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DOI: 10.1055/s-0029-1219351
An Approach to the Oxazoline-Containing Fragments of the Oroidin Dimers Nagelamide R and T
Publikationsverlauf
Publikationsdatum:
25. Januar 2010 (online)
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
- 1
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nagelamide T which is the desbromo analogue of nagelamide R, see:
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References and Notes
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.
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.
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.
20
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.