Iron-Catalyzed Contrasteric Functionalization of Allenic C(sp2)-H Bonds: Synthesis of α-Aminoalkyl 1,1-Disubstituted Allenes.

An iron-catalyzed C-H functionalization of simple monosubstituted allenes is reported. An efficient protocol for this process was made possible by the use of a newly developed electron-rich and sterically hindered cationic cyclopentadienyliron dicarbonyl complex as the catalyst and N-sulfonyl hemiaminal ether reagents as precursors to iminium ion electrophiles. Under optimized conditions, the use of a mild, functional-group-tolerant base enabled the conversion of a range of monoalkyl allenes to their allenylic sulfonamido 1,1-disubstituted derivatives, a previously unreported and contrasteric regiochemical outcome for the C-H functionalization of electronically unbiased and directing-group-free allenes.

Photoredox/nickel dual-catalyzed regioselective alkylation of propargylic carbonates for trisubstituted allenes.

Herein, a highly regioselective alkylation of propargylic carbonates for trisubstituted allenes with alkyl 1,4-dihydropyridine derivatives (1,4-DHPs) is developed via a photoredox/nickel dual-catalyzed process, which represents the first direct approach to access alkylated allene products without alkyl organometallic reagents. This method features a broad substrate scope and mild conditions. A hypothetical mechanism with an alkyl radical and an allenyl Ni(III) species is proposed. Benzylation products were also obtained to be the complement building blocks for the potential synthesis of pharmaceuticals.

Substituted dienes prepared from betulinic acid - Synthesis, cytotoxicity, mechanism of action, and pharmacological parameters.

A set of new substituted dienes were synthesized from betulinic acid by its oxidation to 30-oxobetulinic acid followed by the Wittig reaction. Cytotoxicity of all compounds was tested in vitro in eight cancer cell lines and two noncancer fibroblasts. Almost all dienes were more cytotoxic than betulinic acid. Compounds 4.22, 4.30, 4.33, 4.39 had IC50 below 5 µmol/L; 4.22 and 4.39 were selected for studies of the mechanism of action. Cell cycle analysis revealed an increase in the number of apoptotic cells at 5 × IC50 concentration, where activation of irreversible changes leading to cell death can be expected. Both 4.22 and 4.39 led to the accumulation of cells in the G0/G1 phase with partial inhibition of DNA/RNA synthesis at 1 × IC50 and almost complete inhibition at 5 × IC50. Interestingly, compound 4.39 at 5 × IC50 caused the accumulation of cells in the S phase. Higher concentrations of tested drugs probably inhibit more off-targets than lower concentrations. Mechanisms disrupting cellular metabolism can induce the accumulation of cells in the S phase. Both compounds 4.22 and 4.39 trigger selective apoptosis in cancer cells via intrinsic pathway, which we have demonstrated by changes in the expression of the crucial apoptosis-related protein. Pharmacological parameters of derivative 4.22 were superior to 4.39, therefore 4.22 was the finally selected candidate for the development of anticancer drug.

Novel penta-1,4-diene-3-one derivatives containing quinazoline and oxime ether fragments: Design, synthesis and bioactivity.

A series of novel penta-1,4-diene-3-one derivatives containing quinazoline and oxime ether moieties were designed and synthesized. Their anticancer activities were evaluated by MTT assay, the results showed that most compounds exhibited extremely inhibitory effects against hepatoma SMMC-7721 cells. In particular, compounds Q2 and Q8 displayed the more potent inhibitory activity with IC50 values of 0.64 and 0.63 µM, which were better than that of gemcitabine (1.40 µM). Further mechanism studies indicated that compounds Q2, Q8, Q13 and Q19 could control the migration of SMMC-7721 cells effectively, and inhibit the proliferation of cancer cells by inhibiting the DNA replication. Western-blot results showed that compounds Q2 and Q8 induced irreversible apoptosis of SMMC-7721 cells by regulating the expression level of apoptose-related proteins. Those studies demonstrated that the penta-1,4-diene-3-one derivatives containing quinazoline and oxime ether fragments merited further research as potential anticancer agents.

