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Synlett 2011(2): 249-253  
DOI: 10.1055/s-0030-1259296
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Organocatalyzed Michael Addition Reaction by Novel (2R,3aS,7aS)-Octa-hydroindole-2-carboxylic Acid, a New Fused Proline

David Roca-Lópeza, Pedro Merino*a, Francisco J. Sayagob, Carlos Cativielab, Raquel P. Herrera*a,c
a Laboratorio de Síntesis Asimétrica, Dpto. de Química Orgánica, ICMA (CSIC-UZ), 50009 Zaragoza, Spain
b Laboratorio de Aminoácidos y Péptidos, Dpto. de Química Orgánica, ICMA (CSIC-UZ), 50009 Zaragoza, Spain
c ARAID, Fundación Aragón I+D, 50004 Zaragoza, Spain
Fax: +34(976)762075; e-Mail: raquelph@unizar.es;
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Publication History

Received 27 November 2010
Publication Date:
04 January 2011 (online)

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Abstract

We present here the results obtained in our study on organocatalytic enantioselective Michael addition reaction of acetone to different nitroolefines using (2R,3aS,7aS)-octahydroindole-2-carboxylic acid [(R,S,S)-Oic] as a new and suitable catalyst for this process. Computational calculations support the results obtained with (R,S,S)-Oic versus its diastereomeric form (S,S,S)-Oic. The final products are obtained in good yields and moderate enantioselectivities (up to 58% ee).

Key words

Michael addition - nitroolefines - ketones - Oic - organocatalysis - enantioselectivity

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15

Typical Experimental Procedure To a suspension of catalyst (10 mol%) and nitroalkene (0.5 mmol) in DMF (4 mL), acetone (13.5 mmol, 1 mL) was added, and the resulting mixture was stirred at 25 ˚C for the time indicated in Table  [³] . After that time the reaction was quenched with sat. NH4Cl (2 × 20 mL), the layers were separated and the aqueous layer extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with brine (2 × 20 mL), dried (MgSO4), filtered, and rotatory evaporated to give a residue which was purified by flash chromatography using hexane-EtOAc (7:3) as an eluent.
Selected Spectral Data
Compound 8j: Following the general procedure, compound 8j was obtained after 10 d at r.t. as a white solid in 68% yield; mp 135-136 ˚C. ¹H NMR (400 MHz, CD3OD): δ = 2.05 (s, 3 H), 2.88 (dd, J = 2.6, 7.2 Hz, 2 H), 3.82-3.89 (m, 1 H), 4.57 (dd, J = 9.2, 12.4 Hz, 1 H), 4.70 (dd, J = 6.3, 12.4 Hz, 1 H), 6.70-6.74 (m, 2 H), 7.06-7.10 (m, 2 H). ¹³C NMR (100 MHz, CD3OD): δ = 30.4, 40.0, 47.2, 80.9, 116.5, 129.8, 131.5, 157.9, 208.8. The ee of the product was determined by HPLC using a Daicel Chiralpak IA column (n-hexane-i-PrOH = 90:10, flow rate 1 mL/min, λ = 230 nm): t R(major) = 29.1 min; t R(minor) = 26.9 min. HRMS: m/z calcd for C11H13NNaO4: 246.0737; found: 246.0728 [M+ + Na]. [α]D ²² 7.3 (c 1.0, MeOH, 33% ee).
Compound 8k: Following the general procedure, compound 8k was obtained after 10 d at r.t. as a yellow oil in 74% yield; mp 131-133 ˚C. ¹H NMR (400 MHz, CDCl3): δ = 2.11 (s, 3 H), 2.88 (d, J = 7.1 Hz, 2 H), 3.96 (q, J = 7.1 Hz, 1 H), 4.55 (dd, J = 7.8, 12.2 Hz, 1 H), 4.65 (dd, J = 6.8, 12.2 Hz, 1 H), 5.02 (s, 1 H), 6.91-6.95 (m, 2 H), 7.12-7.15 (m, 2 H), 7.31-7.44 (m, 5 H). ¹³C NMR (100 MHz, CDCl3): δ = 30.3, 38.3, 46.2, 70.0, 79.6, 115.2, 127.4, 128.0, 128.4, 128.5, 130.9, 136.7, 158.3, 205.5. The ee of the product was determined by HPLC using a Daicel Chiralpak IA column (n-hexane-i-PrOH = 97:3, flow rate 1 mL/min, λ = 230 nm): t R(major) = 44.5 min; t R(minor) = 41.1 min. HRMS: m/z calcd for C18H19NNaO4: 336.1206; found: 336.1215 [M+ + Na].
Compound 8l: Following the general procedure, compound 8l was obtained after 2 d at r.t. as a yellow oil in 67% yield. ¹H NMR (300 MHz, CDCl3): δ = 2.13 (s, 3 H), 2.88 (d, J = 6.9 Hz, 2 H), 3.97 (q, J = 6.9 Hz, 1 H), 4.56 (dd, J = 8.1, 12.6 Hz, 1 H), 4.67 (dd, J = 6.3, 12.6 Hz, 1 H), 7.07 (dd, J = 2.1, 8.4 Hz, 1 H), 7.32 (d, J = 2.1 Hz, 1 H), 7.39 (d, J = 8.4 Hz, 1 H). ¹³C NMR (75 MHz, CDCl3): δ = 30.2, 38.0, 45.7, 78.8, 126.9, 129.4, 130.9, 132.0, 133.0, 139.1, 204.6. The ee of the product was determined by HPLC using a Daicel Chiralpak IA column (n-hexane-i-PrOH = 97:3, flow rate 1 mL/min, λ = 230 nm): t R(major) = 29.1 min; t R(minor) = 26.1 min. HRMS: m/z calcd for C11H11Cl2NNaO3: 298.0008; found: 298.0007 [M+ + Na]. [α]D ²² -1.53 (c 1.0, CHCl3, 44% ee).

26

See ref. 25b. Whereas the mean error is estimated of about 2.0 kcal/mol for M062X functional, for B3LYP deviations up to more than 10 kcal/mol could be observed. For this reason, although B3LYP correctly predict the observed enantioselectivity for 4, it cannot be considered representative.