Asymmetric Synthesis of 2‑Substituted Oxetan-3-ones via Metalated

ABSTRACT: 2-Substituted oxetan-3-ones can be prepared in good yields and enantioselectivities (up to 84 % ee) by the metalation of the SAMP/RAMP hydrazones of oxetan-3-one, followed by reaction with a range of electrophiles that include alkyl, allyl, and benzyl halides. Additionally, both chiral 2,2- and 2,4-disubstituted oxetan-3-ones can be made in high ee (86−90%) by repetition of this lithiation/alkylation sequence under appropriately controlled conditions. Hydrolysis of the resultant hydrazones with aqueous oxalic acid provides the 2-substituted oxetan-3-ones without detectable racemization. There is considerable current interest in the preparation ofoxetanes for use in medicinal chemistry.1,2 As a result of the pioneering work of Carreira and Rogers-Evans,1 these 4-membered oxygen heterocycles are increasingly being used as bioisosteric replacements for common functional groups such as gem-dimethyl or carbonyl groups.2 Their introduction can induce profoundly beneficial effects on the aqueous solubility, lipophilicity, metabolic stability, and conformational preferenc