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Synlett 2003(6): 0894-0898
DOI: 10.1055/s-2003-38756
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Stereoselective Preparation of Chiral Building Blocks having 1,3-syn-Dimethyl Group from d-Glucose

Hirofumi Shiono, Yuki Mochizuki, Hironori Tsutsui, Yuji Mikami, Takashi Morohoshi, Oyo Mitsunobu*
Department of Chemistry, College of Science and Engineering, Aoyama Gakuin University, 6-16-1, Chitosedai, Setagayaku, Tokyo 157-8572, Japan
e-Mail: mitsu@chem.aoyama.ac.jp;
Further Information

Publication History

Received 13 November 2002
Publication Date:
17 April 2003 (online)

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Abstract

Reaction of (2S,3R,5S,6S)-2-methoxy-3,5-dimethyl-tetrahydro-2H-pyran-6-carbaldehyde (α-8) with MeMgCl gave (6′S)-α-9 as a single isomer which was converted into (5S,6R)-epoxide (cis-12) by a sequence of reactions involving tosylation, ring-opening by the reaction with HS(CH2)3SH, and treatment with NaOMe. When α-8 and its β-anomer (β-8) respectively reacted with MeTi(Oi-Pr)3 and the resulting alcohols were subjected to similar transformation as above, (5S,6S)-epoxide (trans-12) was obtained irrespective of the anomeric configuration. The reaction of trans-12 with lithium alkynylaluminates 13a and 13b took place at the position 6 to afford the corresponding alkynes 14a and 14b.

Key words

stereoselectivity - regioselectivity - chelation control - non-chelation control - chiral building block

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  • Experimental Procedures.
  • 8a

    Preparation of [2S,3R,5S,6S,6(1S)]-2-methoxy-3,5-dimethyl-6-(1-hydroxyethyl)tetra-hydropyran [(6′S)-α-9]. To a solution of oxalyl chloride (0.61 mL; 7.2 mmol) in CH2Cl2 (5 mL) was added DMSO (1.02 mL, 14.4 mmol) in CH2Cl2 (5 mL) at
    -78 °C over a period of 20 min. After the mixture was stirred for 30 min, a solution of (2S,3R,5S,6S)-2-methoxy-3,5-dimethyl-6-(hydroxymethyl)tetrahydropyran (α-7: 419 mg, 2.4 mmol) in CH2Cl2 (5 mL) was added at -78 °C over a period of 10 min and the resulting solution was stirred at -78 °C for 1 h, followed by the addition of triethylamine (5.02 mL, 36 mmol) in CH2Cl2 (5 mL). The mixture was allowed to warm to 0 °C and the reaction was quenched by the addition of saturated aqueous NH4Cl. After CH2Cl2 was added, the organic layer was separated, dried with MgSO4, concentrated to a small volume, filtered through silica gel, and concentrated to dryness to afford crude (2S,3R,5S,6S)-2-methoxy-3,5-dimethyl-6-formyltetrahydropyran (α-8) which was used in the subsequent step without purification. Thus, to a solution of the aldehyde in THF (24 mL) was added a solution of MeMgCl (3 M in THF, 2.4 mL, 7.2 mmol) at 0 °C. After the mixture was stirred at 0 °C for 17 h, the reaction was quenched by the addition of saturated aqueous NH4Cl. Ethyl acetate was added to the mixture and the organic layer was separated, dried with MgSO4 and concentrated. The residue was separated by silica gel column chromatography (n-hexane-ethyl acetate = 4:1) to afford (6′S)-α-9 as a syrup (301.6 mg, 67%). [α]D 20 = +133 (c = 0.273 g/100 mL CHCl3). 1H NMR (500 MHz, CDCl3); δ 0.83 (d, 3 H, C5-Me, J 5,Me = 2.3Hz), 0.84 (d, 3 H, C3-Me, J 3,Me = 2.3 Hz), 1.22 (ddd, 1 H, C4-Hax, J 3,4ax = J 4ax,5 =
    J 4ax,4eq = 12.4 Hz), 1.25 (d, 3 H, CH 3-CH(OH)-, J = 6.4 Hz), 1.44 (ddd, 1 H, C4-Heq, J 3,4eq = J 4eq,5 = 4.1 Hz), 1.72-1.81 (m, 2 H, C5-H, C3-H), 3.07 (d, 1 H, C6-H, J 5,6 = -10.5 Hz), 3.30 (s, 3 H, MeO), 3.90 [dt, 1 H, CH3-CH(OH)-], 4.49
    (d, 1 H, C2-H, J 2,3 = 3.2 Hz).

