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Synlett 2007(2): 0324-0326  
DOI: 10.1055/s-2007-967995
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Pilar M. Fresneda*, Marta Castañeda, Mathias Blug, Pedro Molina*
Departamento de Química Orgánica, Facultad de Química, Universidad de Murcia, Campus de Espinardo, 30100 Murcia, Spain
Fax: +34(968)364149; e-Mail: fresneda@um.es; e-Mail: pmolina@um.es;
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Publication History

Received 19 July 2006
Publication Date:
24 January 2007 (online)

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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.

Key words

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

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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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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.