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Synlett 2011(1): 89-93  
DOI: 10.1055/s-0030-1259084
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Unexpected Formation of Optically Active 4-Substituted 5-Hydroxy-γ-
lactams by Organocatalyzed Reaction of 3-Substituted Cyclobutanones with Nitrosobenzene

Francesca Capittaa,b, Angelo Frongia*a, Jean Ollivierb, Pier Paolo Piras*a, Francesco Seccia
a Dipartimento di Scienze Chimiche, Università di Cagliari, Complesso Universitario di Monserrato, S.S. 554, Bivio per Sestu, 09042 Monserrato (Cagliari), Italy
Fax: +39(070)6754388; e-Mail: angelo.frongia@gmail.com; e-Mail: pppiras@unica.it;
b UMR 8182, Laboratoire de Synthèse Organique et Méthodologie, ICMMO, Université Paris-Sud 11, 91405 Orsay Cedex, France
Further Information

Publication History

Received 7 September 2010
Publication Date:
07 December 2010 (online)

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Abstract

An organocatalyzed enantioselective desymmetrization reaction for converting 3-substituted cyclobutanones into 4-substituted 5-hydroxy-γ-lactams is presented. This involves a ring-expanding O-nitroso aldol-cyclization domino sequence. This synthetic protocol provides access to five-membered ring systems in good yields with the generation of two new stereogenic centers.

Key words

rearrangements - ring expansion - ketones - organocatalysis

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A reviewer proposed a plausible alternative mechanism for the tandem asymmetric formation of γ-lactams 3 from the intermediate C. He suggests that a fragmentation of N-O bond (in the bicyclic intermediate C) could occur to give a nitrogen cation, stabilized by resonance into the phenyl group, prior to migration.

