Lewis Acid Promoted Mukaiyama Aldol-Prins (MAP) Cyclizations of Acetals, Ketals, α-Acetoxy Ethers, and Orthoformates

Abstract

The Mukaiyama aldol-Prins (MAP) cyclization of acetals stereoselectively provided substituted tetrahydropyrans. The scope of the reaction has been expanded to include other electrophiles, including ketals and α-acetoxy ethers. Finally, a double MAP cyclization with orthoformates is described.

Key words

tandem reactions - aldol reactions - annulations - acetals - carbocations

References and Notes

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9

Representative Experimental (Table 2, Entry 4)A solution of 2,6-di-tert-butyl-4-methylpyridine (77 mg, 0.38 mmol), homoallylic vinyl ether 13 (50 mg, 0.25 mmol), and 2,2-dimethoxypropane (0.022 mL, 0.25 mmol) in CH₂Cl₂ (2.5 mL) was cooled to -78 °C. Titanium tetrabromide (0.32 M in CH₂Cl₂, 3.1 mL, 1.0 mmol) was then added dropwise over 10 min. After 2 h, a 1:1 mixture of MeOH and Et₃N (5 mL) was added and the reaction mixture was allowed to warm to r.t. Then, sat. aq NaHCO₃ (10 mL) was added and the mixture was extracted with Et₂O (2 × 10 mL). The combined organic layers were washed with brine (1 × 10 mL), dried over MgSO₄, and concentrated under reduced pressure. Purification by flash chromatography (15:1 hexanes-Et₂O) yielded 54 mg (61%) of the expected THP as a colorless oil; R _f = 0.31 (hexanes-Et₂O, 9:1). ¹H NMR (500 MHz, CDCl₃): δ = 7.29 (t, J = 7.9 Hz, 2 H), 7.19 (t, J = 7.4 Hz, 3 H), 4.15 (tt, J = 12.0, 4.5 Hz, 1 H), 3.55-3.49 (m, 1 H), 3.32-3.26 (m, 1 H), 3.29 (s, 3 H), 2.83-2.77 (m, 1 H), 2.68-2.58 (m, 1 H), 2.24-2.16 (m, 2 H), 1.93-1.60 (m, 6 H), 1.26 (s, 3 H), 1.22 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 142.0, 128.53, 128.49, 126.0, 76.5, 74.3, 74.1, 49.3, 47.0, 45.9, 44.6, 43.4, 37.7, 32.0, 26.2, 25.3. IR (neat): 2925, 2860, 1603, 1454, 1080 cm^{- 1}. HRMS (ES/MeOH): m/z calcd for C₁₈H₂₇BrO₂ [M + Na]⁺: 377.1092; found: 377.1088.

11

Cyclic α-methoxy ethers and more complicated sugar moieties provided no THP products when employed as electrophiles.

13

Neither orthoacetates nor orthocarbonates were reactive towards nucleophilic addition.

14

Synthesis of bis -THP (21)A solution of 2,6-di-tert-butyl-4-methylpyridine (35 mg, 0.58 mmol), homoallylic vinyl ether 20 (48 mg, 0.22 mmol), and triethyl orthoformate (0.018 mL, 0.11 mmol) in CH₂Cl₂ (1.1 mL) was cooled to -78 °C. Titanium tetrabromide (0.32 M in CH₂Cl₂, 1.4 mL, 0.44 mmol) was then added dropwise over 10 min. After 2 h, a 1:1 mixture of MeOH and Et₃N (5 mL) was added and the reaction mixture was allowed to warm to r.t. Then, sat. aq NaHCO₃ (5 mL) was added and the mixture was extracted with Et₂O (2 × 5 mL). The combined organic layers were washed with brine (1 × 5 mL), dried over MgSO₄, and concentrated under reduced pressure. Purification by flash chromatography (hexanes-Et₂O, 20:1 to 15:1) yielded 37 mg (52%) of the title compound as a colorless oil; [α]_D ²⁴ +1.1 (c 1.9, CHCl₃); R _f = 0.33 (hexanes-Et₂O, 9:1). ¹H NMR (500 MHz, CDCl₃): δ = 7.32-7.06 (m, 10 H), 4.07-3.99 (m, 1 H), 3.93 (td, J = 11.6, 4.6 Hz, 1 H), 3.84 (td, J = 11.3, 4.5 Hz, 1 H), 3.75-3.65 (m, 1 H), 3.55-3.43 (m, 1 H), 3.38-3.29 (m, 2 H), 3.21 (t, J = 9.1 Hz, 1 H), 3.04 (t, J = 9.5 Hz, 1 H), 2.85-2.60 (m, 4 H), 2.35-2.22 (m, 2 H), 2.00-1.58 (m, 12 H), 1.23 (t, J = 6.9 Hz, 3 H), 1.13 (d, J = 6.5 Hz, 3 H), 1.10 (d, J = 6.4 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 141.9, 128.8, 128.5, 126.0, 79.3, 78.4, 76.4, 75.8, 72.3, 64.9, 57.7, 57.2, 45.8, 45.6, 44.6, 44.5, 39.2, 38.8, 37.5, 32.1, 31.5, 16.4, 15.8. IR (neat): 2927, 2854, 1456, 1086 cm^{- 1}. HRMS (ES/MeOH): m/z calcd for C₃₃H₄₆Br₂O₃ [M + Na]⁺: 671.1711; found: 671.1719.