H/D Exchange of Aromatic Sulfones via Base Promotion and Silver Catalysis.

Aromatic sulfones are the prevailing scaffolds in pharmaceutical and material sciences. However, compared to their widespread application, the selective deuterium labeling of these structures is restricted due to their electron-deficient properties. This study presents two comprehensive strategies for the deuteration of aromatic sulfones. The base-promoted deuteration uses DMSO-d6 as the deuterium source, resulting in a rapid H/D exchange within 2 h. Meanwhile, a silver-catalyzed protocol offers a much milder option by using economical D2O to furnish the labeled sulfones.

Pd-Catalyzed Regioselective Deuteration of Indole's C4-Position with Transient Directing Groups.

As a representative scaffold of alkaloids, indoles have been extensively subjected to deuteration, but the regioselective C4 labeling has not been achieved due to its low reactivity. In this work, a Pd-catalyzed deuterium labeling at the indole's C4 position has been developed under the strategy of transient directing, using D2O as a deuterium source. The substituent effect is found to be crucial in facilitating this H/D exchange process, where the reversing C-D bond formation favors an electron-enriched ligation contrary to its C-H halogenation counterpart.

Anticancer Activities of Novel Nicotinamide Phosphoribosyltransferase Inhibitors in Hematological Malignancies.

Targeting cancer cells that are highly dependent on the nicotinamide adenine dinucleotide (NAD+) metabolite is a promising therapeutic strategy. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme catalyzing NAD+ production. Despite the high efficacy of several developed NAMPT inhibitors (i.e., FK866 (APO866)) in preclinical studies, their clinical activity was proven to be limited. Here, we report the synthesis of new NAMPT Inhibitors, JJ08, FEI191 and FEI199, which exhibit a broad anticancer activity in vitro. Results show that these compounds are potent NAMPT inhibitors that deplete NAD+ and NADP(H) after 24 h of drug treatment, followed by an increase in reactive oxygen species (ROS) accumulation. The latter event leads to ATP loss and mitochondrial depolarization with induction of apoptosis and necrosis. Supplementation with exogenous NAD+ precursors or catalase (ROS scavenger) abrogates the cell death induced by the new compounds. Finally, in vivo administration of the new NAMPT inhibitors in a mouse xenograft model of human Burkitt lymphoma delays tumor growth and significantly prolongs mouse survival. The most promising results are collected with JJ08, which completely eradicates tumor growth. Collectively, our findings demonstrate the efficient anticancer activity of the new NAMPT inhibitor JJ08 and highlight a strong interest for further evaluation of this compound in hematological malignancies.

Asymmetric Synthesis of Chiral 1,4-Enynes through Organocatalytic Alkenylation of Propargyl Alcohols with Trialkenylboroxines.

A highly enantioselective synthesis of 1,4-enynes is described that proceeds through an organocatalytic reaction between propargyl alcohols and trialkenylboroxines. Our strategy relies on acid-mediated generation of the carbocationic intermediate from propargyl alcohols followed by enantioselective alkenylation with trialkenylboroxines. A range of chiral 1,4-enynes were obtained in moderate to good yields with high levels of enantioselectivity. Use of a highly acidic chiral N-triflyl phosphoramide catalyst, which has two distant Lewis basic oxygen atoms, was found to be crucial for both high reactivity and selectivity in the present reaction.

Synthesis of 1-Aminoindenes through Aza-Prins-Type Cyclization.

An acid-catalyzed aza-Prins-type endo cyclization of 2-alkenylbenzaldehydes with BocNH2 or aniline derivatives through in situ generation of iminium intermediates has been developed, and various 1-aminoindene derivatives were readily obtained. The first catalytic asymmetric variant of the present reaction has also been demonstrated.

Nickel-catalyzed regioselective hydrogen isotope exchange accelerated by 2-pyridones.

A nickel-catalyzed hydrogen isotope exchange has been developed with acetone-d6 as the deuterium source. The reaction showed an improved kinetic feature of H/D exchange under the assistance of 2-pyridones, efficiently affording regioselective labeled aryl and alkyl carboxamides.

Site-Selective Deuteration of α-Amino Esters with 2-Hydroxynicotinaldehyde as a Catalyst.

An efficient method has been developed for the synthesis of α-deuterated α-amino esters via hydrogen isotope exchange of α-amino esters in D2O with 2-hydroxynicotinaldehyde as a catalyst under mild conditions. This methodology exhibits a wide range of substrate scopes, remarkable functional group tolerance, and affording the desired products in good yields with excellent deuterium incorporation. Notably, the ortho-hydroxyl group and the pyridine ring of the catalyst play a crucial role in the catalytic activity, which not only stabilizes the carbon-anion intermediates but also enhances the acidity of the amino esters' α-C-H bond.

B(C6F5)3-Catalyzed Intramolecular Hydroalkoxylation Deuteration Reactions of Unactivated Alkynyl Alcohols.

