Abstract
The asymmetric introduction of the CF3 unit is a powerful tool for modifying pharmacokinetic properties and slowing metabolic degradation in medicinal chemistry. A catalytic and enantioselective addition of α-CF3 enolates allows for expeditious access to functionalized chiral building blocks with CF3-containing stereogenicity. The computational studies reveal that the choice of ligand in a designed palladium-complex system regulates the regioselectivity and stereoselectivity of the asymmetric allylic alkyation of α-CF3 ketones and Morita-Baylis-Hillman adducts.
Highlights
The wide application of fluorinated compounds in agrochemicals, pharmaceuticals and materials science has triggered every endeavor to develop efficient methods for selective incorporation of a trifluoromethyl group into organic molecules.[1,2,3,4,5,6,7,8,9,10,11,12] The reliable methodology to access CF3-containing stereogenicity is still underdeveloped in the context of matured asymmetric synthesis.[13]
A catalytic and enantioselective addition of α-CF3 enolates allows for expeditious access to functionalized chiral building blocks with CF3-containing stereogenicity
The computational studies reveal that the choice of ligand in a designed palladiumcomplex system regulates the regioselectivity and stereoselectivity of the asymmetric allylic alkyation (AAA) of α-CF3 ketones and Morita–Baylis–Hillman (MBH) adducts
Summary
The wide application of fluorinated compounds in agrochemicals, pharmaceuticals and materials science has triggered every endeavor to develop efficient methods for selective incorporation of a trifluoromethyl group into organic molecules.[1,2,3,4,5,6,7,8,9,10,11,12] The reliable methodology to access CF3-containing stereogenicity is still underdeveloped in the context of matured asymmetric synthesis.[13] The electrophilic trifluoromethylation of ketones has shown low reactivity and enantioselectivity, even with the aid of chiral auxiliary (Fig. 1a).[14] the exploitation of α-CF3 enolate as an active nucleophile for enantioselective C − C bond-forming reactions is a viable strategy for pursuing this end, allowing rapid access to densely functionalized chiral building blocks.[15,16] Despite the significant advances in enolatebased chemistry over the past decades, 17–19 α-CF3 enolates have only been scarcely explored because of the M-F elimination of their metal enolates.[20] Electrophilic alkylation of prefunctionalized α-CF3 ketones provided remarkable outcomes by the use of chiral auxiliaries or directing groups (Fig. 1b).[21,22,23,24] In contrast, the direct asymmetric alkylation of naked α-CF3 ketones represents unmet challenges in terms of reactivity and selectivity that has not been addressed.[25,26]. By only switching the chiral ligands of the palladium complexes, excellent regio- and stereocontrol can be achieved on both C1 and C3 adducts for the construction of CF3-bearing quaternary centers (Fig. 1c)
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