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Synlett 2007(17): 2667-2670  
DOI: 10.1055/s-2007-991049
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of the C15-C35 Segment of Chivosazole A

Dominic Janssen, Markus Kalesse*
Institut für Organische Chemie, Leibniz-Universität Hannover, Schneiderberg 1B, 30167 Hannover, Germany
Fax: +49(511)7623011; e-Mail: Markus.Kalesse@oci.uni-hannover.de;
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Publication History

Received 21 August 2007
Publication Date:
25 September 2007 (online)

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Abstract

The synthesis of the C15-C35 segment of chivosazole A is reported using a convergent approach that incorporates an E-selective Wittig olefination for joining both subunits of this fragment.

Key words

chivosazole - natural product - antibiotic - myxobacteria

14

Synthesis of Alkene 15
Reagent 14 (14 mg, 44 µmol) was dissolved in THF (1 mL) and cooled to 0 °C. Then, NaH (2.5 mg, 62 µmol, 60% dispersion on mineral oil) was added, the solution stirred for 15 min at 0 °C, and then cooled to -78 °C. Aldehyde 13 (27 mg, 49 µmol) was added and the mixture was warmed over 2 h to 0 °C and then quenched with sat. NH4Cl solution (5 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (1 × 10 mL) and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified via flash chromatography. The reaction yielded 21 mg of the Z-olefin (0.03 mmol, 69%). R f = 0.29 (EtOAc-hexane, 1:30); [α]D 23 +6.5 (c 1.07, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.29 (d, J = 8.5 Hz, 2 H), 6.87 (d, J = 8.5 Hz, 2 H), 6.40 (dd, J = 11.6, 10.2 Hz, 1 H), 5.82 (d, J = 11.6 Hz, 1 H), 4.57 (d, J = 10.6 Hz, 1 H), 4.52 (d, J = 10.6 Hz, 1 H), 4.15 (q, J = 7.1 Hz, 2 H), 3.95-3.90 (m, 1 H), 3.88-3.83 (m, 1 H), 3.80 (s, 3 H), 3.23 (dd, J = 5.8, 3.8 Hz, 1 H), 1.77-1.73 (m, 2 H), 1.57 (ddd, J = 14.0, 8.0, 1.9 Hz, 1 H), 1.41 (ddd, J = 13.7, 9.1, 4.1 Hz, 1 H), 1.28 (t, J = 7.2 Hz, 3 H), 1.15 (d, J = 6.2 Hz, 3 H), 1.11 (d, J = 6.8 Hz, 3 H), 0.95 (d, J = 6.8 Hz, 3 H), 0.90 (s, 9 H), 0.87 (s, 9 H), 0.10 (s, 3 H), 0.09 (s, 3 H), 0.02 (s, 3 H), -0.01 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 195.6, 166.1, 159.1, 156.3, 152.4, 131.4, 129.4, 119.8, 113.8, 83.8, 74.3, 72.2, 66.9, 59.8, 55.4, 43.7, 37.1, 26.2, 26.1, 25.4, 18.2, 17.7, 14.4, 9.5, -3.6, -3.8, -4.3, -4.3. ESI-HRMS: m/z calcd for C33H62O6NaSi2: 645.3983 [M + Na+]; found: 645.3975.
Synthesis of Lactone 28
Acid 25 (10 mg, 22.1 µmol) was dissolved in THF (0.25 mL) and treated with pyridine (0.25 mL). A HF-pyridine complex (ca. 70% HF, ca. 30% pyridine, 0.4 mL, 15.3 mmol) was added. The reaction mixture was stirred for 16 h at r.t. and then poured into sat. NaHCO3 solution (10 mL). The layers were separated and the aqueous layer was extracted with MTBE (5 × 5 mL). The combined organic layers were washed with sat. NH4Cl solution (5 mL) and brine (5 mL) and dried over MgSO4. The solvent was removed under reduced pressure and the residue purified via flash chromatography. The reaction yielded 4 mg of lactone 28 (12.5 µmol, 56%). R f = (EtOAc-hexane, 1:4); [α]D 23
