Asymmetric synthesis of unnatural α-amino acids through photoredox-mediated C-O bond activation of aliphatic alcohols.

Unnatural α-amino acids constitute a fundamental class of biologically relevant compounds. However, despite the interest in these motifs, synthetic strategies have traditionally employed polar retrosynthetic disconnections. These methods typically entail the use of stoichiometric amounts of toxic and highly sensitive reagents, thereby limiting the substrate scope and practicality for scale up. In this work, an efficient protocol for the asymmetric synthesis of unnatural α-amino acids is realized through photoredox-mediated C-O bond activation in oxalate esters of aliphatic alcohols as radical precursors. The developed system uses a chiral glyoxylate-derived N-sulfinyl imine as the radical acceptor and allows facile access to a range of functionalized unnatural α-amino acids through an atom-economical redox-neutral process with CO2 as the only stoichiometric byproduct.

Ultralight aerogels via supramolecular polymerization of a new chiral perfluoropyridine-based sulfonimidamide organogelator.

Chiral and enantiopure perfluorinated sulfonimidamides act as low-molecular weight gelators at low critical gelation concentration (<1 mg mL-1) via supramolecular polymerization in nonpolar organic solvents and more heterogenic mixtures, such as biodiesel and oil. Freeze-drying of the organogel leads to ultralight aerogel with extremely low density (1 mg mL-1). The gelation is driven by hydrogen bonding resulting in a helical molecular ordering and unique fibre assemblies as confirmed by scanning electron microscopy, CD spectroscopy, and computational modeling of the supramolecular structure.

Highly congested spiro-compounds via photoredox-mediated dearomative annulation cascade.

Photo-mediated radical dearomatization involving 5-exo-trig cyclizations has proven to be an important route to accessing spirocyclic compounds, whereas 6-exo-trig spirocyclization has been much less explored. In this work, a dearomative annulation cascade is realized through photoredox-mediated C-O bond activation of aromatic carboxylic acids to produce two kinds of spirocyclic frameworks. Mechanistically, the acyl radical is formed through oxidation of triphenylphosphine and subsequent C-O bond cleavage, followed by a 6-exo-trig cyclization/SET/protonation sequence to generate the spiro-chromanone products in an intramolecular manner. Furthermore, the protocol was extended to more challenging intermolecular tandem sequences consisting of C-O bond cleavage, radical addition to an alkene substrate, and 5-exo-trig cyclization to yield complex spirocyclic lactams.

Accessing Perfluoroaryl Sulfonimidamides and Sulfoximines via Photogenerated Perfluoroaryl Nitrenes: Synthesis and Application as a Chiral Auxiliary.

Sulfonimidamides (SIAs) and sulfoximines (SOIs) have attracted attention due to their potential in agriculture and in medicinal chemistry as bioisosteres of biologically active compounds, and new synthetic methods are needed to access and explore these compounds. Herein, we present a light-promoted generation of perfluorinated aromatic nitrenes, from perfluorinated azides, that subsequently are allowed to react with sulfinamides and sulfoxides, generating achiral and chiral SIAs and SOIs. One of the enantiopure SIAs was evaluated as a novel chiral auxiliary in Grignard additions to the imines yielding the product in up to 96:4 diastereomeric ratio.

Stereoselective synthesis of unnatural α-amino acid derivatives through photoredox catalysis.

A protocol for stereoselective C-radical addition to a chiral glyoxylate-derived N-sulfinyl imine was developed through visible light-promoted photoredox catalysis, providing a convenient method for the synthesis of unnatural α-amino acids. The developed protocol allows the use of ubiquitous carboxylic acids as radical precursors without prior derivatization. The protocol utilizes near-stoichiometric amounts of the imine and the acid radical precursor in combination with a catalytic amount of an organic acridinium-based photocatalyst. Alternative mechanisms for the developed transformation are discussed and corroborated by experimental and computational studies.

Asymmetric Synthesis of Adjacent Tri- and Tetrasubstituted Carbon Stereocenters: Organocatalytic Aldol Reaction of an Hydantoin Surrogate with Azaarene 2-Carbaldehydes.

