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

Souad Khaliel; Mecheril Valsan Nandakumar; Harald Krautscheid; Christoph Schneider

doi:10.1055/s-0028-1083377

LETTER

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

Souad Khaliel^a, Mecheril Valsan Nandakumar^a, Harald Krautscheid^b, Christoph Schneider*^a
^a Institut für Organische Chemie, Universität Leipzig, Johannisallee 29, 04103 Leipzig, Germany
^b Institut für Anorganische Chemie, Universität Leipzig, Johannisallee 29, 04103 Leipzig, Germany
Fax: +49(341)9736599; e-Mail: schneider@chemie.uni-leipzig.de;

Abstract

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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

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References

References and Notes

<A NAME="RG22008ST-1A">1a</A> Schneider C. Rehfeuter M. Synlett 1996, 212

<A NAME="RG22008ST-1B">1b</A> Schneider C. Rehfeuter M. Tetrahedron 1997, 53: 133

<A NAME="RG22008ST-1C">1c</A> Schneider C. Synlett 2001, 1079

<A NAME="RG22008ST-1D">1d</A> Schneider C. Khaliel S. Synlett 2006, 1413

For the application of the Cope products in organic synthesis, see:

<A NAME="RG22008ST-2A">2a</A> Schneider C. Synlett 1997, 815

<A NAME="RG22008ST-2B">2b</A> Schneider C. Schuffenhauer A. Eur. J. Org. Chem. 2000, 73

<A NAME="RG22008ST-2C">2c</A> Schneider C. Börner C. Synlett 1998, 652

<A NAME="RG22008ST-2D">2d</A> Schneider C. Börner C. Schuffenhauer A. Eur. J. Org. Chem. 1999, 3353

<A NAME="RG22008ST-2E">2e</A> Schneider C. Eur. J. Org. Chem. 1998, 1661

<A NAME="RG22008ST-2F">2f</A> Schneider C. Rehfeuter M. Tetrahedron Lett. 1998, 39: 9

<A NAME="RG22008ST-2G">2g</A> Schneider C. Rehfeuter M. Chem. Eur. J. 1999, 5: 2850

<A NAME="RG22008ST-2H">2h</A> Schneider C. Reese O. Angew. Chem. Int. Ed. 2000, 39: 2948 ; Angew. Chem. 2000, 112, 3074

<A NAME="RG22008ST-2I">2i</A> Schneider C. Reese O. Chem. Eur. J. 2002, 8: 2585

<A NAME="RG22008ST-2J">2j</A> Schneider C. Tolksdorf F. Rehfeuter M. Synlett 2002, 2098

For leading recent reviews about organoenamine catalysis, see:

<A NAME="RG22008ST-3A">3a</A> Mukherjee S. Yang JW. Hoffmann S. List B. Chem. Rev. 2007, 107: 5471

<A NAME="RG22008ST-3B">3b</A> List B. Chem. Commun. 2006, 819

<A NAME="RG22008ST-3C">3c</A> List B. Acc. Chem. Res. 2004, 37: 548

<A NAME="RG22008ST-3D">3d</A> 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:

<A NAME="RG22008ST-4A">4a</A> Sunden H. Ibrahem I. Eriksson L. Cordova A. Angew. Chem. Int. Ed. 2005, 44: 4877 ; Angew. Chem. 2005, 117, 4955

<A NAME="RG22008ST-4B">4b</A> Rueping M. Azap C. Angew. Chem. Int. Ed. 2006, 45: 7832 ; Angew. Chem. 2006, 118, 7996

<A NAME="RG22008ST-5">5</A> Cordova A. Watanabe S. Tanaka F. Notz W. Barbas CF. III J. Am. Chem. Soc. 2002, 124: 1866

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.

For general reviews, see:

<A NAME="RG22008ST-7A">7a</A> Tietze LF. Brasche G. Gericke K. Domino Reactions in Organic Synthesis Wiley-VCH; Weinheim: 2006.

<A NAME="RG22008ST-7B">7b</A> Tietze LF. Chem. Rev. 1996, 96: 115

<A NAME="RG22008ST-7C">7c</A> 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

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.