-14.2 (c 0.30, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.26 (d, J = 8.5 Hz, 2 H), 6.88 (d, J = 8.7 Hz, 2 H), 5.91 (dt, J = 15.5, 5.2 Hz, 1 H), 5.82 (dd, J = 15.7, 6.0 Hz, 1 H), 4.75 (ddd, J = 10.6, 5.3, 5.3 Hz, 1 H), 4.46 (s, 2 H), 4.02 (d, J = 5.0 Hz, 2 H), 3.81 (s, 3 H), 3.73 (ddd, J = 6.8, 4.6, 4.6 Hz, 1 H), 3.31 (s, 3 H), 2.75 (dq, J = 6.8, 4.6 Hz, 1 H), 2.25 (ddd, J = 14.5, 6.9, 4.4 Hz, 1 H), 1.87 (ddd, J = 14.6, 11.2, 4.6 Hz, 1 H), 1.28 (d, J = 6.9 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 173.5, 159.4, 130.2, 130.1, 129.6, 129.5, 114.0, 76.2, 75.9, 72.3, 69.4, 56.8, 55.4, 39.6, 34.0, 11.5. ESI-HRMS: m/z calcd for C18H24O5Na: 343.1521 [M + Na+]; found: 343.1533.
Synthesis of the C15-C35 Segment (29) Wittig salt 16 (17 mg, 20 µmol) was dissolved in toluene (1 mL) and cooled to 0 °C. A solution of the aldehyde 27 (10 mg, 24 µmol) in toluene (0.2 mL) was added to the mixture. The reaction mixture was then treated with a KOt-Bu solution (18 µL, 28 µmol, 1 M solution in THF). After 30 min H2O (2 mL) was added, the layers separated, and the aqueous layer was extracted with MTBE (2 × 5 mL). The combined organic layers were dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified via flash chromatography. The reaction yielded 11 mg of compound 29 (15 µmol, 57%). R f = 0.32 (EtOAc-hexane, 1:10); [α]D 23 +3.9 (c 1.02, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 8.17 (s, 1 H), 7.29 (d, J = 8.5 Hz, 2 H), 6.85 (d, J = 8.9 Hz, 2 H), 6.42-6.36 (m, 1 H), 6.18-6.09 (m, 2 H), 6.04 (t, J = 11.1 Hz, 1 H), 5.62 (t, J = 10.4 Hz, 1 H), 5.59 (dd, J = 14.0, 8.2 Hz, 1 H), 5.32-5.54 (m, 2 H), 4.51 (s, 2 H), 4.32-4.27 (m, 1 H), 3.97-3.92 (m, 1 H), 3.91 (s, 3 H), 3.84-3.81 (m, 1 H), 3.79 (s, 3 H), 3.78-3.76 (m, 1 H), 3.42 (dq, J = 6.8, 5.0 Hz, 1 H), 3.37 (s, 3 H), 3.12 (dd, J = 6.5, 3.8 Hz, 1 H), 2.93-2.84 (m, 1 H), 1.86-1.79 (m, 1 H), 1.43-1.37 (m, 4 H), 1.34 (d, J = 6.8 Hz, 3 H), 1.16 (d, J = 5.8 Hz), 1.06 (d, J = 6.8 Hz, 3 H), 0.95 (d, J = 6.8 Hz, 3 H), 0.92 (s, 9 H), 0.86 (s, 9 H), 0.85 (s, 9 H), 0.10 (s, 6 H), 0.04 (s, 3 H), -0.01 (s, 3 H), -0.02 (s, 6 H). 13C NMR (100 MHz, CDCl3): δ = 166.9, 162.0, 159.1, 144.1, 137.2, 134.6, 133.2, 132.6, 131.3, 130.0, 129.5, 128.9, 128.4, 113.8, 84.7, 79.1, 74.6, 71.7, 70.3, 66.7, 57.6, 55.4, 52.3, 43.1, 40.3, 36.2, 32.1, 29.9, 26.2, 26.1, 26.0, 25.6, 22.9, 18.8, 18.2, 14.3, 11.5, 9.2, 7.5, 1.2, -3.3, -3.5, -3.8, -4.1, -4.3, -4.8. ESI-HRMS: m/z calcd for C52H91NO9Si3Na: 980.5899 [M + Na+]; found: 980.5900.