Pd-Catalysed asymmetric allylic alkylation of heterocycles: a user's guide.

This review provides an in-depth analysis of recent advances and strategies employed in the Pd-catalysed asymmetric allylic alkylation (Pd-AAA) of nucleophilic prochiral heterocycles. The review is divided into sections each focused on a specific family of heterocycle, where optimisation data and reaction scope have been carefully analysed in order to bring forward specific reactivity and selectivity trends. The review eventually opens on how computer-based technologies could be used to predict an ideally matched catalytic system for any given substrate. This user-guide targets chemists from all horizons interested in running a Pd-AAA reaction for the preparation of highly enantioenriched heterocyclic compounds.

Synthesis of CHF2-Containing Heterocycles through Oxy-difluoromethylation Using Low-Cost 3D Printed PhotoFlow Reactors.

We report here a highly straightforward access to a variety of CHF2-containing heterocycles, including lactones, tetrahydrofurans, tetrahydropyrans, benzolactones, phthalanes, and pyrrolidines, through a visible light-mediated intramolecular oxy-difluoromethylation under continuous flow. The method, which relies on the use of readily available starting materials, low-cost 3D printed photoflow reactors, and difluoromethyltriphenylphosphonium bromide used here as a CHF2 radical precursor, is practical and scalable and provides the desired products in moderate to excellent yields and excellent regio- and stereoselectivities.

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.

Expanding the 'aplysinospin cascade' through DNA-templated [2+2] photocycloaddition.

Inspired by the unique ability of nucleic acids to template chemical transformations that are otherwise impossible in solution, we embarked on the generalisation of our DNA-templated [2+2] photo-induced homo- and heterodimerization of aplysinopsins. Our process ensures a straightforward access to cyclobutane containing natural products and analogues thereof. Most importantly, this conceptual biomimetic achievement presents interesting arguments to build a biosynthetic scenario.

Nucleoside/Nucleotide or Nucleic Acid Modification & Applications.

"The field of nucleosides, nucleotides, and nucleic acids has been in existence for some decades, leading to a notion that the area is well-explored and/or specialized, but is that true? Despite the constant reliance on this field for various aspects of biochemical, biological, and biomedical research, recent advances have brought this area into a greater focus, with the potential and benefits becoming increasingly evident. Explore this Special Collection for rich, diverse, and state-of-the art research presented in the form of Personal Accounts, Reviews, and Research Articles."

New Benchmark in DNA-Based Asymmetric Catalysis: Prevalence of Modified DNA/RNA Hybrid Systems.

By harnessing the chirality of the DNA double helix, chemists have been able to obtain new, reliable, selective, and environmentally friendly biohybrid catalytic systems with tailor-made functions. Nonetheless, despite all the advances made throughout the years in the field of DNA-based asymmetric catalysis, many challenges still remain to be faced, in particular when it comes to designing a "universal" catalyst with broad reactivity and unprecedented selectivity. Rational design and rounds of selection have allowed us to approach this goal. We report here the development of a DNA/RNA hybrid catalytic system featuring a covalently attached bipyridine ligand, which exhibits unmatched levels of selectivity throughout the current DNA toolbox and opens new avenues in asymmetric catalysis.

Phase-Transfer-Catalyzed Alkylation of Hydantoins.

A highly efficient, cost-effective, and environmentally friendly protocol is reported for the C5-selective alkylation of hydantoins under phase-transfer catalysis. The reactions are scalable and only require a catalytic amount of tetrabutylammonium bromide (TBAB) to achieve high yields under mild reaction conditions. Moreover, the method is applicable to a wide range of electrophiles, including alkyl-, allyl-, propargyl-, and benzyl halides, as well as acrylates and dibromoalkanes, but also to virtually any hydantoin precursor. We also highlight the potential for an enantioselective adaptation using a chiral phase-transfer catalyst.

Synthesis of α-Difluoromethyl Aryl Ketones through a Photoredox Difluoromethylation of Enol Silanes.

We report here an efficient and highly straightforward access to α-difluoromethylated ketones through a visible light-mediated difluoromethylation of readily available enol silanes. The method, which takes advantage of the polyvalence of Hu's reagent, N-tosyl-S-difluoromethyl-S-phenylsulfoximine, used here as a CHF2 radical precursor under catalytic photoredox conditions, is practical, scalable, and provides the corresponding α-CHF2 ketones in good to excellent yields.

