Regiocontrolled Ring Opening of Monoprotected 2,3-Epoxy-1,4-diols by Using Alkynyl Aluminum Reagents: Synthesis of Differentially Monoprotected Alkynyl Triol Derivatives

Abstract

The regioselectivity of the epoxide ring-opening reaction of cis and trans TIPS-monoprotected 2,3-epoxy-1,4-diols with diethylalkynyl aluminum reagents was studied. Alane and alanate conditions in toluene or dichloromethane were explored. Alkynyl attack at the C2 epoxide carbon was favored under both the alane and alanate conditions in toluene, whereas C3 attack was preferred in dichloromethane. The best regioselectivities were obtained by using the alanate conditions in toluene. This methodology provides access to differentially monoprotected alkynyl triols with high diastereoselectivity. These compounds are useful building blocks for polypropionate synthesis and are precursors for the introduction of the hydroxymethyl moiety found in some polyketide systems.

Key words

epoxide cleavage - epoxy alcohols - alkynes - regioselectivity - diastereoselectivity

• References and Notes

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• 8 Alkynyl Substitution of Epoxy Alcohols with Diethylalkynyl Aluminum (Protocol I, Alane Procedure); General Procedure: A flame-dried flask, equipped with a dry-ice condenser, was charged with 12.0 mL of toluene (protocol IA) or dichloromethane (protocol IB) and cooled to 0 °C. Then, n-BuLi (2.1 mL, 4.6 mmol, 3.8 equiv) was added and an excess of propyne gas was bubbled through the solution. After stirring for 30 min, Et₂AlCl (2.6 mL, 4.6 mmol, 3.8 equiv) was added and the mixture was stirred for 3 h at 0 °C. To the reaction mixture was added epoxide (0.30 g, 1.2 mmol, 1.0 equiv) and the mixture was stirred overnight. The reaction was quenched by the slow addition of 5% aq H₂SO₄ (9.2 mL) at 0 °C. The reaction mixture was transferred to a separatory funnel and the phases were separated. The aqueous phase was extracted with hexane (3 × 10 mL) and the combined organic extracts were dried over MgSO₄. The solvent was removed in vacuo and the crude product mixture was purified by column chromatography (hexane–EtOAc, 4:1). Compound 6b (for all other compounds, see the Supporting Information): ¹H NMR (500 MHz, CDCl₃): δ = 4.02 (dd, J = 9.9, 4.2 Hz, 1 H), 3.91–3.70 (m, 4 H), 2.75 (dtq, J = 9.4, 6.6, 2.4 Hz, 1 H), 1.77 (d, J = 2.4 Hz, 3 H), 1.11 (m, 21 H). ¹³C NMR (500 MHz, CDCl₃): δ = 80.5, 75.4, 74.9, 67.1, 65.1, 36.4, 17.9, 11.6, 3.5. Anal. Calcd for C₁₆H₃₂O₃Si: C, 63.95; H, 10.73. Found: C, 63.94; H, 10.73. Alkynyl Substitution of Epoxy Alcohols with Diethylalkynyl Aluminum (Protocol II, Alanate Procedure); General Procedure: A flame-dried flask equipped with a dry-ice condenser was charged with anhydrous toluene (protocol IIA; 23.0 mL) and the flask was cooled to 0 °C. Then, n-BuLi (3.1 mL, 6.9 mmol, 4.0 equiv) was added and an excess of propyne gas was bubbled through the solution. After stirring for 30 min, Et₂AlCl (3.8 mL, 6.9 mmol, 4.0 equiv) was added at 0 °C. In a separate flash, a solution of the lithium alkoxide of the epoxy alcohol was prepared from the alcohol (0.26 g, 1 mmol, 1.0 equiv) in toluene (7.7 mL, 0.15 M final solution) and n-BuLi (0.6 mL, 1.7 mmol, 1.1 equiv), and the mixture was stirred at 0 °C for 30 min. The alane reaction mixture was cooled to –78 °C and the lithium alkoxide solution was transferred by using a double-ended needle and stirred overnight while reaching r.t. The reaction was quenched by the slow addition of 5% aq H₂SO₄ at 0 °C. The reaction mixture was transferred to a separatory funnel and the phases were separated. The aqueous layer was extracted with hexane (3 × 20 mL) and the combined organic extracts were dried over MgSO₄. The solvent was removed in vacuo and the crude product was purified by column chromatography (hexane–EtOAc, 5:1). Compound 5b (for all other compounds, see the Supporting Information): ¹H NMR (500 MHz, CDCl₃): δ = 3.93 (dd, J = 9.8, 3.2 Hz, 1 H), 3.85–3.77 (m, 3 H), 3.72 (ddd, J = 8.3, 5.6, 2.7 Hz, 1 H), 2.87 (d, J = 3.6 Hz, 1 H), 2.82 (br s, 1 H), 2.65 (m, 1 H), 1.65 (d, J = 2.4 Hz, 3 H), 1.10 (m, 21 H). ¹³C NMR (125 MHz, CDCl₃): δ = 80.3, 75.9, 73.8, 65.6, 64.5, 37.5, 17.9, 11.9, 3.5. Anal. Calcd for C₁₆H₃₂O₃Si: C, 63.95; H, 10.73. Found: C, 63.66; H, 10.96.