Chiral Phosphoramidite Ligands Research Articles

Palladium-Catalyzed Branch-Selective Allylic C-H Amination Enabled by Nucleophile Coordination.

Regiochemical control is a central subject in the field of synthetic chemistry. Here we unveil an innovative approach for the branch-selective allylic C-H amination of α-alkenes with amine nucleophiles facilitated by phosphoramidite-palladium catalysis. A diverse array of α-alkenes has been effectively utilized to produce a variety of structurally distinct allylamines with moderate to excellent regioselectivity. Furthermore, the asymmetric version of this reaction is feasible through the use of chiral phosphoramidite ligands, albeit with currently modest enantioselectivity.

Pd-Catalyzed Enantioselective Desymmetrizing 1,7-Enyne Cycloisomerization of Alkyne-Tethered Cyclopentenes.

An enantioselective Pd-catalyzed intramolecular desymmetrizing cycloisomerization of N-(cyclopent-3-en-1-yl)propiolamides has been developed by employing a new chiral phosphoramidite ligand. A series of structurally unique bridged azabicycles are achieved in moderate to excellent yields with good E/Z selectivity and high enantioselectivity. Synthetic transformations are conducted to demonstrate the practical utility of this reaction.

Pd-catalyzed asymmetric Larock reaction for the atroposelective synthesis of N─N chiral indoles.

Atropisomeric indoles defined by a N─N axis are an important class of heterocycles in synthetic and medicinal chemistry and material sciences. However, they remain heavily underexplored due to limited synthetic methods and challenging stereocontrol over the short N─N bonds. Here, we report highly atroposelective access to N─N axially chiral indoles via the asymmetric Larock reaction. This protocol leveraged the powerful role of chiral phosphoramidite ligand to attenuate the common ligand dissociation in the original Larock reaction, forming N─N chiral indoles with excellent functional group tolerance and high enantioselectivity via palladium-catalyzed intermolecular annulation between readily available o-iodoaniline and alkynes. The multifunctionality in the prepared chiral indoles allowed diverse post-coupling synthetic transformations, affording a broad array of functionalized chiral indoles. Experimental and computational studies have been conducted to explore the reaction mechanism, elucidating the enantio-determining and rate-limiting steps.

A Simple Tool to Benchmark Reactivity in Asymmetric Catalysis

AbstractHerein, we report a simple and noninvasive experimental protocol in which a series of relative reaction rates may be obtained by way of single competition experiments. This approach permits a quantitative comparison of any given number of chiral catalysts relative to a ‘benchmarking’ chiral catalyst – a particularly useful tool since catalyst design and selection have remained largely dependent on chemical intuition. We apply this benchmarking approach towards an asymmetric N-heterocyclic carbene (NHC) catalyzed intramolecular Stetter reaction as a proof-of-concept study. In doing so, we demonstrate a rapid method to assess the complex interplay between catalyst reactivity and stereoelectronic effects – an analytical approach that has heretofore not been attempted for NHCs. To showcase the generality of this method, we apply it to an enantioselective Rh(I)-catalyzed [2+2+2] cycloaddition of alkenyl isocyanates and aryl alkynes for a series of chiral phosphoramidite ligands. The results described herein demonstrate that this inexpensive and easily adoptable protocol can reveal complex yet subtle steric and stereoelectronic effects of vastly different chiral catalyst structures, which can further aid with catalyst development and selection for a clearly defined application.

P(III)-Directed Asymmetric C-H Arylation toward Planar Chiral Ferrocenes by Palladium Catalysis.

Planar chiral ferrocenyl phosphines have been employed as highly valuable ligands in metal-catalyzed asymmetric reactions. However, their preparation remains a formidable challenge due to the requirement for intricate, multistep synthetic sequences. In addressing this issue, we have developed a groundbreaking enantioselective C-H activation strategy facilitated by P(III) directing groups, enabling the efficient construction of planar chiral ferrocenyl phosphines in a single step. Our innovative approach entails the combination of a palladium catalyst, a parent ferrocenyl phosphine, and a chiral phosphoramidite ligand, leading to exceptional reactivity and enantioselectivity. Remarkably, these novel ligands exhibit remarkable efficacy in silver-catalyzed asymmetric 1,3-dipolar cycloadditions. We carried out a combination of experimental and computational studies to obtain a more comprehensive understanding of the reaction pathway and the factors contributing to enantioselectivity.

