Regioselective Formation of endo- and exo-Cyclic Enamines: Both Enantio­meric Products Accessible by the Same Chiral Auxiliary

Abstract

The copper-catalyzed conversion of exo-cyclic enamines 4a-c with methyl vinyl ketone (2) yields spirocyclic products 6a-c in a sequence of Michael and aldol reaction. The application of the chiral auxiliary l-valine diethylamide results in the formation of quaternary stereocenters with high enantiomeric excess. The configuration of intermediate imine 5a is determined to be S. Thus, exo-cyclic enamines 4 yield S-configured spiroketones 6, whereas, as shown for spiroketone ent-6c, reaction of endo-cyclic enamines such as 1 generates the opposite configuration in the products applying the same auxiliary l-valine diethylamide 9.

chiral auxiliaries - copper - Michael additions - regio­selectivity - stereoselectivity

References

Reviews:

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<A NAME="RG00103ST-1B">1b</A> Corey EJ. Guzman-Perez A. Angew. Chem. Int. Ed.  1998,  37:  388 ; Angew. Chem. 1998, 110, 402

<A NAME="RG00103ST-1C">1c</A> Fuji K. Chem. Rev.  1993,  93:  2037 

<A NAME="RG00103ST-1D">1d</A> Martin SF. Tetrahedron  1980,  36:  419 

Reviews:

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<A NAME="RG00103ST-2B">2b</A> Sibi MP. Manyem S. Tetrahedron  2000,  56:  8033 

<A NAME="RG00103ST-2C">2c</A> Christoffers J. Eur. J. Org. Chem.  1998,  1259 

<A NAME="RG00103ST-2D">2d</A> Yamamoto Y. Pyne SG. Schinzer D. Feringa BL. Jansen JFGA. In Methoden Org. Chem. (Houben-Weyl)   Vol. E21b:  Helmchen G. Hoffmann RW. Mulzer J. Schaumann E. Thieme; Stuttgart: 1995.  p.2011-2155  

<A NAME="RG00103ST-2E">2e</A> Rossiter BE. Swingle NM. Chem. Rev.  1992,  92:  771 

<A NAME="RG00103ST-2F">2f</A> d’Angelo J. Desmaele D. Dumas F. Guingant A. Tetrahedron: Asymmetry  1992,  3:  459 

<A NAME="RG00103ST-3A">3a</A> Christoffers J. Mann A. Angew. Chem. Int. Ed.  2000,  39:  2752 ; Angew. Chem. 2000, 112, 2871

<A NAME="RG00103ST-3B">3b</A> Christoffers J. Mann A. Chem.-Eur. J.  2001,  7:  1014 

<A NAME="RG00103ST-3C">3c</A> Christoffers J. Scharl H. Eur. J. Org. Chem.  2002,  1505 

<A NAME="RG00103ST-4">4</A> Christoffers J. Werner T. Unger S. Frey W. Eur. J. Org. Chem.  2003,  425 

