Enantioconvergent transformations of secondary alcohols through borrowing hydrogen catalysis.

Direct substitution of readily available alcohols is recognized as a key research area in green chemical synthesis. Starting from simple racemic secondary alcohols, the achievement of catalytic enantioconvergent transformations of the substrates will be highly desirable for efficient access to valuable enantiopure compounds. To accomplish such attractive yet challenging transformations, the strategy of the enantioconvergent borrowing hydrogen methodology has proven to be uniquely effective and versatile. This review aims to provide an overview of the impressive progress made on this topic of research that has only thrived in the past decade. In particular, the conversion of racemic secondary alcohols to enantioenriched chiral amines, N-heterocycles, higher-order alcohols and ketones will be discussed in detail.

Enantioselective Construction of Eight-Membered N-Heterocycles from Simple 1,3-Dienes via Pd(0) Lewis Base Catalysis.

We report herein an unprecedented enantioselective (4+4) cycloaddition of simple 1,3-dienes with azadienes for the construction of fused eight-membered N-heterocycles. In this transformation, the π-Lewis basic Pd(0) catalyst achieves activation of 1,3-dienes to induce nucleophilic addition to azadienes followed by ring cyclization via a selective terminal allylic substitution. Furthermore, highly efficient and diastereoselective derivatizations of the eight-membered rings provide a facile access to diverse enantiopure fused tetra- to hexacyclic compounds with potential application in medicinal chemistry.

Iridium-Catalyzed Enantioconvergent Borrowing Hydrogen Annulation of Racemic 1,4-Diols with Amines.

We present an enantioconvergent access to chiral N-heterocycles directly from simple racemic diols and primary amines, through a highly economical borrowing hydrogen annulation. The identification of a chiral amine-derived iridacycle catalyst was the key for achieving high efficiency and enantioselectivity in the one-step construction of two C-N bonds. This catalytic method enabled a rapid access to a wide range of diversely substituted enantioenriched pyrrolidines including key precursors to valuable drugs such as aticaprant and MSC 2530818.

Atroposelective Synthesis of 1,1'-Bipyrroles Bearing a Chiral N-N Axis: Chiral Phosphoric Acid Catalysis with Lewis Acid Induced Enantiodivergence.

We present herein a highly efficient atroposelective synthesis of axially chiral 1,1'-bipyrroles bearing an N-N linkage from simple hydrazine and 1,4-diones. Further product derivatizations led to axially chiral bifunctional compounds with high potential in asymmetric catalysis. For this chrial phosphoric acid (CPA)-catalyzed double Paal-Knorr reaction, an intriguing Fe(OTf)3 -induced enantiodivergence was also observed.

Organocatalytic Asymmetric Tandem Nazarov Cyclization/Semipinacol Rearrangement: Rapid Construction of Chiral Spiro[4.4]nonane-1,6-diones.

A novel organocatalytic asymmetric tandem Nazarov cyclization/semipinacol rearrangement reaction using "unactivated" substrates has been developed, generating a series of chiral spiro[4.4]nonane-1,6-diones in up to 96% yield and 97% enantiomeric excess. Significantly, it is the first direct example for asymmetric synthesis of cyclopentanones with four stereocenters using Nazarov cyclization. DFT calculations have been applied to understand the reaction mechanism, stereochemistry, and substituent effects.

Visible Light-Induced Radical Cascade Difluoromethylation/Cyclization of Unactivated Alkenes: Access to CF2H-Substituted Polycyclic Imidazoles.

An efficient and mild protocol for the visible light-induced radical cascade difluoromethylation/cyclization of imidazoles with unactivated alkenes using easily accessible and bench-stable difluoromethyltriphenylphosphonium bromide as the precursor of the -CF2H group has been developed to afford CF2H-substituted polycyclic imidazoles in moderate to good yields. This strategy, along with the construction of Csp3-CF2H/C-C bonds, is distinguished by mild conditions, no requirement of additives, simple operation, and wide substrate scope. In addition, the mechanistic experiments have indicated that the difluoromethyl radical pathway is essential for the methodology.

Chiral Acid-Catalyzed Atroposelective Indolization Enables Access to 1,1'-Indole-Pyrroles and Bisindoles Bearing a Chiral N-N Axis.

We present herein a highly atroposelective indolization for the efficient synthesis of 1,1'-biheteroaryls bearing a chiral N-N axis. Under the cooperative catalysis of chiral phosphoric acid and InBr3, the reactions between 2,3-diketoesters and 1,3-dione-derived enamines resulted in a highly enantioselective construction of 1,1'-pyrrole-indoles with up to 92% yield, 94% enantiomeric excess (ee), or bisindoles in up to 92% ee. Derivatizations of these compounds to diverse functionalized N-N linked axially chiral biheteroaryls have also been demonstrated.

Organocatalytic asymmetric fluorination/semipinacol rearrangement: an efficient approach to chiral ß-fluoroketones.

An asymmetric fluorination/semipinacol rearrangement of 2-oxa allylic alcohols, as catalyzed by cinchona-alkaloid derivatives, gives chiral ß-fluoro ketones with moderate to high levels of enantioselectivity (see scheme). Both enantiomers of the product could be obtained by using the appropriate catalyst.

Spiro-fused six-membered N-heterocyclic carbene: a new scaffold toward unique properties and activities.

A six-membered N-heterocyclic carbene fused with a spiro-scaffold is designed. The new NHC shows stronger σ-donation ability than typical 5-membered NHCs. This property leads to interesting reactivities of this spiro-fused six-membered NHC. For example, the NHC-BF3 Lewis pair complex can be readily prepared by using LiBF4 as the BF3 source, or through a direct bond-reconstruction of the tetrafluoroborate salt NHC·HBF4.