Using D2O as a deuterium source, a method for the deuteration of intra- and extra-cyclic methylene has been developed for cyclic ethers with moderate yield and excellent deuterium incorporation. This transformation features superb functional group tolerance in a wide range of alkynols. Notably, the critical factor to achieve high deuterium incorporation is determined by the hydrogen isotope exchange reaction of an unstable oxonium ion. This novel methodology provides an efficient and concise synthetic route to a number of valuable deuterated cyclic ethers that are often difficult to prepare with other methods.

Asymmetric Michael addition of α-substituted isocyanoacetates with maleimides catalyzed by chiral tertiary amine thiourea.

A highly diastereoselective and enantioselective Michael addition of α-substituted isocyanoacetates with maleimides catalyzed by bifunctional tertiary amine thioureas has been developed. Various chiral succinimide derivatives bearing adjacent quaternary and tertiary stereocenters were prepared in excellent yields (up to 98%), diastereoselectivities (up to 99:1), and enantioselectivities (up to 98% ee). The synthetic utility of chiral succinimide derivatives is also demonstrated in the preparation of h5-HT(1d) receptor agonist motifs.

Direct asymmetric vinylogous Mannich reaction of 3,4-dihalofuran-2(5H)-one with aldimine catalyzed by quinine.

The direct asymmetric vinylogous Mannich reaction of 3,4-dihalofuran-2(5H)-one with aldimine catalyzed by quinine was first reported, and γ-butenolides have been obtained in excellent yield (up to 98%) and enantioselectivities (up to 95% ee). The synthetic applications of this protocol are demonstrated in the preparations of γ-substituted amino butyrolactones and vicinal amino alcohols.

Asymmetric hydroxyamination of oxindoles catalyzed by chiral bifunctional tertiary amine thiourea: construction of 3-amino-2-oxindoles with quaternary stereocenters.

Chiral bifunctional tertiary amine thiourea was applied to catalyze the asymmetric hydroxyamination of 3-subsituted oxindoles with nitrosobenzene to construct 3-amino-2-oxindoles with quaternary stereocenters in good yields (up to 91%) and enantioselectivities (up to 90% ee).

Regioselective Cycloaddition and Substitution Reaction of Tertiary Propargylic Alcohols and Heteroareneboronic Acids via Acid Catalysis.

We report an acid-catalyzed formal cycloaddition and dehydrative substitution reaction of tertiary propargylic alcohols and heteroareneboronic acids. The properties of the substituents on the alkynyl moiety determines the regioselectivity of the reaction, which could selectively construct fused heterocycles, tetrasubstituted allenes, or 1,3-dienes. This reaction proceeds efficiently with a wide array of substrate scope in up to 89% yield. A significant advantage of this protocol is the transition-metal-free and mild conditions needed.

CO2 -Promoted Direct Acylation of Amines and Phenols by the Activation of Inert Thioacid Salts.

Herein a carbon dioxide-promoted synthetic approach for the direct amidation between unactivated thioacid salts and amines under mild conditions was developed for a wide range of substrates. The method afforded amides in good to excellent yields under transition-metal-free and activation-reagent-free conditions, in sharp contrast to early methodologies on amide synthesis based on transition-metal catalysis. The method offered a greener and transition metal-free protocol applicable to pharmaceuticals preparations. Phenolic compounds were also found to be suitable acylation substrates with potassium thiosulfide KHS as the only byproduct. Moreover, this approach was applied to amide synthesis of valuable bio-active molecules such as moclobemide, melatonin, and a fungicide. Insights into the reaction mechanism involving carbon dioxide were provided through NMR spectroscopy and computational calculations. A plausible mechanism was proposed that involves weak interactions between carbon dioxide and potassium thioacetate in a dynamic equilibrium state formation of a six-membered ring.

Catalytic Cyanation of C-N Bonds with CO2/NH3.

Cyanation of benzylic C-N bonds is useful in the preparation of important α-aryl nitriles. The first general catalytic cyanation of α-(hetero)aryl amines, analogous to the Sandmeyer reaction of anilines, was developed using reductive cyanation with CO2/NH3. A broad array of α-aryl nitriles was obtained in high yields and regioselectivity by C-N cleavage of intermediates as ammonium salts. Good tolerance of functional groups such as ethers, CF3, F, Cl, esters, indoles, and benzothiophenes was achieved. Using 13CO2, a 13C-labeled tryptamine homologue (five steps, 31% yield) and Cysmethynil (six steps, 37% yield) were synthesized. Both electronic and steric effects of ligands influence the reactivity of alkyl nickel species with electrophilic silyl isocyanates and thus determine the reactivity and selectivity of the cyanation reaction. This work contributes to the understanding of the controllable activation of CO2/NH3 and provides the promising potential of the amine cyanation reaction in the synthesis of bio-relevant molecules.

