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Synlett 2008(16): 2526-2528  
DOI: 10.1055/s-2008-1078046
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of l-Cladinose Using Enantioselective Desymmetrization

Hyoung Cheul Kima, Joo-Hack Younb, Sung Ho Kang*a
a Department of Chemistry, School of Molecular Science (BK21), KAIST, Daejeon 305-701, Korea
Fax: +82(42)8692810; e-Mail: shkang@kaist.ac.kr;
b Department of Chemical Engineering, Sun Moon University, Asan Si, Chung-Nam 336-840, Korea
Further Information

Publication History

Received 8 July 2008
Publication Date:
10 September 2008 (online)

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Abstract

l-Cladinose, a neutral sugar found in erythromycins and azithromycins, has been synthesized efficiently using enantioselective monobenzoylation of 2-propenylglycerol in the presence of the imine-CuCl2 catalysts to elaborate the stereogenic quaternary center.

Key words

l-mycarose - l-cladinose - desymmetrization - quaternary centers - imine-CuCl2

    References and Notes

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15

Compound 12: ¹H NMR (400 MHz, CDCl3): δ = 1.26 (s, 3 H), 1.64 (br s, 1 H), 1.70 (d, J = 5.2 Hz, 3 H), 2.11-2.48 (m, 2 H), 5.07-5.21 (m, 2 H), 5.59 (d, J = 14.0 Hz, 1 H), 5.71-5.92 (m, 2 H). ¹³C NMR (100 MHz, CDCl3): δ = 17.6, 27.7, 47.2, 71.8, 118.7, 122.9, 133.9, 137.6. HRMS (EI): m/z calcd for C8H14O: 126.1044; found: 126.1041.

17

Synthesis of Epoxide 14 Vanadyl(acetylacetonate) (25 mg, 0.095 mmol) and
t-BuO2H (2.0 M in CH2Cl2, 2.38 mL, 4.76 mmol) were added to diene 12 (400 mg, 3.17 mmol) in CH2Cl2 (3 mL) at 0 ˚C in sequence. The mixture was stirred at 0 ˚C for 30 min and then at r.t. for 6 h. After quenching the excess peroxide with 10% aq Na2S2O3 (10 mL), the following extraction with EtOAc (3 × 5 mL), drying over MgSO4 (500 mg), filtration and evaporation under reduced pressure gave the crude product, which was separated by column chromatography (SiO2, 230-400 mesh, EtOAc-hexane, 1:3) to furnish the desired epoxide (374 mg, 83%) along with the regioisomeric epoxide (35 mg, 7%). Sodium hydride (60% dispersion in mineral oil, 126 mg, 3.16 mmol) was added to the disubstituted epoxide (374 mg, 2.63 mmol) in THF (3 mL) at 0 ˚C portionwise. To the generated alkoxide was injected MeI (0.25 mL, 4.0 mmol), and the resulting solution was stirred at 0 ˚C for 15 min and then at r.t. for 3 h. After quenching the methylation with sat. NH4Cl (3 mL), the workup was done by extraction with EtOAc (3 × 4 mL), drying with MgSO4 (300 mg), filtration and evaporation in vacuo. The residual material was purified chromato-graphically (SiO2, 230-400 mesh, EtOAc-hexane, 1:4) to render the epoxy methyl ether 14 (329 mg, 80%).
Compound 14: ¹H NMR (400 MHz, CDCl3): δ = 1.21 (s, 3 H), 1.33 (d, J = 5.2 Hz, 3 H), 1.91-2.10 (m, 2 H), 2.71 (d, J = 2.3 Hz, 1 H), 3.12 (qd, J = 5.2, 2.3 Hz, 1 H), 3.31 (s, 3 H), 5.10-5.25 (m, 2 H), 5.78-5.94 (m, 1 H). ¹³C NMR (100 MHz, CDCl3): δ = 17.3, 25.1, 39.1, 51.5, 52.6, 62.4, 63.5, 118.1, 133.6. HRMS (EI): m/z calcd for C9H16O2: 156.1150; found: 156.1145.

18

Synthesis of Lactone 15
To epoxide 14 (300mg, 1.92 mmol), dissolved in a mixture of CH2Cl2 (4 mL), MeCN (4 mL), and H2O (6 mL), were added NaIO4 (1.68 g, 7.87 mmol) and RuCl3˙3H2O (16 mg) sequentially at r.t., and the mixture was stirred at that temperature for 8 h. After addition of CH2Cl2 (50 mL) to the mixture, the resulting solution was washed with aq HCl (1.0 M, 30 mL) twice and then brine (20 mL) once. The remaining organic layer was dried over MgSO4 (1 g), filtered and evaporated in vacuo. The residue was purified by column chromatography (SiO2, 230-400 mesh, EtOAc-hexane, 1:2) to give the corresponding carboxylic acid (267 mg, 80%). The carboxylic acid (267 mg, 1.53 mmol) in CH2Cl2 (4 mL) was stirred in the presence of BF3˙OEt2 (58 µL, 0.46 mmol) at 0 ˚C for 10 min and then at r.t. for 5 h. After addition of H2O (3 mL), the resulting solution was extracted with EtOAc (3 × 5 mL), the organic layer was dried over MgSO4 (400 mg), filtered and evaporated in vacuo. The residue was separated by column chromatography (SiO2, 230-400 mesh, EtOAc-hexane, 1:2) to afford the lactone 15 (229 mg, 86%).
Compound 15: ¹H NMR (400 MHz, CDCl3): δ = 1.28 (d, J = 6.3 Hz, 3 H), 1.42 (s, 3 H), 2.52 (d, J = 17.1 Hz, 1 H), 2.66 (d, J = 17.1 Hz, 1 H), 3.24 (s, 3 H), 3.88-3.95 (m, 1 H), 4.06 (d, J = 7.1 Hz, 1 H). ¹³C NMR (100 MHz, CDCl3): δ = 17.6, 20.4, 41.5, 51.1, 66.5, 80.6, 87.9, 174.0. HRMS (EI): m/z calcd for C8H14O4: 174.0892; found: 174.0889.

19

Synthesis of l -Cladinose (2) Diisobutylaluminum hydride (1.0 M in THF, 2.87 mL, 2.87 mmol) was added to 15 (200 mg, 1.15 mmol) in THF (5 mL) dropwise at -78 ˚C and the resulting mixture was stirred at that temperature for 3 h. The reaction was quenched with a 4:1 mixture of MeOH and H2O at -78 ˚C, and then the temperature was raised to r.t. After addition of sat. NaHCO3 (0.5 mL) and MgSO4 (200 mg) to the mixture, it was filtered using EtOAc (10 mL), and the organic layer was evaporated in vacuo. The remaining residue was purified by column chromatography (SiO2, 230-400 mesh, EtOAc-hexane, 1:1) to deliver l-cladinose (2, 164 mg, 81%).