Prochiral Nucleophiles Research Articles

Copper-Catalyzed Regio-, Diastereo-, and Enantioselective Allylic Alkylation with 1,1-Diborylalkanes.

We report a copper-catalyzed regio-, diastereo-, and enantioselective allylic alkylation of allyl bromides using 1,1-diborylalkanes as prochiral nucleophiles. This methodology employs copper(I) bromide as a catalyst, an (R)-BINOL-derived phosphoramidite as a ligand, and lithium benzoate as a crucial additive. The reaction affords enantioenriched homoallylic boronic esters possessing vicinal stereocenters in good yields and high diastereo- and enantioselectivity. The developed method demonstrates a broad substrate scope with respect to a wide range of 1,1-diborylalkanes and allyl bromides. Mechanistic studies, including deuterium-labeling experiments and DFT calculations, provide insights into the reaction pathway and the origin of the stereoselectivity. The synthetic utility of this method is showcased through various transformations of the obtained enantioenriched homoallylic boronic esters into valuable chiral building blocks.

Pd/Cu-Cocatalyzed Asymmetric Cascade Heck/Tsuji-Trost Reaction to Access Non-natural Tryptophans.

A Pd-catalyzed asymmetric Heck cascade reaction involving the intramolecular carbopalladation of unsaturated hydrocarbons, followed by nucleophilic trapping of the resulting palladium species, is a powerful approach for constructing chiral N-heterocycles. However, the use of prochiral nucleophiles in these reactions remains significantly underexplored. Herein, we report a novel Pd/Cu catalytic system for the asymmetric cascade Heck/Tsuji-Trost reaction of allenamides and aldimine esters. This robust method allows for the rapid synthesis of a wide range of enantiopure non-natural α-substituted tryptophans in high yields (up to 99% yield) with excellent enantioselectivities (up to 98% ee). Additionally, the synthetic utility of this protocol is demonstrated through scale-up experiments and diverse valuable transformations.

Dual-Catalysis-Enabled Construction of Vicinal Stereogenic Centers through Diastereo- and Enantioselective Allylic Substitution

AbstractVicinal stereogenic centers represent prevalent structural motifs in organic synthetic chemistry, and their construction poses a longstanding challenge. Transition-metal-catalyzed asymmetric allylic substitution has become a well-established enantioselective C–C bond-forming reaction. When these reactions involve a prochiral nucleophile and an allylic electrophile with a terminal substituent, the creation of vicinal stereogenic centers becomes feasible. However, despite remarkable achievements having been accomplished, realizing this transformation with precise control over both the enantio- and diastereoselectivity remains a significant challenge. To address the stereoselective challenges, the introduction of a second catalyst to the transition-metal-catalyzed asymmetric allylic alkylation to control the diastereoselectivity during C–C bond formation has proven particularly fruitful. In this short review, we aim to highlight recent advances in dual catalysis that enable diastereo- and enantioselective allylic substitutions.1 Introduction2 Construction of Vicinal Stereogenic Centers by Organo and Metal Dual Catalysis2.1 Chiral Phase-Transfer Catalysis and Transition-Metal Dual Catalysis2.2 Chiral Amine and Transition-Metal Dual Catalysis2.3 NHC and Transition-Metal Dual Catalysis2.4 Chiral Aldehyde and Transition-Metal Dual Catalysis2.5 Chiral Lewis Base and Transition-Metal Dual Catalysis3 Construction of Vicinal Stereogenic Centers by Metal and Metal Dual Catalysis3.1 Lewis Acidic Metal and Iridium Dual Catalysis3.2 Lewis Acidic Metal and Palladium Dual Catalysis3.3 Palladium and Ruthenium Dual Catalysis3.4 Other Advancements in the Construction of Vicinal Stereogenic Centers through Synergistic Bimetallic Catalysis Enabling Asymmetric Allylic Alkylation4 Conclusions and Future Outlook

The Catalytic Asymmetric Allylic Alkylation of Acyclic Enolates for the Construction of Quaternary and Tetrasubstituted Stereogenic Centres.

