. Chem.  2005,  3:  719 
• 1d Ramón DJ. Yus M. Angew. Chem. Int. Ed.  2005,  44:  1602 ; Angew. Chem. 2005, 117, 1628
• For examples and reviews of asymmetric organocatalytic domino reactions, see:
• 2a Lelais G. MacMillan DWC. Aldrichimica Acta  2006,  39:  79 
• 2b Enders D. Grondal C. Hüttl MRM. Angew. Chem. Int. Ed.  2007,  46:  1570 ; Angew. Chem.; 2007, 119: 1590
• 2c Yamamoto Y. Momiyama N. Yamamoto H. J. Am. Chem. Soc.  2004,  126:  5962 
• 2d Huang Y. Walji AM. Larsen CH. MacMillan DWC. J. Am. Chem. Soc.  2005,  127:  15051 
• 2e Marigo M. Bertelsen S. Landa A. Jørgensen KA. J. Am. Chem. Soc.  2006,  128:  5475 
• 2f Marigo M. Jørgensen KA. Chem. Commun.  2006,  2001 
• 2g Wang W. Li H. Wang J. Zu LS. J. Am. Chem. Soc.  2006,  128:  10354 
• 2h Rueping M. Azap C. Angew. Chem. Int. Ed.  2006,  45:  7832 ; Angew. Chem. 2006, 118, 7996
• 2i Carlone A. Cabrera S. Marigo M. Jørgensen KA. Angew. Chem. Int. Ed.  2007,  46:  1101 ; Angew. Chem. 2007, 119, 1119
• 2j Li H. Wang J. E-Nunu T. Zu LS. Jiang W. Wei S. Wang W. Chem. Commun.  2007,  507 
• 2k Wang BM. Wu FH. Wang Y. Liu XF. Deng L. J. Am. Chem. Soc.  2007,  129:  768 
• 2l Zu LS. Wang J. Li H. Xie HX. Jiang W. Wang W. J. Am. Chem. Soc.  2007,  129:  1036 
• 3 For a review concerning the application of organocatalysis to natural product synthesis, see: de Figueiredo RM. Christmann M. Eur. J. Org. Chem.  2007,  in press 
• 4a Enders D. Hüttl MRM. Grondal C. Raabe G. Nature (London)  2006,  441:  861 
• 4b Enders D. Hüttl MRM. Runsink J. Raabe G. Wendt B. Angew. Chem. Int. Ed.  2007,  46:  467 ; Angew. Chem. 2007, 119, 471
• For reviews of organocatalytic Michael additions of stabilized carbon nucleophiles, including nitroalkanes, to enals and enones, see:
• 5a Ballini R. Bosica G. Fiorini D. Palmieri A. Petrini M. Chem. Rev.  2005,  105:  933 
• 5b Tsogoeva SB. Eur. J. Org. Chem.  2007,  1701 
• 5c Almaºi D. Alonso DA. Nájera C. Tetrahedron: Asymmetry  2007,  18:  299 
• 6a Wynberg H. Helder R. Tetrahedron Lett.  1975,  4057 
• 6b Colonna S. Hiemstra H. Wynberg H. J. Chem. Soc., Chem. Commun.  1978,  238 
• 6c Matsumoto K. Uchida T. Chem. Lett.  1981,  1673 
• 6d Latvala A. Stanchev S. Linden A. Hesse M. Tetrahedron: Asymmetry  1993,  4:  173 
• 6e Bakó P. Szöllõsy A. Bombicz P. Tõke L. Synlett  1997,  291 
• 6f Yamaguchi M. Shiraishi T. Igarashi Y. Hirama M. Tetrahedron Lett.  1994,  35:  8233 
• 6g Arai S. Nakayama K. Ishida T. Shioiri T. Tetrahedron Lett.  1999,  40:  4215 
• 6h Corey EJ. Zhang F.-Y. Org. Lett.  2000,  2:  4257 
• 6i Hanessian S. Pham V. Org. Lett.  2000,  2:  2975 
• 6j Kim DY. Huh SC. Tetrahedron  2001,  57:  8933 
• 6k Halland N. Hazell RG. Jørgensen KA. J. Org. Chem.  2002,  67:  8331 
• 6l Halland N. Aburel PS. Jørgensen KA. Angew. Chem. Int. Ed.  2003,  42:  661 ; Angew. Chem. 2003, 115, 685
• 6m Halland N. Hansen T. Jørgensen KA. Angew. Chem. Int. Ed.  2003,  42:  4955 ; Angew. Chem. 2003, 115, 5105
• 6n Tsogoeva SB. Jagtap SB. Ardemasova ZA. Kalikhevich VN. Eur. J. Org. Chem.  2004,  4014 
• 6o Tsogoeva SB. Jagtap SB. Synlett  2004,  2624 
• 6p Hanessian S. Govindan S. Warrier JS. Chirality  2005,  17:  540 
• 6q Vakulya B. Varga S. Csámpai A. Soós T. Org. Lett.  2005,  7:  1967 
• 6r Prieto A. Halland N. Jørgensen KA. Org. Lett.  2005,  7:  3897 
• 6s Ooi T. Takada S. Fujioka S. Maruoka K. Org. Lett.  2005,  7:  5143 
• 6t Mitchell CET. Brenner SE. Ley SV. Chem. Commun.  2005,  5346 
• 6u Tsogoeva SB. Jagtap SB. Ardemasova ZA. Tetrahedron: Asymmetry  2006,  17:  989 
• 6v Brandau S. Landa A. Franzén J. Marigo M. Jørgensen KA. Angew. Chem. Int. Ed.  2006,  45:  4305 ; Angew. Chem. 2006, 118, 4411
• 6w Knudsen KR. Mitchell CET. Ley SV. Chem. Commun.  2006,  66 
• 6x Mitchell CET. Brenner SE. Garcia-Fortanet J. Ley SV. Org. Biomol. Chem.  2006,  4:  2039 
• 6y Hanessian S. Shao Z. Warrier JS. Org. Lett.  2006,  8:  4787 
• 6z Hansen HM. Longbottom DA. Ley SV. Chem. Commun.  2006,  4838 
• For examples of organocatalytic intramolecular aldol reactions with a ketone as electrophile, see:
• 7a Takano S. Kasahara C. Ogasawara K. Chem. Commun.  1981,  635 
• 7b Halland N. Aburel PS. Jørgensen KA. Angew. Chem. Int. Ed.  2004,  43:  1272 ; Angew. Chem. 2004, 116, 1292
• 7c Hechavarria Fonseca MT. List B. Angew. Chem. Int. Ed.  2004,  43:  3958 ; Angew. Chem. 2004, 116, 4048
• 7d Enders D. Niemeier O. Straver L. Synlett  2006,  3399 
• 8 Both enantiomers of TMS-diphenylprolinol ether 4 are readily available from d- or l-proline in multigram quantities in a four-step synthesis. For a review regarding the use of this catalyst, see: Palomo C. Mielgo A. Angew. Chem. Int. Ed.  2006,  45:  7876 ; Angew. Chem. 2006, 118, 8042
• 10 Flack HD. Acta Crystallogr., Sect. A.  1983,  39:  876 

