Asymmetric Allylic Alkylation Reactions Research Articles

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.

Chiral, air stable, and reliable Pd(0) precatalysts applicable to asymmetric allylic alkylation chemistry

Stereoselective carbon-carbon bond formation via palladium-catalyzed asymmetric allylic alkylation is a crucial strategy to access chiral natural products and active pharmaceutical ingredients. However, catalysts based on the privileged Trost and Pfaltz-Helmchen-Williams PHOX ligands often require high loadings, specific preactivation protocols, and excess chiral ligand. This makes these reactions uneconomical, often unreproducible, and thus unsustainable. Here we report several chiral single-component Pd(0) precatalysts that are active and practically-applicable in a variety of asymmetric allylic alkylation reactions. Despite the decades-long history and widespread use of Trost-type ligands, the precatalysts in this work are the only reported examples of stable, isolable Pd(0) complexes with these ligands. Evaluating these precatalysts across nine asymmetric allylic alkylation reactions reveals high reactivity and selectivity at low Pd loading. Importantly, we also report an unprecedented Pd-catalyzed enantioselective allylation of a hydantoin, achieved on gram scale in high yield and enantioselectivity with only 0.2 mol% catalyst.

Enantioselective Rh(I)-Catalyzed C-H Arylation of Ferroceneformaldehydes.

As an important class of platform molecules, planar chiral ferrocene carbonyl compounds could be transformed into various functional groups offering facile synthesis of chiral ligands and catalysts. However, developing efficient and straightforward methods for accessing enantiopure planar chiral ferrocene carbonyl compounds, especially ferroceneformaldehydes, remains highly challenging. Herein, we report a rhodium(I)/phosphoramidite-catalyzed enantioselective C-H bond arylation of ferroceneformaldehydes. Readily available aryl halides such as aryl iodides, aryl bromides, and even aryl chlorides are suitable coupling partners in this transformation, leading to a series of planar chiral ferroceneformaldehydes in good yields and excellent enantioselectivity (up to 83% yield and >99% ee). The aldehyde group could be transformed into diverse functional groups smoothly, and enantiopure Ugi's amine and PPFA analogues could be synthesized efficiently. The latter was found to be a highly efficient ligand in Pd-catalyzed asymmetric allylic alkylation reactions. Mechanistic experiments supported the formation of imine intermediates as the key step during the reaction.

Recyclable Silica-Support Taniaphos/Copper(Ⅰ) complex for asymmetric allylic alkylation reactions

The first immobilization of recyclable Taniaphos/copper(Ⅰ) complex on a commercial accessible silica by thiol-ene coupling reaction has been achieved. The immobilization strategy and linker length are found to have significant impact on catalyst selectivities. Furthermore, we have realized the first heterogeneous asymmetric allylic alkylation reactions involving organometallic reagents using this catalyst system, and three types of cinnamyl bromide substrates are found to be suitable with up to 95% enantioselectivity and 96% yield. Notably, the catalyst shows good stability and cyclicity after five recycles without loss of selectivity and the products can be easily isolated with > 95% purity without chromatography purification.

Nickel-Catalyzed Asymmetric Allylic Alkylation of β-Dicarbonyl Compounds via C–C Bond Activation of 2-Allylated Cyclic 1,3-Diketones

The asymmetric allylic alkylation (AAA) reaction using less reactive, stable allylic sources is challenging. We achieved a nickel(0)-catalyzed AAA reaction of β-dicarbonyl compounds under ambient conditions through unstrained C–C bond activation of 2-allylated 2-methylcyclohexane-1,3-dione derivatives to afford the corresponding quaternary chiral compounds in high yield with high enantioselectivity. The reaction proceeded almost irreversibly due to the low solubility of the side-product, 2-methylcyclohexane-1,3-dione. Control experiments and DFT calculations allowed for the elucidating the mechanism of the AAA reaction with the Ni(0)-(S)-tol-MeO-BIPHEP catalyst system; the turnover limiting step is C–C bond formation, and the reverse reaction requires 7.6 kcal mol–1 higher activation energy than the forward reaction.

Simple selenide-phosphoramidite as chiral ligand for Pd-catalyzed asymmetric allylic alkylation reactions

Simple selenide-phosphoramidite as chiral ligand for Pd-catalyzed asymmetric allylic alkylation reactions

Regio- and Enantioselective Synthesis of Dihydropyrido[1,2-a]indoles via Catalytic Asymmetric Annulative Allylic Alkylation.

