Enantioselective Synthesis of Allylic Sulfones via Rhodium-Catalyzed Direct Hydrosulfonylation of Allenes and Alkynes.

A highly regio- and enantioselective hydrosulfonylation using commercially available sodium sulfinates is reported, providing the first direct asymmetric rhodium-catalyzed hydrosulfonylation of allenes/alkynes to synthesize chiral allylic sulfones. Ligand screening studies demonstrated the indispensable role of the -symmetric P,N-ligand (,,)-StackPhim for achieving both high regioselecitivity (>20:1) and enantioselectivity (up to 97% ee). Notably, the operationally simple method and mild conditions allow for the rapid preparation of chiral allylic sulfones with a wide scope of functional groups.

Chemoselective Diazine Dearomatization: The Catalytic Enantioselective Dearomatization of Pyrazine.

Despite much progress in the area of dearomatization, the enantioselective dearomatization of heterocycles is limited to those with a single heteroatom. Here we report a highly enantioselective copper-catalyzed dearomatization of pyrazine, a diazine, leading to chiral C-substituted piperazines. When exposed to a chloroformate and an alkyne in the presence of a catalyst derived from a copper salt and the chiral ligand StackPhos, pyrazine is readily dearomatized to provide a 2,3-disubstituted dihydropyrazine as single diastereomer in high enantiomeric excess.

Catalytic Enantioselective Alkyne Addition to Nitrones Enabled by Tunable Axially Chiral Imidazole-Based P,N-Ligands.

Although catalytic enantioselective alkyne addition is an established method for the synthesis of chiral propargylic alcohols and amines, addition to nitrones presents unique challenges, and no general chiral catalyst system has been developed. In this manuscript, we report the first Cu-catalyzed enantioselective alkyne addition to nitrones utilizing tunable axially chiral imidazole-based ,-ligands. Our approach effectively overcomes difficulties in both reactivity and selectivity, resulting in a simple Cu-catalyzed protocol.

Catalytic Enantioselective Synthesis of Axially Chiral Imidazoles by Cation-Directed Desymmetrization.

Axially chiral five-membered heterobiaryls synthesized by enantioselective catalysis typically feature large ortho-substituents or a heteroatom in the chiral axis to maintain a stable configuration. Herein we report a cation-directed catalytic enantioselective desymmetrization method that enables rapid access to axially chiral imidazoles with the basic nitrogen at the ortho position and efficiently integrates π-stacking moieties to ensure a stable axial configuration for further applications. The process is operationally simple, is highly enantioselective, and can be performed on the gram scale.

Enantio- and Regioselective Copper-Catalyzed 1,2-Dearomatization of Pyridines.

A copper-catalyzed dearomative alkynylation of pyridines is reported with excellent regio- and enantioselectivities. The synthetically valuable enantioenriched 2-alkynyl-1,2-dihydropyridine products afforded are generated from the readily available feedstock, pyridine, and commercially available terminal alkynes. The three-component reaction between a pyridine, a terminal alkyne, and methyl chloroformate employs copper chloride and StackPhos, a chiral biaryl P,N- ligand, as the catalytic system.

PLA-Triggered Activation of Cyclosporine-Phospholipid Prodrug as a Drug Targeting Approach in Inflammatory Bowel Disease Therapy.

Oral medication with activity specifically at the inflamed sites throughout the gastrointestinal tract and limited systemic exposure would be a major advance in our therapeutic approach to inflammatory bowel disease (IBD). For this purpose, we have designed a prodrug by linking active drug moiety to phospholipid (PL), the substrate of phospholipase A (PLA). PLA expression and activity is significantly elevated in the inflamed intestinal tissues of IBD patients.

Prodrug-Based Targeting Approach for Inflammatory Bowel Diseases Therapy: Mechanistic Study of Phospholipid-Linker-Cyclosporine PLA-Mediated Activation.

Therapeutics with activity specifically at the inflamed sites throughout the gastrointestinal tract (GIT) would be a major advance in our therapeutic approach to inflammatory bowel disease (IBD). We aimed to develop the prodrug approach that can allow such site-specific drug delivery. Currently, using cyclosporine as a drug of choice in IBD is limited to the most severe cases due to substantial systemic toxicities and narrow therapeutic index of this drug.

Enantioselective Lactonization by π-Acid-Catalyzed Allylic Substitution: A Complement to π-Allylmetal Chemistry.

Asymmetric allylic alkylation (AAA) is a powerful method for the formation of highly useful, non-racemic allylic compounds. Here we present a complementary enantioselective process that generates allylic lactones via π-acid catalysis. More specifically, a catalytic enantioselective dehydrative lactonization of allylic alcohols using a novel Pd -catalyst containing the imidazole-based P,N-ligand (S)-StackPhos is reported.