To facilitate the discovery and development of new pharmaceuticals, the demand for novel stereofunctionalised building blocks has never been greater. Whilst molecules bearing quaternary and tetrasubstituted stereogenic centres are ideally suited to explore untapped areas of chemical space, the asymmetric construction ofsterically congested carbon centres remains a longstanding challenge in organic synthesis. The enantioselective assembly of acyclic stereogenic centres is even more demanding due to the need to restrict a much wider range of geometries and conformations of the intermediates involved. In this context, the catalytic asymmetric allylicalkylation (AAA) of acyclic prochiral nucleophiles, namely enolates, has become an indispensable tool to access a range of linearα-quaternary andα-tetrasubstituted carbonyl compounds. However, unlike the AAA of cyclic enolates with a fixed enolate geometry, to achieve high levels of stereocontrol in the AAA of acyclic enolates, the stereoselectivity of enolisation must be considered. The aim of this review is to offer acomprehensivediscussion of catalytic AAA reactions of acyclic prochiral enolates and their analogues to generate congested quaternary and tetrasubstituted chiral centres using metal, non-metal and dual catalysis, with particular focus given to the control of enolate geometry and its impact on the stereochemical outcome of the reaction.

Synergistic catalysis for stereocontrol of prochiral nucleophiles in palladium-catalyzed asymmetric allylic substitution

Synergistic catalysis for stereocontrol of prochiral nucleophiles in palladium-catalyzed asymmetric allylic substitution

Dispersion and Steric Effects on Enantio-/Diastereoselectivities in Synergistic Dual Transition-Metal Catalysis.

Comprehensive computational studies were carried out to explore the mechanisms of enantioselective Cu/Pd and stereodivergent Cu/Ir dual-catalytic syntheses of α,α-disubstituted α-amino acids (α-AAs). A chiral copper azomethine ylide undergoes facile α-allylation with racemic π-allylpalladium species or stereopure π-allyliridium complex to stereoconvergently or stereodivergently furnish single/double stereocenters, respectively. Stereoselectivity at the α-center is controlled by the facial selectivity of α-allylation with respect to the prochiral nucleophile. Despite apparently similar transition-state assemblies, computational models and distortion/interaction analyses disclose versatile modes of stereoinduction wherein the copper azomethine ylide species can face-selectively intercept metal-π-allyl intermediates utilizing attractive dispersion interactions and/or sterically caused distortions. Generation of the β-stereocenter in the Cu/Ir system relies on a stereospecifically generated allyliridium complex and electronically controlled branched-to-linear selectivity, while the dual Cu/Pd system yields a linear monochiral product due to steric factors and π-π stacking interactions. The studies demonstrate on a molecular level how ligand-encoded chiral information is transferred to the α-/β-sites of the resulting α-AAs and how the mode of regio-/stereoselection is altered by differences in transition-metal-stabilized coupling partners. To facilitate studies of stereoselective catalysis, a suite of analytical tools to extract controlling factors for asymmetric induction is demonstrated.

Catalytic Enantioselective Alkylation of Prochiral Enolates.

The asymmetric alkylation of enolates is a particularly versatile method for the construction of α-stereogenic carbonyl motifs, which are ubiquitous in synthetic chemistry. Over the past several decades, the focus has shifted to the development of new catalytic methods that depart from classical stoichiometric stereoinduction strategies (e.g., chiral auxiliaries, chiral alkali metal amide bases, chiral electrophiles, etc.). In this way, the enantioselective alkylation of prochiral enolates greatly improves the step- and redox-economy of this process, in addition to enhancing the scope and selectivity of these reactions. In this review, we summarize the origin and advancement of catalytic enantioselective enolate alkylation methods, with a directed emphasis on the union of prochiral nucleophiles with carbon-centered electrophiles for the construction of α-stereogenic carbonyl derivatives. Hence, the transformative developments for each distinct class of nucleophile (e.g., ketone enolates, ester enolates, amide enolates, etc.) are presented in a modular format to highlight the state-of-the-art methods and current limitations in each area.

Iridium-Catalyzed Asymmetric Allylic Alkylation of Deconjugated Butyrolactams.

Compared with the ever-growing list of nonprochiral nucleophiles in Ir-catalyzed asymmetric allylic substitution reactions, prochiral nucleophiles are less studied. We present a new prochiral nucleophile, namely, deconjugated butyrolactam, for Ir-catalyzed asymmetric allylic alkylation (AAA). This reaction provides access to α-allyl deconjugated butyrolactams with a moderate to good dr and an excellent er. This is the first AAA reaction of deconjugated butyrolactams. Allyl transposition through Cope rearrangement appears to proceed stereospecifically to form γ-allyl conjugated butyrolactams.