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  • 8b

    Preparation of [2S,3R,5S,6S,6(1S)]-2-methoxy-3,5-dimethyl-6-(1-tosyl-oxyethyl)tetrahydropyran [(6′S)-α-10]. To a solution of (6′S)-α-9 (161.3 mg, 0.86 mmol) in pyridine (8.6 mL) at 0 °C was successively added tosyl chloride (819 mg, 4.3 mmol) and DMAP (catalytic amount). After the mixture was stirred at room temperature for 24 h, the reaction was quenched by the addition of saturated aqueous NH4Cl and ethyl acetate was added. Organic layer was separated, dried with MgSO4, and concentrated. The residue was separated by silica gel column chromatography (n-hexane-ethyl acetate = 8: 1) to afford (6′S)-α-10 as a syrup (282.4 mg, 96%). [α]D 20 = +8.1 (c = 1.90 g/100 mL CHCl3). 1H NMR (500 MHz, CDCl3, CHCl3 = 7.24 ppm); δ 0.77 (d, 3 H, C5-Me, J 5,Me = 7.6 Hz), 0.83 (d, 3 H, C3-Me, J 3,Me = 6.9 Hz), 1.19 (ddd, 1 H, C4-Hax, J 3,4ax = J 4ax,5 = J 4ax,4eq = 12.8 Hz), 1.33 [d, 3 H, CH 3-CH(OTs)-, J = 6.4 Hz], 1.45 (ddd, 1 H, C4-Heq, J 3,4eq = J 5,4eq = 4.1 Hz), 1.71-1.80 (m, 2 H, C3-H, C5-H), 2.43 (s, 3 H, CH 3-C6H4-), 3.18 (dd, 1 H, C6-H, J 5,6 = 6.4 Hz, J 6,-CH(Me)Ots = 1.4 Hz), 3.27 (s, 3 H, CH3O), 4.50 (d, 1 H, C2-H, J 2,3 = 3.7 Hz), 4.91 [dt, 1 H, CH3-CH(OTs)-], 7.31-7.81 (m, 4 H, aromatic-H). Anal. Found C: 59.35%, H: 7.63%. Calcd for C17H26O5S, C: 59.62%, H 7.65%

