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Synlett 2009(17): 2872-2874  
DOI: 10.1055/s-0029-1218017
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Diastereo- and Enantioselective Synthesis of α,β-Disubstituted γ-Bisalkoxycarbonyl Sulfonates

Dieter Enders*a, Hamdollah Saeidiana,b, Zohreh Mirjafarya,b, Dirk Ifflanda, Gerhard Raabea, Jan Runsinka
a Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax: +49(241)8092127; e-Mail: enders@rwth-aachen.de;
b Department of Chemistry, Sharif University of Technology, Tehran, Iran
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Publication History

Received 16 July 2009
Publication Date:
10 September 2009 (online)

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Abstract

The asymmetric synthesis of α,β-disubstituted γ-bisalkoxycarbonyl sulfonates is reported. The synthesis is based on the Michael addition of a lithiated enantiopure sulfonate bearing a cheap chiral sugar auxiliary to Knoevenagel acceptors. The reaction proceeds with high asymmetric inductions (ds = 69-96%) and good yields (62-79%). The absolute configuration was determined by X-ray crystal-structure analysis.

Key words

sulfonate - asymmetric synthesis - Michael addition - sugar auxiliary - Knoevenagel acceptor

    References and Notes

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6

CCDC-739752 (3i) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallo-graphic Data Centre via www.ccdc.cam.ac.uk/data-request/cif.