A palladium-catalyzed asymmetric annulative allylic alkylation reaction of 2-[(1H-indol-2-yl)methyl]malonates with (E)-but-2-ene-1,4-diyl dicarbonates is described, leading to the regio- and enantioselective synthesis of dihydropyrido[1,2-a]indoles with a chiral cyclic allyl stereocenter adjacent to the ring-junction nitrogen atom in moderate to good yields. The salient features of this protocol include mild conditions, a broad substrate scope, and good compatibility with substituents as well as high regio- and stereoselectivities, providing a catalytic asymmetric entry for fabricating chiral pyridoindole scaffolds.

Copper‐Catalyzed Asymmetric Allylic Alkylation of Racemic Cyclic Allyl Bromides with Organolithium Compounds

AbstractOrganolithium reagents are one of the most widely used reagents in chemical synthesis. Herein, we reported the first study of organolithium reagents used in asymmetric allylic alkylation (AAA) reactions with racemic cyclic substrates. A simple and efficient Cu‐catalyzed synthesis of enantiomerically enriched cycloalkene derivatives from various racemic cyclic allylic bromides was developed. The standard method employed 5 % CuBr⋅SMe2 in combination with phosphoramidite ligand L2 in DCM. Meanwhile, transfer of the reactions into flow condition for more convenient application was also studied. This new Cu‐catalyzed protocol was speculated to undergo an enantioconvergent transformation mechanism here.

Synthesis of enantioenriched 2,2-disubstituted pyrrolidines via sequential asymmetric allylic alkylation and ring contraction

The synthesis of a variety of enantioenriched 2,2-disubstituted pyrrolidines is described. A stereogenic quaternary center is first formed utilizing an asymmetric allylic alkylation reaction of a benzyloxy imide, which can then be reduced to a chiral hydroxamic acid. This compound can then undergo a thermal “Spino” ring contraction to afford a carbamate protected 2,2-disubstituted pyrrolidine stereospecifically. These pyrrolidines can be further advanced to enantioenriched indolizidine compounds. This reaction sequence allows access to new molecules that could be useful in the development of pharmaceutical agents.

Catalytic Enantioselective Synthesis of α-Difunctionalized Cyclic Sulfones.

As saturated heterocyclic building blocks become increasingly popular in medicinal chemistry and drug discovery programs, expansion of the synthetic toolkit to novel stereofunctionalized heterocycles is a priority. Herein, we report the development of a palladium-catalyzed decarboxylative asymmetric allylic alkylation reaction to access a broad range of enantioenriched α-difunctionalized 5- and 6-membered sulfones from easily accessible racemic starting materials. The allylic alkylation step was found to occur with high levels of enantioselectivity as a result of a palladium-mediated dynamic kinetic resolution of E/Z enolate intermediates. This methodology paves the way to hitherto unexplored stereodefined cyclic sulfones for medicinal chemistry applications.

Introducing C2 asymmetry in chromans—a brief story

The Trost group made notable attempts in the 1990s to synthesize several natural products such as vitamin E and its analogs, clusifoliol, rhododaurichromanic acid A, siccanin, and calanolide A and B through the palladium-catalyzed asymmetric allylic alkylation (AAA) reaction.

ProPhenol Derived Ligands to Simultaneously Coordinate a Main-Group Metal and a Transition Metal: Application to a Zn-Cu Catalyzed Reaction.

A new bifunctional ligand bearing chiral N-heterocyclic carbene (NHC) and prolinol moieties is presented. Utilizing the designed ligand, an in situ formed Cu/Zn hetero-bimetallic complex unlocks the asymmetric allylic alkylation reactions of allyl phosphates with zinc keto-homoenolates, leading to the formation of various γ-vinyl ketones with good regio- and enantio-selectivity. DF sT calculation supports that the chelation of allyl phosphates with catalyst promotes the SN 2' addition and the ligand-substrate steric interactions account for the stereoselective outcome.

Palladium-catalyzed asymmetric allylic alkylation of 3-amino-2-oxindoles: Synthesis of 3-allyl-3-amino-2-oxindoles

Tartrate derived bi(oxazoline) ligand with palladium (II) species catalyzed asymmetric allylic alkylation reaction to access highly valuable 3-allyl-3-amino-2-oxindoles with vicinal quaternary and tertiary stereocenters in very good yields (up to 91%) and excellent enantioselectivity (up to 98% ee) with moderate to good diastereoselectivity (up to 5:1). The synthetic utility of 3-allyl-3-amino-2-oxindole was further demonstrated to construct spiro(oxindole-3,2′-pyrrolidine) with consecutive one quaternary and three tertiary chiral centers in good stereoselectivity (dr = 8:1 and 80% ee) through metal-free intramolecular iodocyclization reaction.

Stereoselective Access to Spirooxindoles and Bisoxindoles Through Organocatalyzed Asymmetric Divergent Transformations of Isatin-derived MBH Carbonates.

