Synlett 2006(5): 0713-0716  
DOI: 10.1055/s-2006-933122
LETTER
© Georg Thieme Verlag Stuttgart · New York

Enolate Conjugate Addition to Alkylidene Bis-Sulfoxides: Sphaeric Acid Synthesis and Absolute Configuration Determination

Franck Brebion, Jean-Philippe Goddard, Catherine Gomez, Louis Fensterbank*, Max Malacria*
Université Pierre et Marie Curie, UMR CNRS 7611, Institut de chimie moléculaire FR 2769, case 229, 4 place Jussieu, 75252 Paris Cedex 05, France
e-Mail: louis.fensterbank@upmc.fr; e-Mail: max.malacria@upmc.fr;
Further Information

Publication History

Received 16 December 2005
Publication Date:
09 March 2006 (online)

Abstract

The first stereoselective synthesis of sphaeric acid is described. The key step of this synthesis is an efficient ester enolate conjugate addition onto alkylidene bis-sulfoxides with good to high diastereoselectivity. Formation of sphaeric acid allowed the determination of its absolute configuration as 2R,3R.

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Enolate Conjugate AdditionGeneral Procedure A ( E -Enolate): To a solution of LDA (2 equiv) in THF (2.4 mL/mmol) at -78 °C, a solution of ester (2 equiv) in THF (1.4 mL/mmol) was added. After
45 min at -78 °C, a solution of alkylidene bis-sulfoxide (1 equiv) in THF (4.8 mL) was added via cannula. The reaction mixture was stirred at -78 °C for 15 min, quenched with an aq sat. solution of NH4Cl, and diluted with CH2Cl2. The organic layer was washed with water, brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel chromatography.
Procedure B ( Z -Enolate): To a solution of LDA (2 equiv) in THF (2.4 mL/mmol) at -78 °C, freshly distilled HMPA (8 equiv) and a solution of ester (2 equiv) in THF (1.4 mL/mmol) was added. After 45 min at -78 °C, a solution of alkylidene bis-sulfoxide (1 equiv) in THF (4.8 mL) was added via cannula. The reaction mixture was stirred at
-78 °C for 15 min, quenched with an aq sat. solution of NH4Cl and diluted with CH2Cl2.The organic layer was washed with water, brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel chromatography. ( S S , S S ,3 R )-3-[Bis( p -tolylsulfinyl)methyl]undecanoic Acid tert -Butyl Ester ( 7): Prepared by general procedure A from 1 (50 mg, 0.12 mmol). Column chromatography (pentane-EtOAc, 90:10 to 80:20) afforded 52 mg (81%) of 6 as a colorless oil; [α]D 20 +79.0 (c 0.4, CHCl3). IR (neat): 2926, 2855, 1728, 1492, 1367, 1152, 1086, 1058, 811, 755 cm-1. 1H NMR (400 MHz, CDCl3): δ = 0.85 (t, J = 7.0 Hz, 3 H, CH2CH 3), 0.90-1.27 (m, 14 H, 7 × CH2), 1.42 [s, 9 H, C(CH3)3], 2.31 (s, 3 H, p-Tol), 2.44 (s, 3 H, p-Tol), 2.69 [dd, J = 16.6, 8.6 Hz, 1 H, CHHCO2C(CH3)3], 2.82 [m, 1 H, CHCH(SOp-Tol)2], 3.18 [dd, J = 16.6, 3.3 Hz, 1 H, CHHCO2C(CH3)3], 3.60 [d, J = 4.4 Hz, 1 H, CH(SOp-Tol)2], 6.88 (d, J = 8.2 Hz, 2 H, Ar), 7.12 (d, J = 8.0 Hz, 2 H, Ar), 7.37 (d, J = 8.0 Hz, 2 H, Ar), 7.54 (d, J = 8.2 Hz, 2 H, Ar). 13C NMR (100 MHz, CDCl3): δ = 14.4 (CH2 CH3), 21.5 (p-Tol), 21.8 (p-Tol), 22.9, 26.7, 29.2, 29.3, 29.6, 32.1, 32.6 (7 × CH2), 28.4 [C(CH3)3], 31.5 [CHCH(SOp-Tol)2], 37.3 [CH2CO2C(CH3)3], 80.8 [CO2 C(CH3)3], 89.2 [CH(SOp-Tol)2], 124.0 (2 C, ArCH), 125.0 (2 C, ArCH), 130.1 (2 C, ArCH), 130.4 (2 C, ArCH), 139.2, 140.9, 141.2, 142.3 (4 C, ArCH), 171.8 (CO). HRMS: m/z calcd for C30H44O4NaS2 [M + Na]+: 555.2579; found: 555.2584.

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epi -Sphaeric Acid ( 14): White solid; mp 121-125 °C (dec.); [α]D 20 +18.9 (c 1.1, CH3OH). IR (neat): 3100, 2918, 2852, 2615, 1689, 1462, 1419, 1275, 1198, 945 cm-1. 1H NMR (400 MHz, CD3OD): δ = 0.93 (t, J = 7.1 Hz, 3 H, CH2CH 3), 1.19 (d, J = 6.6 Hz, 3 H, CH 3CH), 1.32 (br s, 12 H, 6 × CH2), 1.51 (m, 1 H, CH2), 1.63 (m, 1 H, CH2), 2.54-2.62 (m, 2 H, 2 × CHCOOH). 13C NMR (100 MHz, CD3OD): δ = 15.3 (CH3), 16.9 (CH3CH), 24.6, 29.3, 31.2, 31.3 (2 C), 32.9, 33.9 (7 × CH2), 44.4, 51.0 (2 × CHCOOH), 178.9, 179.5 (2 × COOH). HRMS: m/z calcd for C13H24NaO4 [M + Na]+: 267.1572; found: 267.1602.

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Sphaeric Acid ( 16): Colorless oil; [α]D 20 +8.1 (c 0.78, MeOH). IR (neat): 3027, 3018, 2924, 2855, 2680, 1705, 1464, 1416, 1282, 1240, 932 cm-1. 1H NMR (400 MHz, CDCl3): δ = 0.90 (t, J = 6.6 Hz, 3 H, CH2CH 3), 1.27-1.36 (m, 15 H, 6 × CH2, CH2CH 3), 1.56-1.63 (m, 2 H, CH2), 2.57 (dt, 1 H, J = 9.6, 4.3 Hz, CH), 2.72 (dq, J = 9.8, 4.2 Hz, 1 H, CH), 11.04 (br s, 2 H, CO2H). 13C NMR (100 MHz, CDCl3): δ = 14.1 (CH3), 15.2 (CH3), 22.7, 26.5, 29.2 (2 C), 29.3, 29.5, 31.8 (7 × CH2), 40.9, 47.9 (2 CHCOOH), 181.9, 182.5 (2 × COOH).