9

CCDC number 642547 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

11

All new compounds were fully characterized (mp, optical rotation, NMR, IR, MS, elemental analysis) and the spectroscopic and analytical data are in agreement with the assigned structures.

12

General Procedure
To a solution of nitroketone 2 (3.0 mmol) and TMS-ether (S)-4 (0.60 mmol, 20 mol%) in toluene (3.0 mL) was added enal 3 (3.75 mmol, 1.25 equiv) and benzoic acid (20 mol%). The reaction vessel was then flushed with argon gas, stoppered and stirred at 9 °C for 6-15 d.
Workup A: Direct purification of the reaction mixture by flash chromatography (2:1 pentane-Et₂O) afforded cyclohexenes 1.
Workup B: The crude reaction mixture was diluted with CHCl₃ (8.0 mL) and heated in the presence of PhCO₂H (150 mg) at 65 °C for 2.5 h. Following dilution with Et₂O (75 mL), the organic layer was washed with sat. aq NaHCO₃ (15 mL) and brine (15 mL), dried (MgSO₄), concentrated and purified by flash chromatography (2:1 pentane-Et₂O) to afford cyclohexenes 1.¹¹ (5 R ,6 R )-2-Methyl-5-nitro-6-phenylcyclohex-1-ene Carbaldehyde (1a)
Isolated after 7 d as a pale yellow solid (315 mg, 43%). The ee was determined by HPLC on a chiral stationary phase (Daicel Chiralpak IA, n-heptane-i-PrOH = 95:5, 1.0 mL/min), t _R = 13.7 min(major), 17.0 min(minor). An analytical sample was prepared by recrystallization (CH₂Cl₂-Et₂O-hexane, slow evaporation); mp 89 °C; [α]_D ²⁴ -347 (c 1.02, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 2.02 (dddd, J = 14.7, 10.3, 7.0, 3.5 Hz, 1 H, CHHCH₂), 2.32 (s, 3 H, Me), 2.33-2.60 (m, 3 H, CHHCH ₂), 4.67 (dd, J = 7.3, 3.6 Hz, 1 H, CHNO₂), 4.80 (br s, 1 H, CHPh), 7.13-7.18 (m, 2 H, o-Ph), 7.22-7.26 (m, 1 H, p-Ph), 7.28-7.34 (m, 2 H, m-Ph), 10.11 (s, 1 H, CHO) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 18.4 (Me), 20.8 (C-4), 29.6 (C-3), 41.4 (C-6), 85.7 (C-5), 127.4 (p-Ph), 127.9 (o-Ph), 128.9 (m-Ph), 131.1 (ipso-Ph), 140.1 (C-1), 155.7 (C-2), 189.1 (CHO) ppm. IR (KBr): 3061, 3024, 2973, 2891, 1668, 1639, 1544, 1446, 1371, 1236, 759, 702 cm^-1. MS (CI, CH₄): m/z (%) = 246 (20) [M⁺ + 1]. Anal. Calcd for C₁₄H₁₅NO₃: C, 68.56; H, 6.16; N, 5.71. Found: C, 68.28; H, 6.08; N, 5.53.