Organocatalytic Domino Mannich Aza-Michael Reactions towards the Stereoselective Synthesis of Highly Substituted Pipecolic Esters

Abstract

Readily available chiral 7-oxo-2-enimides have been converted into highly substituted pipecolic esters in moderate yields and excellent stereocontrol through a proline-catalyzed domino Mannich aza-Michael reaction.

Key words

aza-Michael reaction - Cope rearrangement - domino reaction - Mannich reaction - organocatalysis - pipecolic ester

References and Notes

• 1a Schneider C. Rehfeuter M. Synlett  1996,  212 
• 1b Schneider C. Rehfeuter M. Tetrahedron  1997,  53:  133 
• 1c Schneider C. Synlett  2001,  1079 
• 1d Schneider C. Khaliel S. Synlett  2006,  1413 
• For the application of the Cope products in organic synthesis, see:
• 2a Schneider C. Synlett  1997,  815 
• 2b Schneider C. Schuffenhauer A. Eur. J. Org. Chem.  2000,  73 
• 2c Schneider C. Börner C. Synlett  1998,  652 
• 2d Schneider C. Börner C. Schuffenhauer A. Eur. J. Org. Chem.  1999,  3353 
• 2e Schneider C. Eur. J. Org. Chem.  1998,  1661 
• 2f Schneider C. Rehfeuter M. Tetrahedron Lett.  1998,  39:  9 
• 2g Schneider C. Rehfeuter M. Chem. Eur. J.  1999,  5:  2850 
• 2h Schneider C. Reese O. Angew. Chem. Int. Ed.  2000,  39:  2948 ; Angew. Chem. 2000, 112, 3074
• 2i Schneider C. Reese O. Chem. Eur. J.  2002,  8:  2585 
• 2j Schneider C. Tolksdorf F. Rehfeuter M. Synlett  2002,  2098 
• For leading recent reviews about organoenamine catalysis, see:
• 3a Mukherjee S. Yang JW. Hoffmann S. List B. Chem. Rev.  2007,  107:  5471 
• 3b List B. Chem. Commun.  2006,  819 
• 3c List B. Acc. Chem. Res.  2004,  37:  548 
• 3d Notz W. Tanaka F. Barbas CF. III Acc. Chem. Res.  2004,  37:  580 
• For a related aza-Diels-Alder reaction which proceeds by a domino Mannich aza-Michael mechanism, see:
• 4a Sunden H. Ibrahem I. Eriksson L. Cordova A. Angew. Chem. Int. Ed.  2005,  44:  4877 ; Angew. Chem. 2005, 117, 4955
• 4b Rueping M. Azap C. Angew. Chem. Int. Ed.  2006,  45:  7832 ; Angew. Chem. 2006, 118, 7996
• 5 Cordova A. Watanabe S. Tanaka F. Notz W. Barbas CF. III J. Am. Chem. Soc.  2002,  124:  1866 
• For general reviews, see:
• 7a Tietze LF. Brasche G. Gericke K. Domino Reactions in Organic Synthesis   Wiley-VCH; Weinheim: 2006. 
• 7b Tietze LF. Chem. Rev.  1996,  96:  115 
• 7c For a specific review about asymmetric organocatalytic domino reactions, see: Enders D. Grondal C. Hüttl MRM. Angew. Chem. Int. Ed.  2007,  46:  1570 ; Angew. Chem. 2007, 119, 1590

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Typical Experimental Procedure: To a stirred solution of N-PMP-protected α-imino ethyl glyoxalate (3a; 47 mg, 0.228 mmol) and l-proline (3.5 mg, 20 mol%) in DMF
(0.5 mL) at -20 ˚C was added aldehyde 2b (R^¹ = Et; 50 mg, 0.152 mmol) and the stirring was continued for 20 h at
-20 ˚C. The reaction mixture was then diluted with EtOAc
(1 mL) and added to a solution of sodium triacetoxyboro-hydride (3 equiv) in EtOAc at 0 ˚C. After the reaction mixture had been stirred for further 15 min, the reaction was quenched with phosphate buffer (pH 7) and the crude product was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO₄, filtered and concentrated. The residue was purified by flash column chromatography (PE-EtOAc, 1:2 → 1:1) to afford the product 4d (40 mg, 49%) as a viscous oil, which was recrystallized from EtOAc-PE; mp 50 ˚C; [α]_D ^²¹ +15.8˚ (c = 0.07, CHCl₃). ^¹H NMR (300 MHz, CDCl₃): δ = 0.96 (t, J = 7.2 Hz, 3 H, Me), 1.14 (t, J = 7.2 Hz, 3 H, Me), 1.31-1.88 (m, 6 H, 4-CH, 5-CH₂, CH₂CH₃, OH), 2.43 (m, 1 H, 3-CH), 2.60 (dd, J = 13.5, 9.6 Hz, 1 H, CH-benzyl), 3.10 (dd,
J = 17.7, 3.0 Hz, 1 H, CHCO), 3.21 (dd, J = 13.5, 3.0 Hz,
1 H, CH-benzyl), 3.53 (dd, J = 17.7, 10.0 Hz, 1 H, CHCO), 3.61-3.72 (m, 2 H, CH₂OH), 3.73 (s, 3 H, MeO), 4.09-4.14 (m, 4 H, OCH₂CH₃, 5′′-CH₂), 4.40-4.46 (m, 1 H, 6-CH), 4.50 (d, J = 4.2 Hz, 1 H, 2-CH), 4.62 (m_c, 1 H, 4′′-CH), 6.81 (d, J = 8.8 Hz, 2 H, phenyl-CH), 7.04 (d, J = 8.8 Hz, 2 H, phenyl-CH), 7.14 (d, J = 6.8 Hz, 2 H, phenyl-CH), 7.25-7.29 (m, 3 H, phenyl-CH). ^¹³C NMR (75 MHz, CDCl₃): δ = 11.79 (Me), 14.22 (Me), 24.01 (CH₂CH₃), 27.03 (C₄), 31.71 (CH₂CO), 32.04 (C₅), 37.99 (benzyl-C), 42.55 (C₃), 49.59 (C₆), 55.24 (C′′₄), 55.97 (OMe), 59.86 (C₂), 59.97 (CH₂CO), 61.06 (CH₂OH), 66.22 (C′′₅), 114.5, 118.7, 127.4, 129.05, 129.4, 135.4, 142.3, 153.7 (phenyl-C), 153.2 (CO-urethane), 172.4 (CO-amide), 174.0 (CO-ester). IR (film): 3500 (OH), 3029, 2959, 2875, 2833 (CH), 1785 (CO-urethane), 1720 (CO-ester), 1695 (CO-amide), 1605, 1512, 1454, 1384, 1351 (Me, CH₂), 1244, 1180, 1087, 1043, 970, 941, 788, 702, 626 cm^-¹. MS (ESI, Na): m/z = 539.2 [M + H]⁺, 561.2 [M + Na]⁺. Anal. Calcd for C₃₀H₃₈N₂O₇ (538.63): C, 66.90; H, 7.11; N, 5.20. Found: C, 66.46; H, 7.00; N, 5.19.

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The structural data have been deposited with the Cambridge Crystallographic Data Centre and allocated the deposition number CCDC 686773, which contains the supplementary crystallographic data for this paper.