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

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.

two-directional - elimination - isooxazolidine - ketolactam - desymmetrisation

References and Notes

1a Magnuson SR. Tetrahedron  1995,  51:  2167 

1b Poss C. Schreiber S. Acc. Chem. Res.  1994,  24:  9 

2 Bruce R. Tetrahedron  1995,  51:  13103 

3 For the previous paper in this series, see: Rejzek M. Stockman RA. van Maarseveen JH. Hughes DL. Chem. Commun.  2005,  4461 

4a Stockman RA. Tetrahedron Lett.  2000,  41:  9163 

4b Stockman RA. Sinclair A. Arini LG. Szeto P. Hughes DL. J. Org. Chem.  2004,  69:  1598 

5 Rejzek M. Stockman RA. Org. Biomol. Chem.  2005,  3:  73 

6 McDermott P. Stockman RA. Org. Lett.  2005,  7:  27 

7 Arini LG. Szeto P. Hughes DL. Stockman RA. Tetrahedron Lett.  2004,  45:  8371 

8 A similar epimerisation was reported by Holmes: Horsley HT. Holmes AB. Davies JE. Goodman JM. Silva MA. Pascu SI. Collins I. Org. Biomol. Chem.  2004,  2:  1258 

9 Alexander R. Ko ECF. Parker AJ. Broxton TJ. J. Am. Chem. Soc.  1968,  90:  5049 

10

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.