Enantioselective Formation of Quaternary Centers by Allylic Alkylation with First-Row Transition-Metal Catalysts.

Asymmetric allylic alkylation mediated by transition metals provides an efficient strategy to form quaternary stereogenic centers. While this transformation is dominated by the use of second- and third-row transition metals (e.g., Pd, Rh, and Ir), recent developments have revealed the potential of first-row transition metals, which provide not only a less expensive and potentially equally efficient alternative but also new mechanistic possibilities. This review summarizes examples for the assembly of quaternary stereocenters using prochiral allylic substrates and hard, achiral nucleophiles in the presence of copper complexes and highlights the complementary approaches with soft, prochiral nucleophiles catalyzed by chiral cobalt and nickel complexes.

Enantioselective C(sp3)-C(sp3) cross-coupling of non-activated alkyl electrophiles via nickel hydride catalysis.

Cross-coupling of two alkyl fragments is an efficient method to produce organic molecules rich in sp3-hybridized carbon centers, which are attractive candidate compounds in drug discovery. Enantioselective C(sp3)–C(sp3) coupling is challenging, especially of alkyl electrophiles without an activating group (aryl, vinyl, carbonyl). Here we report a strategy based on nickel hydride addition to internal olefins followed by nickel-catalyzed alkyl-alkyl coupling. This strategy enables enantioselective cross-coupling of non-activated alkyl halides with alkenyl boronates to produce chiral alkyl boronates. Employing readily available and stable olefins as pro-chiral nucleophiles, the coupling proceeds under mild conditions and exhibits broad scope and high functional group tolerance. Applications for the functionalization of natural products and drug molecules, as well as the synthesis of chiral building blocks and a key intermediate to (S)-(+)-Pregabalin, are demonstrated.

Desymmetrization of Phosphinic Acids via Pd-Catalyzed Asymmetric Allylic Alkylation: Rapid Access to P-Chiral Phosphinates.

The synthesis of P-chiral compounds is challenging, especially since useful catalytic methods for preparing such molecules are scarce. Herein we disclose a desymmetrization that employs phosphinic acids as prochiral nucleophiles in a Pd-catalyzed asymmetric allylic alkylation reaction, furnishing phosphinates with high enantio- and diastereoselectivity. This new method has broad scope and is applied to the synthesis of an enantioenriched tertiary phosphine oxide.

Rhodium-Catalyzed Asymmetric Allylic Dearomatization of β-Naphthols: Enantioselective Control of Prochiral Nucleophiles.

A highly enantioselective rhodium-catalyzed allylic dearomatization of β-naphthols with racemic aryl vinyl carbinol is described. In the presence of a Rh-catalyst derived from [Rh(C2H4)Cl]2 and chiral (P, olefin)-ligand with TFA as an additive, the functionalized β-naphthalenone compounds bearing an all-carbon-substituted quaternary stereogenic center were obtained in good yields with excellent enantioselectivity. In addition, this protocol features the enantioselective control of prochiral nucleophiles and provides the first illustration of Rh-catalyzed asymmetric allylic dearomatization.

Synthesis of Enantioenriched 3‐Amino‐3‐Substituted Oxindoles by Stereoselective Mannich Reaction Catalyzed by Supported Bifunctional Thioureas.

AbstractEnantioenriched 3‐amino‐3‐substituted oxindoles have been obtained by addition of different nucleophiles to N‐Boc ketimines derived from isatin catalyzed by chiral bifunctional supported thioureas. The Mannich reaction occurs with excellent enantioselection, but poor diastereoselection when prochiral nucleophiles were used. The supported catalyst were recovered and reused for five times without loss of activity. The mixture of diastereoisomers formed when a prochiral structure was used as nucleophile was converted into a single enantioenriched pyrazolyl derivative.magnified image

Diastereoselective Electrophile‐Directed Alkylations

Electrophile‐directed alkylations in which a chiral, sp3‐hybridized electrophile, dictates the facial attack on a prochiral nucleophile, provides a powerful method of asymmetric induction. The strategy is inherently efficient because the asymmetry of an sp3‐hybridized electrophile is propagated to install two contiguous chiral centers, the first through an SN2 displacement and the second through preferential facial recognition. The two primary modes of topological matching are through steric approach control and chelation between the electrophile and nucleophile. Electrophiles capable of chelation generally induce higher diastereoselectivity for secondary and primary electrophiles. Key parameters that influence the stereoselectivity are those expected for enolate/anion alkylations: solvent, cation, complexing agents. A generalized enolate‐electrophile alkylation model is used to provide an evaluative framework for collecting related alkylations with the aim of providing insight into the origin of the electrophile‐directed diastereoselectivity as a powerful synthetic strategy.

