Asymmetric Construction of Halogenated Cyclic Quaternary Carbon Center through Enolate Activation of Aldehydes

Abstract

The construction of a chiral halogenated cyclic quaternary carbon center through various catalytic strategies is an emerging hot topic in the field of asymmetric synthesis. Herein, we give a summary of recently developed synthetic methods for preparing such structures. In addition, a novel enolate activation mode of aldehydes is highlighted, which provides an elegant pathway to access enantiopure heterocycles featuring a halogenated quaternary stereocenter through organocatalytic [4+2] cycloaddition.

Probing α‐Amino Aldehydes as Weakly Acidic Pronucleophiles: Direct Access to Quaternary α‐Amino Aldehydes by an Enantioselective Michael Addition Catalyzed by Brønsted Bases

“…Although these pioneering works set the basis for further studies to address the problem of α‐amino aldehyde α‐alkylation through the enamine pathway in a much broader sense, as an alternative to this activation strategy, BB catalysis relies on the deprotonation of a C−H pronucleophile as a primary activation element and, in theory, presents no apparent inherent limitation [18] . However, in addition to the problems associated with the α‐functionalization of aldehydes noted above, there is a rather specific example that documents the reaction of α‐chloroaldehydes with β‐alkylidene α‐keto amides, wherein the final cyclization of the resultant addition adduct appears to be the driving force of the process [19] . Therefore the utility of this type of catalysis for aldehyde activation is still an open question.…”

“…[18] However,i na ddition to the problemsa ssociated with the a-functionalizationo fa ldehydes noted above,t here is ar ather specific example that documentst he reactiono fa-chloroaldehydes with b-alkylidene a-keto amides, wherein the final cyclization of the resultant addition adduct appearst ob et he driving force of the process. [19] Therefore the utility of this type of catalysis for aldehyde activation is still an open question. Inspired by the well-known tendency of aamino aldehydest ou ndergo racemization, asw ellb yt he fact that this tendency increases if aw eak base is present, [1,20] we reasoned that, upon exposure to aw eak chiral BB, N-protected a-amino aldehydesc ould easily generate at ransiente nolate ion pair (Figure 2c), which should be more reactivet han that of the corresponding enamine, and thus, eventually drive the catalytic addition process forward.…”

syn‐Selective Michael Reaction of α‐Branched Aryl Acetaldehydes with Nitroolefins Promoted by Squaric Amino Acid Derived Bifunctional Brønsted Bases

“…[2] Despite this progress, the use of these tertiary amine catalysts has been mainly limited to relatively acidic substrates (pKa < 17) [3] and their application with aldehydes as pronucleophiles has been hardly investigated. [4] The inherent high reactivity of the carbon atom in that oxidation state which hamper effective control of side reactions, [5] may account for this lack of studies, a complication that has to be added to the usual problems associated with aldehyde activation and reaction enantiocontrol. Aminocatalysis [6] has shown to be an excellent option to solve these problems and, at present, a broad range of efficient reactions to access α-functionalized aldehydes in high stereoselectivity is available.…”

Catalytic Strategies for the Asymmetric Construction of Cyclic Frameworks with a Halogenated Tetrasubstituted Stereocenter

“…They are also considered as important building blocks in synthetic chemistry, because the halogen atom can be readily converted into other diverse functional groups through S N 2 substitution . Therefore, great efforts have been made by synthetic chemists, and many excellent stereoselective methods of constructing carbon–halogen bonds have been developed in a highly diastereo‐ and enantioselective manner . In recent years, this filed has already become a hotspot in organic chemistry and attracted the attention from synthesis community: Baeza reviewed the construction of chlorinated tetrasubstituted stereocenters through organocatalytic methods; Shibatomi summarized the construction of halogenated tetrasubstituted stereocenters through the asymmetric functionalizations of α ‐haloenolates or enols, and the asymmetric transformation of haloalkenes; Hii discussed the enantioselective halogenation of carbonyl compounds via transition‐metal catalytic strategies; Toste reviewed the asymmetric construction of tetrasubstituted C−F stereocenters.…”

“…Using chiral small organic molecules or transition‐metal complexes as catalysts provided reliable and efficient protocols, which can address the challenges of generating cyclic products with a halogenated tetrasubstituted carbon center, especially sterically hindered tetrasubstituted carbon centers. In general, cyclic molecules bearing a chiral halocarbon center are constructed through two main strategies (Scheme ): (1) the C−X tetrasubstituted stereocenters are generated from C−C bond formation of pre‐halogenated substrates; (2) the C−X tetrasubstituted stereocenters are constructed through a direct halogenation process by using various electrophilic and nucleophilic halogenation reagents (Figure ) …”