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  • 8c

    (2R,4S,5S,6S)-1-(1,3-dithian-2-yl)-5-hydroxy-2,4-dimethyl-6-O-tosyloxyheptane [(6S)-11]. To a solution of (6′S)-α-10 (171 mg, 0.50 mmol) and 1,3-propanedithiol (0.15 mL, 1.5 mmol) in CH2Cl2 (0.5 mL) was added BF3×OEt2 (0.03 mL, 0.3 mmol) at 0 °C and the solution was stirred at this temperature for 24 h. The reaction was quenched by the addition of saturated aqueous NaHCO3 and then CH2Cl2 was added. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with diluted aqueous NaOH solution, dried with MgSO4, and concentrated. The residue was separated by silica gel column chromatography (n-hexnane-ethyl acetate = 3:1) to afford (6S)-11 as a syrup (213.6 mg, quant). [α]D 20 = -0.5 (c = 2.20 g/100 mL CHCl3). 1H NMR (500 MHz, CDCl3, CHCl3 = 7.24 ppm); δ 0.89 (d, 3 H, C4-Me, J 4,Me = 6.4 Hz), 1.04 (d, 3 H, C2-Me, J 2,Me = 6.9 Hz), 1.08 (m, 1 H, C3-Ha), 1.28 [d, 3 H, CH 3-CH(OTs)-, J = 6.4 Hz], 1.66-1.82 (m, 3 H, C4-H, C3-Hb,
    -SCH2CH 2CH2S-), 1.95-2.08 (m, 3 H, C2-H, C3-Hb,
    -SCH2CH 2CH2S-), 2.41 (s, 3 H, CH 3-C6H4-), 2.74-2.92 (m, 4 H, -SCH 2CH2CH 2S-), 3.21 (dd, 1 H, C5-H, J 5,4 =
    J 5,6 = 5.5 Hz), 4.10 (d, 1 H, -SCH2S-, J = 3.2 Hz), 4.75 (dq, 1 H, C6-H), 7.30-7.79 (m, 4 H, aromatic-H). Anal. Found C: 54.78%, H: 7.22%. Calcd for C19H30O4S3, C: 54.51%, H: 7.22%.

