Thalidomide and its metabolite 5-hydroxythalidomide induce teratogenicity via the cereblon neosubstrate PLZF.

Thalidomide causes teratogenic effects by inducing protein degradation via cereblon (CRBN)-containing ubiquitin ligase and modification of its substrate specificity. Human P450 cytochromes convert thalidomide into two monohydroxylated metabolites that are considered to contribute to thalidomide effects, through mechanisms that remain unclear. Here, we report that promyelocytic leukaemia zinc finger (PLZF)/ZBTB16 is a CRBN target protein whose degradation is involved in thalidomide- and 5-hydroxythalidomide-induced teratogenicity. Using a human transcription factor protein array produced in a wheat cell-free protein synthesis system, PLZF was identified as a thalidomide-dependent CRBN substrate. PLZF is degraded by the ubiquitin ligase CRL4CRBN in complex with thalidomide, its derivatives or 5-hydroxythalidomide in a manner dependent on the conserved first and third zinc finger domains of PLZF. Surprisingly, thalidomide and 5-hydroxythalidomide confer distinctly different substrate specificities to mouse and chicken CRBN, and both compounds cause teratogenic phenotypes in chicken embryos. Consistently, knockdown of Plzf induces short bone formation in chicken limbs. Most importantly, degradation of PLZF protein, but not of the known thalidomide-dependent CRBN substrate SALL4, was induced by thalidomide or 5-hydroxythalidomide treatment in chicken embryos. Furthermore, PLZF overexpression partially rescued the thalidomide-induced phenotypes. Our findings implicate PLZF as an important thalidomide-induced CRBN neosubstrate involved in thalidomide teratogenicity.

Synthesis of Both Enantiomers of Nine-Membered CF3 -Substituted Heterocycles Using a Single Chiral Ligand: Palladium-Catalyzed Decarboxylative Ring Expansion with Kinetic Resolution.

The two enantiomers of trifluoromethyl-benzo[c][1,5]oxazonines, (R)-4 and (S)-4, can be selectively accessed with high enantiopurity by the Pd-catalyzed ring-expansion reaction of trifluoromethyl-benzo[d][1,3]oxazinones (1) with vinyl ethylene carbonates (3) using one antipode of a chiral ligand. Initially, the reaction proceeds by a double decarboxylative ring-expansion with kinetic resolution of 1 in the presence of a Pd-catalyst/chiral ligand to provide (R)-4 with high enantiopurity. At the same time, the nonreactive antipode of 1, (S)-1, which was recovered with an impeccable s factor of up to 713 and an ideal chemical yield, was transferred into the antipode of the products, (S)-4, with high enantiopurity by a second run of the Pd-catalyzed double decarboxylation reaction, but this time without any chiral auxiliary. Thus, both antipodes of the chiral trifluoromethyl heterocycles 4 can be obtained in excellent enantiopurity using only a single antipode of the chiral catalyst.

Synthesis of fluoro-functionalized diaryl-λ3-iodonium salts and their cytotoxicity against human lymphoma U937 cells.

Conscious of the potential bioactivity of fluorine, an investigation was conducted using various fluorine-containing diaryliodonium salts in order to study and compare their biological activity against human lymphoma U937 cells. Most of the compounds tested are well-known reagents for fluoro-functionalized arylation reactions in synthetic organic chemistry, but their biological properties are not fully understood. Herein, after initially investigating 18 fluoro-functionalized reagents, we discovered that the ortho-fluoro-functionalized diaryliodonium salt reagents showed remarkable cytotoxicity in vitro. These results led us to synthesize more compounds, previously unknown sterically demanding diaryliodonium salts having a pentafluorosulfanyl (SF5) functional group at the ortho-position, that is, unsymmetrical ortho-SF5 phenylaryl-λ3-iodonium salts. Newly synthesized mesityl(2-(pentafluoro-λ6-sulfanyl)phenyl)iodonium exhibited the greatest potency in vitro against U937 cells. Evaluation of the cytotoxicity of selected phenylaryl-λ3-iodonium salts against AGLCL (a normal human B cell line) was also examined.

Synthesis of Sulfur Perfluorophenyl Compounds Using a Pentafluorobenzenesulfonyl Hypervalent Iodonium Ylide.

A novel pentafluorobenzenesulfonyl hypervalent iodonium ylide 3 was designed and synthesized as a useful tool for the preparation of sulfur pentafluorophenyl compounds containing a C6F5S or C6F5SO2 unit. Electrophilic pentafluorophenylthiolation of enamines, formal [3+2] cycloaddition reaction of nitriles and alkynes, and intramolecular SNAr cyclization were achieved using iodonium ylide 3. The fluoro-click reaction was also demonstrated using one of the products via an intermolecular SNAr reaction with heterocentered nucleophiles.

Asymmetric Desymmetrization via Metal-Free C-F Bond Activation: Synthesis of 3,5-Diaryl-5-fluoromethyloxazolidin-2-ones with Quaternary Carbon Centers.

We disclose the first asymmetric activation of a non-activated aliphatic C-F bond in which a conceptually new desymmetrization of 1,3-difluorides by silicon-induced selective C-F bond scission is a key step. The combination of a cinchona alkaloid based chiral ammonium bifluoride catalyst and N,O-bis(trimethylsilyl)acetoamide (BSA) as the silicon reagent enabled the efficient catalytic cycle of asymmetric Csp3 -F bond cleavage under mild conditions with high enantioselectivities. The ortho effect of the aryl group at the prostereogenic center is remarkable. This concept was applied for the asymmetric synthesis of promising agrochemical compounds, 3,5-diaryl-5-fluoromethyloxazolidin-2-ones bearing a quaternary carbon center.

