Resin Linked Dipolarophiles to Mask Nitrones

Abstract

Acrylate and maleate functionalized resins were used to mask the nitrone moiety of a chiral pyrroline N-oxide to prevent the racemization at the C-3 stereogenic center and to link them to a solid phase. After the elaboration of the linked cycloadducts, the product was disconnected from the resin through a 1,3-dipolar cycloreversion/intramolecular cycloaddition domino process.

Key words

solid-phase synthesis - protecting groups - 1,3-dipolar cycloadditions - domino reactions - nitrones

References

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7

Compound (-)-7 has been employed in a total synthesis of (-)-rosmarinecine, see ref. [1b]

8

Methyl (2a R ,3 S ,6a R ,6b R )-2-Oxo-hexahydro-1,4-dioxa-4a-aza-cyclopenta[ cd ]pentalene-3-carboxylate [(-)-(7)] (see ref. [1b] ): R _f = 0.31 (EtOAc), mp 140-141 °C; [α]_D ²³ = -53.5 (c = 0.39, CHCl₃). ¹H NMR: δ = 5.13 (m, 1 H, 6a-H), 4.74 (d, J = 6.3 Hz, 1 H, 3-H), 4.45 (dd, J = 7.8, 7.7 Hz, 1 H, 6b-H), 3.84 (s, 3 H, Me), 3.80-3.74 (m, 2 H, 5-H_a, 2a-H), 3.10-3.03 (m, 1 H, 5-H_b), 2.45-2.41 (m, 2 H, 6-H). ¹³C NMR: δ = 174.1 (s, CO), 166.3 (s, CO), 83.2 (d, C-6a), 79.1 (d, C-3), 71.5 (d, C-6b), 54.5 (t, C-5), 52.6 (q, Me), 52.2 (d, C-2a), 32.4 (t, C-6). MS: m/z (%) = 213 (3) [M⁺], 183 (1), 169 (4), 154 (86), 108 (49), 83 (100). IR (CCl₄): ν = 3007, 1775, 1768, 1169 cm^-1. Elemental analysis calcd for C₉H₁₁NO₅ (213.19): C, 50.71; H, 5.20; N, 6.57. Found: C, 50.70; H, 5.34; N, 6.73.

10

The excess of chiral nitrone 1 was recovered spectroscopically pure and without any loss of optical purity after a filtration through a short pad of silica gel and was as such used in other cycloadditions.

12

Synthesis of REM Resin 2e (see ref. 13): Hydroxymethyl polystyrene resin (100-200 mesh, 1% DVB; substitution: 0.68 mmol/g) (500 mg, 0.34 mmol) was swollen in CH₂Cl₂ (5 mL), then acryloyl chloride (240 µL, 2.92 mmol) and i-Pr2NEt (500 µL, 2.92 mmol) were added in turn dropwise at r.t. The mixture was shaken overnight, and then was filtered. Resin 2e was washed in turn with CH₂Cl₂, MeOH and Et₂O and dried under vacuum. The IR spectrum (KBr pellet) of resin 2e showed the appearance of the C=O stretching band (1724 cm^-1). Cycloaddition reaction: Resin 2e was swollen in CH₂Cl₂ (5 mL) and nitrone 1 (255 mg, 1.36 mmol) was added at r.t. The mixture was shaken for 24 h, and then was filtered and the unchanged nitrone 1 (189.9 mg, 1.03 mmol) was recovered from the solution, after concentration and filtration through a short pad of silica gel (Eluent: CH₂Cl₂/MeOH 25:1), in a spectroscopically pure form and without any loss of optical purity. Resin 3e was washed in turn with CH₂Cl₂, MeOH and Et₂O and dried under vacuum. The IR spectrum (KBr pellet) of resin 3e showed the disappearance of the C=C stretching band (1634 cm^-1). Deprotection of the Hydroxyl Functionality: Resin 3e was swollen in CH₂Cl₂ (5 mL) and MeOH (0.5 mL) and TMSCl (173 µL, 1.36 mmol) were added at r.t. The mixture was shaken for 1 h, and then was filtered and a 5:1 solution of CH₂Cl₂ and Et3N was added. The mixture was shaken overnight and then filtered. Resin 4e was washed in turn with CH₂Cl₂, MeOH, Et₂O and dried under vacuum. The IR spectrum (KBr pellet) of resin 4e showed the appearance of the OH stretching band (3441 cm^-1). Mitsunobu Reaction: DEAD (161 µL, 1.02 mmol) was added dropwise at 0 °C to a mixture of resin 4e, 5 (88.4 mg, 0.68 mmol) and PPh₃ (267 mg, 1.02 mmol) in THF (5 mL). The mixture was shaken overnight, and then filtered. Resin 6e was washed in turn with CH₂Cl₂, MeOH, Et₂O and dried under vacuum. The IR spectrum (KBr pellet) of resin 6e showed the disappearance of the OH stretching band (3441 cm^-1) and the appearance of the C=C stretching band (1641 cm^-1). Retrocycloaddition/Cycloaddition Reaction: Resin 6e was swollen in xylenes (30 mL) and refluxed for 7 h. The mixture was allowed to cool to r.t., and then filtered. The resin was dried under vacuum to be recycled. The solution was filtered through silica gel eluting initially with petroleum ether to remove the high boiling solvent, and then with EtOAc to recover isoxazolidine (-)-7 (28.4 mg, 42%) as a pale yellow solid (see ref. [8] ).

14

All the solid-phase reactions were monitored by FT-IR.