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  • 8d (2R,4S,5S,6R)-5,6-epoxy-1-(1,3-dithian-2-yl)-2,4-dimethylheptane (cis-12). To a solution of (6S)-11 (187.0 mg, 0.447 mmol) in CH2Cl2 (10 mL) was added NaOMe (2 M in MeOH, 0.45 mL, 0.9 mmol) at 0 °C and the mixture was stirred at this temperature for 1.5 h. The reaction was quenched by the addition of water and CH2Cl2 was added. The organic layer was separated, dried with MgSO4, and concentrated. The residue was separated by silica gel column chromatography (n-hexnane-ethyl acetate = 8: 1) to afford cis-12 as a syrup (91.2 mg, 78%). [α]D 20 = +13.0 (c = 0.164 g/100 mL CHCl3). 1H NMR (500 MHz, CDCl3, CHCl3 = 7.24 ppm); δ 0.92 (d, 3 H, C4-Me, J 4,Me = 6.4 Hz), 1.09 (d, 3 H, C2-Me, J 2,Me = 6.4 Hz), 1.25 [d, 3 H, CH3-(epoxy), J = 5.6 Hz], 1.38 (m, 1 H, C3-Ha), 1.44-1.50 (m, 1 H, C4-H), 1.76-1.85 (m, 2 H, -SCH2CH 2CH2S-, C3-Hb), 2.07 (m, 1 H, -SCH 2CH2CH2S-), 2.20-2.26 (m, 1 H, C2-H), 2.57 (dd, 1 H, C5-H, J 4,5 = 9.8, J 5,6 = 4.2 Hz), 2.80-2.88 (m, 4 H, -SCH 2CH2CH 2S-), 2.94 (dt, 1 H, C6-H), 4.11 (d, 1 H, C1-H, J 1,2 = 4.1 Hz). Anal. Found C: 58.55%, H: 9.02%. Calcd for C12H22OS2, C: 58.49%, H 9.00%.
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  • 8e Preparation of [2R,3R,5S,6S,6(1R)]-2-methoxy-3,5-dimethyl-6-(1-hydroxyethyl)tetrahydropyran [(6′R)-β-9]. To a solution of oxalyl chloride (1.73 mL; 20.3 mmol) in CH2Cl2 (20 mL) was added DMSO (2.89 mL, 40.7 mmol) in CH2Cl2 (20 mL) at -78 °C over a period of 30 min. After the mixture was stirred for 30 min, a solution of (2R,3R,5S,6S)-2-methoxy-3,5-dimethyl-6-(hydroxymethyl)tetrahydro-pyran (β-7: 1.179 g, 6.77 mmol) in CH2Cl2 (20 mL) was added at -78 °C over a period of 20 min and the resulting solution was stirred at -78 °C for 1 h, followed by the addition of triethylamine (14.2 mL, 102 mmol) in CH2Cl2 (20 mL). The mixture was allowed to warm to 0 °C and the reaction was quenched by the addition of saturated aqueous NH4Cl. After CH2Cl2 was added, the organic layer was separated, dried with MgSO4, concentrated to a small volume, filtered through silica gel, and concentrated to dryness to afford crude (2R,3R,5S,6S)-2-methoxy-3,5-dimethyl-6-formyltetrahydropyran (β-8) which was used in the subsequent step without purification. Thus, the β-8 in THF (50.5 mL) was added to a solution of MeTi(Oi-Pr)3 [prepared by the reaction of (i-PrO)3TiCl (8.51 mL, 33.9 mmol) in 101 mL THF with MeLi (1.04 M in ether; 32.54 mL, 33.85 mmol)] at -30 °C. The resulting mixture was stirred at 0 °C for 12 h and the reaction was quenched by the addition of saturated aqueous NH4Cl. Diluted HCl and ethyl acetate was successively added to the mixture and the organic layer was separated, dried with MgSO4 and concentrated. The residue was separated by silica gel column chromatography (n-hexane-ethyl acetate = 4:1) to afford (6′R)-β-9 as a syrup (690.6 mg, 57%). [α]D 20 = -49.8 (c = 0.31 g/100 mL CHCl3). 1H NMR (500 MHz, CDCl3); δ 0.74 (d, 3 H, C5-Me, J 5,Me = 6.9 Hz), 0.83 (d, 3 H, C3-Me, J 3,Me = 6.9 Hz), 0.89 (ddd, 1 H, C4-Hax, J 3,4ax = J 4ax,5 = J 4ax,4eq = 13.3 Hz), 1.13 (d, 3 H, CH3-CH(OH)-, J = 6.4 Hz), 1.39 (m, 1 H, C5-H), 1.47 (m, 1 H, C3-H), 1.67 (ddd, 1 H, C4-Heq, J 3,4eq = J 4eq,5 = 4.1 Hz), 3.13 (dd, 1 H, C6-H, J = 3.2, J = 10.1 Hz), 3.42 (s, 3 H, MeO), 3.81 [m, 1 H, CH3-CH(OH)-], 3.87 (d, 1 H, C2-H, J 2,3 = 8.6 Hz)
