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Synlett 2004(4): 720-722  
DOI: 10.1055/s-2004-817744
LETTER
© Georg Thieme Verlag Stuttgart · New York

Stereoselective Syntheses of the C1-C5, C7-C15 and C17-C24 Fragments of (+)-Discodermolide Using a Catalytic and Asymmetric Vinylogous Mukaiyama Reaction

Belén Bazán-Tejeda, Marie Georgy, Jean-Marc Campagne*
ICSN-CNRS, Avenue de la Terrasse, 91198 Gif sur Yvette, France
Fax: +33(1)69077247; e-Mail: campagne@icsn.cnrs-gif.fr;
Further Information

Publication History

Received 10 November 2003
Publication Date:
29 January 2004 (online)

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Abstract

The stereoselective syntheses of C1-C5, C7-C15 and C17-C24 fragments of (+)-discodermolide are described from a common intermediate: an α,β-unsaturated six-membered lactone obtained in one step using a catalytic and asymmetric vinylogous Mukaiyama (CAVM) reaction.

Key words

asymmetric - lactones - stereoselectivity - catalysis - ­copper

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Experimental Procedure for Fragment C17-C24 5. DIBAL-H (0.55 mL, 1 M in hexanes) is added to a solution of 2 (200 mg, 0,49 mmol) in toluene (6 mL) at -78 °C. After 15 min at -78 °C, sat. NH4Cl (10 mL) is added and the reaction mixture is allowed to warm up to r.t. After extraction with CH2Cl2 and classical work-up, lactol (196 mg) is obtained without further purification as a colorless oil. Triphenylmethylphosphonium bromide (59 mg, 0,16 mmol) is suspended in THF (0.5 mL) at 0 °C. NaHMDS (63 µL, 0,127 mmol, 2 M in THF) is then added dropwise. After 2.5 h at 0 °C, the reaction mixture is cooled to -78 °C and a solution of crude lactol (26 mg, 0.063 mmol) in THF (0.6 mL) is added. The reaction mixture is allowed to warm up to r.t. and after 15 h the solvent is evaporated. The crude residue is purified by column chromatography (pentane/ CH2Cl2 8:2 to 6:4). Diene 5 is obtained (18 mg, 70% yield) as a colorless oil.
Analytical data: Rf = 0.38 (heptane/EtOAc 9:1). IR: 3503, 3071, 3049, 2999, 2961, 2930, 2858 cm-1. 1H NMR (CDCl3): δ = 0.95 (3 H, d, J = 6.7 Hz, H10), 0.97 (3 H, d, J = 7.0 Hz, H9), 1.07 (9 H, s, t- Bu), 1.81-1.93 (1 H, m, H7), 2.27 (1 H, d, J = 2.6 Hz, OH), 2.73-2.85 (1 H, m, H5), 3.63 (1 H, dt, J = 2.5 and 8.1 Hz, H6), 3.72 (2 H, d, J = 2 Hz, H8), 5.12 (1 H, d, J = 10.1 Hz, H1), 5.22 (1 H, d, J = 16.8 Hz, H1′), 5.42 (1 H, t, J = 10.4 Hz, H4), 6.12 (1 H, d, J = 11 Hz, H3), 6.61 (1 H, dt, J = 10.4 and 16.8 Hz, H2), 7.36-7.46 (6 H, m, Ph), 7.66-7.72 (4 H, m, Ph). 13C RMN (CDCl3): δ = 9.67 (C9), 17.41 (C10), 19.20 (t-Bu), 26.98 (3 C, t-Bu), 35.79 (C5), 36,82 (C7), 68.12 (C8), 76.38 (C6), 117.89 (C1), 127.64 (4 C, Ph), 129.65 (2 C, Ph), 130.20 (C3), 132.25 (C2), 133.31 (Ph), 133.45 (Ph), 135.50 (C4), 135.67 (4 C, Ph). [α]D 25 +43.5 (c 1, CHCl3). HRMS (ESI+) [MNa]+: calcd m/z = 431.2382, found m/z = 431.2379.

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The same reaction carried out under ‘regular’ HWE conditions led to a 95:5 Z/E mixture.