Enantioselective and Diastereodivergent Access to α‐Substituted α‐Amino Acids via Dual Iridium and Copper Catalysis

AbstractThe work reported within this paper describes an example of the application of bimetallic catalysts system in allylic substitution reactions. The development of new nucleophiles and the control of enantio‐ and diastereoselectivity are the main research topics in this area. An improvement in the reactivity and diastereoselectivity has been realized for the dual Ir/Cu catalyzed allylic alkylation of inactive prochiral nucleophiles, under mild reaction conditions. Furthermore, the choice of the metallacyclic iridium complex and chiral Cu‐Phox complex combination allows for access to all four stereoisomers from the same starting materials with excellent enantioselectivity and diastereoselectivity (up to >99% ee and >20:1 dr). Significantly, this method provides a stereodivergent access to 2‐amino‐3‐methylpent‐4‐acid ester, an important fragment for the synthesis of Halipeptin A.magnified image

Asymmetric Rhodium-Catalyzed Allylic Substitution Reactions: Discovery, Development and Applications to Target-Directed Synthesis.

The transition metal-catalyzed allylic substitution reaction is a particularly versatile method for the construction of carbon-carbon and carbon-heteroatom bonds. In this regard, the rhodium-catalyzed variant has emerged as a powerful method for the regioselective and stereospecific allylic substitution of chiral nonracemic secondary and tertiary allylic carbonates with a variety of carbon- and heteroatom-based nucleophiles. In addition, recent developments have made the analogous enantioselective process possible using prochiral nucleophiles with achiral allylic electrophiles, which represents a significant advance in this area. In this Perspective, the discovery, development and applications of these conceptually orthogonal strategies to target-directed synthesis are discussed, with a particular emphasis given to those methods developed in our laboratory.

Chiral phase-transfer catalysis in the asymmetric α-heterofunctionalization of prochiral nucleophiles.

Chiral phase-transfer catalysis is one of the major catalytic principles in asymmetric catalysis. A broad variety of different catalysts and their use for challenging applications have been reported over the last decades. Besides asymmetric C–C bond forming reactions the use of chiral phase-transfer catalysts for enantioselective α-heterofunctionalization reactions of prochiral nucleophiles became one of the most important field of application of this catalytic principle. Based on several highly spectacular recent reports, we thus wish to discuss some of the most important achievements in this field within the context of this review.

ChemInform Abstract: Highly Regio and Enantioselective Synthesis of Chiral Polysubstituted 2H‐Pyrroles

AbstractReview: 3 refs.

ChemInform Abstract: Phosphine‐Catalyzed Enantioselective γ‐Addition of 3‐Substituted Oxindoles to 2,3‐Butadienoates and 2‐Butynoates: Use of Prochiral Nucleophiles.

The first phosphine-catalyzed enantioselective γ-addition with prochiral nucleophiles and 2,3-butadienoates as the reaction partners has been developed. Both 3-alkyl- and 3-aryl-substituted oxindoles could be employed in this process, which is catalyzed by a chiral phosphine that is derived from an amino acid, thus affording oxindoles that bear an all-carbon quaternary center at the 3-position in high yields and excellent enantioselectivity. The synthetic value of these γ-addition products was demonstrated by the formal total synthesis of two natural products and by the preparation of biologically relevant molecules and structural scaffolds.

ChemInform Abstract: Ir‐Catalyzed Intermolecular Asymmetric Allylic Dearomatization Reaction of Indoles.

AbstractThe presented approach is the first example where the asymmetric construction of all‐carbon quaternary stereogenic centers is realized through the discrimination of the enantiotopic faces of a prochiral nucleophile without forming an allylic chiral center under iridium catalysis.