Configuration Sampling With Five-Membered Atropisomeric P,N-Ligands.

Here we report a strategy for the systematic variation of atropisomeric C -symmetric P,N ligands to incrementally change the position of the groups within the chiral pocket without modifying their steric parameters. More specifically, the effects of systematic modification of the nitrogen heterocycle in atropisomeric C -symmetric stack ligands have been investigated in this study. The versatility and applicability of this approach has been demonstrated in mechanistically distinct catalytic enantioselective transformations, resulting in the identification of a P,N-ligand for a highly enantioselective synthesis of organoboranes.

Synthesis and Biological Evaluation of the Southern Hemisphere of Spirastrellolide A and Analogues.

The synthesis and biological evaluation of truncated spirastrellolide A analogues comprised of the southern hemisphere against protein phosphatase 2A are described. A convergent synthesis was designed featuring two gold-catalyzed cyclization reactions, specifically, a dehydrative cyclization of monoallylic diols for the synthesis of the tetrahydropyran (A-ring) and a regioselective spiroketalization for the efficient generation of the [6,6]-spiroketal (B, C-ring system). The synthesis of the southern hemisphere of spirastrellolide A was achieved involving the longest linear sequence of 19 steps.

Phospholipid Cyclosporine Prodrugs Targeted at Inflammatory Bowel Disease (IBD) Treatment: Design, Synthesis, and in Vitro Validation.

Novel phospholipid (PL)-cyclosporine conjugates were prepared and studied as potential prodrugs for inflammatory bowel disease (IBD). Our approach relies on phospholipase A (PLA ), which is overexpressed in the inflamed intestinal tissues, as the prodrug activator to potentially release cyclosporine at the site of inflammation. PL-cyclosporine prodrug conjugates with methylene linkers of various lengths between the sn-2 position of the PL and cyclosporine were synthesized and evaluated for in vitro activation.

Lipids and Lipid-Processing Pathways in Drug Delivery and Therapeutics.

The aim of this work is to analyze relevant endogenous lipid processing pathways, in the context of the impact that lipids have on drug absorption, their therapeutic use, and utilization in drug delivery. Lipids may serve as biomarkers of some diseases, but they can also provide endogenous therapeutic effects for certain pathological conditions. Current uses and possible clinical benefits of various lipids (fatty acids, steroids, triglycerides, and phospholipids) in cancer, infectious, inflammatory, and neurodegenerative diseases are presented.

The prospects of lipidic prodrugs: an old approach with an emerging future.

Nowadays, prodrugs are no longer used as a last resort, rather, they are intentionally designed at the early stages of drug development. Lipidic prodrug strategy, where a drug moiety is covalently bound to a lipid carrier, was initially proposed half a century ago, yet, this approach still remains to be explored. Lipidic prodrugs can join physiological lipid metabolic pathways, and hence provide drug targeting via lymphatic transport or site-specific drug release, improve drugs' pharmacokinetic profile, overcome obstacles originating from biological barriers and bypass hepatic first-pass metabolism.

Lactone Synthesis by Enantioselective Orthogonal Tandem Catalysis.

In this work, we report enantioselective orthogonal tandem catalysis for the one pot conversion of Meldrum's acid derivatives and alkynes into δ-lactones. This new transformation, which resembles a formal [4+2] cycloaddition with concomitant decarboxylation and loss of acetone, proceeds in high yields and excellent enantioselectivity (up to 99 % ee) over a broad substrate scope. The products are densely functionalized and ripe for further transformations, as demonstrated here by both ring-opening reactions and reduction to saturated lactones.

Molecular Modeling-Guided Design of Phospholipid-Based Prodrugs.

The lipidic prodrug approach is an emerging field for improving a number of biopharmaceutical and drug delivery aspects. Owing to their structure and nature, phospholipid (PL)-based prodrugs may join endogenous lipid processing pathways, and hence significantly improve the pharmacokinetics and/or bioavailability of the drug. Additional advantages of this approach include drug targeting by enzyme-triggered drug release, blood-brain barrier permeability, lymphatic targeting, overcoming drug resistance, or enabling appropriate formulation.

A Facile Enantioselective Alkynylation of Chromones.

The first catalytic enantioselective alkynylation of chromones is reported. In this process, chromones are silylated to form silyloxybenzopyrylium ions that lead to silyl enol ethers after Cu-catalyzed alkyne addition using StackPhos as a ligand. The outcome of the reaction is impacted by distal ligand substituents with differing electronic character and it was found that successful reactions could be achieved with different ligand congeners by using different solvents.