A bifunctional amine/squaramide catalyst promoted direct aldol addition of an hydantoin surrogate to pyridine 2-carbaldehyde N-oxides to afford adducts bearing two vicinal tertiary/quaternary carbons in high diastereo- and enantioselectivity (d.r. up to >20:1; ee up to 98 %) is reported. Acid hydrolysis of adducts followed by reduction of the N-oxide group yields enantiopure carbinol-tethered quaternary hydantoin-azaarene conjugates with densely functionalized skeletons. DFT studies of the potential energy surface (B3LYP/6-31+G(d)+CPCM (dichloromethane)) of the reaction correlate the activity of different catalysts and support an intramolecular hydrogen-bond-assisted activation of the squaramide moiety in the transition state of the catalytic reaction.

Catalytic Reductions and Tandem Reactions of Nitro Compounds Using in Situ Prepared Nickel Boride Catalyst in Nanocellulose Solution.

A mild and efficient method for the in situ reduction of a wide range of nitroarenes and aliphatic nitrocompounds to amines in excellent yields using nickel chloride/sodium borohydride in a solution of TEMPO-oxidized nanocellulose in water (0.01 wt %) is described. The nanocellulose has a stabilizing effect on the catalyst, which increases the turnover number and enables low loading of nickel catalyst (0.1-0.25 mol % NiCl2). In addition, two tandem protocols were developed in which the in situ formed amines were either Boc-protected to carbamates or further reacted with an epoxide to yield ß-amino alcohols in excellent yields.

A mechanistic investigation of the kinetic resolution of secondary aromatic alcohols using a ferrocene-based planar chiral 4-(dimethylamino)pyridine catalyst.

A detailed computational and kinetic analysis of the acetylation of 1-phenylethanol with acetic anhydride catalyzed by planar chiral 4-(dimethylamino)pyridine (DMAP) catalyst (-)-1 is presented. The study includes a computational investigation of the potential-energy surface including the acylation and stereoselective transition states at the DFT level of theory. Experimentally, the kinetic study shows that the reaction proceeds in a first-order manner in catalyst, whereas both substrates, acetic anhydride and 1-phenylethanol, show fractional order, which is in accordance with steady-state conditions. The fractional order depends on an equilibrium between the free catalyst and the acetylated catalyst.

Selective inhibition of RET mediated cell proliferation in vitro by the kinase inhibitor SPP86.

BACKGROUND: The RET tyrosine kinase receptor has emerged as a target in thyroid and endocrine resistant breast cancer. We previously reported the synthesis of kinase inhibitors with potent activity against RET. Herein, we have further investigated the effect of the lead compound SPP86 on RET mediated signaling and proliferation. Based on these observations, we hypothesized that SPP86 may be useful for studying the cellular activity of RET. METHODS: We compared the effects of SPP86 on RET-induced signaling and proliferation in thyroid cancer cell lines expressing RET-PTC1 (TPC1), or the activating mutations BRAFV600E (8505C) and RASG13R (C643). The effect of SPP86 on RET- induced phosphatidylinositide 3-kinases (PI3K)/Akt and MAPK pathway signaling and cell proliferation in MCF7 breast cancer cells was also investigated. RESULTS: SPP86 inhibited MAPK signaling and proliferation in RET/PTC1 expressing TPC1 but not 8505C or C643 cells. In TPC1 cells, the inhibition of RET phosphorylation required co-exposure to SPP86 and the focal adhesion kinase (FAK) inhibitor PF573228. In MCF7 cells, SPP86 inhibited RET- induced phosphatidylinositide 3-kinases (PI3K)/Akt and MAPK signaling and estrogen receptorα (ERα) phosphorylation, and inhibited proliferation to a similar degree as tamoxifen. Interestingly, SPP86 and PF573228 inhibited RET/PTC1 and GDNF- RET induced activation of Akt and MAPK signaling to a similar degree. CONCLUSION: SPP86 selectively inhibits RET downstream signaling in RET/PTC1 but not BRAFV600E or RASG13R expressing cells, indicating that downstream kinases were not affected. SPP86 also inhibited RET signaling in MCF7 breast cancer cells. Additionally, RET- FAK crosstalk may play a key role in facilitating PTC1/RET and GDNF- RET induced activation of Akt and MAPK signaling in TPC1 and MCF7 cells.

