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

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.

asymmetric - lactones - stereoselectivity - catalysis - ­copper

References

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12 Bluet G. Bazan-Tejeda B. Campagne JM. Org. Lett.  2001,  3:  3807 

13 Trost BM. Gunzner JL. Dirat O. Rhee YH. J. Am. Chem. Soc.  2002,  124:  10396 

14 Kruger J. Carreira EM. J. Am. Chem. Soc.  1998,  120:  837 

15 Konno K. Fujishima T. Maki S. Liu Z. Miura D. Chokki M. Ishizuka S. Yamaguchi K. Kan Y. Kurihara M. Miyata N. Smith C. DeLuca HF. Takayama H. J. Med. Chem.  2000,  43:  4247 

16

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: R_f = 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.

17 Still WC. Gennari C. Tetrahedron Lett.  1983,  24:  4405 

18

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

19

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: R_f = 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).

20 Carlsen HJ. Katsuki T. Martin VS. Sharpless KB. J. Org. Chem.  1981,  46:  3936 

21

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.

22 Patois C. Savignac P. Synth. Commun.  1991,  21:  2391