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.

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."

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.

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.

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.

Palladium-Catalyzed Asymmetric Allylic Alkylation of 4-Substituted Isoxazolidin-5-ones: Straightforward Access to ß2,2 -Amino Acids.

We report here an unprecedented and highly enantioselective palladium-catalyzed allylic alkylation applied to 4-substituted isoxazolidin-5-ones. Ultimately, the process provides a straightforward access to ß2,2 -amino acids bearing an all-carbon quaternary stereogenic center in great yields and a high degree of enantioselectivity.

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.

A decade of DNA-hybrid catalysis: from innovation to comprehension.

In a little over a decade, the unique chirality of oligonucleotides has allowed the development of a variety of asymmetric synthetic transformations. The concept lies in embedding an achiral transition metal catalyst in a DNA double helix, which provides the necessary chiral microenvironment to selectively form one enantiomer of a given reaction product. The most recent efforts at unveiling new reactivities have been accompanied by the desire to understand the mechanisms by which the chirality is transferred and the influence of the interaction between DNA and the metallic co-factor on the selectivity. By offering a complete overview of the field, this review aims to highlight the intricate correlation between the structure of the chiral bio-inorganic scaffold and its catalytic efficacy.

High spatiotemporal control of spontaneous reactions using ultrasound-triggered composite droplets.

Achieving high spatial and temporal control over a spontaneous reaction is a particularly challenging task with potential breakthroughs in various fields of research including surface patterning and drug delivery. We report here an exceptionally effective method that allows attaining such control. This method relies on a remotely triggered ultrasound-induced release of a reactant encapsulated in a composite microdroplet of liquid perfluorohexane. More specifically, the demonstration was achieved by locally applying a focused 2.25 MHz transducer onto a microfluidic channel in which were injected composite microdroplets containing a solution of an azidocoumarin and an external flow containing a reactive alkyne.

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.

Visible light-mediated difluoromethylation/cyclization in batch and flow: scalable synthesis of CHF2-containing benzimidazo- and indolo[2,1-a]isoquinolin-6(5H)-ones.

We report here a practical and cost-effective method for the synthesis of CHF2-containing benzimidazo- and indolo[2,1,a]-isoquinolin-6(5H)-ones through a visible light-mediated difluoromethylation/cyclization cascade. The method, which affords functionalized multifused N-heterocyclic scaffolds in moderate to high yields under mild reaction conditions, is also easily scalable using low-cost 3D printed photoflow reactors.

DNA vs. mirror-image DNA: a universal approach to tune the absolute configuration in DNA-based asymmetric catalysis.

Mirror mirror on the wall: By taking advantage of the unique structural features of L-DNA, the first examples of left-helical enantioselective induction in the field of DNA-based asymmetric catalysis were realized. Most importantly, this approach is the only one that allows a reliable and predictable access to both enantiomers for any given reaction.

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.

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.

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.

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.

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.

Total synthesis and structural revision of vannusals A and B: synthesis of the originally assigned structure of vannusal B.

The total synthesis of the originally assigned structure of vannusal B (2) and its diastereomer (d-2) are described. Initial forays into these structures with model systems revealed the viability of a metathesis-based approach and a SmI(2)-mediated strategy for the key cyclization to forge the central region of the molecule, ring C. The former approach was abandoned in favor of the latter when more functionalized substrates failed to enter the cyclization process. The successful, devised convergent strategy based on the SmI(2)-mediated ring closure utilized vinyl iodide (-)-26 and aldehyde fragment (+/-)-86 as key building blocks, whose lithium-mediated coupling led to isomeric coupling products (+)-87 and (-)-88 (as shown in Scheme 17 in the article). Intermediate (-)-88 was converted, via (-)-89 and (-)-90/(+)-91, to vannusal B structure 2 (as shown in Scheme 18 in the article), whose spectroscopic data did not match those reported for the natural product. Similarly, intermediate (+)-25, obtained through coupling of vinyl iodide (-)-26 and aldehyde (+/-)-27 (as shown in Scheme 13 in the article) was transformed via intermediates (-)-97 and (+)-98 (as shown in Scheme 19 in the article) to diastereomeric vannusal B structure (+)-d-2 (as shown in Scheme 19 in the article) which was also proven spectroscopically to be non-identical to the naturally occurring substance. These investigations led to the discovery and development of a number of new synthetic technologies that set the stage for the solution of the vannusal structural conundrum.

Amine, alcohol and phosphine catalysts for acyl transfer reactions.

An overview of the area of organocatalytic asymmetric acyl transfer processes is presented including O- and N-acylation. The material has been ordered according to the structural class of catalyst employed rather than reaction type with the intention to draw mechanistic parallels between the manner in which the various reactions are accelerated by the catalysts and the concepts employed to control transfer of chiral information from the catalyst to the substrates.