Synlett 2006(14): 2321-2324  
DOI: 10.1055/s-2006-949634
CLUSTER
© Georg Thieme Verlag Stuttgart · New York

Combining Two-Directional Synthesis and Tandem Reactions, Part 8: A Novel Condensation/Michael Addition/Cycloaddition/Fragmentation/Lactamisation Cascade

Alex Sinclaira, Louise G. Arinia, Martin Rejzeka, Peter Szetob, Robert A. Stockman*a
a School of Chemical Sciences and Pharmacy, University of East Anglia, Norwich, NR4 7TJ, UK
Fax: +44(1603)592003; e-Mail: r.stockman@uea.ac.uk;
b GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts, SG1 2NY, UK
Further Information

Publication History

Received 24 April 2006
Publication Date:
24 August 2006 (online)

Abstract

A tandem oxime formation/Michael addition/1,4-prototopic shift/[3+2]-cycloaddition of an acyclic symmetrical precursor results in a tricyclic isooxazolidine which then undergoes a further fragmentation/lactamisation cascade to generate a non-symmetrical tricyclic a-ketolactam as a single diastereomer.

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Isoxazolidine 2. To a solution of ketodiester 1 (7.90 g, 24.3 mmol) in MeOH (250 mL) was added NH2OH·HCl (1.91 g, 27.5 mmol) and NaOAc (5.13 g, 62.5 mmol). The solution was stirred at r.t. for 24 h, then the reaction was quenched with a sat. aq solution of NaHCO3 (50 mL) and the organics were extracted with CH2Cl2 (3 × 50 mL), dried (Na2SO4) and concentrated. The crude product was then taken up in MeCN (150 mL) and heated at reflux for 1 h. The solvent was then evaporated and the product was purified by column chromatography over silica gel (hexane-EtOAc, 4:1) to give 2 as colourless crystals (5.05 g, 15.5 mmol, 64%); mp 45-48 °C (pentane). IR (thin film): 1732 cm-1. 1H NMR (400 MHz, CDCl3): δ = 4.19 (5 H, m), 3.18 (1 H, dd, J = 15.6, 2.8 Hz), 3.05 (1 H, dd, J = 5.5, 5.7 Hz), 2.90 (1 H, dd, J = 10.4, 2.8 Hz), 2.30 (1 H, dd, J = 15.6, 10.4 Hz), 2.10-1.54 (12 H, m), 1.27 (6 H, m). 13C NMR (100 MHz, CDCl3): δ = 173.9, 172.1, 83.4, 77.5, 61.4, 60.5, 60.1, 51.0, 39.2, 39.1, 32.9, 29.9, 29.2, 20.7, 20.6, 14.3, 14.0; MS (CI): m/z (%) = 326 (M + 1, 100). HRMS: m/z calcd for C17H28NO5: 326.1967; found: 326.1965. Ketolactam 6; Method 1: To a stirred solution of Na metal (200 mg found, 8.5 mmol) dissolved in absolute EtOH (25 mL) was added a solution of tricyclic diester 2 (275 mg, 0.85 mmol) in absolute EtOH (10 mL) and the reaction was stirred for 1 h. The reaction was then quenched with a sat. aq solution of NH4Cl (10 mL) and stirred for a further 30 min, then extracted with EtOAc (3 × 30 mL), dried (Na2SO4) and concentrated. The product was purified by column chromatography over silica gel (hexane-EtOAc, 2:1) to yield 6 as a colourless solid (163 mg, 0.58 mmol, 69%). Method 2: To a solution of tricyclic hydroxylactam 7 (131 mg, 0.46 mmol) in CH2Cl2 (25 mL) was added silica gel (200 mg) followed by PCC (177 mg, 0.51 mmol). The solution was then stirred for 12 h before the addition of Et2O (50 mL) and filtration. The filtrate was then concentrated and purified by column chromatography over silica gel (hexane-EtOAc, 2:1) to give 6 (88 mg, 0.32 mmol, 62%). Method 3: To a stirred solution of Na metal (50 mg, 2.1 mmol) dissolved in absolute EtOH (5 mL) was added a solution of ketodiester 1 (130 mg, 0.4 mmol) and hydroxy-amine hydrochloride (35 mg, 0.5 mmol) in absolute EtOH (5 mL) and the reaction was stirred for 45 min. The reaction was then quenched with a sat. aq solution of NH4Cl (5 mL) and stirred for a further 30 min then extracted with EtOAc (3 x 10 mL), dried (Na2SO4) and concentrated. The product was purified by column chromatography over silica gel (hexane-EtOAc, 2:1) to yield 6 (14 mg, 0.05 mmol, 12%). IR (thin film): 1762, 1731, 1701 cm-1. 1H NMR (400 MHz, CDCl3): δ = 4.94 (1 H, dd, J = 8.2, 6.0 Hz), 4.07 (2 H, q, J = 7.2 Hz), 2.63 (2 H, dd, J = 8.2, 7.6 Hz), 2.45 (1 H, dd, J = 5.2, 4.8 Hz), 2.03-1.34 (12 H, m), 1.19 (3 H, t, J = 7.2 Hz). 13C NMR (100 MHz, CDCl3): δ = 202.1, 170.3, 158.9, 77.9, 66.2, 61.0, 54.9, 46.3, 37.9, 37.2, 28.0, 26.1, 16.5, 14.0. MS (EI): m/z (%) = 279 (M + 1, 100). HRMS: m/z calcd for C15H21NO4: 280.154; found: 280.1543. Hydroxylactam 7. To a stirred solution of tricyclic diester 2 (1.17 g, 3.6 mmol) in 50% aq AcOH (100 mL) was added activated Zn metal (3.5 g, 54 mmol) and the solution was heated at 70 °C for 24 h. The solvent was then evaporated and the resulting slurry was taken up in CH2Cl2 (75 mL) and washed with H2O (50 mL). The organic layer was then washed with a sat. aq solution of NaHCO3 (50 mL), dried (Na2SO4) and con-centrated. The product was purified by column chromatog-raphy over silica gel (hexane-EtOAc, 2:1) to give 7 as colourless crystals (789 mg, 2.8 mmol, 79%); mp 98-100 °C (hexane). IR (thin film): 3324, 1731, 1664 cm-1. 1H NMR (400 MHz, CDCl3): δ = 4.74 (1 H, m), 4.30 (1 H, d, J = 9.6 Hz), 4.14 (2 H, q, J = 7.2 Hz), 2.64 (2 H, m), 2.41 (1 H, m), 1.98-1.36 (12 H, m), 1.26 (3 H, m). 13C NMR (100 MHz, CDCl3): δ = 173.6, 170.7, 77.3, 69.3, 60.7, 48.1, 45.9, 38.8, 37.6, 36.8, 27.9, 25.8, 23.9, 17.4, 14.2. MS (CI): m/z (%) = 282 (M + 1, 100). HRMS: m/z calcd for C15H24NO4: 282.1705; found: 282.1705.