The Enantioselective Allylation and Crotylation of Sterically Hindered and Functionalized Aryl Ketones: Convenient Access to Unusual Tertiary Carbinol Structures.

Abstract

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Enantioselective Allylation Using Allene, a Petroleum Cracking Byproduct

“…We further demonstrated the utility of the reaction in the synthesis of the antipsychotic drug clopenthixol (Sordinol, 4d), first introduced by Lundbeck in 1961 and one of several structurally related thioxanthene antagonists of dopamine receptor D2, commercially available as either a mixture of E/ Z-isomers or as the pure Z-isomer, obtained by selective crystallization 25 (Figure 2C). The traditional synthesis of this substance relies on cyclopropyl or allyl Grignard reagents, presenting challenges for scale-up or implementation in continuous flow processes 14 due to large exotherm and formation of insoluble magnesium salts. In our synthesis, the unpurified reaction mixture resulting from the allene−ketone coupling reaction was directly subjected to copper-catalyzed hydroamination conditions previously reported by our group.…”

“…13 Finally, asymmetric reactions of ketones in general are difficult to achieve due to the reduced steric differentiation between carbonyl substituents and attenuated reactivity in relation to aldehydes. Many stereoselective ketone allylation reactions exist, using either stoichiometric chiral controllers 14 or asymmetric catalysis. 15−17 However, highly enantioselective installation of the parent allyl group is particularly challenging due to the existence of multiple potential pathways leading to the minor enantiomer (see the Supporting Information for additional discussion).…”