Iminophosphorane-Based Preparation of 2,5-Disubstituted Oxazole ­Derivatives: Synthesis of the Marine Alkaloid Almazole C

Abstract

A four-steps synthesis (32% overall yield) of marine alkaloid almazole C isolated from the red seaweed Haraldiophylum sp. is described. The key step, construction of the central 2,5-disubstituted oxazole ring is based on the aza-Wittig reaction of the iminophosphorane derived from the α-azidoacetyl indole and (S)-N-phthaloylphenylalanyl chloride.

oxazoles - marine alkaloids - iminophosphoranes - indoles - aza-Wittig reaction

References and Notes

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17

2-[( S )-1-{5-[ N -(Methoxymethyl)-1 H -indol-3-yl]oxazol-2-yl}-2-phenylethyl]isoindoline-1,3-dione ( 7).
To a solution of 3-(α-azidoacetyl) indole 5 (0.2 g, 0.82 mmol) in dry THF (32 mL), n-tributylphosphine (0.3 mL, 1.23 mmol) was added dropwise at 0 °C under N₂. Then, a solution of (S)-N-phthaloylphenylalanyl chloride 6 (0.26 g, 0.82 mmol) in the same solvent (20 mL) was added. The resultant mixture was stirred at r.t. for 1 h, and then dry Et₃N (0.17 mL, 1.23 mmol) was added and stirred for 2 h. The resultant solution was concentrated to dryness under reduced pressure and the residue was chromatographed on a silica gel column using CH₂Cl₂-EtOAc (8:2) as eluent to give 7 (0.27 g, 70% yield). Mp 157-160 °C ¹H NMR (300 MHz, CDCl₃): δ = 3.17 (s, 3 H, OCH₃), 3.79 (m, 2 H, CH₂), 5.37 (s, 2 H, OCH₂), 5.78 (dd, 1 H, J = 10.2, 6.3 Hz, CH), 7.08-7.22 (m, 8 H, H-5, H-6, H-4′, 2 Ho, 2 Hm and Hp), 7.37 (s, 1 H, H-2), 7.41 (d, 1 H, J = 8.1 Hz, H-7), 7.59 (dd, 2 H, J = 5.4, 3.0 Hz, 2 Hm′’), 7.68 (d, 1 H, J = 7.8 Hz, H-4), 7.71 (dd, 2 H, J = 5.4, 3.0 Hz, 2 Ho′). ¹³C NMR (75 MHz, CDCl₃): δ = 35.6 (CH₂), 49.3 (CH), 56.0 (OCH₃), 77.6 (OCH₂), 105.3 (C-3), 110.4 (C-7), 120.1 (C-4), 120.6 (C-4′), 121.4 (C-7), 121.4 (C-5), 123.2 (C-6), 123.4 (Co′), 125.2 (C-3a), 125.6 (C-2), 126.9 (Cp), 128.6 (Cm), 129.0 (Co), 131.6 (C-i′), 134.0 (Cm′), 136.5 (C-7a), 136.6 (Ci), 147.9 (C-5′), 158.4 (C-2′), 167.4 (CO). MS (FAB positive): m/z (%) = 478 (100) [M + 1], 477 (75) [M⁺], 326 (29) [M⁺ - Bn], 331 ]M⁺ - phthalimido]. Anal. Calcd for C₂₉H₂₃N₃O₄: C, 72.94; H, 4.85; N, 8.80. Found: C, 72.86; H, 4.80; N, 8.85.

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20

Almazole C ( 1).
To a suspension of 7 (0.32 g, 0.68 mmol) in EtOH (20 mL), hydrazine monohydrate (0.14 mL, 2.68 mmol) was added at 0 °C. The reaction mixture was stirred for 36 h at r.t. The precipitated solid was separated by filtration, slurried with CH₂Cl₂ and filtered. The filtrate was dried (MgSO₄) and the solvent removed under reduce pressure to give (S)-1-{5-[N-(Methoxymethyl)-1H-indol-3-yl]oxazol-2-yl}-2-phenyl-ethanamine (8, 0.21 g, 90% yield). A mixture of the amine 8 (0.4 g, 1,16 mmol), formaldehyde 37% (0.86 mL, 9.54 mmol) and 10% Pd on charcoal (0.24 g, 2.3 mmol) in EtOH (25 mL) was stirred at r.t. under nitrogen for 17 h. The reaction mixture was filtered under celite and the solvent removed under reduce pressure to give (S)-1-{5-[1-(methoxymethyl)-1H-indol-3-yl]oxazol-2-yl}-N,N-dimethyl-2-phenylethanamine (9, 0.388g, 90% yield). A mixture of N-methoxymethyl almazole C (9, 0.3 g, 0.8 mmol), 85% formic acid (40 mL), THF (25 mL), and H₂O (5 mL) was heated at reflux temperature for 30 h. After cooling the solvents were removed under reduced pressure. The residue was purified by chromatography on a silica-amine gel column using Et₂O-EtOAc (9:1) as eluent to give 1 (0.146 g, 55% yield); spectroscopic and optical properties {[α]_D ²⁰ +141 (c 0.1, MeOH)} were identical to natural almazole C.