Identification of new FK866 analogues with potent anticancer activity against pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases for which chemotherapy has not been very successful yet. FK866 ((E)-N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide) is a well-known NAMPT (nicotinamide phosphoribosyltransferase) inhibitor with anti-cancer activities, but it failed in phase II clinical trials. We found that FK866 shows anti-proliferative activity in three PDAC cell lines, as well as in Jurkat T-cell leukemia cells. More than 50 FK866 analogues were synthesized that introduce substituents on the phenyl ring of the piperidine benzamide group of FK866 and exchange its buta-1,4-diyl tether for 1-oxyprop-3-yl, (E)-but-2-en-1,4-diyl and 2- and 3-carbon tethers. The pyridin-3-yl moiety of FK866 was exchanged for chlorinated and fluorinated analogues and for pyrazin-2-yl and pyridazin-4-yl groups. Several compounds showed low nanomolar or sub-nanomolar cell growth inhibitory activity. Our best cell anti-proliferative compounds were the 2,4,6-trimethoxybenzamide analogue of FK866 ((E)-N-(4-(1-(2,4,6-trimethoxybenzoyl)piperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide) (9), the 2,6-dimethoxybenzamide (8) and 2-methoxybenzamide (4), which exhibited an IC50 of 0.16 nM, 0.004 nM and 0.08 nM toward PDAC cells, respectively.

Highly enantioselective aldol reaction of acetone with ß,γ-unsaturated α-keto esters promoted by simple chiral primary-tertiary diamine catalysts.

A series of primary-tertiary diamine catalysts were successfully applied to promote the enantioselective aldol reaction of acetone with ß,γ-unsaturated α-keto esters in excellent yields (up to 99%) and enantioselectivities (up to 96% ee).

Peri-implant keratinized gingiva augmentation using xenogeneic collagen matrix and platelet-rich fibrin: A case report.

BACKGROUND: Keratinized gingival insufficiency is a disease attributed to long-term tooth loss, can severely jeopardizes the long-term health of implants. A simple and effective augmentation surgery method should be urgently developed. CASE SUMMARY: A healthy female patient, 45-year-old, requested implant restoration of the her left mandibular first molar and second molar. Before considering a stage II, as suggested from the probing depth measurements, the widths of the mesial, medial, and distal buccal keratinized gingiva of second molar (tooth #37) were measured and found to be 0.5 mm, 0.5 mm, and 0 mm, respectively. This suggested that the gingiva was insufficient to resist damage from bacterial and mechanical stimulation. Accordingly, modified apically repositioned flap (ARF) surgery combined with xenogeneic collagen matrix (XCM) and platelet-rich fibrin (PRF) was employed to increase the width of gingival tissue. After 1 mo of healing, the widths of mesial, medial, and distal buccal keratinized gingiva reached 4 mm, 4 mm, and 3 mm, respectively, and the thickness of the augmented mucosa was 4.5 mm. Subsequently, through the second-stage operation, the patient obtained an ideal soft tissue shape around the implant. CONCLUSION: For cases with keratinized gingiva widths around implants less than 2mm，the soft tissue width and thickness could be increased by modified ARF surgery combined with XCM and PRF. Moreover, this surgery significantly alleviated patients' pain and ameliorated oral functional comfort.

Organocatalytic Formal (3 + 2) Cycloaddition toward Chiral Pyrrolo[1,2-a]indoles via Dynamic Kinetic Resolution of Allene Intermediates.

We report the chiral phosphoric acid catalyzed formal (3 + 2) cycloaddition of 3-substituted 1H-indoles and propargylic alcohols containing a functional directing group (p-NHAc or p-OH). This work represents a straightforward method to synthesize chiral pyrrolo[1,2-a]indole bearing a tetrasubstituted carbon stereocenter. The reaction proceeds smoothly with a wide array of substrate tolerance to deliver various chiral pyrrolo[1,2-a]indoles in up to 93% yield and 98% ee. The utility of this method is highlighted by the diverse transformations of the products into various indole derivatives.

In situ generation of N-Boc-protected alkenyl imines: controlling the E/Z geometry of alkenyl moieties in the Mukaiyama-Mannich reaction.

Readily available Boc-protected Z-alkenyl aminals could be used as Z-alkenyl and E-alkenyl imine precursors under acidic conditions. In the Mukaiyama-Mannich reaction of Z-alkenyl Boc-aminals, the E/Z geometry of the products was controlled by the catalyst used. The present method was also applied to asymmetric Mukaiyama-Mannich reactions.

Organocatalytic stereocontrolled synthesis of 3,3'-pyrrolidinyl spirooxindoles by [3+2] annulation of isocyanoesters with methyleneindolinones.

A stereoselective [3+2] cycloaddition of isocyanoesters to methyleneindolinones catalyzed by a quinine-based thiourea-tertiary amine has been successfully developed. Just by tuning the protecting groups on substrates, a variety of optically enriched 3,3'-pyrrolidinyl spirooxindole diastereomers could be obtained in excellent enantioselectivities (up to 99% ee).