Regio- and Chemoselective Double Allylic Substitution of Alkenyl vic-Diols.

Double allylic substitution is an attractive approach to building molecular complexity from simple starting materials by creating two new bonds in one pot. However, this type of reaction has been doomed by chemoselectivity and regioselectivity issues. In this letter, we describe a new approach to introduce a-la-carte two new C-C, C-N, C-O, or C-S bonds in a chemo- and regioselective fashion. The reaction relies on sequential dual catalysis with a Lewis acid and palladium. The scope is remarkably broad, and the reaction can be diastereoselective by using secondary alcohols as the first nucleophile.

Palladium-Catalyzed ortho-C-H Alkoxycarbonylation of Aromatic Aldehydes via a Transient Directing Group Strategy.

Transient directing groups (TDGs) can be a powerful strategy for directly functionalizing C-H bonds of aldehydes. We report a palladium-catalyzed o-C-H alkoxycarbonylation of benzaldehydes using a catalytic amount of aromatic amine to form a transient imine that plays the role of a monodentate TDG. The reaction conditions were applied to a broad range of aldehydes, and the corresponding 2-formyl benzoates were used as direct precursors for the synthesis of phthalides and 1-isoindolinones.

Regioselective C-H Functionalization of Naphthalenes: Reactivity and Mechanistic Insights.

Naphthalene is a very important skeleton in chemistry as evidenced by the large number of active compounds that contain it. For this reason, methods that can achieve easy functionalization of naphthalene derivatives are of great importance. This Minireview summarizes reactions that allow regioselective functionalization of 1-substituted naphthalenes based on directed C-H activation strategies. Indeed, over the past ten years, many research groups have tried to develop new methodologies to directly introduce different functional groups on every position of naphthalene. In addition to the possible reactions reported in the literature, special attention has been paid to mechanistic aspects in order to explain the observed regioselectivities.

Palladium-Catalyzed C8-Arylation of Naphthalenes through C-H Activation: A Combined Experimental and Computational Study.

Herein, a direct C8-arylation reaction of 1-amidonaphthalenes is described. By using diaryliodonium salts as arylating agents, the palladium-catalyzed C-H activation reaction showed perfect C8 regioselectivity and a wide functional group tolerance. In most cases, the desired polyaromatic compounds were isolated in good to excellent yields. To explain the observed regioselectivity, DFT calculations were performed and highlighted the crucial role of the amide directing group. Finally, the utility of this method is showcased by the synthesis of benzanthrone derivatives.

Azetidine-Containing Alkaloids Produced by a Quorum-Sensing Regulated Nonribosomal Peptide Synthetase Pathway in Pseudomonas aeruginosa.

Pseudomonas aeruginosa displays an impressive metabolic versatility, which ensures its survival in diverse environments. Reported herein is the identification of rare azetidine-containing alkaloids from P. aeruginosa PAO1, termed azetidomonamides, which are derived from a conserved, quorum-sensing regulated nonribosomal peptide synthetase (NRPS) pathway. Biosynthesis of the azetidine motif has been elucidated by gene inactivation, feeding experiments, and biochemical characterization in vitro, which involves a new S-adenosylmethionine-dependent enzyme to produce azetidine 2-carboxylic acid as an unusual building block of NRPS. The mutants of P. aeruginosa unable to produce azetidomonamides had an advantage in growth at high cell density in vitro and displayed rapid virulence in Galleria mellonella model, inferring functional roles of azetidomonamides in the host adaptation. This work opens the avenue to study the biological functions of azetidomonamides and related compounds in pathogenic and environmental bacteria.

Palladium triggered diene formation from nitro allylic compounds: a versatile entry into naphthalene derivatives.

Nitro allylic derivatives were converted into dienes through the elimination of the nitro group under basic treatment, in the presence of a palladium catalyst. This reaction probably involves the formation of a palladium π-allyl complex followed by a base-promoted ß-hydride elimination. This reaction, combined with the condensation of ketones with nitromethane and the functionalization of the resulting nitrocycloalkenes, constitutes a very powerful synthetic tool for the formation of dienes. Particular attention has been brought to the application of this methodology to the formation of 1-substituted naphthalenes from 1-tetralone.

Multifaceted Study on a Cytochalasin Scaffold: Lessons on Reactivity, Multidentate Catalysis, and Anticancer Properties.

An intramolecular Diels-Alder (IMDA) reaction efficiently accelerated by Schreiner's thiourea is reported, to build a functionalized cytochalasin scaffold (periconiasin series) for biological purposes. DFT calculation highlighted a unique multidentate cooperative hydrogen bonding in this catalysis. The deprotection end game afforded a collection of diverse structures and showed the peculiar reactivity of the Diels-Alder cycloadducts upon functionalization. Biological studies revealed strong cytotoxicity of a few compounds on breast cancer cell lines while actin polymerization is preserved.

Reoptimization of the Organocatalyzed Double Aldol Domino Process to a Key Enal Intermediate and Its Application to the Total Synthesis of Δ12 -Prostaglandin J3.

