Stereoselective Sulfonate Aldol Reactions: Asymmetric Synthesis of α,β-Substituted β-Hydroxy Sulfonates

Wacharee Harnying; Wipaporn Kitisriworaphan; Manat Pohmakotr; Dieter Enders

doi:10.1055/s-2007-986642

LETTER

Stereoselective Sulfonate Aldol Reactions: Asymmetric Synthesis of α,β-Substituted β-Hydroxy Sulfonates

Wacharee Harnying*^a, Wipaporn Kitisriworaphan^a, Manat Pohmakotr^b, Dieter Enders^c
^a Department of Chemistry, Faculty of Science, Khon Kaen University, Khon Kaen 40002, Thailand
Fax: +66(43)202373; e-Mail: hwacha@kku.ac.th;
^b Department of Chemistry, Faculty of Science, Mahidol University, Rama VI Road, Bangkok 10400, Thailand
^c Institut für Organische Chemie, Rheinisch-Westfälische Technische Hochschule, Landoltweg 1, 52074 Aachen, Germany

Abstract

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Abstract

An efficient asymmetric synthesis of β-hydroxy sulfonates is described via stereocontrolled aldol reactions of sulfonates using 1,2:5,6-di-O-isopropylidene-α-d-allofuranose as the chiral auxiliary. The aldol reactions with aromatic aldehydes yielded predominantly syn adducts in very good yields and excellent diastereo- and enantiomeric excesses (de, ee ≥98%).

Key words

asymmetric synthesis - sulfonates - aldol reaction - sugar auxiliary - hydroxy sulfonates

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References

References and Notes

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General Procedure for Aldol Reactions of the Sulfonate 1: To a cooled (-78 °C) solution of freshly generated lithium diisopropylamide [prepared by treatment of diisopropyl-amine (1.1 mmol) in anhyd THF (3 mL) with n-BuLi (1 mmol) at -78 °C for 30 min] was added dropwise a solution of the sulfonate 1 (1 mmol) in THF (2 mL) under N₂. After stirring for 1 h, a mixture of aldehyde (2 mmol) and 1 M ZnCl₂ in THF (1.2 mmol) was added dropwise. The reaction mixture was stirred at -78 °C for 1 h and then quenched with sat. NH₄Cl. The mixture was poured into an ice-cooled 1 N HCl solution (10 mL) and extracted with EtOAc. The combined organic layers were washed with H₂O, brine and dried over Na₂SO₄. The solvent was removed under reduced pressure to give the crude product. The diastereomeric ratio was determined at this stage by ¹H NMR (400 MHz). The crude product was purified by flash column chromatography (SiO₂, EtOAc-hexane) to give the aldol product 2.
(1S,2R)-2a: colorless solid; de ≥ 98%; mp 103-104 °C; [α]_D ²⁹ +93.1 (c = 0.105, EtOH). IR (KBr): 3446 (s), 2986, 1630, 1375, 1344 (s), 1217, 1150 (s), 1059 (s), 1017 (s), 886, 705 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.29, 1.30, 1.37, 1.57 (4 × s, 12 H, 4 × Me), 3.65 (br s, 1 H, OH), 3.75 (dd, J = 6.6, 8.7 Hz, 1 H, CHH), 3.95 (dd, J = 6.7, 8.7 Hz, 1 H, CHH), 4.09 [dd, J = 4.1, 8.6 Hz, 1 H, CH₂CHCHO), 4.25 (dt, J = 4.1, 6.6 Hz, 1 H, CH₂CHCHO), 4.46 [t, J = 4.4 Hz, 1 H, OCHCH(OC)₂], 4.47 (d, J = 2.2 Hz, 1 H, CHSO₃), 4.81 (dd, J = 4.7, 8.6 Hz, 1 H, CHOSO₂), 5.71 [d, J = 3.7 Hz, 1 H, CH(OC)₂], 5.80 (br d, J = 1.8 Hz, 1 H, CHOH), 7.01-7.30 (m, 10 H, ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 25.2, 26.1, 26.6, 26.7 (4 × Me), 65.4 (CH₂), 72.1 (CHOH), 74.0 (CHSO₃), 74.6, 76.4, 76.9, 77.6 (4 × CHO), 103.8 (OCHO), 110.3, 113.8 [2 × C(CH₃)₂], 126.0 (ArCH), 127.76 (ArC), 127.83, 128.1, 128.2, 129.1, 131.3 (ArCH), 139.2 (ArC). MS (EI, 70 eV): m/z (%) = 520 (0.2)[M⁺], 505 (22), 399 (16), 341 (23), 292 (17), 197 (31), 167 (31), 127 (51), 91 (100), 77 (33), 55 (17). Anal. Calcd for C₂₆H₃₂O₉S (520.59): C, 59.99; H, 6.20. Found: C, 60.13; H, 6.19.

(1S,2R)-4: colorless solid; de, ee ≥ 98%; mp 169-170 °C; [α]_D ²⁹ +122.0 (c = 0.115, EtOH). IR (KBr): 3467 (s), 1220, 1163 (s), 1049 (s), 795, 713, 651, 572 cm^-1. ¹H NMR (400 MHz, CDCl₃-CD₃OD): δ = 3.87 (br s, 1 H, OH), 4.02 (d, J = 1.8 Hz, 1 H, CHSO₃), 5.71 (d, J = 1.8 Hz, 1 H, CHOH), 6.93-6.97 (m, 2 H, ArH), 7.02-7.11 (m, 6 H, ArH), 7.17-7.21 (m, 2 H, ArH). ¹³C NMR (100 MHz, CDCl₃-CD₃OD): δ = 71.7, 73.1 (2 × CH), 126.0, 127.0, 127.19, 127.22, 127.6, 130.7 (ArCH), 132.5, 140.7 (2 × ArC). MS (EI, 70 eV): m/z (%) = 179 (100)[PhCH=C(Ph)⁺], 165 (55), 152 (20).

epi-4 obtained from the cleavage of the anti isomer 3a under the same conditions exhibits a different ¹H NMR spectrum. ¹H NMR (400 MHz, CDCl₃-CD₃OD): δ = 3.67 (br s, 1 H, OH), 4.16 (d, J = 10.1 Hz, 1 H, CHSO₃), 5.29 (d, J = 10.1 Hz, 1 H, CHOH), 7.00-7.30 (m, 10 H, ArH).