<A NAME="RG00103ST-5">5</A>

( Z )- N -[1-(Tetrahydro-2-furanon-3-ylidene)ethyl ]-l-valine dimethylamide ( 4a). To a solution of α-acetyl-γ-butyrolactone (445 mg, 3.47 mmol), l-valine dimethylamide (500 mg, 3.47 mmol) and molecular sieves (4 Å) in toluene (4 mL) was added a drop of trifluoromethanesulfonic acid, and the mixture was heated at 55 °C for 16 h. The reaction mixture was filtered with CH₂Cl₂ and the solvent was evaporated. The residue was purified by chromatography on SiO₂ (EtOAc-MeOH, 20:1, R_f 0.24) to give 4a as a colorless oil (750 mg, 2.95 mmol, 85%), [α]_D ²⁰ +160 (c 7.5, CHCl₃). ¹H NMR (CDCl₃, 300 MHz): δ (ppm) = 1.01 (d, J = 6.6 Hz, 3 H), 1.03 (d, J = 5.9 Hz, 3 H), 1.88 (s, 3 H), 2.10 (dq, J = 13.5 Hz, J = 6.8 Hz, 1 H), 2.82 (t, J = 7.9 Hz, 2 H), 2.98 (s, 3 H), 3.10 (s, 3 H), 4.14 (dd, J = 6.5 Hz, J = 9.1 Hz, 1 H), 4.26 (t, J = 8.0 Hz, 2 H), 8.61 (br d, J = 8.9 Hz, 1 H). ¹³C{¹H} NMR (CDCl₃, 75 MHz): δ (ppm) = 16.85 (CH₃), 18.02 (CH₃), 19.65 (CH₃), 26.53 (CH₂), 31.76 (CH), 36.03 (CH₃), 37.02 (CH₃), 59.03 (CH), 65.04 (CH₂), 86.82 (C), 155.06 (C), 171.50 (C), 173.77 (C). In the ¹³C NMR spectrum a second set of signals was observed which was assigned to the E-isomer of 4a (ratio E/Z = 1:3 by integration of the NH resonance in the ¹H NMR spectrum): ¹³C{¹H} NMR (CDCl₃, 75 MHz): δ (ppm) = 12.78 (CH₃), 17.48 (CH₃), 19.44 (CH₃), 26.17 (CH₂), 32.62 (CH), 35.77 (CH₃), 37.21 (CH₃), 56.14 (CH), 63.24 (CH₂), 89.25 (C), 153.68 (C), 171.67 (C), 172.68 (C). IR (ATR): 3285 (w, br), 2964 (s), 1690 (vs), 1646 (vs), 1611 (s), 1229 (vs), 1026 (s) cm^-1. HRMS calcd for C₁₃H₂₂N₂O₃: 254.1630. Found: 254.1636 [M⁺].

<A NAME="RG00103ST-6A">6a</A> Andrews DM. Carey SJ. Chaignot H. Coomber BA. Gray NM. Hind SL. Jones PS. Mills G. Robinson JE. Slater MJ. Org. Lett.  2002,  4:  4475 

<A NAME="RG00103ST-6B">6b</A> Tsujimoto T. Ishihara J. Horie M. Murai A. Synlett  2002,  399 

<A NAME="RG00103ST-6C">6c</A> Ishihara J. Horie M. Shimada Y. Tojo S. Murai A. Synlett  2002,  403 

<A NAME="RG00103ST-6D">6d</A> Hughes RC. Dvorak CA. Meyers AI. J. Org. Chem.  2001,  66:  5545 

<A NAME="RG00103ST-6E">6e</A> Enders D. Teschner P. Raabe G. Runsink J. Eur. J. Org. Chem.  2001,  4463 

<A NAME="RG00103ST-7">7</A>

( S , S )- N -(8-Methyl-1-oxo-2-oxaspiro[4.5]dec-7-en-6-ylidene)- l -valine dimethylamide ( 5a). A solution of 4a (304 mg, 1.20 mmol) and Cu(OAc)₂·H₂O (12.0 mg, 0.060 mmol) in acetone (5 mL) was stirred at r.t. for 1 h. After addition of 2 (0.17 g, 2.4 mmol), the reaction mixture was stirred for 16 h. All volatile materials were removed under high vacuum and the crude product was purified by chromatography on SiO₂ (EtOAc, R_f 0.26) to give 5a as a colorless solid (197 mg, 0.643 mmol, 54%), mp 87-89 °C, [α]_D ²⁰ +15 (c 2.5, CHCl₃). ¹H NMR (CDCl₃, 400 MHz): δ (ppm) = 0.85 (d, J = 6.5 Hz, 3 H), 0.95 (d, J = 6.7 Hz, 3 H), 1.76-1.84 (m, 1 H), 1.91 (s, 3 H), 2.10-2.42 (m, 6 H), 2.85 (s, 3 H), 3.03 (s, 3 H), 3.98 (d, J = 9.8 Hz, 1 H), 4.28-4.42 (m, 2 H), 6.26 (br s, 1 H). ¹³C{¹H} NMR (CDCl₃, 50 MHz): δ (ppm) = 19.46 (CH₃), 20.57 (CH₃), 24.43 (CH₃), 27.96 (CH₂), 30.96 (CH₂), 31.27 (CH), 34.34 (CH₂), 36.20 (CH₃), 37.11 (CH₃), 51.02 (C), 65.31 (CH₂), 73.56 (CH), 114.43 (CH), 152.92 (C), 165.06 (C), 171.59 (C), 178.72 (C). IR (ATR): 2961 (s), 2931 (s), 1772 (vs), 1635 (vs), 1386 (s), 1216 (s), 1184 (vs), 1030 (s) cm^-1. HRMS calcd for C₁₇H₂₆N₂O₃: 306.1943. Found: 306.1945. Anal. Calcd for C₁₇H₂₆N₂O₃: C, 66.64; H, 8.55; N, 9.14. Found: C, 66.27; H, 8.17; N, 8.96.