Direct Access to Highly Enantioenriched α-Branched Acrylonitriles through a One-Pot Sequential Asymmetric Michael Addition/Retro-Dieckmann/Retro-Michael Fragmentation Cascade.

A highly enantioselective synthesis of α-branched acrylonitriles is reported featuring a one-pot sequential asymmetric Michael addition/retro-Dieckmann/retro-Michael fragmentation cascade. The method, which relies on a solid, bench-stable, and commercially available acrylonitrile surrogate, is practical, scalable, and highly versatile and provides a direct access to a wide range of enantioenriched nitrile-containing building blocks. Most importantly, the method offers a new tool to incorporate an acrylonitrile moiety in an asymmetric fashion.

O-Allylated Pudovik and Passerini Adducts as Versatile Scaffolds for Product Diversification.

The palladium-catalyzed O-allylation of α-hydroxyphosphonates and α-hydroxyamides obtained from Pudovik and Passerini multicomponent reactions has allowed interesting and highly straightforward access to a variety of building blocks for product diversification. These post-functionalizations include a selective base- or ruthenium hydride-mediated isomerization/Claisen rearrangement cascade and a ring-closing metathesis that allows access to a variety of diversely functionalized phosphono-oxaheterocycles.

DNA-Based Asymmetric Inverse Electron-Demand Hetero-Diels-Alder.

While artificial cyclases hold great promise in chemical synthesis, this work presents the first example of a DNA-catalyzed inverse electron-demand hetero-Diels-Alder (IEDHDA) between dihydrofuran and various α,ß-unsaturated acyl imidazoles. The resulting fused bicyclic O,O-acetals containing three contiguous stereogenic centers are obtained in high yields (up to 99 %) and excellent diastereo- (up to >99:1 dr) and enantioselectivities (up to 95 % ee) using a low catalyst loading. Most importantly, these results show that the concept of DNA-based asymmetric catalysis can be expanded to new synthetic transformations offering an efficient, sustainable, and highly selective tool for the construction of chiral building blocks.

Sequential Palladium-Catalyzed Allylic Alkylation/retro-Dieckmann Fragmentation Strategy for the Synthesis of α-Substituted Acrylonitriles.

A straightforward synthesis of α-substituted acrylonitriles is described using 4-cyano-3-oxotetrahydro-thiophene (c-THT) as an acrylonitrile surrogate. This unprecedented two-step sequence featuring a palladium-catalyzed allylic alkylation (Pd-AA) and a retro-Dieckmann fragmentation provides a general entry into diversely substituted 1,4-dienes.

A Unified Strategy for the Synthesis of Difluoromethyl- and Vinylfluoride-Containing Scaffolds.

Here, we report a general method for the synthesis of quaternary and tertiary difluoromethylated compounds and their vinylfluoride analogues. The strategy, which relies on a two-step sequence featuring a C-selective electrophilic difluoromethylation and either a palladium-catalyzed decarboxylative protonation or a Krapcho decarboxylation, is practical, scalable, and high yielding. Considering the generality of the method and the attractive properties offered by the difluoromethyl group, this approach provides a valuable tool for late-stage functionalization and drug development.

A rational quest for selectivity through precise ligand-positioning in tandem DNA-catalysed Friedel-Crafts alkylation/asymmetric protonation.

Covalent anchorage of a metallic co-factor to a DNA-based architecture is merely the only way to ensure an accurate positioning of a catalytic site within the chiral micro-environment offered by the DNA double helix. Ultimately, it also allows a fine-tuning of the catalytic pocket through simple synthetic modifications of the DNA sequence. Here, we report highly selective copper(ii)-catalysed asymmetric Friedel-Crafts conjugate addition/enantioselective protonation, which is due to a careful positioning of a bipyridine ligand within a DNA framework. Most importantly, this study unveils specific structural features that account for an optimal chirality transfer from the duplex to the Friedel-Crafts adducts.

A Sequential Pd-AAA/Cross-Metathesis/Cope Rearrangement Strategy for the Stereoselective Synthesis of Chiral Butenolides.