A Review on Biological Properties and Synthetic Methodologies of Diarylpentadienones.

Medicinal chemists have continuously shown interest in new curcuminoid derivatives, diarylpentadienones, owing to their enhanced stability feature and easy preparation using a one-pot synthesis. Thus far, methods such as Claisen-Schmidt condensation and Julia- Kocienski olefination have been utilised for the synthesis of these compounds. Diarylpentadienones possess a high potential as a chemical source for designing and developing new and effective drugs for the treatment of diseases, including inflammation, cancer, and malaria. In brief, this review article focuses on the broad pharmacological applications and the summary of the structure-activity relationship of molecules, which can be employed to further explore the structure of diarylpentadienone. The current methodological developments towards the synthesis of diarylpentadienones are also discussed.

Development of diarylpentadienone analogues as alpha-glucosidase inhibitor: Synthesis, in vitro biological and in vivo toxicity evaluations, and molecular docking analysis.

A series of aminated- (1-9) and sulfonamide-containing diarylpentadienones (10-18) were synthesized, structurally characterized, and evaluated for their in vitro anti-diabetic potential on α-glucosidase and DPP-4 enzymes. It was found that all the new molecules were non-associated PAINS compounds. The sulfonamide-containing series (compounds 10-18) selectively inhibited α-glucosidase over DPP-4, in which compound 18 demonstrated the highest activity with an IC50 value of 5.69 ± 0.5 µM through a competitive inhibition mechanism. Structure-activity relationship (SAR) studies concluded that the introduction of the trifluoromethylbenzene sulfonamide moiety was essential for the suppression of α-glucosidase. The most active compound 18, was then further tested for in vivo toxicities using the zebrafish animal model, with no toxic effects detected in the normal embryonic development, blood vessel formation, and apoptosis of zebrafish. Docking simulation studies were also carried out to better understand the binding interactions of compound 18 towards the homology modeled α -glucosidase and the human lysosomal α -glucosidase enzymes. The overall results suggest that the new sulfonamide-containing diarylpentadienones, compound 18, could be a promising candidate in the search for a new α-glucosidase inhibitor, and can serve as a basis for further studies involving hit-to-lead optimization, in vivo efficacy and safety assessment in an animal model and mechanism of action for the treatment of T2DM patients.

Design, Synthesis, Conjugation, and Reactivity of Novel trans,trans-1,5-Cyclooctadiene-Derived Bioorthogonal Linkers.

The tetrazine/trans-cyclooctene (TCO) inverse electron-demand Diels-Alder (IEDDA) reaction is the fastest bioorthogonal "click" ligation process reported to date. In this context, TCO reagents have found widespread applications; however, their availability and structural diversity is still somewhat limited due to challenges connected with their synthesis and structural modification. To address this issue, we developed a novel strategy for the conjugation of TCO derivatives to a biomolecule, which allows for the creation of greater structural diversity from a single precursor molecule, i.e., trans,trans-1,5-cyclooctadiene [(E,E)-COD] 1, whose preparation requires standard laboratory equipment and readily available reagents. This two-step strategy relies on the use of new bifunctional TCO linkers (5a-11a) for IEDDA reactions, which can be synthesized via 1,3-dipolar cycloaddition of (E,E)-COD 1 with different azido spacers (5-11) carrying an electrophilic function (NHS-ester, N-succinimidyl carbonate, p-nitrophenyl-carbonate, maleimide) in the ω-position. Following bioconjugation of these electrophilic linkers to the nucleophilic residue (cysteine or lysine) of a protein (step 1), the resulting TCO-decorated constructs can be subjected to a IEDDA reaction with tetrazines functionalized with fluorescent or near-infrared (NIR) tags (step 2). We successfully used this strategy to label bovine serum albumin with the TCO linker 8a and subsequently reacted it in a cell lysate with the fluorescein-isothiocyanate (FITC)-derived tetrazine 12. The same strategy was then used to label the bacterial wall of Gram-positive Staphylococcus aureus, showing the potential of these linkers for live-cell imaging. Finally, we determined the impact of structural differences of the linkers upon the stability of the bioorthogonal constructs. The compounds for stability studies were prepared by conjugation of TCO linkers 6a, 8a, and 10a to mAbs, such as Rituximab and Obinutuzumab, and subsequent labeling with a reactive Cy3-functionalized tetrazine.

