Catalytic Enantioselective α‐Chlorination of Carbonyl Compounds

Abstract

Stereoselective construction of chlorinated chiral carbon centers is a highly valuable operation because the resulting chiral chlorides serve as versatile intermediates for producing many chiral molecules by SN2‐type displacement with inversion of stereochemistry. Despite the synthetic utility of chiral alkyl chlorides, catalytic methods for achieving enantioselective chlorination were only developed in the last ten years. This Focus Review covers the progress of catalytic asymmetric α‐chlorination of carbonyl compounds over the last decade. Some stereospecific transformations of the resulting alkyl chlorides are also introduced.

Organocatalyzed Assembly of Chlorinated Quaternary Stereogenic Centers

“…[1] Additionally,m olecules with stereocenterst hat have ac hlorine atom are considered highly versatile buildingb locks in organics ynthesis, as they can be furthere laborated by converting the chloro group into another functionality through aS N 2d isplacementr eaction. [2] Nevertheless,t he installation of ac hlorine atom in an enantioselective manner is not an easy task. The difficulties associated with this transformation are mostly related to the high reactivity of the chlorinating agents, which can sometimes promote the chlorination of prochiral centers through an uncatalyzed pathway.…”

“…The first successful approach involved the use of metal catalysis. [2,3] However,t he wave of interest in asymmetrico rganocatalysis over the last fifteen years has allowed this task to be performed in the absence of metals. [4] Althought he construction of chlorinated tertiary stereocenters by meanso fo rganocatalytic methods has been widely explored in the recent years by strategies such as enamine catalysis, [5] only af ew successful catalysts have been shown as highly selectivei nt he enantioselective construction of chlorinated quaternary stereocenters.…”

Organocatalytic Asymmetric α-Chlorination of 1,3-Dicarbonyl Compounds Catalyzed by 2-Aminobenzimidazole Derivatives

“…From a synthetic point of view, optically active bi-functionalized compounds such as α-chlorinated carbonyls are especially attractive due to their high value as linchpin derivatives [2][3][4]. Due to the potential of these compounds, their catalytic asymmetric synthesis has been intensively investigated in the past few years [5][6][7]. Despite the breakthrough asymmetric organocatalysis has experienced during the last fifteen years, not only from a synthetic point of view [8], but also as a strategy for the preparation of natural-occurring and pharmaceutically active compounds [9][10][11], only a few privileged catalysts have been shown to be highly selective in the electrophilic α-chlorination of carbonyl compounds.…”

Williamson Ether Synthesis with Phenols at a Tertiary Stereogenic Carbon: Formal Enantioselective Phenoxylation of β‐Keto Esters

“…Meanwhile, it is well known that enantioselective heteroatomf unctionalization of active methine compounds can be used to produce av ariety of heteroatom-substituted quaternary stereogenic centers. [4] Examples of such functionalization methods include halogenation, [5,6] sulfenylation, [7] amination, [8] and hydroxylation [9] (Scheme 1). On the otherh and, there have been no reports on the enantioselective a-aryloxylation of active methine compounds.…”