Total Syntheses of (±)-Vestitol
and Bolusanthin III Using a Wittig Strategy

Amarjit Luniwal; Paul W. Erhardt

doi:10.1055/s-0030-1260783

LETTER

Total Syntheses of (±)-Vestitol and Bolusanthin III Using a Wittig Strategy

Amarjit Luniwal, Paul W. Erhardt*
Department of Medicinal and Biological Chemistry, Center for Drug Design and Development, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, 2801 W. Bancroft Street, Toledo, Ohio 43606, USA
Fax: +1(419)5307946; e-Mail: paul.erhardt@utoledo.edu;

Abstract

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Abstract

An intramolecular Wittig olefination was utilized to produce the key isoflav-3-ene intermediate needed to prepare (±)-vestitol and bolusanthin III in ca. 30% and 20% respective yields after eight steps.

Key words

vestitol - bolusanthin III - total syntheses - intramolecular Wittig olefination

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Referenzen

References and Notes

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Khupse, R. S.; Sarver, J. G.; Trendel, J. A.; Ellis, N. R.; Reese, M. D.; Wiese, T. E.; Boue, S. M.; Burrow, M. E.; Cleveland, T. E.; Bhatnagar, D.; Erhardt, P. W. J. Med. Chem. 2011, submitted.

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<A NAME="RS01011ST-8I">8i</A> Yuan Y. Men H. Lee C. J. Am. Chem. Soc. 2004, 126: 14720

<A NAME="RS01011ST-9">9</A> Yin G. Gao M. She N. Hu S. Wu A. Pan Y. Synthesis 2007, 3113

1-(2′-Benzyloxy-4-methoxyphenyl)ethanone
To a solution of 4-methoxy-2-hydroxyacetophenone (5.0 g, 30 mmol) in MeCN (80 mL), K₂CO₃ (5.0 g, 36 mmol) and benzyl bromide (5.0 g, 29 mmol) were added. The reaction mixture was stirred under reflux while progress was followed by TLC and ^¹H NMR. After 24 h solvent was evaporated under vacuum. The off-white residue was dissolved in EtOAc and washed with 2 M NaOH, 0.1 M HCl, H₂O, and brine. After drying over anhyd Na₂SO₄ and then filtration, the volatiles were evaporated under vacuum to obtain the desired ketone (7.4 g, 28.8 mmol, 96%) as a white solid; mp 84-88 ˚C. TLC: R _f = 0.40 (EtOAc-hexanes = 1:3). ^¹H NMR (600 MHz, CDCl₃): δ = 7.85 (1 H, d, J = 8.4 Hz), 7.40 (5 H, m), 6.53 (2 H, m), 5.13 (2 H, s), 3.83 (3 H, s), 2.56 (3 H, s). ^¹³C NMR (150 MHz, CDCl₃): δ = 197.8, 164.3, 160.1, 135.9, 132.7, 128.7, 128.2, 127.6, 121.4, 105.3, 99.4, 70.6, 55.5, 32.2
Compound 5
To a solution of protected ketone from the previous step (22.7 g, 88.6 mmol) in anhyd CH₂Cl₂ (100mL) and anhyd MeOH (500 mL), Selectfluor^TM (18.9 g, 53.3 mmol) was added followed by addition of elemental iodine (11.25 g, 44.3 mmol). The reaction mixture was stirred for 20 h. Progress was monitored by TLC and ^¹H NMR. After completion, the reaction mixture was filtered and the precipitate was washed with CH₂Cl₂. The combined filtrate was evaporated under vacuum, and the solid residue was dissolved in CH₂Cl₂ (200 mL) and washed with freshly prepared 10% Na₂S₂O₃ solution (3 × 125 mL). The organic layer was dried over anhyd Na₂SO₄, filtered, and evaporated to dryness. The solid residue was purified by recrystall-ization from Me₂CO-MeOH (1:10, 100 mL) to obtain 5 (28.4 g, 74.3 mmol, 84%) as yellowish crystals; mp 96-100 ˚C. TLC: R _f = 0.54 (EtOAc-hexanes = 1:3). ^¹H NMR (600 MHz, CDCl₃): δ = 7.91 (1 H, d, J = 9.0 Hz), 7.44 (5 H, m), 6.57 (1 H, dd, J = 9.0 Hz), 6.53 (1 H, d, J = 2.4 Hz), 5.17 (2 H, s), 4.40 (2 H, s), 3.84 (3 H, s). ^¹³C NMR (150 MHz, CDCl₃): δ = 165.1, 159.7, 135.5, 134.1, 128.8, 128.5, 127.9, 117.4, 106.0, 99.3, 71.0, 55.6, 9.9. Anal. Calcd (%) for C₁₆H₁₅IO₃˙0.5H₂O: C, 49.13; H, 4.12. Found: C, 48.82; H, 3.78.

