Asymmetric Preparation of α-Quaternary Fluorinated β-keto Esters. Review

Abstract

In this review, recent advances over the past decade in the preparation of fluorinated stereogenic quaternary centers on β-keto esters compounds are analyzed. Since the incorporation of fluorine and fluorinated groups is of special interest in pharmaceutical chemistry, a range of metal-catalyzed and organocatalyzed methods have been developed. Herein, we review the enantioselective fluorination, trifluoromethylation and trifluoromethylthiolation of 3-oxo esters. The scope, the induction of enantioselectivity and mechanistic investigations are presented.

Asymmetric Methods for Carbon‐Fluorine Bond Formation

“…For asymmetric fluorination of cyclic (conformationally restricted) β‐keto esters, a wide variety of methods are available. Ti(IV), Pd(II), Cu(II), and Ni(II) complexes are the most common or important catalysts [22g,24,27–33] . Asymmetric fluorination of acyclic β‐keto esters is much more difficult because of their higher conformational freedom, and only a handful of methods with sufficient enantioselectivity are known [27,31,34] …”

“…[22g,24,27-33] Asymmetric fluorination of acyclic β-keto esters is much more difficult because of their higher conformational freedom, and only a handful of methods with sufficient enantioselectivity are known. [27,31,34] Xu and coworkers reported a rapid and efficient mechanochemical procedure for the enantioselective fluorination of cyclic β-keto esters. First, Cu(OTf) 2 and ligand (S,S)-L1 were ground for 5 minutes.…”

Difluoroalkylation of Anilines via Photoinduced Methods

“…The presence of tethered fluorinated groups in bioactive molecules is a well-known strategy for altering their chemical properties, including conformational bias, reactivity, stability, and lipophilicity . Thus, in the last decades, synthetic organic chemists have done great efforts to develop efficient methods for the introduction of fluorinated motifs in organic architectures . Nowadays, around 20% of the marketed drugs are fluoropharmaceuticals, and in 2019, 13 new fluorinated compounds were approved by US Food and Drug Administration (FDA) accounting for 41% of all small-molecule drugs .…”

Alkali Carbonates Improve β,β-Diaryl Serine-Catalyzed Enantioselective α-Fluorination of β-Dicarbonyl Compounds

“…Asymmetric fluorination has gained significant attention in medicinal chemistry due to its high potential for enhancing biological activity. − β-Dicarbonyl compounds have been often used as key starting materials to construct biologically relevant compounds; therefore, β-dicarbonyl compounds bearing asymmetric fluorinated carbons can serve as useful building blocks for fluorinated medicines. , For this purpose, many transition-metal-catalyzed and organocatalyzed enantioselective α-fluorinations of β-dicarbonyl compounds have been explored to date. − For example, the enantioselective α-fluorination of both acyclic and cyclic β-ketoesters has been extensively investigated using transition-metal catalysis, which often shows excellent enantioselectivity.…”