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

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

References

• For reviews of macrolide antibiotics, see for example:
• 1a Tatsuta K. Makurorido Koseibushitsu, In Koseibushitsu no Saisentan   Ohno M. Ohmura S. Tokyo Kagakudojinn; Tokyo: 1987.  p.252-281  
• 1b Paterson I. Mansuri MM. Tetrahedron  1985,  41:  3569 
• 1c Norcross RD. Paterson I. Chem. Rev.  1995,  95:  2041 
• 1d Ohmura S. Macrolide Antibiotics: Chemistry, Biology, and Practice   2nd ed:  Academic Press; New York: 2002. 
• See for example:
• 2a Hanessian S. Total Synthesis of Natural Products: The Chiron Approach   Pergamon Press; Oxford: 1983. 
• 2b Bols M. Carbohydrate Building Blocks   John Wiley & Sons, Inc.; New York: 1996. 
• For the preparation of 4a and 4b, see:
• 3a Svirudov AF. Yashunskii DV. Ermolenko MS. Kochetkov NK. Izvestiya Akademii Nauk SSSR, Seriya Kimicheskaya  1984,  723 
• 3b Hodges PJ. Procter G. Tetrahedron Lett.  1985,  26:  4111 ; and refs therein
• 3c Wakamatsu T. Nakamura H. Nishikimi Y. Yoshida K. Noda T. Taniguchi M. Ban Y. Tetrahedron Lett.  1986,  27:  6071 
• 3d Nakamura H. Arata K. Wakamatsu T. Ban Y. Shibasaki M. Chem. Pharm. Bull.  1990,  38:  2435 
• 3e Magdzinski L. Fraser-Reid B. Can. J. Chem.  1988,  66:  2819 
• 3f See also: Edwards MP. Ley SV. Lister SG. Palmer BD. J. Chem. Soc., Chem. Commun.  1983,  630 
• 4a Sviridov AF. Yashunskii DV. Ermolenko MS. Borodkin VS. Kochetkov NK. Izvestiya Akademii Nauk SSSR, Seriya Kimicheskaya  1985,  1166 
• 4b Mori M. Chuman T. Kato K. Mori K. Tetrahedron Lett.  1982,  23:  4593 
• 4c Mori M. Chuman T. Kato K. Carbohydr. Res.  1984,  129:  72 
• For the preparation of α-7 and analogous compounds, see:
• 6a Isobe M. Ichikawa Y. Goto T. Tetrahedron Lett.  1981,  22:  4287 
• 6b Jarosz S. Fraser-Reid B. Tetrahedron Lett.  1981,  27:  2533 
• 6c Kawauchi N. Hashimoto H. Bull. Chem. Soc. Jpn.  1987,  60:  1441 
• 6d Chen S.-H. Horvath RF. Joglar J. Fisher MJ. Danishefsky SJ. J. Org. Chem.  1991,  56:  5834 
• 7a Reetz MT. Angew. Chem. Int. Ed. Engl.  1984,  23:  556 
• 7b Mead K. Macdonald TL. J. Org. Chem.  1985,  50:  422 
• 7c For a related paper, see: Takahashi S. Nakata T. J. Org. Chem.  2002,  67:  5739 
• 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).

• 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%

• 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%.

• 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%.
• 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)
• 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)
• 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%.
• (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%
• 9 Alexakis A. Jachiet D. Tetrahedron Lett.  1989,  45:  6197 

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.