<A NAME="RS01011ST-11">11</A> Kraus GA. Kim I. Org. Lett. 2003, 5: 1191

Compound 7
To a solution of salicyl alcohol 6 (0.19 g, 0.82 mmol) and
α-iodo ketone 5 (0.28 g, 0.74 mmol) in Me₂CO (15 mL), K₂CO₃ (0.14 g, 0.98 mmol) was added under a flow of N₂. The reaction mixture was refluxed for 16-18 h. Progress was followed by TLC. After completion, the solvent was evaporated under reduced pressure. The solid residue was dissolved in EtOAc (120 mL) and washed with 1 M NaOH, H₂O, brine, dried over anhyd Na₂SO₄, and evaporated to dryness under vacuum. The solid residue was purified using flash column chromatography to obtain 7 (0.28 g, 0.57 mmol, 78%) as off-white solid; mp 150-153 ˚C. TLC: R _f = 0.17 (EtOAc-hexanes = 1:2). ^¹H NMR [600 MHz, (CD₃)₂CO)]: δ = 7.89 (1 H, d, J = 8.4 Hz), 7.45 (10 H, m), 7.22 (1 H, d, J = 9.0 Hz), 6.83 (1 H, d, J = 2.4 Hz), 6.68 (1 H, dd, J = 2.4, 9.0 Hz), 6.56 (1 H, dd, J = 2.4, 8.4 Hz), 6.26 (1 H, d, J = 2.4 Hz), 5.33 (2 H, s), 5.21 (2 H, s), 4.99 (2 H, s), 4.57 (2 H, d, J = 6.6 Hz), 4.15 (1 H, t, J = 6.6 Hz), 3.90 (3 H, s). ^¹³C NMR [100 MHz, (CD₃)₂CO): δ = 193.7, 161.7, 160.1, 158.0, 138.2, 137.0, 133.2, 129.6, 129.5, 129.3, 129.2, 129.1, 128.6, 107.5, 106.0, 101.0, 99.8, 74.6, 71.7, 70.5, 60.9, 56.1. Anal. Calcd (%) for C₃₀H₂₈O₆˙0.25H₂O:
C, 73.68; H, 5.87. Found: C, 73.33; H, 5.71.

<A NAME="RS01011ST-13">13</A> Yaun Y. Men H. Lee C. J. Am. Chem. Soc. 2004, 126: 14720

Compound 8
To a suspension of 7 (97 mg, 0.2 mmol) in anhyd MeCN (4 mL), Ph₃P˙HBr (70 mg, 0.2 mmol) was added under a flow of N₂. The reaction mixture was stirred at r.t. and followed by TLC. After completion, solvent was evaporated under vacuum to obtain an off-white residue which was directly used in the next step without further purification.
To a solution of the above phosphonium salt in anhyd MeOH (15 mL), KOt-Bu (45 mg, 0.4 mmol) was added under a flow of N₂. The reaction mixture was refluxed for 16-20 h. Progress was monitored by TLC. After completion, the mixture was reduced to one-third of original volume under vacuum and then filtered. The precipitate was dissolved in CH₂Cl₂ (30 mL). The organic phase was washed with H₂O, brine, dried over anhyd Na₂SO₄, and evaporated to dryness under vacuum to obtain 8 (50 mg, 0.11 mmol, 70% over 2 steps) as an off-white solid; mp 119-122 ˚C. TLC: R _f = 0.65 (EtOAc-hexanes = 1:2). ^¹H NMR [600 MHz, (CD₃)₂CO]:
δ = 7.41 (10 H, m), 7.28 (1 H, d, J = 8.4 Hz), 7.01 (1 H, d, J = 7.8 Hz), 6.70 (1 H, d, J = 2.4 Hz), 6.60 (1 H, s), 6.57 (2 H, m), 6.46 (1 H, d, J = 1.8 Hz), 5.16 (2 H, s), 5.10 (2 H, s), 4.93 (2 H, s), 3.80 (3 H, s). ^¹³C NMR [150 MHz, (CD₃)₂CO]: δ = 161.7, 160.3, 158.2, 155.5, 138.2, 137.8, 130.0, 129.9, 129.3, 129.4, 129.23, 128.7, 128.6, 128.5, 128.3, 128.2, 121.5, 121.4, 118.1, 108.9, 106.3, 102.8, 100.5, 71.0, 70.4, 68.9, 55.6. Anal. Calcd (%)for C₃₀H₂₆O₄˙0.5H₂O: C, 78.41; H, 5.92. Found: C, 78.30; H, 5.69.

