A Scalable Synthesis of (R,R)‑2,6-Dimethyldihydro‑2H‑pyran-4(3H)‑one

A scalable synthesis of (R,R)-2,6-dimethyldihydro-2H-pyran-4­(3H)-one is reported. Key to this strategy is the Ti­(OiPr)4-catalyzed Kulinkovich cyclopropanation of silyl protected (R)-ethyl 3-hydroxybutanoate, and subsequent oxidative fragmentation of the cyclopropanol. The resulting vinyl ketone in...

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Published inOrganic process research & development Vol. 19; no. 10; pp. 1360 - 1368
Main Authors Young, Ian S, Haley, Matthew W, Tam, Annie, Tymonko, Steven A, Xu, Zhongmin, Hanson, Ronald L, Goswami, Animesh
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 16.10.2015
Amer Chemical Soc
Subjects
Chemistry
Chemistry, Applied
Chemistry, Organic
Physical Sciences
Science & Technology
CYCLIC ENONES
ACID
ASYMMETRIC CONJUGATE ADDITION
STRATEGY
ME3SICL
GRIGNARD-REAGENTS
OLD YELLOW ENZYME
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Summary:A scalable synthesis of (R,R)-2,6-dimethyldihydro-2H-pyran-4­(3H)-one is reported. Key to this strategy is the Ti­(OiPr)4-catalyzed Kulinkovich cyclopropanation of silyl protected (R)-ethyl 3-hydroxybutanoate, and subsequent oxidative fragmentation of the cyclopropanol. The resulting vinyl ketone intermediate was then subjected to oxidative Heck cyclization to form the enone substrate required for conjugate addition. A diastereoselective copper-catalyzed Grignard addition procedure was implemented to install the requisite methyl group, with the inclusion of 1,3-bis­(diphenylphosphino)­propane and trimethylsilyl chloride greatly increasing the robustness of this process.
ISSN:1083-6160
1520-586X
DOI:10.1021/op500135x