Palladium-Catalyzed Asymmetric (3 + 2) Cycloaddition of 5-Allenyloxazolidine-2,4-Diones with Barbiturate-Derived Alkenes: Synthesis of Spirobarbiturate-γ-Lactams.

The 5-allenyloxazolidine-2,4-diones had been synthesized as novel precursors of π-allyl palladium zwitterion and were applied in a palladium-catalyzed enantioselective (3 + 2) annulation by using barbiturate-derived alkenes as the reaction partner in the presence of an axially chiral phosphoramidite ligand. This reaction proceeded smoothly under mild reaction conditions, affording highly functionalized spirobarbiturate-γ-lactam derivatives in excellent yields along with high diastereo- and enantioselectivities. The scale-up reaction and further transformation of the product were also successful.

Cover Picture

Pd‐catalyzed asymmetric allylic C—H functionalization has grown to be a general platform to access densely functionalized chiral molecules from easily available alkenes. In recent years, the adoption of asymmetric organo/palladium cooperative catalysis and building up a library of structurally tunable and bulky chiral phosphoramidite ligands have opened new avenues to create regio‐ and enantioselective Pd‐catalyzed allylic C—H functionalization reactions. Gong and coworkers describe their journey to the identification of asymmetric catalytic systems, mechanism of allylic C—H activation, control of stereo‐ and regioselectivity, and applications in asymmetric synthesis. More details are discussed in the article by Gong et al. on page 1841—1848.image

Atroposelective desymmetrization of 2-arylresorcinols via Tsuji-Trost allylation

Palladium-catalyzed asymmetric allylic alkylation has proven to be a powerful method for the preparation of a wide variety of chiral molecules. However, the catalytic and atroposelective allylic alkylation is still rare and challenging, especially for biaryl substrates. Herein, we report the palladium-catalyzed desymmetric and atroposelective allylation, in which the palladium complex with a chiral phosphoramidite ligand enables desymmetrization of nucleophilic 2-arylresorcinols in a highly enantioselective manner. With the aid of the secondary kinetic resolution effect, a wide variety of substrates containing a hydroxymethyl group at the bottom aromatic ring are able to provide O-allylated products up to 98:2 er. Computational studies show an accessible quadrant of the allylpalladium complex and provide three plausible transition states with intra- or intermolecular hydrogen bonding. The energetically favorable transition state is in good agreement with the observed enantioselectivity and suggests that the catalytic reaction would proceed with an intramolecular hydrogen bond.

Palladium-catalyzed intramolecular asymmetric hydrocyclopropanylation of alkynes: synthesis of cyclopropane-fused γ-lactams.

A palladium-catalyzed intramolecular asymmetric hydrocyclopropanylation of alkynes via C(sp3)-H activation has been developed for the synthesis of cyclopropane-fused γ-lactams. The presented strategy proceeds in a selective and 100% atom-economical manner. A range of cyclopropane-fused γ-lactams were prepared from readily available substrates in good yields and enantioselectivities with a chiral phosphoramidite ligand.

Inherently chiral calixarenes by a catalytic enantioselective desymmetrizing cross-dehydrogenative coupling.

Under the catalysis of PdBr2 and a chiral phosphoramidite ligand, the upper-rim mono (2-bromoaroyl)-substituted calix[4]arene derivatives underwent a facile enantioselective desymmetrization reaction to afford 9H-fluorene-embedded inherently chiral calixarenes in good yields with excellent enantioselectivities. The transannular dehydrogenative arene-arene coupling reaction proceeded most probably through an oxidative addition of the Caryl-Br bond to a ligated palladium catalyst followed by a sequence of an enantioselective 1,5-palladium migration and an intramolecular C-H arylation sequence. This new family of inherently chiral calixarenes possesses unique chiroptical properties thanks to their highly rigid structure induced by the 9H-fluorene segment.

