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Synlett 2007(2): 0219-0222  
DOI: 10.1055/s-2007-968004
LETTER
© Georg Thieme Verlag Stuttgart · New York

A New, Highly Stereoselective Synthesis of β-Unsubstituted (Z)-γ-Alkylidenebutenolides Using Bromine as a Removable Stereocontrol Element

John Boukouvalas*, Paola P. Beltrán, Nicolas Lachance, Sébastien Côté, François Maltais, Martin Pouliot
Département de Chimie, Université Laval, Quebec City, Quebec G1K 7P4, Canada
Fax: +1(418)6567916; e-Mail: john.boukouvalas@chm.ulaval.ca;
Further Information

Publication History

Received 1 November 2006
Publication Date:
24 January 2007 (online)

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Abstract

Several β-unsubstituted (Z)-γ-alkylidenebutenolides have been prepared in highly stereocontrolled fashion by implementing a steric directing group stratagem in the vinylogous aldol condensation of butenolides with aldehydes. Applications to the synthesis of the antitumor heptene (S)-melodorinol and a thiophenelactone from Chamaemelum nobile L. are described.

Key words

aldol reaction - bromobutenolides - dehalogenation - 2-silyloxyfurans - stereoselectivity

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The major isomers (syn) of all aldol products described herein (5 and 10a-d) were clearly distinguished from their anti counterparts by the upfield shift of their γ-proton
(Δδ ≈ 0.2-0.3 ppm). Their stereochemistry was deduced by debromination of syn-10a/anti-10a to the corresponding butenolides syn-13a/anti-13a whose stereostructures were unambiguously assigned from the diagnostic shift of the β-proton [5a] (Scheme [4] ).

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Typical Procedure: To a solution of 8 [13] (147 mg, 0. 903 mmol) in anhyd CH2Cl2 (3 mL) at 0 °C were successively added TBSOTf (207 µL, 0. 903 mmol) and Et3N (125 µL, 0. 903 mmol). The mixture was stirred for 30 min at 0 °C, then cooled to -78 °C, and then p-anisaldehyde (100 µL, 0.821 mmol) was added. After stirring at -78 °C for 1 h, DBU (251 µL, 1.64 mmol) was added and the resulting dark purple solution was allowed to warm to r.t. and stirred for an additional 1.5 h before quenching with 15% aq tartaric acid. The aqueous phase was extracted with CH2Cl2 (3 ×) and the combined organic layers were washed with sat. aq NaHCO3, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; EtOAc-CH2Cl2-hexanes, 1:3:10) to afford 6b (196 mg, 85%) as a pale red-brown solid; mp 129-130 °C. 1H NMR (400 MHz, CDCl3): δ = 3.86 (s, 3 H), 6.33 (s, 1 H), 6.35 (s, 1 H), 6.95 (d, J = 8.6 Hz, 2 H), 7.79 (d, J = 8.6 Hz, 2 H). 13C NMR (100 MHz, CDCl3): δ = 55.2, 113.5, 114.3, 117.4, 124.8, 132.7, 138.1, 145.0, 160.9, 167.3. MS (CI): m/z = 281 [MH+]. Anal. Calcd for C12H9BrO3: C, 51.27; H, 3.23. Found: C, 51.29; H, 2.99.
Data for 6c: yellow solid; mp 138-139 °C. 1H NMR (400 MHz, CDCl3): δ = 2.55 (br d, J = 1.0 Hz, 3 H), 6.33 (s, 1 H), 6.55 (s, 1 H), 6.78 (dq, J = 3.7, 1.0 Hz, 1 H), 7.26 (d, J = 3.7 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ = 15.7, 107.6, 117.7, 126.6, 133.0, 133.5, 136.7, 144.2, 147.8, 166.8. MS (CI): m/z = 271 [MH+]. Anal. Calcd for C10H7BrO2S: C, 44.30; H, 2.60; S, 11.83. Found: C, 44.25; H, 2.43; S, 12.19.
Compounds 6a (white solid; mp 84-85 °C) and 6d (yellow oil) exhibited NMR data commensurate with those reported by Brückner. [7a]