Access to optically pure ß-hydroxy esters via non-enzymatic kinetic resolution by a planar-chiral DMAP catalyst.

The development of new approaches to obtain optically pure ß-hydroxy esters is an important area in synthetic organic chemistry since they are precursors of other high value compounds. Herein, the kinetic resolution of racemic ß-hydroxy esters using a planar-chiral DMAP derivative catalyst is presented. Following this procedure, a range of aromatic ß-hydroxy esters was obtained in excellent selectivities (up to s = 107) and high enantiomeric excess (up to 99% ee). Furthermore, the utility of the present method was demonstrated in the synthesis of (S)-3-hydroxy-N-methyl-3-phenylpropanamide, a key intermediate for bioactive molecules such as fluoxetine, tomoxetine or nisoxetine, in its enantiomerically pure form.

Azastilbenes: a cut-off to p38 MAPK inhibitors.

Inhibitors with vicinal 4-fluorophenyl/4-pyridine rings on a five- or six-membered heterocyclic ring are known to inhibit the p38 mitogen-activated protein kinase (MAPK), which is a potential target for rheumatoid arthritis and several different types of cancer. Several substituted azastilbene-based compounds with vicinal 4-fluorophenyl/4-pyridine rings were designed using computational docking, synthesized, and evaluated in a cell-free radiometric p38α assay. The biochemical evaluation shows that the best inhibition (down to 110 nM) is achieved for azastilbene-based compounds having an isopropylamine substituent in the 2-position of the pyridine ring. The inhibition of p38 signaling in human breast cancer cells was observed for two of the compounds.

Multi-faceted reactivity of alkyltellurophenols towards peroxyl radicals: catalytic antioxidant versus thiol-depletion effect.

Hydroxyaryl alkyl tellurides are effective antioxidants both in organic solution and aqueous biphasic systems. They react by an unconventional mechanism with ROO(·) radicals with rate constants as high as 10(7) M(-1) s(-1) at 303 K, outperforming common phenols. The reactions proceed by oxygen atom transfer to tellurium followed by hydrogen atom transfer to the resulting RO(·) radical from the phenolic OH. The reaction rates do not reflect the electronic properties of the ring substituents and, because the reactions occur in a solvent cage, quenching is more efficient when the OH and TeR groups have an ortho arrangement. In the presence of thiols, hydroxyaryl alkyl tellurides act as catalytic antioxidants towards both hydroperoxides (mimicking the glutathione peroxidases) and peroxyl radicals. The high efficiency of the quenching of the peroxyl radicals and hydroperoxides could be advantageous under normal cellular conditions, but pro-oxidative (thiol depletion) when thiol concentrations are low.

Non-enzymatic dynamic kinetic resolution of secondary aryl alcohols: planar chiral ferrocene and ruthenium catalysts in cooperation.

"Ruth" helps iron! A novel method for the non-enzymatic dynamic kinetic resolution (DKR) of secondary aryl alcohols by the use of the planar chiral ferrocene derivative (+)-1 in combination with the ruthenium racemization catalyst 2 yields acetylated alcohols in high enantioselectivity and yield. This development opens opportunities for new developments in the field of non-enzymatic dynamic kinetic resolution.

Superacid-promoted ionization of alkanes without carbonium ion formation: a density functional theory study.

The carbonium ion has been suggested to be the intermediate in superacid-promoted reactions (SbF(5)-HF) such as hydrogen-deuterium exchange and in the electrophilic C-H cleavage into hydrogen and the carbenium ion. In this study, the superacid-promoted C-H cleavage into hydrogen and the carbenium ion was studied using density functional theory (B3LYP and M062X) and ab initio methods (MP2 and CCSD). The calculations suggest that the superacid-promoted C-H cleavage proceeds via a concerted transition state leading to hydrogen (H(2)) and the carbenium ion without the formation of the elusive carbonium ion. The reactivity for the superacid-promoted C-H cleavage decreases upon going from isobutane (tertiary) > propane (secondary) > isobutane (primary) > propane (primary) > ethane >> methane.