Discovery of 1,4-pentadien-3-one derivatives containing quinoxaline scaffolds as potential apoptosis inducers.

Aim: To synthesize novel antiproliferative agents. Results & methodology: A variety of 1,4-pentadien-3-one derivatives bearing quinoxaline scaffolds was designed and synthesized and their antiproliferative activities were evaluated. Notably, compounds N3 and N4 exhibited markedly greater antiproliferative activities against SMMC-7721 cells in vitro compared with the well-known antitumor drug gemcitabine. The mechanistic investigation showed that compounds N3 and N4 induced SMMC-7721 cell apoptosis by regulating the expression levels of apoptosis-related proteins. In addition, the molecular docking model further revealed that compound N3 could be a potential peroxisome proliferator-activated receptor inhibitor. Conclusion: These compounds might serve as bioactive fragments and lead compounds for developing more potent apoptosis inducers.

Diastereo- and Enantioselective 1,4-Difunctionalization of Borylenynes by Catalytic Conjunctive Cross-Coupling.

Enantioselective conjunctive cross-coupling of enyne-derived boronate complexes occurs with 1,4 addition of the electrophile and migrating group across the π system. This reaction pathway furnishes α-boryl allenes as the reaction product. In the presence of a chiral catalyst, both the central and axial chirality of the product can be controlled during product formation.

Synthesis and biological evaluation of myricetin-pentadienone hybrids as potential anti-inflammatory agents in vitro and in vivo.

Some important pro-inflammatory cytokines such as interleukin-6, tumor necrosis factor-α and nitric oxide are thought to play key roles in the destruction of cartilage and bone tissue in joints affected by rheumatoid arthritis. In the present study, a series of new myricetin-pentadienone hybrids were designed and synthesized. Majority of them effectively inhibited the expressions liposaccharide-induced secretion of IL-6, TNF-α and NO in RAW264.7. The most prominent compound 5o could significantly decrease production of above inflammatory factors with IC50 values of 5.22 µM, 8.22 µM and 9.31 µM, respectively. Preliminary mechanism studies indicated that it could inhibit the expression of thioredoxin reductase, resulting in inhibiting of cell signaling pathway nuclear factor (N-κB) and mitogen-activated protein kinases. Significantly, compound 5o was found to effectively inhibit Freund's complete adjuvant induced rat adjuvant arthritis in vivo.

Copper Hydride Catalyzed Enantioselective Synthesis of Axially Chiral 1,3-Disubstituted Allenes.

The general enantioselective synthesis of axially chiral disubstituted allenes from prochiral starting materials remains a long-standing challenge in organic synthesis. Here, we report an efficient enantio- and chemoselective copper hydride catalyzed semireduction of conjugated enynes to furnish 1,3-disubstituted allenes using water as the proton source. This protocol is sufficiently mild to accommodate an assortment of functional groups including keto, ester, amino, halo, and hydroxyl groups. Additionally, applications of this method for the selective synthesis of monodeuterated allenes and chiral 2,5-dihydropyrroles are described.

Preparation of Chiral Allenes through Pd-Catalyzed Intermolecular Hydroamination of Conjugated Enynes: Enantioselective Synthesis Enabled by Catalyst Design.

In this study, we establish that conjugated enynes undergo selective 1,4-hydroamination under Pd catalysis to deliver chiral allenes with pendant allylic amines. Several primary and secondary aliphatic and aryl-substituted amines couple with a wide range of mono- and disubstituted enynes in a nonenantioselective reaction where DPEphos serves as the ligand for Pd. Benzophenone imine acts as an ammonia surrogate to afford primary amines in a two-step/one-pot process. Examination of chiral catalysts revealed a high degree of reversibility in the C-N bond formation that negatively impacted enantioselectivity. Consequently, an electron-poor ferrocenyl-PHOX ligand was developed to enable efficient and enantioselective enyne hydroamination.

