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

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

References and Notes

• 1a Namsylo JC. Kaufmann DE. Chem. Rev.  2003,  103:  1485 
• 1b Lee-Ruff E. Mladenova G. Chem. Rev.  2003,  103:  1449 
• 1c Fu N.-Y. Chan S.-H. In The Chemistry of Cyclobutanes   Rappoport Z. Liebman JF. J. Wiley and Sons; Chichester/New York: 2005.  p.357 
• 1d Lee-Ruff E. In The Chemistry of Cyclobutanes   Rappoport Z. Liebman JF. J. Wiley and Sons; Chichester/New York: 2005.  p.281 
• 2a Aubé J. Wang Y. Hammond M. Tanol M. Takusagawa F. Vander Velde D. J. Am. Chem. Soc.  1990,  112:  4879 
• 2b Aubé J. Chem. Soc. Rev.  1997,  26:  269 
• 2c Mihovilovic MD. Chen G. Wang S. Kyte B. Rochon F. Kayser MM. Stewart JD. J. Org. Chem.  2001,  66:  733 
• 2d Paneghetti C. Gavagnin R. Pinna F. Strukul G. Organometallics  1999,  18:  5057 
• 2e Sahasrabudhe K. Gracias V. Furness K. Smith BT. Katz CE. Reddy DS. Aubé J. J. Am. Chem. Soc.  2003,  125:  7914 
• 2f Trost BM. Xie J. J. Am. Chem. Soc.  2008,  130:  6231 
• 2g Fenster E. Smith BT. Gracias V. Milligan GL. Aubé J. J. Org. Chem.  2008,  73:  201 
• 3a Mazzini C. Lebreton J. Alphand V. Furstoss R. Tetrahedron Lett.  1997,  38:  1195 
• 3b Resende P. Almeida W. Coelho F. Tetrahedron: Asymmetry  1999,  10:  2113 
• 4 Malkov AV. Friscourt F. Bell M. Swarbrick ME. Kocovsky P. J. Org. Chem.  2008,  73:  3996 
• 5a Murahashi S.-I. Ono S. Imada Y. Angew. Chem. Int. Ed.  2002,  41:  2366 
• 5b Xu S. Wang Z. Zhang X. Zhang X. Ding K. Angew. Chem. Int. Ed.  2008,  47:  2840 
• 6 Aubé J. Wang Y. Ghosh S. Langhans KL. Synth. Commun.  1991,  21:  693 
• 7a Bernard AM. Frongia A. Guillot R. Piras PP. Secci F. Spiga M. Org. Lett.  2007,  9:  541 
• 7b Frongia A. Ollivier J. Piras PP. Secci F. Synthesis  2007,  999 
• 7c Frongia A. Girard C. Ollivier J. Piras PP. Secci F. Synlett  2008,  2823 
• 7d Alberti G. Bernard AM. Floris C. Frongia A. Piras PP. Secci F. Spiga M. Org. Biomol. Chem.  2009,  7:  3512 
• For some recent reviews on organocatalysis, see:
• 8a Erkkila A. Majander I. Pihko PM. Chem. Rev.  2007,  107:  5416 
• 8b Mukherjee S. Yang JW. Hoffmann S. List B. Chem. Rev.  2007,  107:  5471 
• 8c Dalko PI. Enantioselective Organocatalysis   Wiley-VCH; Weinheim: 2007. 
• 8d Melchiorre P. Marigo M. Carlone A. Bartoli G. Angew. Chem. Int. Ed.  2008,  47:  6138 ; Angew. Chem. 2008, 120, 6232
• For references to important direct and enantioselective organocatalytic α-oxidation of aldehydes and ketones literature, see:
• 9a Brown SP. Brochu MP. Sinz CJ. MacMillan DWC. J. Am. Chem. Soc.  2003,  125:  10808 
• 9b Hayashi Y. Yamaguchi J. Hibino K. Shoji M. Tetrahedron Lett.  2003,  44:  8293 
• 9c Momiyama N. Torii H. Saito S. Yamamoto H. Proc. Natl. Acad. Sci. U.S.A.  2004,  101:  5374 
• 9d Hayashi Y. Yamaguchi J. Sumiya T. Shoji M. Angew. Chem. Int. Ed.  2004,  43:  1112 
• 9e Bogevig A. Sundén H. Cordova A. Angew. Chem. Int. Ed.  2004,  43:  1109 
• 9f Hayashi Y. Yamaguchi J. Sumiya T. Hibino K. Shoji M. J. Org. Chem.  2004,  69:  5966 
• 9g Ramachary D. Barbas CFIII. Org. Lett.  2005,  7:  1577 
• 10 Brabandt WV. De Kimpe N. J. Org. Chem.  2005,  70:  3369 
• 11a Kakeya H. Takahashi I. Okada G. Isono K. Osada H. J. Antibiot.  1995,  48:  733 
• 11b Winterfeldt E. Synthesis  1975,  617 
• 12 Speckamp WN. Moolenaar MJ. Tetrahedron  2000,  56:  3817 
• For coupling constant value of trans-substituted γ-lactams, see:
• 14a Kar GK. Roy BC. Das Adhikari S. Ray JK. Brahma NK. Bioorg. Med. Chem.  1998,  6:  2397 
• 14b Kar GK. Chatterjee BG. Ray JK. Synth. Commun.  1993,  23:  1953 
• 14c For coupling constant value of cis-substituted γ-lactams, see: Ghosh M. Kar GK. Ray JK. Chatterjee BG. Synth. Commun.  1983,  13:  667 
• 15a Mazzini C. Lebreton J. Alphand V. Furstoss R. Tetrahedron Lett.  1997,  38:  1195 
• 15b Resende P. Almeida W. Coelho F. Tetrahedron: Asymmetry  1999,  10:  2113 
• 16a Enders D. Grondal C. Huttl MRM. Angew. Chem. Int. Ed.  2007,  46:  1570 
• 16b Tietze LF. Brasche G. Gericke KM. Domino Reactions in Organic Synthesis  Wiley-VCH: Weinheim,  2006; 
• 16c Yu X. Wang W. Org. Biomol. Chem.  2008,  6:  2037 
• 16d Guillena G. Ramón DJ. Yus M. Tetrahedron: Asymmetry  2007,  18:  693 

13

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.

17

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.