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  • 8f Preparation of [2R,3R,5S,6S,6(1R)]-2-methoxy-3,5-dimethyl-6-(1-tosyloxyethyl)tetrahydropyran [(6′R)-β-10]. By a similar procedure used in the tosylation of (6′S)-α-9, (6′R)-β-9 (690.6 mg, 3.67 mmol) was converted into (6′R)-β-10 (syrup; 1.059 g, yield; 84%). [α] D 20 = -8 (c = 0.217 g/100 mL CHCl3). 1H NMR (500 MHz, CDCl3, CHCl3 = 7.24 ppm); δ 0.75 (d, 3 H, C5-Me, J 5,Me = 6.2 Hz), 0.85 (d, 3 H, C3-Me, J 3,Me = 6.9 Hz), 0.89 (m, 1 H, C4-Hax), 1.24 [d, 3 H, CH3-CH(OTs)-, J = 6.9 Hz], 1.36 (m, 1 H, C5-H), 1.46 (m, 1 H, C3-H), 1.69 (ddd, 1 H, C4-Heq, J 3,4eq = J 5,4eq = 4.1 Hz, J 4ax,4eq = 10.1 Hz), 2.44 (s, 3 H, CH 3-C6H4-), 3.23 (d, 1 H, C6-H, J = 2.3 Hz, 10.1 Hz), 3.43 (s, 3 H, CH3O), 3.79 (d, 1 H, C2-H, J 2,3 = 8.7 Hz), 4.73 [m, 1 H, CH3-CH(OTs)-], 7.33-7.80 (m, 4 H, aromatic-H)
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  • 8g (2R,4S,5S,6R)-1-(1,3-dithian-2-yl)-5-hydroxy-2,4-dimethyl-6-O-tosyloxyheptane [(6R)-11]. By the similar procedure used in the conversion of (6′S)-α-10 to (6R)-11, (6′R)-β-10 (1.059 g, 3.10 mmol) reacted with 1,3-propanedithiol (12.5 mL, 12.4 mmol) in the presence of BF3×OEt2 (0.2 mL, 1.9 mmol) to give (6R)-11 as a syrup (1.296 g, quant). [α]D 20 = +18 (c = 0.200 g/100 mL CHCl3). 1H NMR (500 MHz, CDCl3, CHCl3 = 7.24 ppm); 0.78 (d, 3 H, C4-Me, J 4,Me = 6.9 Hz), 0.95 (m, 1 H, C3-Ha), 1.04 (d, 3 H, C2-Me, J 2,Me = 6.4 Hz), 1.19 (d, 3 H, CH3-CH(OTs)-, J = 6.4 Hz), 1.58 (m, 1 H, C4-H), 1.78 (m, 1 H, -SCH2CH 2CH2S-), 1.95-2.08 (m, 3 H, C2-H, C3-H, -SCH2CH 2CH2S-), 2.42 (s, 3 H, CH 3-C6H4-), 2.78-2.92 (m, 4 H, -SCH 2CH2CH 2S-), 3.41 (d, 1 H, C5-H, J 5,6 = 3.2 Hz), 4.11 (d, 1 H, -SCH2S-, J = 3.2 Hz), 4.70 (dq, 1 H, C6-H), 7.31-7.77 (m, 4 H, aromatic-H). Anal. Found C: 54.54%, H: 7.23%. Calcd for C19H30O4S3, C: 54.51%, H: 7.22%.
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  • (2R,4S,5S,6S)-5,6-epoxy-2-(1,3-dithian-2-yl)-2,4-dimethylheptane (trans-12). The title compound was prepared as a syrup from (2R,4S,5S,6R)-1-(1,3-dithian-2-yl)-5-hydroxy-2,4-dimethyl-6-O-tosyloxyheptane [(6R)-11: 1.296 g, 3.10 mmol] by a similar procedure used in the synthesis of cis-12 in 81% yield. [α]D 20 = -4.0 (c = 0.244 g/100 mL CHCl3). 1H NMR, (500 MHz, CDCl3); δ. 0.88 (d, 3 H, C4-Me, J 4,Me = 6.9 Hz), 1.04 (d, 3 H, C2-Me, J 2,Me = 6.9 Hz), 1.22 (d, 3 H, CH3-(epoxy), J = 5.0 Hz), 1.35 (m, 1 H, C3-Ha), 1.40 (m, 1 H, C4-H), 1.71-1.81 (m, 2 H, -SCH2CH2 CH2S-, C3-Hb), 2.02-2.13 (m, 2 H, -SCH2CH2CH2S-,C2-H), 2.38 (dd, 1 H, C5-H, J 4,5 = 7.3 Hz, J 5,6 = 2.1 Hz), 2.69 (dq 1 H, C6-H), 2.76-2.87 (m, 4 H, -SCH2CH2CH2S-), 4.07 (d, 1 H, C1-H, J 1,2 = 3.7 Hz). Anal. Found C: 58.70%, H: 8.94%. Calcd for C12H22O16S2, C: 58.49%, H 9.00%
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5

1H NMR (500 MHz, CDCl3) for 3: δ(ppm) 1.12 (d, C2-Me, J = 9.6 Hz), 1.27 (d, C4-Me, J = 7.7 Hz), 4.25 (d, C5-H, J = 5.5 Hz), 3.80 (dd, C6-Ha, J = 5.6 Hz, 6.9 Hz), and 3.87 (dd, C6-Hb).

10

Yields were not optimized.