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Silyloxyfuran 9 was prepared in 98% yield by silylation (TBSOTf, Et3N, CH2Cl2, r.t.) of the readily available β-bromo-α-methylbutenolide: Svendsen, J. S.; Sydnes, L. K. Acta Chem. Scand. 1990, 44, 202.
Data for 9: colorless oil. 1H NMR (300 MHz, CDCl3): δ = 0.22 (s, 6 H), 0.97 (s, 9 H), 1.80 (s, 3 H), 6.86 (s, 1 H).). 13C NMR (75 MHz, CDCl3): δ = -4.5, 7.4, 17.9, 25.4, 94.0, 104.3, 129.2, 152.4. HRMS (EI): m/z calcd for C11H19BrO2Si: 290.0338; found: 290.0331.

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Data for 11a: orange oil. 1H NMR (400 MHz, CDCl3): δ = 0.93 (t, J = 7.3 Hz, 3 H), 1.37 (m, 2 H), 1.49 (m, 2 H), 2.41 (q, J = 7.6 Hz, 2 H), 5.62 (dt, J = 0.5, 8.0 Hz, 1 H), 6.34 (d, J = 0.5 Hz, 1 H). 13C NMR (75 MHz, CDCl3): δ = 13.7, 22.3, 26.1, 30.8, 117.3, 119.6, 136.9, 148.1, 167.0. HRMS (EI): m/z calcd for C9H11BrO2: 229.9942; found: 229.9938.
Data for 11b: orange oil. 1H NMR (300 MHz, CDCl3): δ = 0.90 (t, J = 7.1 Hz, 3 H), 1.31-1.50 (m, 4 H), 1.96 (s, 3 H), 2.37 (q, J = 7.4 Hz, 2 H), 5.47 (t, J = 7.9 Hz, 1 H). 13C NMR (75 MHz, CDCl3): δ = 10.2, 13.7, 22.3, 25.8, 31.0, 114.5, 128.1, 132.2, 147.0, 167.9. HRMS (EI): m/z calcd for C10H13BrO2: 244.099; found: 244.0098.
Data for 11c: yellow oil. 1H NMR (300 MHz, CDCl3): δ = 2.65 (m, 2 H), 2.72 (m, 2 H), 5.54 (t, J = 7.6 Hz, 1 H), 6.25 (s, 1 H), 7.11-7.25 (m, 5 H). 13C NMR (75 MHz, CDCl3): δ = 28.0, 34.7, 115.7, 119.8, 126.2, 128.2, 128.4, 136.9, 140.3, 148.3, 166.8. HRMS (EI): m/z calcd for C13H11BrO2: 277.9942; found: 277.9938.
Data for 11d: white solid; mp 66-67 °C. 1H NMR (300 MHz, CDCl3): δ = 3.74 (d, J = 8.1 Hz, 2 H), 5.76 (t, J = 8.1 Hz, 1 H), 6.40 (s, 1 H), 7.22-7.36 (m, 5 H). 13C NMR (75 MHz, CDCl3): δ = 32.6, 114.9, 120.3, 126.8, 128.6, 128.8, 137.1, 137.9, 148.2, 166.8. Anal. Calcd for C12H9BrO2: C, 54.55; H, 3.44. Found: C, 54.76; H, 3.53.
Data for 11e: white solid; mp 29-31 °C; [α]D 23 +32.5 (c = 1.03, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 1.40 (s, 3 H), 1.47 (s, 3 H), 3.73 (dd, J = 6.7, 8.2 Hz, 1 H), 4.23 (dd, J = 6.7, 8.2 Hz, 1 H), 5.12 (dt, J = 6.7, 8.2 Hz, 1 H), 5.64 (d, J = 8.2 Hz, 1 H), 6.43 (s, 1 H). 13C NMR (75 MHz, CDCl3): δ = 25.4, 26.5, 69.0, 70.6, 110.0, 112.8, 121.2, 137.0, 148.9, 165.9. HRMS (CI): m/z calcd for C10H11BrO4: 274.9919; found: 274.9915.