An interesting β-isoquinidine catalyzed divergent reaction was developed to produce either spirocyclopentene oxindoles, spirocyclopentadiene oxindoles or bisoxindoles in a high enantioselective fashion. The utility of this protocol was demonstrated by the versatile transformations of the products. This work not only represents the first highly stereoselective intermolecular catalytic asymmetric allylic alkylation reaction between two isatin-derived MBH carbonate molecules but also constitutes a rare example of isatin-derived MBH carbonate-based enantioselective and α-regioselective [3+2] cycloaddition reactions.

Enantioselective Synthesis of Quaternary Carbon Stereocenters by Asymmetric Allylic Alkylation: A Review.

Quaternary stereocenters are of great importance to the three-dimensionality and enhanced properties of new molecules, but the synthetic challenges in creating quaternary stereocenters greatly hinder their wide use in drug discovery, organic material design, and natural product synthesis. The asymmetric allylic alkylation (AAA) of allylic substrates has proven to be a powerful methodology for enantioselective formation of structure skeletons bearing single or more quaternary carbon centers in modern asymmetric organocatalysis. AAA has certain advantages in constructing the tetrasubstituted stereocenters, including but not limited to mild reactive conditions, effective reaction rates, new functional group introduction, and carbon chains length extension. This review outlines the key considerations in the application of AAA reactions and summarizes the recent progress of AAA reactions in the enantioselective synthesis of products containing quaternary stereocenters. Meanwhile, a detailed discussion of the AAA reactions such as ligands, scope of substrates, transformations and the general reaction mechanisms is also provided. We hope this review could stimulate further advances in much broader areas, including organic synthesis, asymmetric catalysis, C-H activation, and symmetrical pharmaceutical chemistry.

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.

Organocatalytic asymmetric allylic alkylation of 2-methyl-3-nitroindoles: a route to direct enantioselective functionalization of indole C(sp3)-H bonds.

We here described a direct catalytic asymmetric functionalization of 2-methylindoles using organocatalysis. An efficient asymmetric allylic alkylation reaction with respect to 2-methyl-3-nitroindoles and racemic Morita-Baylis-Hillman carbonate has been achieved by using a chiral biscinchona alkaloid catalyst, which provided the functionalized indole derivatives in good yields and enantioselectivities.

The Pd-catalysed asymmetric allylic alkylation reactions of sulfamidate imines.

The Pd-catalysed asymmetric allylic alkylation (Pd-AAA) of prochiral enamide anions derived from 5H-oxathiazole 2,2-dioxides has been developed. Various 4,5-disubstituted and 4-substituted cyclic sulfamidate imines have participated in the transformation with a range of allyl carbonates—as well as 2-vinyl oxirane, 2-vinyl-N-tosylaziridine, and 2-vinyl-1,1-cyclopropane dicarboxylate—to furnish the desired C-allylated products in moderate to high yields, with high regioselectivites and generally high enantioselectivities. Conversion between N- and C-allyl products was observed, with the N-allylated products converting to the C-allylated products over time. The resulting high-value allylated heterocyclic products all bear a tetrasubstituted stereogenic centre and can be reduced to an allylated chiral sulfamidate or an amino alcohol.

Iridium-Catalyzed Enantioselective α-Allylic Alkylation of Amides Using Vinyl Azide as Amide Enolate Surrogate

Among the unstabilized enolates used as nucleophiles in iridium-catalyzed asymmetric allylic alkylation reactions, amide enolates are the least explored. Vinyl azides are now employed as amide enolate surrogates in Ir-catalyzed asymmetric allylic alkylation with branched allylic alcohols as the allylic electrophile. Competing reaction pathways are suppressed through the systematic tuning of the steric and electronic properties of vinyl azide to effect the α-allylic alkylation of secondary acetamides with high atom economy, exclusive branched selectivity, and mostly excellent enantioselectivity.

Reaction Mechanism, Origins of Enantioselectivity, and Reactivity Trends in Asymmetric Allylic Alkylation: A Comprehensive Quantum Mechanics Investigation of a C(sp3)-C(sp3) Cross-Coupling.

We utilize quantum mechanics to evaluate a variety of plausible mechanistic pathways for the entirety of the catalytic cycle for asymmetric decarboxylative allylic alkylation of allyl β-ketoesters. We present a mechanistic picture that unites all current experimental observations, including enantioinduction, reaction rate, catalyst resting state, enolate crossover experiments, water tolerance, and the effects of solvation on inner- and outer-sphere mechanisms. Experiments designed to evaluate the fidelity and predictive power of the computational models reveal the methods employed herein to be highly effective in elucidating the reactivity of the catalytic system. On the basis of these findings, we highlight a computational framework from which chemically accurate results are obtained and address the current limitations of the decarboxylative asymmetric allylic alkylation reaction.