Regio- and Diastereoselective Iron-Catalyzed [4+4]-Cycloaddition of 1,3-Dienes.

A family of single-component iron precatalysts for the [4+4]-cyclodimerization and intermolecular cross-[4+4]-cycloaddition of monosubstituted 1,3-dienes is described. Cyclooctadiene products were obtained with high regioselectivity, and catalyst-controlled access to either cis- or trans-diastereomers was achieved using 4-substituted diene substrates. Reactions conducted either with single-component precatalysts or with iron dihalide complexes activated in situ proved compatible with common organic functional groups and were applied on multigram scale (up to >100 g). Catalytically relevant, S = 1 iron complexes bearing 2-(imino)pyridine ligands, (RPI)FeL2 (RPI = [2-(2,6-R2-C6H3-N═CMe)-C5H4N] where R = iPr or Me, L2 = bis-olefin), were characterized by single-crystal X-ray diffraction, Mößbauer spectroscopy, magnetic measurements, and DFT calculations. The structural and spectroscopic parameters are consistent with an electronic structure description comprised of a high spin iron(I) center ( SFe = 3/2) engaged in antiferromagnetically coupling with a ligand radical anion ( SPI = -1/2). Mechanistic studies conducted with these single-component precatalysts, including kinetic analyses, 12C/13C isotope effect measurements, and in situ Mößbauer spectroscopy, support a mechanism involving oxidative cyclization of two dienes that determines regio- and diastereoselectivity. Topographic steric maps derived from crystallographic data provided insights into the basis for the catalyst control through stereoselective oxidative cyclization and subsequent, stereospecific allyl-isomerization and C-C bond-forming reductive elimination.

Nickel-Catalyzed Hydrocyanation of Allenes and Its Application.

Cyano (CN) groups are equivalent to carbonyl as well as amino- and hydroxymethyl groups. Therefore, their catalytic introduction under metal catalysis is an important issue in synthetic organic chemistry. Ni-catalyzed hydrocyanation is one of the most well-investigated, powerful tools for installing a CN group. However, it is still difficult to control chemo- and regioselectivity. In this review, the author uses allenes to enable regio-, stereo-, and face-selective transformations to natural product synthesis and axial chirality transfer.

Polymerization-Induced Self-Assembly (PISA) of 1,5-Cyclooctadiene Using Ring Opening Metathesis Polymerization.

Ring opening metathesis polymerization (ROMP) is a technique that allows the synthesis of well-defined linear polyolefins. Polymerization-induced self-assembly (PISA) involves the synthesis of amphiphilic block copolymers: a hydrophilic block is first polymerized homogeneously in solution (usually water) followed by polymerization of a second hydrophobic block, resulting in a diblock copolymer that self-assembles. In this communication, preliminary results of the development of PISA for the synthesis of amphiphilic block linear polyolefins via ROMP using a water-soluble PEGylated ruthenium alkylidene catalyst are presented. In the first step, a water-soluble modified-norbornene monomer was polymerized in water, then 1,5-cyclooctadiene was added to the system to produce amphiphilic block polyolefins. By varying the concentrations of hydrophilic versus hydrophobic monomer, stable latexes with final particles of ≈200 nm diameter were prepared.

Cationic Alkynyl Heck Reaction toward Substituted Allenes Using BobCat: A New Hybrid Pd(0)-Catalyst Incorporating a Water-Soluble dba Ligand.

The cationic alkynyl Heck reaction between aryl triflates and alkynes to give substituted allenes is described. Key to the success of this method was the discovery and development of a new hybrid Pd(0)-catalyst, BobCat, that incorporates a water-soluble dba-ligand and biaryl phosphine ligand to provide substituted allenes in good yields under mild reaction conditions.