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Experimental Procedure for Fragment C7-C15 9. To a solution of fluorophosphonate [22] (70 mg, 0.2 mmol) and 18-C-6 (64 mg, 0.24 mmol) at -78 °C, is added KHMDS (0.4 mL, 0.5 M in toluene). After 15 min, a solution of aldehyde 8 (18 mg, 0.1 mmol) in THF (0.2 mL) is added. After 8 min, in an ice-water bath, starting aldehyde has disappeared (CCM monitoring). After quenching using sat. NH4Cl (15 min) and classical work-up, the crude residue is purified by column chromatography (heptane/EtOAc 7:3) to give 9 (20 mg, 75%) as a colorless oil.
Analytical data: Rf = 0,66 (heptane/EtOAc 7:3). IR: 2965, 2930, 2865, 2821, 1705, 1602 cm-1. 1H NMR (CDCl3): δ = 0.98 (3 H, d, J = 7.2 Hz, H12). 1.03 (3 H, d, J = 6.8 Hz, H13), 1,07 (3 H, dd, J = 1.6 and 6.7 Hz, H11), 1.30 (3 H, t, J = 7.2 Hz, H16), 2.24-2.35 (1 H, m, H5), 3.38 (3 H, s, H14), 3.45-3.61 (2 H, m, H6-H7), 4.20 (2 H, q, J = 7.2 Hz, H15), 4.85 (1 H, bs, H2), 5.68 (1 H, dt, J = 2.6 and 10 Hz, H3), 5.79 (1 H, bd, J = 10 Hz, H4), 6.14 (1 H, dd, J = 1.4 and 8.4 Hz, H8). 13C NMR (CDCl3): δ = 13.05 (C12), 14.2 (C16), 16.3 (C13), 20.8 (C11), 30.9 (C5), 33.3 (C7), 55.0 (C14), 60.0 (C15), 75.3 (C6), 95.4 (C2), 124.0 (C3), 136.2 (C4), 140.5 (C9), 146.6 (C8), 167.7 (C10), [α]D 25 +138.9 (c 0.58, CHCl3). Anal. Calcd for (%): C, (67.14); H, (9.01). Found (%): C, (67.23); H (9.11).

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Experimental Procedure for Fragment C1-C5 11. To a solution of lactone 2 (60 mg, 0.15 mmol) in CCl4 (0.15 mL), CH3CN (0.15 mL) and H2O (0.27 mL) are added. RuCl3·H2O (15 µL, 6% in H2O) and NaIO4 (135 mg, 0.6 mmol) are then added and the reaction is stirred at r.t. for 24 h. The reaction mixture is diluted with H2O (1 mL) and extracted with CH2Cl2. Organic phases are discarded and the aqueous phase is acidified with 1 N HCl and extracted with CH2Cl2. Organic phases are dried over MgSO4, filtered and evaporated to give a mixture of compounds 10 and 11. The crude product is dissolved in MeOH (2 mL) and a solution of NaOH (2 mL) is then added. After 1 h stirring at r.t., the reaction mixture is evaporated. The residue is taken up in H2O and then acidified (1 N HCl). Extraction with CH2Cl2 and classical work-up gave acid 11 (42 mg, 68%).
Analytical data: IR: 3435, 2929, 1713, 1112 cm-1. 1H NMR (CDCl3): δ = 0.95 (3 H, d, J = 7.0 Hz, H6), 1.07 (9 H, s, t-Bu), 1.15 (3 H, d, J = 7.1 Hz, H7), 1.73-1.84 (1 H, m, H4), 2.61 (1 H, m H2), 3.60 (1 H, dd, J = 5.7 and 10 Hz, H5), 3.82 (1 H, dd, J = 3.9 and 10 Hz, H5′), 4.12 (1 H, d, J = 10.1 Hz, H3), 7.36-7.46 (6 H, m, Ph), 7.66-7.72 (4 H, m, Ph). 13C NMR (CDCl3): δ = 9.3 (C6), 17.4 (C7), 19.2 (1 C, t-Bu), 26.9 (3 C, t-Bu), 36.8 (C4), 43.7 (C2), 68.3 (C5), 74.8 (C3), 127.7 (4 C, Ph), 129.7 (2 C, Ph), 133.3 (1 C, Ph), 134.7 (1 C, Ph), 135.6 (4 C, Ph), 179.0 (C=O). HRMS (ESI+) [MNa]+: calcd m/z = 423.197, found m/z = 423.200.