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

Ian B. Seiple; Daniel T. Hog; Andrew G. Myers

doi:10.1055/s-0035-1560972

Synlett, Table of Contents

Synlett 2016; 27(01): 57-60
DOI: 10.1055/s-0035-1560972

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

Ian B. Seiple

Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA Email: myers@chemistry.harvard.edu

,

Daniel T. Hog

Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA Email: myers@chemistry.harvard.edu

,

Andrew G. Myers*

Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA Email: myers@chemistry.harvard.edu

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Abstract

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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.

Key words

enantioselective synthesis - macrolide antibiotics - asymmetric addition - organozinc reagent - Nugent protocol

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References

References and Notes
1 Racemic 1b has been synthesized by a seven-step sequence from propionaldehyde, see: Amarante GW, Cavallaro M, Coelho F. J. Braz. Chem. Soc. 2011; 22: 1568
2 (R)-3-Benzyloxypentan-2-one has been prepared by resolution of (±)-2, see: Overman LE, Lin NH. J. Org. Chem. 1985; 50: 3669
3 A synthesis of (R)-2-methylpent-1-en-3-ol tert-butyldimethylsilyl ether has been reported, see: Cossy J, Bauer D, Bellosta V. Synlett 2002; 715
4 Bellemin-Laponnaz S, Tweddell J, Ruble JC, Breitling FM, Fu GC. Chem. Commun. 2000; 1009
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6 Discordia RP, Dittmer DC. J. Org. Chem. 1990; 55: 1414
7 For a report of a five-step synthesis of (+)-2 of 65% ee, see: Guarna A, Occhiato EG, Pizzetti M, Scarpi D, Sisi S, van Sterkenburg M. Tetrahedron: Asymmetry 2000; 11: 4227
8 For a report of a two-step synthesis of (+)-2, see: Geurts K, Fletcher SP, Feringa BL. J. Am. Chem. Soc. 2006; 128: 15572
9 For a report of a three-step synthesis of (+)-2 of 76% ee, see: Jones S, Valette D. Org. Lett. 2009; 11: 5358
10 Sato T, Soai K, Suzuki K, Mukaiyama T. Chem. Lett. 1978; 601
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15 Qiu J, Guo C, Zhang XM. J. Org. Chem. 1997; 62: 2665
16 Nugent WA. Chem. Commun. 1999; 1369
17 Morinaka BI, Pawlik JR, Molinski TF. J. Org. Chem. 2010; 75: 2453
18 Nugent WA. Org. Lett. 2002; 4: 2133
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.
20 Yu W, Mei Y, Kang Y, Hua Z, Jin Z. Org. Lett. 2004; 6: 3217
21 Because 1b has no UV chromophore its ee could not be conveniently determinded by chiral HPLC analysis.
22 Cossy J, Bauer D, Bellosta V. Tetrahedron 2002; 58: 5909

Supplementary Material

Supporting Information