Racemic vestitol [(±)-1]
To a solution of 8 (50 mg, 0.11 mmol) in EtOAc (15 mL) at 0 ˚C, 10% w/w Pd/C (15-20 mg) was added. The mixture was stirred at r.t. under hydrogen atmosphere (2.4 bar). Progress was followed by TLC. After completion, the reaction mixture was passed through a pad of Celite. Solvent was evaporated under vacuum, and the residue further purified using flash column chromatography (EtOAc-hexanes = 1:1) to obtain (±)-1 (25 mg, 90 µmol, 84%) as an off-white powder; mp 172-179 ˚C (lit.^²d 171-173 ˚C). TLC: R _f = 0.44 (EtOAc-hexanes = 1:1). ^¹H NMR [600 MHz, (CD₃)₂CO]: δ = 8.52 (1 H, br), 8.10 (1 H, br), 7.05 (1 H, d, J = 8.4 Hz), 6.88 (1 H, d, J = 8.4 Hz), 6.50 (1 H, d, J = 2.4 Hz), 6.42 (1 H, dd, J = 2.4, 8.4 Hz), 6.35 (1 H, dd, J = 2.4, 8.4 Hz), 6.27 (1 H, d, J = 2.4 Hz), 4.23 (1 H, m), 3.97 (1 H, t, J = 10.2 Hz), 3.71 (3 H, s), 3.47 (1 H, m), 2.96 (1 H, m), 2.79 (1 H, m). ^¹³C NMR [100 MHz, (CD₃)₂CO]: δ = 160.3, 157.4, 156.6, 156.0, 130.9, 128.6, 120.8, 114.2, 108.6, 105.5, 103.4, 102.4, 70.4, 55.2, 32.5, 30.9. Anal. Calcd (%) for C₁₆H₁₆O₄: C, 70.57; H, 5.92. Found: C, 70.22; H, 5.98.

<A NAME="RS01011ST-16">16</A> Yoshino H. Tsuchiya Y. Saito I. Tsujii M. Chem. Pharm. Bull. 1987, 35: 3438

<A NAME="RS01011ST-17">17</A> Ward DE. Gai Y. Kaller BF. J. Org. Chem. 1995, 60: 7830

<A NAME="RS01011ST-18">18</A> Okano K. Okuyama K.-I. Fukuyama T. Tokuyama H. Synlett 2008, 1977

Bolusanthin III (2)

To a solution of 8 (0.45 g, 1 mmol) and pentamethylbenzene (1.48 g, 10 mmol) in anhyd CH₂Cl₂ (30 mL) at -78 ˚C, BCl₃ (0.2 mmol) was added dropwise under N₂. The mixture was stirred at -78 ˚C, and after 15-20 min the reaction was quenched with a CHCl₃-MeOH (10:1, 20 mL) mixture. The resulting mixture was warmed to r.t. The organic solvent was evaporated under vacuum. The residue was purified by column chromatography [silica gel 35 mm dia, 8 inch thick, EtOAc-hexanes (1:2)] to obtain 2 (0.17 g, 0.61 mmol, 61%) as a brownish solid; mp 150-154 ˚C (lit. reports an amor-phous material⁵ or a brown paste⁴ after isolation from natural sources). TLC: R _f = 0.48 (EtOAc-hexanes = (1:2). ^¹H NMR (600 MHz, CD₃OD): d = 7.14 (1 H, d, J = 8.4 Hz), 6.88 (1 H, d, J = 8.4 Hz), 6.53 (1 H, s), 6.42 (1 H, dd, J = 2.4, 8.4 Hz), 6.37 (1 H, d, J = 2.4 Hz), 6.33 (1 H, dd, J = 2.4, 8.4 Hz), 6.24 (1 H, d, J = 1.8 Hz), 4.94 (2 H, s), 3.74 (3 H, s). ^¹³C NMR (150 MHz, CD₃OD): d = 161.8, 159.1, 157.3, 155.9, 130.1, 130.0, 128.4, 121.4, 119.9, 117.6, 109.4, 106.1, 103.4, 102.4, 69.2, 55.6. Anal. Calcd (%) for C₁₆H₁₄O₄˙0.1H₂O: C, 70.63; H, 5.26. Found: C, 70.42; H, 5.20.

Portions of this work were described previously as a poster presentation at the 239^th American Chemical Society meeting in San Francisco during March, 2010. The published abstract was denoted as ORGN-941.