<A NAME="RG00103ST-8">8</A>

( S )-8-Methyl-2-oxaspiro[4.5]dec-7-ene-1,6-dione ( 6a). To a solution of 5a (95.0 mg, 0.296 mmol) in H₂O (15.0 mL) at 0 °C was added concd H₂SO₄ (2 drops), and after stirring for 1 h at 0 °C, the reaction mixture was allowed to warm up to r.t. and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried (MgSO₄), the solvent evaporated, and the crude product purified by chromatography on SiO₂ [petroleum ether-EtOAc, 1:2, R_f (MTB-cyclohexane, 5:1) 0.25] to give 6a as a colorless solid (30.0 mg, 0.166 mmol, 56%), mp 66 °C, [α]_D ²⁰ = +115 (c 1.5, CHCl₃), >99% ee; [α]_D ²⁰ +107 (c 3.5, EtOH), >99% ee. [12] ¹H NMR (CDCl₃, 500 MHz): δ (ppm) = 2.00-2.05 (m, 1 H), 2.03 (s, 3 H), 2.11 (dt, J = 12.8 Hz, J = 8.5 Hz, 1 H), 2.30 (dt, J = 19.0 Hz, J = 5.7 Hz, 1 H), 2.44 (ddd, J = 5.4 Hz, J = 6.6 Hz, J = 12.2 Hz, 1 H), 2.71 (ddd, J = 3.7 Hz, J = 7.2 Hz, J = 10.9 Hz, 1 H), 2.75 (dt, J = 12.2 Hz, J = 6.0 Hz, 1 H), 4.34-4.44 (m, 2 H), 5.9 (sextet, J = 1.0 Hz, 1 H). ¹³C{¹H} NMR (CDCl₃, 50 MHz): δ (ppm) = 24.41 (CH₃), 27.96 (CH₂), 30.79 (CH₂), 32.65 (CH₂), 52.66 (C), 65.95 (CH₂), 124.31 (CH), 164.08 (C), 175.64 (C), 194.27 (C). IR (ATR): 2923 (s), 1766 (vs), 1655 (vs), 1630 (s), 1376 (s), 1217 (s), 1185 (vs), 1137 (s), 1060 (s), 1015 (vs), 985 (s) cm^-1. HRMS calcd for C₁₀H₁₂O₃: 180.0786. Found: 180.0781 [M⁺]. Anal. Calcd for C₁₀H₁₂O₃: C, 66.65; H, 6.71. Found: C, 66.82; H, 6.73.

<A NAME="RG00103ST-9">9</A> Compound 6a was reported before with higher optical rotation of [α]_D ²⁰ +149 (c 1.36, EtOH) despite lower optical purity (86% ee), see: Felk A. Revial G. Viossat B. Lemoine P. Pfau M. Tetrahedron: Asymmetry  1994,  5:  1459 

<A NAME="RG00103ST-10">10</A>

Of course, all compounds 6 have been prepared as racemic materials on a larger scale and completely characterized. The identity of the optically active compounds 6 has been established on an analytical scale by ¹H NMR spectroscopy and gas chromatography.

<A NAME="RG00103ST-11">11</A>

Crystallographic data (excluding structure factors) for the structures reported in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC-199252 (5a), no. CCDC-199251 (6c) and no. CCDC-199250 (8). Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: [phone] or e-mail: [e-mail]].

<A NAME="RG00103ST-12">12</A>

The nomenclature is, of course, dependent on constitution. Configurations of structures in Scheme [2] are: (S)-5a, (S)-5b, (R)-5c, (S)-6a, (S)-6b, and (S)-6c.

<A NAME="RG00103ST-13">13</A>

Quantitative enantiomeric purity of 6a was established by GLC on the chiral phase Bondex-un-α-5.6-Et-57. [14]

<A NAME="RG00103ST-14">14</A> For preparation of the chiral phase: Scherr O. Dissertation   Universität Stuttgart: 1997. 

<A NAME="RG00103ST-15">15</A> Stefane B. Polanc S. New J. Chem.  2002,  26:  28