Iridium-catalyzed direct asymmetric reductive amination utilizing primary alkyl amines as the N-sources

Direct asymmetric reductive amination is one of the most efficient methods for the construction of chiral amines, in which the scope of the applicable amine coupling partners remains a significant challenge. In this study we describe primary alkyl amines effectively serve as the N-sources in direct asymmetric reductive amination catalyzed by the iridium precursor and sterically tunable chiral phosphoramidite ligands. The density functional theory studies of the reaction mechanism imply the alkyl amine substrates serve as a ligand of iridium strengthened by a (N)H-O(P) hydrogen-bonding attraction, and the hydride addition occurs via an outer-sphere transition state, in which the Cl-H H-bonding plays an important role. Through this concise procedure, cinacalcet, tecalcet, fendiline and many other related chiral amines have been synthesized in one single step with high yields and excellent enantioselectivity.

Palladium-catalysed branch- and enantioselective allylic C–H alkylation of α-alkenes

Enantioselective functionalization of alkenes is an attractive and straightforward method to assemble molecular complexity from readily available chemical feedstocks. Although regio- and enantioselective transformations of the C=C bond of alkenes have been extensively studied, those of the allylic C–H bonds of unactivated alkenes are yet to be explored. Here we report a palladium-catalysed branch- and enantioselective allylic C–H alkylation that is capable of accommodating diverse types of α-alkenes, ranging from feedstocks annually manufactured on a million-tonne scale to olefins tethering a wide scope of appended functionalities, providing unconventional access to chiral γ,δ-unsaturated amides. Notably, mechanistic studies reveal that regioselectivity is not only governed by the coordination pattern of nucleophiles but also regulated by the ligational behaviours of ligands, highlighting the importance of the monoligation of chiral phosphoramidite ligands in provoking high levels of stereo- and branch-selectivity via a nucleophile coordination-enabled inner-sphere allylation pathway.

Enantioselective Nickel-Catalyzed Si–C(sp2) Bond Activation and Migratory Insertion to Aldehydes: Reaction Scope and Mechanism

Transition-metal-catalyzed silicon–carbon bond activation is one of the most important processes in both organosilicon chemistry and homogeneous catalysis that is still rarely reported in the past decades, and the enantioselective versions based on transition-metal-catalyzed Si–C bond activation remain an ongoing challenge in asymmetric catalysis. Herein, we report a convenient and enantioselective Si–C bond cleavage-initiated [4 + 2] annulation of benzosilacyclobutenes with aldehydes, which provides an access to the direct synthesis of chiral six-membered oxasilacycles and their derivatives with high yields and enantioselectivities (up to 97% ee). The catalytic asymmetric reaction proceeds smoothly with the aid of a chiral TADDOL-derived phosphoramidite ligand and its chiral Ni complex with a suitable cavity. By switching the work-up of the reaction involved, the present strategy may be extended to subsequent downstream transformations of silyl ether-containing oxasilacycles to give chiral o-tolyl arylmethanols with high ees and quantitative conversions. A series of experimental results support that the strategy of silicon-mediated organic synthesis controlled by nickel catalysis demonstrates a powerful potential for the facile synthesis of chiral alcohols and its drug-like derivatives. Finally, mechanistic and computational investigations of the nickel-catalyzed Si–C bond activation offer insights into the origin of the observed stereoselective outcome, and the density functional theory calculation shows that the nickel-controlled Si–C(sp2) bond activation enables the controllable migratory insertion of benzaldehyde into the Ni–Si bond, which is recognized as the enantioselectivity-determining step.

Ligand-Controlled Site- and Enantioselective Carbene Insertion into Carbon-Silicon Bonds of Benzosilacyclobutanes.

We report herein a highly efficient palladium-catalyzed carbene insertion into strained Si-C bonds of benzosilacyclobutanes, which provides an efficient method to access α-chiral silanes. With a sterically hindered ligand, carbene insertion into the C(sp3 )-Si bond of benzosilacyclobutanes occurred in excellent site- and enantioselectivity, while C(sp2 )-Si bond insertion occurred selectively with less sterically hindered ligands. Reaction mechanism, in particular the roles of the chiral ligands in controlling the site-selectivity of the insertion reactions, are elucidated by using hybrid density functional theory.

