Catalytic Asymmetric Synthesis of Enantioenriched Heterocycles Bearing a CCF₃ Stereogenic Center

Abstract

Given the important agricultural and medicinal application of optically pure heterocycles bearing a trifluoromethyl group at the stereogenic carbon center in the heterocyclic framework, the exploration of efficient and practical synthetic strategies to such types of molecules remains highly desirable. Catalytic enantioselective synthesis has one clear advantage that it is more cost-effective than other synthetic methods, but remains limited by challenges in achieving excellent yield and stereoselectivities with a low catalyst loading. Thus far, numerous models of organo- and organometal-catalyzed asymmetric reactions have been exploited to achieve this elusive goal over the past decade. This review article describes recent progress on this research topic, and focuses on an understanding of the catalytic asymmetric protocols exemplified in the catalytic enantioselective synthesis of a wide range of complex enantioenriched trifluoromethylated heterocycles.

Catalytic Asymmetric 1,3‐Dipolar Cycloaddition of β‐Fluoroalkylated α,β‐Unsaturated 2‐Pyridylsulfones with Nitrones for Chiral Fluoroalkylated Isoxazolidines and γ‐Amino Alcohols

“…[4] Thec atalytic asymmetric 1,3-dipolar cycloaddition of nitrones [5] and prochiral fluoroalkylated olefins affords ready access to chiral isoxazolidines (Scheme 1), which is the key study in this report. Over the past two decades,c atalytic asymmetric 1,3-dipolar cycloadditions with nitrones have witnessed tremendous progress, [6] albeit no application for chiral isoxazolidines and gamino alcohols bearing aC F 3 -stereogenic center.A sacontinuous program on the construction of fluorinated heterocycles, [7] we herein report unprecedented prochiral fluoroalkylated building blocks and the corresponding asymmetric 1,3-dipolar cycloadditions assisted by ac hiral Ni II /(S,S)-Phdbfox catalyst (Ph-dbfox = 4,6-dibenzofurandiyl-2,2-bis(4phenyloxazoline)), as well as the synthetic utilities of chiral a-fluoroalkylated g-amino alcohol derivatives.…”

Enantioselective Gold-Catalyzed Synthesis of Heterocyclic Compounds

“…Using DTBM-MeO-BIPHEP(AuCl) 2 and AgClO 4 as an alternative catalytic system, Widenhoefer et al successfully formed enantioenriched pyrrolidines from both terminal and substituted allene substrates, albeit with slightly lower selectivity [62]. Later, a follow-up paper demonstrated racemic unsymmetrical 1,1-disubstituted allenes were able to undergo dynamic kinetic asymmetric [63].…”

“…Their ubiquitous presence in both medicinal and naturally occurring compounds justifies the discovery of new and improvement of existing catalytic methodologies in this field [1,2]. Many functionalized heterocycles can be produced using homogeneous organo-or transition metal catalysis.…”

The Catalytic Asymmetric Construction of Trifluoromethylated Quaternary Carbon-Containing Thiochromans

“…In the field of pharmaceutical, agricultural, and synthetic chemistry, trifluoromethylated heterocyclic compounds have attracted a growing interest. [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] Because the introduction of trifluoromethyl group often enhanced the metabolic stability, lipophilicity, bioavailability, and binding selectivity of drug molecules. [35][36][37][38] Thus constructing optically active compounds incorporating both a trifluoromethyl moiety and a sulfur heterocyclic structure is biologically and synthetically useful, and still remains a challenge.…”