SN2″-Selective and Enantioselective Substitution with Unsaturated Organoboron Compounds and Catalyzed by a Sulfonate-Containing NHC-Cu Complex.

The first broadly applicable strategy for SN2″-selective and enantioselective catalytic substitution is disclosed. Transformations are promoted by 5.0 mol% of a sulfonate-containing NHC-Cu complex (NHC = N-heterocyclic carbene), and are carried out in the presence of commercially available allenyl-B(pin) (pin = pinacolato) or a readily accessible silyl-protected propargyl-B(pin). Acyclic, or aryl-, heteroaryl-, and alkyl-substituted penta-2,4-dienyl phosphates, as well as those bearing either only 1,2-disubstituted olefins or a 1,2-disubstituted and a trisubstituted alkene were found to be suitable starting materials. Cyclic dienyl phosphates may also serve as substrates. The products containing, in addition to a 1,3-dienyl group, a readily functionalizable propargyl moiety (from reactions with allenyl-B(pin)) were obtained in 51-82% yield, 84-97% SN2″ selectivity, 89:11-97:3 E: Z ratio, and 86:14-98:2 enantiomeric ratio (er). Reactions with a silyl-protected propargyl-B(pin) compound led to the formation of the corresponding silyl-allenyl products in 53-89% yield, 69-96% SN2″ selectivity, 98:2 to >98:2 E: Z ratio, and 94:6-98:2 er. Insight regarding several of the unique mechanistic attributes of the catalytic process was obtained on the basis of kinetic isotope effect measurements and DFT studies. These investigations indicate that cationic π-allyl-Cu complexes are likely intermediates, clarifying the role of the s-cis and s-trans conformers of the intermediate organocopper species and their impact on E: Z selectivity and enantioselectivity. The utility of the approach is demonstrated by chemoselective functionalization of various product types, through which the propargyl, allenyl, or 1,3-dienyl sites within the products have been converted catalytically and chemoselectively to several useful derivatives.

Highly Regio- and Stereoselective Catalytic Synthesis of Conjugated Dienes and Polyenes.

Conjugated dienes and polyenes are typically synthesized by sequential introduction of C═C bonds. Here, we report a practical and scalable, catalytic dienylation that is highly regio- and stereoselective for both C═C bonds. The reaction is enabled by a stereoselective palladium-catalyzed cross-coupling that is preceded by a regioselective base-induced ring opening of readily available sulfolenes. The dienylation reaction is particularly useful for the synthesis of synthetically challenging dienes containing cis double bonds. We also show that the reaction can serve as a synthetic platform for the construction of conjugated polyenes.

Acid-Promoted One-Pot Synthesis of Substituted Furan and 6-Methylpyrazin-2(1 H)-one Derivatives via Allene Intermediate Formed in Situ.

Under the acidic conditions, substituted furans were constructed from γ-alkynyl ketones through corresponding allene intermediates in one-pot. The methodology was also tailored to a series of the Ugi reaction products for the synthesis of 6-methylpyrazin-2(1 H)-one derivatives. The current method offered significant advantages for the combinatorial applications of these chemical scaffolds.

Multimetallic Ni- and Pd-Catalyzed Cross-Electrophile Coupling To Form Highly Substituted 1,3-Dienes.

The synthesis of highly substituted 1,3-dienes from the coupling of vinyl bromides with vinyl triflates is reported for the first time. The coupling is catalyzed by a combination of (5,5'-bis(trifluoromethyl)-2,2'-bipyridine)NiBr2 and (1,3-bis(diphenylphosphino)propane)PdCl2 in the presence of a zinc reductant. This method affords tetra- and penta-substituted 1,3-dienes that would otherwise be difficult to access and tolerates electron-rich and -poor substituents, heterocycles, an aryl bromide, and a pinacol boronate ester. Mechanistically, the reaction appears to proceed by an unusual zinc-mediated transfer of a vinyl group between the nickel and palladium centers.