Preparation of 3-substituted-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amines as RET kinase inhibitors.

A series of 3-substituted-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amines have been designed, synthesized, and evaluated as RET protein kinase inhibitors. On the basis of docking results, a small library of pyrazolopyrimidine compounds with an extended hydrophobic side arm was synthesized. The most promising of the compounds (7a) displayed efficient inhibition in vitro and good selectivity when tested on a panel of kinases. Furthermore, 7a inhibited GDNF-induced RET phosphorylation of ERK1/2 in MCF-7 breast cancer cells at concentrations as low as 100 nM.

Design, synthesis, and biological evaluation of chromone-based p38 MAP kinase inhibitors.

3-(4-Fluorophenyl)-2-(4-pyridyl)chromone derivatives were synthesized and evaluated as p38 MAP kinase inhibitors. Introduction of an amino group in the 2-position of the pyridyl moiety gave p38α inhibitors with IC(50) in the low nanomolar range (e.g., IC(50) = 17 nm). The inhibitors showed excellent selectivity profiles when tested on a panel of 62 kinases, as well as efficient inhibition of p38 signaling in human breast cancer cells.

Design, synthesis, and characterization of a highly effective Hog1 inhibitor: a powerful tool for analyzing MAP kinase signaling in yeast.

The Saccharomyces cerevisiae High-Osmolarity Glycerol (HOG) pathway is a conserved mitogen-activated protein kinase (MAPK) signal transduction system that often serves as a model to analyze systems level properties of MAPK signaling. Hog1, the MAPK of the HOG-pathway, can be activated by various environmental cues and it controls transcription, translation, transport, and cell cycle adaptations in response to stress conditions. A powerful means to study signaling in living cells is to use kinase inhibitors; however, no inhibitor targeting wild-type Hog1 exists to date. Herein, we describe the design, synthesis, and biological application of small molecule inhibitors that are cell-permeable, fast-acting, and highly efficient against wild-type Hog1. These compounds are potent inhibitors of Hog1 kinase activity both in vitro and in vivo. Next, we use these novel inhibitors to pinpoint the time of Hog1 action during recovery from G(1) checkpoint arrest, providing further evidence for a specific role of Hog1 in regulating cell cycle resumption during arsenite stress. Hence, we describe a novel tool for chemical genetic analysis of MAPK signaling and provide novel insights into Hog1 action.

Characterization of photophysical and base-mimicking properties of a novel fluorescent adenine analogue in DNA.

To increase the diversity of fluorescent base analogues with improved properties, we here present the straightforward click-chemistry-based synthesis of a novel fluorescent adenine-analogue triazole adenine (A(T)) and its photophysical characterization inside DNA. A(T) shows promising properties compared to the widely used adenine analogue 2-aminopurine. Quantum yields reach >20% and >5% in single- and double-stranded DNA, respectively, and show dependence on neighbouring bases. Moreover, A(T) shows only a minor destabilization of DNA duplexes, comparable to 2-aminopurine, and circular dichroism investigations suggest that A(T) only causes minimal structural perturbations to normal B-DNA. Furthermore, we find that A(T) shows favourable base-pairing properties with thymine and more surprisingly also with normal adenine. In conclusion, A(T) shows strong potential as a new fluorescent adenine analogue for monitoring changes within its microenvironment in DNA.

Synthesis of chiral 1,4-disubstituted-1,2,3-triazole derivatives from amino acids.

A versatile method for the synthesis of chiral 1,4-disubstituted-1,2,3-triazole derivatives starting from easily accessible naturally occurring D-or L-amino acids as chiral synthons is described. The amino acids were converted into azido alcohols, followed by copper catalyzed [3+2] cycloaddition reactions between the azido alcohols and methyl propiolate and subsequent ester aminolysis with primary and secondary amines furnished the target compounds, which were obtained in excellent yields with no racemization. Docking of selected target compounds shows that the chiral 1,4-disubstituted-1,2,3-triazoles derivatives has the potential of mimicking the binding mode of known purine analogues.