7

General Procedure for the Synthesis of α,β-Disubstituted γ-Alkoxycarbonyl Sulfonates 3a-j
To a solution of enantiopure sulfonate 1 (1.0 mmol) in dry THF (10 mL), n-BuLi (1.6 M solution in hexane, 0.63 mL) was added dropwise at -90 ˚C to - 95 ˚C under argon. The solution was stirred for 1 h, after which the Michael acceptor 2 (1.0 mmol in 1 mL dry THF) was added dropwise. The mixture was stirred for 4-6 h at -90 ˚C to - 95 ˚C. The progress of the reaction was monitored by TLC. The mixture was quenched with sat. NH4Cl (3 mL). After separation of the organic layer, the aqueous phase was extracted with CH2Cl2 (4 × 5 mL). The combined organic layers were dried over MgSO4, evaporated, and the crude product was purified by flash column chromatography (silica gel, Et2O-pentane, 1:2) to afford 3a-j.
Dimethyl 2-(2-{5-(2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[2,3- d ][1,3]dioxol-6-yloxy-sulfonyl}-2-phenyl-1- p -tolylethyl)malonate (3b)
Yield 454 mg (70%); colorless solid; ds = 73%; the major diastereomer was separated by preparative HPLC; de  98%; mp 66-68 ˚C. ¹H NMR (400 MHz, CDCl3): δ = 1.32, 1.36, 1.37, 1.70 [4 × s, 12 H, (O)2C(CH3)2], 2.32 (s, 3 H, CH3), 3.33 (dd, J = 7.4, 8.5 Hz, 1 H, CHHOC), 3.44, 3.52 (2 × s, 6 H, OCH3), 3.72 (dd, J = 7.0, 8.5 Hz, 1 H, CHHOC), 3.76 [dd, J = 2.5, 8.8 Hz, 1 H, CH(OC)CH(OC)CH2O], 3.81 [d, J = 7.1 Hz, 1 H, CH(CO2)2], 4.13 [dt, J = 2.5, 7.0 Hz, 1 H, CH(OC)CH2O], 4.20-4.26 [m, 2 H, CH(OC)CH(OC)2, CHCH(CO2)2], 4.47 (dd, J = 4.7, 8.8 Hz, 1 H, CHOSO2), 5.60 (d, J = 9.6 Hz, 1 H, PhCHSO3), 5.64 [d, J = 3.6 Hz, 1 H, CH(OC)2], 7.11 (d, J = 8.0 Hz, 2 H, ArH), 7.38-7.46 (m, 7 H, ArH). ¹³C NMR (100 MHz, CDCl3): δ = 21.1 (CH3), 25.3, 25.9, 26.4, 26.6 [O2C(CH3)2], 47.5 [CHCH(CO2)2], 52.1, 52.3 (OCH3), 54.7 [CH(CO2)2], 64.1 (CH2), 70.7 (PhCHSO3), 73.7 [CH(OC)CH2O], 76.0 [CH(OC)CH(OC)CH2O], 76.6 [CH(OC)CH(OC)2], 76.9 (CHOSO2), 103.2 [CH(OC)2], 109.7, 113.2 [(O)2 C(CH3)2], 128.2, 128.7, 129.2, 129.9, 130.2 (ArCH), 131.4, 132.7, 137.3 (ArC), 167.5, 167.9 (CO2). IR (KBr): 2954, 2986, 1736, 1602, 1516, 1436, 1370, 1163, 1017, 931, 833, 701 cm-¹. MS (EI, 70 eV): m/z (%) = 633.6 (10) [M+ - CH3], 261.3 (37), 235.3 (66), 205.3 (40), 169.2 (89), 135.3 (100), 127.3 (66). Anal. Calcd for C32H40O12S (648.6): C, 59.25; H, 6.21. Found: C, 59.13; H, 6.12.
General Procedure for the Removal of the Chiral Auxiliary The sulfonate 3b (0.5 mmol) was dissolved in a solution of 2% TFA in MeOH-H2O (10:1 mL). The solution was refluxed for 15 h and then evaporated to dryness. The resulting oil was dissolved in CH2Cl2, (i-PrO)3CH (5 mmol) was added dropwise, and the mixture was refluxed for 3 h. The solvent was removed in vacuo, and the crude product was purified by flash column chromatography (SiO2, Et2O-pentane, 1:3) to yield the final product 6.
Dimethyl 2-[2-(Isopropoxysulfonyl)-2-phenyl-1- p -tolylethyl]malonate (6)
Yield 107 mg (48%); colorless solid; mp 72-74 ˚C; de and ee ≥98% (HPLC); [α]D ²² +52.24 (c 0.67, CHCl3). ¹H NMR (400 MHz, CDCl3): δ = 0.89, 1.03 [2 × d, J = 6.0 Hz, 6 H, (CH 3)2CH], 2.32 (s, 3 H, CH3), 3.42, 3.54 (2 × s, 6 H, OCH3), 3.95 [d, J = 8.0 Hz, 1 H, CH(CO2)2], 4.19 [dd, J = 8.0, 9.1 Hz, 1 H, CHCH(CO2)2], 4.47 (sept, J = 6.0 Hz, 1 H, CHOSO2), 5.13 (d, J = 9.1 Hz, 1 H, PhCHSO3), 7.10 (d, J = 8.0 Hz, 2 H, ArH), 7.30-7.42 (m, 7 H, ArH). ¹³C NMR (100 MHz, CDCl3): δ = 21.2 (CH3), 22.3, 23.1 [(CH3)2CH], 47.4 [CHCH(CO2)2], 52.3, 52.6 (OCH3), 55.1 [CH(CO2)2], 70.0 (CHSO3), 77.9 (CHOSO2), 128.6, 128.6, 129.0, 130.0, 130.1 (ArCH), 132.3, 132.7, 137.5 (ArC), 167.8, 168.2 (CO2). IR (KBr): 2987, 2954, 1738, 1596, 1436, 1370, 1213, 1165, 1017, 871, 840, 698 cm-¹. MS (EI, 70 eV): m/z (%) = 448.2 (5.7) [M+], 235.2 (43), 205.2 (21), 135.1 (100). Anal. Calcd for C23H28O7S (448.2): C, 61.59; H, 6.29. Found: C, 61.31; H, 6.78. HRMS: m/z calcd for C23H28O7S: 448.1550; found: 448.1552.