Phospholipid-Based Prodrugs for Colon-Targeted Drug Delivery: Experimental Study and In-Silico Simulations.

In ulcerative colitis (UC), the inflammation is localized in the colon, and one of the successful strategies for colon-targeting drug delivery is the prodrug approach. In this work, we present a novel phospholipid (PL)-based prodrug approach, as a tool for colonic drug targeting in UC. We aim to use the phospholipase A (PLA), an enzyme that is overexpressed in the inflamed colonic tissues of UC patients, as the PL-prodrug activating enzyme, to accomplish the liberation of the parent drug from the prodrug complex at the specific diseased tissue(s).

Enol Acetates: Versatile Substrates for the Enantioselective Intermolecular Tsuji Allylation.

A highly versatile enantioselective intermolecular Tsuji allylation that generates alpha-quaternary stereocenters is reported. The methodology utilizes a prochiral enol acetate as a substrate, which is the last class of the original Tsuji substrates to be successfully employed in an enantioselective variant of the venerable reaction. This development enables a highly convergent approach that lends itself to rapid diversification and analogue synthesis by facilitating the incorporation of the allyl moiety from an allylic alkoxide, obviating the need for the preparation of allylic enol carbonates.

Prospects and Challenges of Phospholipid-Based Prodrugs.

Nowadays, the prodrug approach is used already at the early stages of drug development. Lipidic prodrug approach is a growing field for improving a number of drug properties/delivery/therapy aspects, and can offer solutions for various unmet needs. This approach includes drug moiety bound to the lipid carrier, which can be triglyceride, fatty acids, steroid, or phospholipid (PL).

Lipidic prodrug approach for improved oral drug delivery and therapy.

In the past, a prodrug design was used as a last option to improve bioavailability through controlling transport, distribution, metabolism, or other mechanisms. Prodrugs are currently used even in early stages of drug development, and a significant percentage of all drugs in the market are prodrugs. The focus of this article is lipidic prodrugs, a strategy whereby a lipid carrier is covalently bound to the drug moiety.

Catalytic Dehydrative Lactonization of Allylic Alcohols.

A convenient strategy for the synthesis of phthalides and γ-butyrolactones is reported. The method utilizes readily prepared allylic alcohols in formal Au(I)- and Pd(II)-catalyzed S2' reactions. Using these catalysts, exclusive formation of the desired five-membered lactones is observed, completely avoiding the competing direct lactonization pathway that forms the undesired seven-membered ring with protic acids and alternative metal salts.

Computational modeling and in-vitro/in-silico correlation of phospholipid-based prodrugs for targeted drug delivery in inflammatory bowel disease.

Targeting drugs to the inflamed intestinal tissue(s) represents a major advancement in the treatment of inflammatory bowel disease (IBD). In this work we present a powerful in-silico modeling approach to guide the molecular design of novel prodrugs targeting the enzyme PLA, which is overexpressed in the inflamed tissues of IBD patients. The prodrug consists of the drug moiety bound to the sn-2 position of phospholipid (PL) through a carbonic linker, aiming to allow PLA to release the free drug.

Phospholipid-drug conjugates as a novel oral drug targeting approach for the treatment of inflammatory bowel disease.

The enzyme phospholipase A (PLA) is overexpressed in the inflamed intestine in inflammatory bowel disease (IBD) patients, and in this work we aimed to exploit PLA as a prodrug-activating enzyme for a novel PL-drug conjugate, thereby liberating the free drug specifically in the targeted diseased tissue(s). The proposed prodrug contains a drug moiety covalently bound through a linker to the sn-2 position of a phospholipid (PL). The NSAID diclofenac was used as model molecule, and four different linker lengths (2, 4, 6 and 8 -CH units) were studied.

Enantioselective Alkyne Conjugate Addition Enabled by Readily Tuned Atropisomeric P,N-Ligands.

By the nature of its structure, the 5-membered chiral biaryl heterocyclic scaffold represents a departure from 6-membered P,N-ligands that facilitates tuning and enables ligand evolution to address issues of selectivity and reactivity. In this vein, the Cu-catalyzed enantioselective conjugate alkynylation of Meldrum's acid acceptors is reported using Me-StackPhos. Enabled by this new ligand, the reaction tolerates a wide range of alkynes furnishing the products in high yields and excellent enantioselectivity.

Correction: Regioselectivity in the Au-catalyzed hydration and hydroalkoxylation of alkynes.

Correction for 'Regioselectivity in the Au-catalyzed hydration and hydroalkoxylation of alkynes' by Justin A. Goodwin et al., Chem.