A practical and highly enantio- (up to 94:6 er) and diastereoselective (up to >20:1 dr) synthesis of γ-butenolides bearing two adjacent stereogenic centers is reported featuring a sequential direct palladium-catalyzed asymmetric allylic alkylation/( E)-selective cross-metathesis/[3,3]-sigmatropic Cope rearrangement from readily available α-substituted (5 H)-furan-2-ones.

Asymmetric Synthesis of α-Quaternary γ-Lactams through Palladium-Catalyzed Asymmetric Allylic Alkylation.

The synthesis of chiral unsaturated γ-lactams is reported featuring a highly enantioselective palladium-catalyzed asymmetric allylic alkylation of α,γ-disubstituted 2-silyloxypyrroles. This method allows a straightforward access to optically active γ-lactams bearing an α-quaternary stereogenic center in high yields (up to 93%), high regioselectivities (up to >20:1), and excellent enantioselectivities (up to 95% ee). To further demonstrate the synthetic utility of the method, the resulting allylated products were converted to various versatile chiral building blocks, such as pyrrolidines and pyrrolidinones.

Challenges and Opportunities in DNA-based Asymmetric Catalysis.

The biological importance of nucleic acids for the storage, expression and regulation of genetic information is now well understood. By taming the chemical synthesis of these biomolecules, chemists have been able to engineer new architectures based on the ability of DNA and RNA to fold into secondary or even more complex tertiary structures with applications in medicinal chemistry, diagnostics or even material sciences. Exploiting the fascinating helical structure of DNA and RNA to develop new chiral bio-hybrid catalysts capable of promoting highly stereoselective transformations under mild and eco-compatible conditions is also an emerging area of research. In this short review, we report our recent results in the field of DNA-based asymmetric catalysis as well as the challenges and promising perspectives that lie in front of us.

DNA-Templated [2+2] Photocycloaddition: A Straightforward Entry into the Aplysinopsin Family of Natural Products.

Biosynthetic considerations inspired us to harness the templating properties offered by DNA to promote a [2+2] photoinduced cycloaddition. The method was developed based on the dimerization of (E)-aplysinopsin, which was previously shown to be unproductive in solution. In sharp contrast, exposure of this tryptophan-derived olefin to light in the presence of salmon testes DNA (st-DNA) reproducibly afforded the corresponding homo-dimerized spiro-fused cyclobutane in excellent yields. DNA provides unique templating interactions enabling a singular mimic of the solid-state aggregation necessary for the [2+2] photocycloaddition to occur. This method was ultimately used to promote the prerequisite dimerizations leading to both dictazole B and tubastrindole B, thus constituting the first example of a DNA-mediated transformation to be applied to the total synthesis of a natural product.

Highly Enantioselective, Base-Free Synthesis of α-Quaternary Succinimides through Catalytic Asymmetric Allylic Alkylation.

The synthesis of diversely substituted five-membered ring succinimide derivatives is reported featuring a direct, base-free, palladium-catalyzed asymmetric allylic alkylation. The method allows a straightforward access to the desired heterocyclic scaffold bearing an all-carbon α-quaternary stereogenic center in high yields and good to excellent enantioselectivities. To further demonstrate the synthetic utility of the method, the allylated products were further converted to various versatile chiral building blocks, including a chiral pyrrolidine and a spirocyclic derivative, using selective transformations.

Dinucleating Schiff base ligand in Zn/4f coordination chemistry: synthetic challenges and catalytic activity evaluation.

Four Zn/4f polynuclear coordination clusters (PCCs) formulated as [ZnII2DyIII2L2(CO3)2(NO3)2] (1), [ZnIIYIIIL(NO3)2(o-van) (MeOH)] (MeOH) [2 (MeOH)] and [ZnIILnIIIL(NO3)2Cl(EtOH)] where Ln is Dy (3) and Y (4) and where H2L is the dinucleating Schiff base ligand N,N'-bis(3-methoxysalicylidene)cyclohexane-1,2-diamine and o-van is ortho-vanillin, were prepared and fully characterised for the first time. These air-stable heterometallic PCCs, obtained in high yields from commercially available materials, were shown to remain stable in solution in their dinuclear [ZnIILnIIIL] form. Their catalytic activity was evaluated in various catalytic transformations including the Friedel-Crafts alkylation of 2-acyl imidazoles with indoles.