On the Asymmetric Iridium‐Catalyzed N‐Allylation of Amino Acid Esters: Improved Selectivities through Structural Variation of the Chiral Phosphoramidite Ligand

AbstractThe investigation of the iridium‐catalyzed asymmetric N‐allylation of tert‐butyl glycinate using a “branched” racemic 1‐vinyl‐alkyl methyl carbonate revealed severe limitations of existing protocols. By screening a set of 24 BINOL‐derived chiral phosphoramidites a new superior ligand (L24*) was identified which afforded the amination product with high enantioselectivity (≥95 % ee) under optimized conditions. This ligand also allowed the N‐allylation of other amino acid tert‐butyl esters (derived from alanine, phenylalanine, or proline) with outstanding levels of diastereocontrol (d.r. ≥99 : 1) and negligible matched/mismatched differences.

Pd-Catalyzed Asymmetric Dearomative Arylation of Indoles via a Desymmetrization Strategy.

Pd-catalyzed asymmetric dearomative arylation of C3-substituted indoles is realized via a desymmetrization strategy. A BINOL-derived chiral phosphoramidite ligand is found to be highly efficient for the stereoselective control in this reaction. This method provides a convenient synthesis of spiroindolenines bearing two stereogenic centers in good yields (up to 98%) with excellent diastereo- and enantioselectivities (up to >20:1 dr and 97% ee), which could also be applied in asymmetric dearomative arylation of the simple C3-tethered indoles.

Anti-Selective synthesis of β-boryl-α-amino acid derivatives by Cu-catalysed borylamination of α,β-unsaturated esters.

A copper-catalysed regio- and diastereoselective borylamination of α,β-unsaturated esters with B2pin2 and hydroxylamines has been developed to deliver acyclic β-boryl-α-amino acid derivatives with high anti-diastereoselectivity (up to >99 : 1), which is difficult to obtain by the established methods. A chiral phosphoramidite ligand also successfully induces the enantioselectivity, giving the optically active β-borylated α-amino acids. The products can be stereospecifically transformed into β-functionalised α-amino acids, which are of potent interest in medicinal chemistry.

A New Saddle-Shaped Aza Analog of Tetraphenylene: Atroposelective Synthesis and Application as a Chiral Acylating Reagent

A New Saddle-Shaped Aza Analog of Tetraphenylene: Atroposelective Synthesis and Application as a Chiral Acylating Reagent

Ir-catalyzed enantioselective B\u2212H alkenylation for asymmetric synthesis of chiral-at-cage o\u2011carboranes

The asymmetric synthesis of chiral-at-cage o-carboranes, whose chirality is associated with the substitution patterns on the polyhedron, is of great interest as the icosahedral carboranes have wide applications in medicinal and materials chemistry. Herein we report an intermolecular Ir-catalyzed enantioselective B−H alkenylation for efficient and facile synthesis of chiral-at-cage o-carboranes with new skeletons under mild reaction conditions. Generally very good to excellent yields with up to 99% ee can be achieved in this Ir-catalyzed B−H alkenylation. The enantiocontrol model is proposed based on Density Functional Theory calculations in which the use of chiral phosphoramidite ligand is essential for such asymmetric o-carborane B−H alkenylation.

Control of atroposelectivity via non-covalent interaction in Cu-catalyzed synthesis of axially chiral biaryls from azonaphthalenes and arylboronic acids

DFT calculations were performed to provide mechanistic insights into the title reaction, the first example of copper-catalyzed C(sp2)−H arene arylation with high atroposelectivities for aromatic Michael acceptor reported recently by Tan et al. [J. Am. Chem. Soc. 142 (2020) 7322−7327]. The results indicate that the reaction undergoes four sequential steps: transmetalation, ligand exchange, Michael addition, central-to-axial chirality transfer. The nucleophilic addition is found as the atroposelectivity-, and regioselectivity-determining step with a barrier of 14.9 kcal/mol. The detailed mechanisms obtained lead to an in-depth understanding of the atroposelectivity, which mainly originates from the π–π stacking interaction between two naphthalene rings respectively in the BINOL-derived chiral phosphoramidite ligand and in the arylboronic acid.