Enantioselective Construction of Tertiary α-Alkyl Fluoride via BTM-Catalyzed Fluorination of α-Alkynyl-Substituted Acetic Acids

Abstract

The isothiourea-catalyzed enantioselective construction of tertiary α-fluoro stereogenic centers has been demonstrated by using branched alkynyl-substituted acetic acids as starting materials, providing a broad range of optically active tertiary α-alkyl fluorides in high enantioselectivity (up to 97% ee). Furthermore, this methodology was proven to be scaled up to a Gram scale without loss of enantioselectivity.

Enantioselective α-heterofunctionalization reactions of catalytically generated C1-Lewis base enolates

“…These catalysts are most commonly employed in combination with activated carboxylic acid derivatives (either preformed or in situ formed) which, in the presence of an external base, gives the geometrically well-defined chiral C1-ITU enolate in situ [ 3 ]. Surprisingly however, the potential of these catalysts to facilitate asymmetric α-halogenations has only recently been established [ 22 , 23 ]. In 2021, Zheng’s group introduced the para-cyclophane-based ITU pcpITU which was successfully used for the α-fluorination of free carboxylic acids 12 ( Scheme 5 ) [ 22a ].…”

“…Surprisingly however, the potential of these catalysts to facilitate asymmetric α-halogenations has only recently been established [ 22 , 23 ]. In 2021, Zheng’s group introduced the para-cyclophane-based ITU pcpITU which was successfully used for the α-fluorination of free carboxylic acids 12 ( Scheme 5 ) [ 22a ]. Hereby, acid 12 is in situ activated by using TsCl to form the mixed anhydride.…”

“…Catalyst turnover was hereby achieved by addition of alcohols, thus giving access to the α-fluorinated esters 13 containing a tri-substituted stereogenic center. Furthermore, this in situ acid-activation – fluorination strategy could successfully be expanded to alkyne-based acids 14 , which allow for the synthesis of α-F-esters 15 with a tetrasubstituted stereogenic center [ 22b ]. Hereby, the authors relied on BTM as a readily available ITU derivative instead and isopropanol was found to be the alcohol of choice allowing for good yields and catalyst turnover.…”

Synthesis of Chiral Tertiary Allylic- and Propargylic Fluorides from Nonaflates of Chiral α-Fluorinated β-Keto Dicarbonyl Compounds

“…While optimizing the nonaflation reaction conditions using rac -1a , we observed the overreaction of rac -2a to afford tertiary propargylic fluoride rac -3a as a side product (Table ). Propargylic fluoride is another valuable compound class, and the synthesis of chiral tertiary propargylic fluorides has been less explored . Therefore, we turned our attention to the synthesis of chiral tertiary propargylic fluorides 3 as another application of nonaflates 2 (Scheme ).…”

“…Propargylic fluoride is another valuable compound class, 3 and the synthesis of chiral tertiary propargylic fluorides has been less explored. 16 Therefore, we turned our attention to the synthesis of chiral tertiary propargylic fluorides 3 as another application of nonaflates 2 (Scheme 5). Thus, treating 2a with 2.0 equiv of DBU in THF gave exclusively the corresponding chiral tertiary propargylic fluoride 3a in a good yield, 84%.…”