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General Procedure (Using Catalyst I)
To a CHCl3 (2.7 mL) solution of the prochiral cyclobutanone 1 (3 mmol) and l-proline (0.18 mmol) was added a CHCl3 (0.9 mL) solution of nitrosobenzene (0.6 mmol) over 48 h at 0 ˚C via syringe pump, and the mixture was stirred for 96 h at that temperature. The crude reaction mixture was directly loaded on silica gel column without workup, and pure products were obtained by flash column chromatography (silica gel, hexane-Et2O).
General Procedure (Using Catalyst IV) In a glass vial equipped with a magnetic stirring bar, to 0.375 mmol of the prochiral cyclobutanone 1, catalyst IV (0.075 mmol, 20 mol%) was added, and the reaction mixture was stirred at ambient temperature for 10-15 min. To the reaction mixture nitrosobenzene (1.13 mmol) was added and stirred at 0 ˚C for the time indicated in Tables  [¹] and  [²] . The crude reaction mixture was directly loaded on silica gel column without workup, and pure products were obtained by flash column chromatography (silica gel, mixture of hexane-Et2O).
4-(4-Chlorophenyl)-5-hydroxy-1-phenylpyrrolidin-2-one (3a) Yield 60%; yellow oil. IR (film): ν = 3400, 1650 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 2.68 (dd, 1 H, J = 4.5, 14.1 Hz), 2.93 (t, 1 H, J = 14.4 Hz), 3.26-3.33 (m, 1 H), 5.48 (d, 1 H, J = 5.4 Hz), 7.18-7.72 (m, 9 H). ¹³C NMR (75 MHz, CDCl3): δ = 36.9, 47.86, 103.2, 120.0, 125.6, 128.6, 128.7, 129.2, 133.6, 137.6, 139.3, 169.8. MS: m/z (%) = 269 (100) [M+ - 18], 240 (80), 206 (17), 136 (23), 104 (72). The ee was determined to be 58% ee by chiral-phase HPLC using a Daicel Chiralcel OJ column (hexane-i-PrOH = 80:20, flow rate 1.2 mL/min, λ = 254 nm): t R(major) = 12.1 min; t R(minor) = 14.4 min. 5-Hydroxy-1,4-diphenylpyrrolidin-2-one (3b/3b′)
Spectral data refer to a 95:5 inseparable mixture of two trans- and cis-diastereomers. Yield 40%; yellow oil. IR (film): ν = 3400, 1650 cm-¹. ¹H NMR (300 MHz, CDCl3):
δ = 2.58-2.66 (m, 1 H), 2.74-2.81 (m, 1 H), 2.90 (t, 1 H, J = 14.1 Hz), 3.05 (t, 1 H, J = 13.8 Hz), 3.14-3.20 (m, 1 H), 3.23-3.30 (m, 1 H), 4.58 (br s, 1 H), 4.92 (t, 1 H), 5.48 (d, 1 H, J = 5.4 Hz), 5.55 (dd, 1 H, J = 7.05, 9.6 Hz), 6.74-7.73 (m, 20 H). ¹³C NMR (75 MHz, CDCl3): δ = 37.1, 38.6, 48.5, 48.8, 92.4, 103.5, 114.6, 118.8, 120.1, 124.9, 125.5, 127.0, 127.2, 127.6, 127.8, 128.5, 128.6, 129.0, 129.1, 129.3, 139.3, 139.5, 170.3, 170.8. MS: m/z (%, the same for the two diastereomers) = 235 (100) [M+ - 18], 206 (100), 115 (20), 104 (48), 77 (57), 63 (7), 51 (16). The ee was determined to be 20% ee for the trans-diastereomer by chiral-phase HPLC using a Daicel Chiralcel OJ column (hexane-i-PrOH = 90:10, flow rate 1.2 mL/min, λ = 254 nm): t R(major) =
30.8 min; t R(minor) = 36.6 min.
5-Hydroxy-4-phenethyl-1-phenylpyrrolidin-2-one (3e)
Spectral data worked out from the 94:6 inseparable mixture of two trans- and cis-diastereomers 3e/3e′. Yield 65%; orange oil. IR (film): ν = 3350, 1660 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 1.77-2.14 (m, 3 H), 2.36-2.57 (m, 2 H), 2.71 (t, 2 H, J = 7.5 Hz), 3.41 (br s, 1 H), 5.29 (d, 1 H, J = 5.1 Hz), 7.13-7.69 (m, 10 H). ¹³C NMR (75 MHz, CDCl3): δ = 32.9, 36.0, 42.2, 52.3, 102.7, 119.9, 126.1, 128.2, 128.4, 128.5, 128.6, 139.6, 140.9, 170.4. MS: m/z (%, the same for the two diastereomers) = 263 (31) [M+ - 18], 172 (100), 106 (14), 91 (60), 77 (27), 65 (10), 51 (8). The ee of the trans-diastereomer was determined to be 51% ee by chiral-phase HPLC using a Daicel Chiralcel OJ column (hexane-i-PrOH = 85:15, flow rate 1.0 mL/min, λ = 254 nm): t R(major) = 26.1 min; t R(minor) = 33.6 min. 4-Hexyl-5-hydroxy-1-phenylpyrrolidin-2-one (3f/3f′)
Spectral data refer to a 67:33 inseparable mixture of two trans- and cis-diastereomers. Yield 60%; orange oil. IR (film): ν = 3400, 1660 cm-¹. ¹H NMR (300 MHz, CDCl3):
δ = 0.84-1.59 (m, 26 H), 1.92-2.06 (m, 2 H), 2.27-2.63 (m, 4 H), 4.73 (d, 1 H, J = 9.3 Hz), 5.17 (d, 1 H, J = 4.8 Hz), 5.22 (dd, 1 H, J = 6.9, 9.3 Hz), 6.76-7.72 (m, 10 H). ¹³C NMR (75 MHz, CDCl3): δ = 14.0, 22.5, 26.6, 26.8, 29.1, 31.6, 33.0, 33.8, 36.1, 37.3, 42.7, 43.3, 91.4, 102.8, 114.5, 118.6, 119.9, 125.2, 128.5, 129.3, 139.7, 144.1, 170.7, 171.0. MS: m/z (%, the same for the two diastereomers) = 243 (77) [M+ - 18], 172 (100), 158 (26), 130 (14), 104 (24), 77 (33). The ee was determined to be 38% ee for the trans-diastereomer and 44% ee for the cis-diastereomer by chiral-phase HPLC using a Daicel Chiralcel OJ column (hexane-i-PrOH = 95:5, flow rate 0.8 mL/min, λ = 254 nm): trans-diastereomer: t R(minor) = 14.3 min(minor); t R(major) = 17.4 min; cis-diastereomer: t R(major) = 22.2 min; t R(minor) = 26.9 min. Procedure for the Synthesis of 3-Hexyl-1-phenyl-pyrrolidine-2,5-dione (5)
PCC (85.1 mg, 0.395 mmol) was added to a solution of compounds 3f/3f′ (dr = 67:33; 70 mg, 0.270 mmol) in CH2Cl2 (8 mL), the mixture was then stirred at r.t. for 2 h. The reaction mixture was filtered through a Celite pad, concentrated to give the crude mixture, which was then purified by flash column chromatography (hexane-Et2O = 3:1) on silica gel to give the pure pyrrolidine-2,5-dione 5. Yield 60%; yellow oil. IR (film): ν = 1774,1701, 1443, 1376 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 0.83-1.45 (m, 10 H), 1.58-1.68 (m, 2 H), 1.95-2.03 (m, 1 H), 2.50-2.61 (m, 1 H), 2.91-3.05 (m, 2 H). ¹³C NMR (75 MHz, CDCl3): δ = 14.0, 22.5, 26.6, 28.9, 29.6, 31.51, 31.54, 34.5, 40.0, 126.4, 128.5, 129.1, 131.9, 175.6, 178.9. MS: m/z (%) = 259 (10) [M+], 188 (35), 175 (100), 147 (10), 119 (30), 93 (16), 77 (7), 55 (14). The ee was determined to be 40% ee by chiral-phase HPLC using a Daicel Chiralcel OJ column (hexane-i-PrOH = 95:5, flow rate 1.2 mL/min, λ = 254 nm): t R(major) = 41.8 min; t R(minor) = 44.8 min.