Diastereoselective Synthesis of 2,6-Disubstituted 4-(Dimethoxymethyl)tetra­hydropyrans Using TMSOTf-Promoted Prins–Pinacol Cyclization

Abstract

We have described a highly diastereoselective synthesis of 2,6-disubstituted 4-(dimethoxymethyl)tetrahydropyrans via ­TMSOTf-promoted Prins–pinacol reaction of methylene diol with acetals. This reaction provides an efficient procedure to synthesize functionalized tetrahydropyrans containing an acetal group at the C4 position with all-cis 2,4,6 relative configuration.

Key words

cyclization - Lewis acids - oxonium ion - diastereoselectivity - 2,4,6-trisubstituted tetrahydropyrans

• References and Notes

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• 8 The reaction in the presence of a 1:1 ratio of TMSOTf and i-Pr₂NEt gave only the mixture of mono- or bistrimethylsilyl ethers.
• 9 Experimental Procedure for the Synthesis of 4 (Table 1, Entry 10) To a solution of diol 3 (30 mg, 0.29 mmol), benzaldehyde (60 μL, 0.58 mmol), and DIPEA (60 μL, 0.35 mmol) in anhydrous CH₂Cl₂ (6.0 mL) was added TMSOTf (0.11 mL, 0.58 mmol) at –78 °C. The mixture was stirred at –78 °C for 2 h, quenched with sat. aq NaHCO₃ and extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layers were washed with H₂O and brine, dried over MgSO₄, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (EtOAc–n-hexane, 1:8) to afford cis-4a (42 mg, 56%) and trans- 4a (14 mg, 18%) as a colorless oil. Compound cis- 4a: ¹H NMR (300 MHz, CDCl₃): δ = 9.65 (s, 1 H), 7.36–7.26 (m, 5 H), 4.38 (dd, J = 11.3, 2.1 Hz, 1 H), 4.27 (dd, J = 11.7, 4.5 Hz, 1 H), 3.66 (td, J = 10.9, 2.1 Hz, 1 H), 2.69 (m, 1 H), 2.13 (m, 1 H), 1.91 (m, 1 H), 1.70 (m, 1 H), 1.58 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 202.2, 142.0, 128.4, 127.7, 125.8, 79.3, 78.9, 67.4, 48.2, 33.2, 29.7, 25.4. HRMS (EI⁺): m/z calcd for C₁₂H₁₄O₂: 190.0994 [M]⁺; found: 190.0996. Compound trans- 4a: ¹H NMR (300 MHz, CDCl₃): δ = 9.90 (s, 1 H), 7.36–7.24 (m, 5 H), 4.37 (dd, J = 11.3, 2.4 Hz, 1 H), 4.03 (m, 1 H), 3.60 (td, J = 12.0, 2.9 Hz, 1 H), 2.79 (m, 1 H), 2.34 (m, 1 H), 2.10 (m, 1 H), 2.04 (m, 1 H), 1.95 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 203.8, 142.2, 128.4, 127.5, 125.7, 76.3, 65.3, 44.7, 31.8, 24.3.
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• 11 Experimental Procedure for the Synthesis of 5 (Scheme 2) To a round-bottom flask equipped with a magnetic stir bar and charged with CH₂Cl₂ (6 mL) was added 2-methylene-butane-1,4-diol (3, 30 mg, 0.29 mmol), which was cooled to –78 °C. DIPEA (125 μL, 0.35 mmol) and TMSOTf (130 μL, 0.73 mmol) were added slowly. After diol 3 was completely converted into bistrimethylsilyl ether (monitored by TLC), benzaldehyde dimethoxy acetal (130 μL, 0.88 mmol) and TMSOTf (53 μL, 0.29 mmol) were successively added. The reaction mixture was stirred at –78 °C for 5 min and quenched with sat. aq NaHCO₃. The resulting solution was extracted with CH₂Cl₂ (3 × 10 mL), dried over MgSO₄, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (EtOAc–n-hexane, 1:12) to afford the title compound 5a (47 mg, 68%, cis/trans = 8:1) as a colorless oil along with 4a (4 mg, 7%, cis/trans = 3:1). Compound cis-5a: ¹H NMR (300 MHz, CDCl₃): δ = 7.38–7.24 (m, 5 H), 4.33 (dd, J = 11.3, 1.7 Hz, 1 H), 4.22 (dd, J = 11.5, 3.9 Hz, 1 H), 4.07 (d, J = 7.2 Hz, 1 H), 3.61 (ddd, J = 12.2, 12.2, 1.8 Hz, 1 H), 3.39 (s, 3 H), 3.37 (s, 3 H), 2.00 (m, 1 H), 1.95 (m, 1 H), 1.73 (m, 1 H), 1.50–1.29 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 143.2, 128.4, 127.5, 125.9, 108.0, 79.3, 68.0, 54.2, 53.7, 38.5, 35.9, 27.6. HRMS (EI⁺): m/z calcd for C₁₄H₂₀O₃: 236.1412 [M]⁺; found: 236.1406.
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• 13 Based on our observation that the cis/trans ratio of aldehydes 4 is constant in Table 2, the isomerization via rapid enolization under the acidic reaction conditions may be responsible for this cis/trans selectivity. However, we believed that the kinetic process is still dominant because epimerization did not take place when the isolated cis- or trans-4a was treated with TMSOTf at –78 °C for 2 h.
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• 16 Compound cis -10 (Table 3, entry 1): ¹H NMR (300 MHz, CDCl₃): δ = 7.48 (d, J = 9.0 Hz, 4 H), 7.37 (m, 4 H), 7.27–7.31 (m, 2 H), 4.61 (dd, J = 10.8, 1.0 Hz, 2 H), 4.10 (d, J = 7.2 Hz, 1 H), 3.40 (s, 6 H), 2.32 (m, 1 H), 2.08 (dt, J = 12.7, 1.7 Hz, 2 H), 1.41 (q, J = 12.4 Hz, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 143.0, 128.2, 127.5, 127.3, 125.8, 108.0, 79.2, 54.1, 53.1, 39.1, 35.6, 33.7. HRMS (EI⁺): m/z calcd for C₂₀H₂₄O₃: 312.1725 [M]⁺; found: 312.1722.