A Practical and Scaleable Synthesis of 1R,5S-Bicyclo[3.1.0]hexan-2-one: The Development of a Catalytic Lithium 2,2,6,6-Tetramethylpiperidide (LTMP) Mediated Intramolecular Cyclopropanation of (R)-1,2-Epoxyhex-5-ene
Link: Org Proc & Dev ASAP
Anthony D. Alorati, Matthew M. Bio, Karel M. J. Brands, Ed Cleator,* Antony J. Davies, Robert D. Wilson, and Chris S. Wise
Department of Process Research, Merck Sharp & Dohme, Hertford Road, Hoddesdon, EN11 9BU, UK
The method is pretty unique in obtaining fused 3,5-bicyclic system as shown in 1.
This was achieved by treatment of epoxide 2 with LiTMP. The hindered base would deprotonate the alpha-carbon of epoxide trans- to the beta-alkyl side chain. Then stereospecific cyclization of the carbenoid species would follow to give bicyclic alcohol 4. The reaction could be conducted with catalytic amount of TMP (with slight excess of n-BuLi). The rate of n-BuLi addition (not too fast) was crucial in a successful catalytic reaction.
Compound 4 was found to be acid-sensitive. Compound 4 can be utilized in further transformations. TEMPO/NaOCl treatment of 4 successfully led to 1 in greater than 99.5% ee. This reaction sequence was demonstrated to be amenable to preparing 1 on a 7.5 kg scale. pH of the oxidation step had to be carefully controlled. If the pH was too low (5-8), oxidation was incomplete. If pH was too high (>11), dibrominated compound 12 was formed as a sginificant byproduct.
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