Re-investigation of the l-proline catalyzed double aldol cascade dimerization of succinaldehyde for the synthesis of a key bicyclic enal intermediate, pertinent in the field of stereoselective prostaglandin synthesis, is reported. The yield of this process has been more than doubled, from 14 % to a 29 % isolated yield on a multi-gram scale (32 % NMR yield), through conducting a detailed study of the reaction solvent, temperature, and concentration, as well as a catalyst screen. The synthetic utility of this enal intermediate has been further demonstrated through the total synthesis of Δ12 -prostaglandin J3 , a compound with known anti-leukemic properties.

Activation of olefins via asymmetric Brønsted acid catalysis.

The activation of olefins for asymmetric chemical synthesis traditionally relies on transition metal catalysts. In contrast, biological enzymes with Brønsted acidic sites of appropriate strength can protonate olefins and thereby generate carbocations that ultimately react to form natural products. Although chemists have recently designed chiral Brønsted acid catalysts to activate imines and carbonyl compounds, mimicking these enzymes to protonate simple olefins that then engage in asymmetric catalytic reactions has remained a substantial synthetic challenge. Here, we show that a class of confined and strong chiral Brønsted acids enables the catalytic asymmetric intramolecular hydroalkoxylation of unbiased olefins. The methodology gives rapid access to biologically active 1,1-disubstituted tetrahydrofurans, including (-)-Boivinianin A.

Intramolecular Aryne-Furan Cycloadditions for the Synthesis of Anticancer Naphthalimides.

An intramolecular aryne Diels-Alder reaction with a furan moiety was applied to the synthesis of dihydrobenzo[ de]isochromenes as intermediates toward naphthalimides. After oxidation, this method offers an efficient approach for the synthesis of substituted naphthalimides, which showed potent cytotoxic activity against HT-29 human cancer cell line.

Synthesis of prostaglandin analogues, latanoprost and bimatoprost, using organocatalysis via a key bicyclic enal intermediate.

Two antiglaucoma drugs, bimatoprost and latanoprost, which are analogues of the prostaglandin, PGF2α, have been synthesized in just 7 and 8 steps, respectively. The syntheses employ an organocatalytic aldol reaction that converts succinaldehyde into a key bicyclic enal intermediate, which is primed for attachment of the required lower and upper side chains. By utilizing the crystalline lactone, the drug molecules were prepared in >99% ee.

Catalytic asymmetric synthesis of thiols.

The synthesis of enantiopure thiols is of significant interest for industrial and academic applications. However, direct asymmetric approaches to free thiols have previously been unknown. Here we describe a novel organocascade that is catalyzed by a confined chiral phosphoric acid and furnishes O-protected ß-hydroxythiols with excellent enantioselectivities. The method relies on an asymmetric thiocarboxylysis of meso-epoxides, followed by an intramolecular trans-esterification reaction. By varying the reaction conditions, the intermediate thioesters can also be obtained chemoselectively and enantioselectively.

Catalytic asymmetric Torgov cyclization: a concise total synthesis of (+)-estrone.

An asymmetric Torgov cyclization, catalyzed by a novel, highly Brønsted acidic dinitro-substituted disulfonimide, is described. The reaction delivers the Torgov diene and various analogues with excellent yields and enantioselectivity. This method was applied in a very short synthesis of (+)-estrone.

Organocatalytic asymmetric hydrolysis of epoxides.

The hydrolytic ring opening of epoxides is an important biosynthetic transformation and is also applied industrially. We report the first organocatalytic variant of this reaction, exploiting our recently discovered activation of carboxylic acids with chiral phosphoric acids via heterodimerization. The methodology mimics the enzymatic mechanism, which involves an enzyme-bound carboxylate nucleophile. A newly designed phosphoric acid catalyst displays high stereocontrol in the desymmetrization of meso-epoxides. The methodology shows wide generality with cyclic, acylic, aromatic, and aliphatic substrates. We also apply our method in the first highly enantioselective anti-dihydroxylation of simple olefins.

Synthetic strategy toward the C44-C65 fragment of mirabalin.

A convergent and flexible stereoselective synthesis of one isomer of the C44-C65 fragment of mirabalin is described. The key steps include organocatalytic aldolization, ruthenium-catalyzed asymmetric hydrogenation, amide formation, Marshall stereoselective allenylation, and the Nozaki-Hiyama-Kishi reaction.

Lyngbouilloside and related macrolides from marine cyanobacteria.

Lyngbouilloside and the related macrolides lyngbyaloside, lyngbyaloside B and lyngbyaloside C have attracted a lot of attention over the past decade due to their intriguing architecture, their natural scarcity and their potential biological activities. This review aims to showcase the various strategies that have been used to access these natural products.

Delayed occurrence of complete heart block after ethanol septal ablation for hypertrophic obstructive cardiomyopathy.

Ethanol septal ablation has emerged as a less invasive alternative to surgical myomectomy for treatment of hypertrophic obstructive cardiomyopathy (HOCM). The procedure has very low mortality, but complete heart block (CHB) is a common complication. Prior studies suggested existence of baseline characteristics, ECG features and procedural risk factors, which are highly predictor of CHB requiring permanent pacemaker after ethanol septal ablation. CHB is often preceded by postprocedure conduction abnormalities and generally develops within 48 h after ethanol ablation. We present a unique case of a patient with HOCM who developed a CHB on 8th day postprocedure without preceding conduction abnormalities or other classic risk factors.