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Synlett 2003(4): 0493-0496
DOI: 10.1055/s-2003-37513
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Jens Christoffers*, Burkard Kreidler, Heiko Oertling, Sven Unger, Wolfgang Frey
Institut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart, Germany
Fax: +49(711)6854269; e-Mail: jchr@po.uni-stuttgart.de;
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Publikationsverlauf

Received 2 January 2003
Publikationsdatum:
26. Februar 2003 (online)

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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.

Key words

chiral auxiliaries - copper - Michael additions - regio­selectivity - stereoselectivity

5

( 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, Rf 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+].

7

( 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, Rf 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.

8

( 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, Rf (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.

10

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.

11

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: +44(1223)336033 or e-mail: deposit@ccdc.cam.ac.uk].

12

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.

13

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