Practical Protocols for the Preparation of Highly Enantioenriched Silyl Ethers of (R)-3-Hydroxypentan-2-one, Building Blocks for the Synthesis of Macrolide Antibiotics

 

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Dedicated with respect, admiration, and every good wish to Professor Steven V. Ley on the occasion of his 70^th birthday

Abstract

Methacrolein is transformed in three steps to (R)-3-tert-butyldiphenylsilyloxypentan-2-one or (R)-3-tert-butyldimethylsilyloxypentan-2-one, compounds which serve as building blocks for the construction of macrolide antibiotics. The route is practical, highly enantioselective, and easily scaled.

• References and Notes

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• 19 (R)-2-Methylpent-1-en-3-ol (2) A solution of Et₂Zn in hexanes (800 mL, 1.0 M, 800 mmol, 1.94 equiv) was added via cannula to an ice-cooled, stirring suspension of (1R,2S)-1-cyclohexyl-2-morpholino-2-phenylethanol (5) (1.24 g, 4.28 mmol, 0.01 equiv) in n-hexane (288 mL) in a 3 L round-bottom flask. White vapor formed in the receiving flask during the transfer. The resulting solution was allowed to stir for 30 min at 0 °C, then methacrolein (34 mL, 412 mmol, 1.0 equiv, freshly distilled) was added dropwise over 90 min using a syringe pump, producing a pale yellow, homogeneous solution. After 3 h, HCl (850 mL, 3 M) was added slowly (Caution: exotherm). A white precipitate was visible during the addition, but this redissolved toward the end of the addition (pH 1). The biphasic mixture was transferred to a separating funnel and the layers were separated. The aq layer was further extracted with Et₂O (2 × 500 mL), the organic layers were combined, and the resulting solution was washed with brine (500 mL). The washed solution was dried over Na₂SO₄ and filtered, and the filtrate was concentrated under reduced pressure (~40 Torr) at ≤10 °C. The resulting clear oil was transferred to a 250 mL round-bottom flask, and the transfer was quantitated with Et₂O (2 × 15 mL). The solvent was removed at atmospheric pressure by distillation using a short-path distillation head, heating with a 90 °C oil bath. The heating bath was removed and the distillation flask was allowed to cool to 23 °C whereupon the pressure was carefully reduced to ~40 Torr. The receiving flask was immersed in an ice–water bath, and the distillation resumed upon heating with a 90–105 °C oil bath. The product distilled with a steady boiling point of 65–68 °C at ~40 Torr, providing allylic alcohol 2 as a colorless liquid (31.4 g, 76% yield). The enantiomeric excess was not determined at this stage, but was measured after conversion into 1a (see the Supporting Information). The ¹H NMR and ¹³C NMR data matched literature values.⁵,^2,22 The acidic aqeous layers from the extraction were combined and the resulting solution was made basic with NaOH (~800 mL, 3 M) to pH 14, causing the precipitation of a white solid. The resulting suspension was extracted with CH₂Cl₂ (4 × 300 mL). The organic layers were combined and the resulting solution was dried over Na₂SO₄. The dried solution was filtered, and the filtrate concentrated to provide (1R,2S)-1-cyclohexyl-2-morpholino-2-phenylethanol (5) (1.19 g, 4.12 mmol, 96% recovery) in high purity.
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• 21 Because 1b has no UV chromophore its ee could not be conveniently determinded by chiral HPLC analysis.
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• Supplementary Material