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Synlett 2010(5): 817-821  
DOI: 10.1055/s-0029-1219351
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

An Approach to the Oxazoline-Containing Fragments of the Oroidin Dimers Nagelamide R and T

Sabuj Mukherjee, Rasapalli Sivappa, Muhammed Yousufuddin, Carl J. Lovely*
Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, USA
Fax: +1(817)2723808; e-Mail: lovely@uta.edu;
Further Information

Publication History

Received 15 October 2009
Publication Date:
25 January 2010 (online)

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Abstract

A tandem hydrolysis-intramolecular nucleophilic substitution reaction provides an expedient synthesis of the oxazoline moiety found in the oroidin dimers, nagelamide R and the recently isolated nagelamide T.

Key words

Mitsunobu - tandem hydrolysis - nucleophilic substitution

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CCDC 750494 (Figure  [¹] ) and CCDC 750495 (Figure  [²] ) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

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Synthesis of 4-[2-Chloro-3-(5-bromo-1,3-dioxo-1 H -pyrrolo[1,2- c ]imidazol-2-yl)propyl]imidazole-1-sulfonic Acid Dimethylamide (25) In a round-bottom flask containing the bromohydantoin 23 (120 mg, 0.56 mmol) and Ph3P (150 mg, 0.56 mmol) was dissolved in dry THF (5 mL) under N2 atmosphere. The mixture was cooled to (0 ˚C) and DEAD (0.26 mL, 0.56 mmol, 40 wt% in toluene) was added dropwise. After 30 min, the chloroalcohol 13 (100 mg, 0.37 mmol) dissolved in THF (2 mL) was added to the reaction mixture was dropwise. The reaction mixture was stirred for 12 h, concentrated, and then the crude product was purified by chromatography (hexane-EtOAc, 6:4) providing 25 as a colorless solid (0.15 g, 86%). [α]D -5.0 (c 0.002, MeOH); mp 154-156 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 7.82 (s, 1 H), 7.29 (s, 1 H), 7.16 (s, 1 H), 6.79 (s, 1 H), 4.60-4.56 (m, 1 H), 3.96-3.93 (m, 2 H), 3.10 (dd, J = 15.1, 5.5 Hz, 1 H), 3.06 (dd, J = 14.8, 7.6 Hz, 1 H), 2.85 (s, 6 H). ¹³C NMR (75 MHz, CDCl3): δ = 157.4, 147.6, 138.9, 136.5, 124.8, 118.7, 115.8, 115.7, 105.9, 57.2, 44.7, 38.2, 34.9. FTIR (neat): 1797, 1733, 1562, 1392, 1272, 1166, 1074, 953, 732 cm-¹. HRMS: m/z calcd for [M + H]+ C14H15BrClN5O4S: 463.9795; found: 463.9789.

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Synthesis of 4-[2-(4,5-Dibromo-1 H -pyrrol-2-yl)-4,5-dihydrooxazol-5-ylmethyl]imidazole-1-sulfonic Acid Dimethylamide (20) The Mitsunobu product (80 mg, 0.15 mmol) was dissolved in THF (6 mL) and 20% NaOH (0.4 mL, 80 mg, 2.2 mmol) was added. The reaction mixture was heated to 75 ˚C for 6 h. After cooling to r.t., the organic solution was separated, and the aqueous solution was extracted with EtOAc (3 × 50 mL) times. The organic solution were combined and dried with anhyd Na2SO4 and concentrated. Then the crude product was purified by chromatography (CHCl3-MeOH, 98:2) providing 20 as a white solid (40 mg, 57%). [α]D -22.1 (c 0.002, MeOH); mp 62-64 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 7.82 (s, 1 H), 7.03 (s, 1 H), 6.64 (s, 1 H), 5.00 (quint, J = 5.9 Hz, 1 H), 4.06 (dd, J = 14.4, 7.6 Hz, 1 H), 3.80 (dd, J = 14.2, 6.9 Hz, 1 H), 3.02 (dd, J = 15.1, 6.4 Hz, 1 H), 2.95 (dd, J = 14.7, 5.9 Hz, 1 H), 2.73 (s, 6 H). ¹³C NMR (75 MHz, CDCl3): δ = 157.8, 138.7, 136.6, 121.1, 116.2, 115.3, 106.4, 99.8, 79.3, 57.9, 38.1, 33.5. FTIR (neat): 1701, 1645, 1433, 1389, 1177, 1086, 962, 826, 738 cm-¹. HRMS: m/z calcd for [M + H]+ C13H15Br2N5O3S: 479.9341; found: 479.9335.

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Synthesis of 2-Azido-4-[2-(4,5-dibromo-1 H -pyrrol-2-yl)-4,5-dihydrooxazol-5-ylmethyl]imidazole-1-sulfonic Acid Dimethylamide (22)
Dibromopyrrole 20 (160 mg, 0.25 mol) was dissolved in anhyd THF (8 mL), and the reaction mixture was cooled to -78 ˚C and 0.5 M LDA (2.72 mL, 4.1 equiv) was added dropwise to the reaction mixture. The reaction mixture was left stirring for 30 min at -78 ˚C, and then TsN3 (0.28 g, 1.07 mmol) was added. The reaction mixture was allowed to come to r.t. and then stirred for an additional 1 h, followed by addition of aq NH4Cl to quench the reaction mixture. The organic layer was separated, and the aqueous layer was extracted with EtOAC (3 × 50 mL). The organic solutions were combined, dried with anhyd Na2SO4, and concentrated. Then the crude product was purified by chromatography (CHCl3-MeOH, 98:2) giving 22 as a white solid (120 mg, 71%). [α]D -36.5 (c 0.002, MeOH); mp 70-72 ˚C. ¹H NMR (500 MHz, CDCl3): δ = 6.93 (s, 1 H), 6.69 (s, 1 H), 5.01 (quint, J = 6.4 Hz, 1 H), 4.11 (dd, J = 14.5, 7.6 Hz, 1 H), 3.87 (dd, J = 14.2, 6.8 Hz, 1 H), 2.93 (s, 6 H), 2.91-2.88 (m, 2 H). ¹³C NMR (75 MHz, CDCl3): δ = 143.7, 139.8, 135.1, 129.4, 126.3, 121.3, 116.5, 116.3, 78.7, 57.8, 38.8, 33.3. FTIR (neat): 2145, 1649, 1534, 1509, 1457, 1398, 1336, 1181, 1086, 990 cm-¹. HRMS: m/z calcd for [M + H]+ C13H14Br2N8O3S: 520.9355; found: 520.9355.