Enantioselective Trichloromethylation of MBH-Fluorides with Chloroform Based on Silicon-assisted C-F Activation and Carbanion Exchange Induced by a Ruppert-Prakash Reagent.

Enantioselective trichloromethylation of Morita-Baylis-Hillman (MBH)-type allylic fluorides with chloroform (HCCl3 ) under organocatalysis was achieved with high to excellent enantioselectivities. Silicon-assisted CF bond activation by a Ruppert-Prakash reagent and direct activation of HCCl3 by a carbanion exchange process with trifluoromethyl (CF3 ) carbanion generated in situ from the Ruppert-Prakash reagent realized the direct asymmetric trichloromethylation at a stereogenic allylic positon, without any help from transition metal catalysis, and under very mild conditions. Pre-activation of HCCl3 was not required. This method was extended to the direct enantioselective introduction of other C-H compounds such as alkyne, arene, indene, and FBSM without any pre-activation under a metal-free system.

Organocatalytic Enantioselective Nucleophilic Alkynylation of Allyl Fluorides Affording Chiral Skipped Ene-ynes.

Asymmetric methods for preparation of chiral alkynyl-containing compounds are in extremely high demand in many sectors of chemical research. In this work, we report the discovery of a general organocatalytic enantioselective alkynylation based on the idea of Si/F activation of the allylic C-F bond. This approach features reasonably broad substrate scope, functional group tolerance, and relatively neutral, mild, and operationally convenient reaction conditions; all of which bode well for the synthetic value of the discovered method. In particular, this method provides unique chiral skipped 1,4-ene-ynes having two kinds of versatile functional groups.

Importance of a Fluorine Substituent for the Preparation of meta- and para-Pentafluoro-λ(6) -sulfanyl-Substituted Pyridines.

Although there are ways to synthesize ortho-pentafluoro-λ(6) -sulfanyl (SF5 ) pyridines, meta- and para-SF5 -substituted pyridines are rare. We disclose herein a general route for their synthesis. The fundamental synthetic approach is the same as reported methods for ortho-SF5 -substituted pyridines and SF5 -substituted arenes, that is, oxidative chlorotetrafluorination of the corresponding disulfides to give pyridylsulfur chlorotetrafluorides (SF4 Cl-pyridines), followed by chloride/fluoride exchange with fluorides. However, the trick in this case is the presence on the pyridine ring of at least one fluorine atom, which is essential for the successful transformation of the disulfides into m-and p-SF5 -pyridines. After enabling the synthesis of an SF5 -substituted pyridine, ortho-F groups can be efficiently substituted by C, N, S, and O nucleophiles through an SN Ar pathway. This methodology provides access to a variety of previously unavailable SF5 -substituted pyridine building blocks.

Asymmetric Mannich reaction between (S)-N-(tert-butanesulfinyl)-3,3,3-trifluoroacetaldimine and malonic acid derivatives. Stereodivergent synthesis of (R)- and (S)-3-amino-4,4,4-trifluorobutanoic acids.

Inorganic as well as organic base catalysis was found to be effective for diastereoselective Mannich additions of malonic acid derivatives to (SS)-N-(tert-butanesulfinyl)-3,3,3-trifluoroacetaldimine. In the presence of catalytic amounts of inorganic bases, n-BuLi or DMAP, the reaction gives the corresponding (R,SS)-ß-aminomalonates in good yield and with diastereoselectivity up to 9/1 dr. In contrast, phosphazene bases favour the formation of the (S,SS)-diastereomer with selectivities as high as 99/1. Simple choosing of an appropriate base catalyst for the Mannich addition reaction allowed us to obtain enantiomerically pure (R)- or (S)-configured 3-amino-4,4,4-trifluorobutanoic acids after hydrolysis and decarboxylation of the corresponding ß-aminomalonates.

Kinetic resolution of allyl fluorides by enantioselective allylic trifluoromethylation based on silicon-assisted C-F bond cleavage.

Two birds, one stone! The first kinetic resolution of allyl fluorides was achieved by the development of an organocatalyzed enantioselective allylic trifluoromethylation. Two kinds of chiral fluorinated compounds, which incorporate C*F and C*CF3 units, respectively, can thus be accessed by a single transformation.

S-((phenylsulfonyl)difluoromethyl)thiophenium salts: carbon-selective electrophilic difluoromethylation of ß-ketoesters, ß-diketones, and dicyanoalkylidenes.

S-((Phenylsulfonyl)difluoromethyl)thiophenium salts were designed and prepared by a triflic acid catalyzed intramolecular cyclization of ortho-ethynyl aryldifluoromethyl sulfanes. The thiophenium salts were found to be efficient as electrophilic difluoromehtylating reagents for introduction of a CF2 H group to sp(3) -hybridized carbon nucleophiles such as of ß-ketoesters and dicyanoalkylidenes. The (phenylsulfonyl)difluoromethyl group can be readily transformed into CF2 H under mild reaction conditions. Enantioselective electrophilic difluoromethylation was also achieved in the presence of bis(cinchona) alkaloids.

Trifluoromethanesulfonyl hypervalent iodonium ylide for copper-catalyzed trifluoromethylthiolation of enamines, indoles, and ß-keto esters.

A novel electrophilic-type trifluoromethylthiolation reagent, a trifluoromethanesulfonyl hypervalent iodonium ylide, was designed and reacted well with various nucleophiles to afford the desired CF3S-substituted products. In situ reduction of the trifluoromethanesulfonyl group to give the trifluoromethylthio group, which is the key step in this process, was realized in the presence of copper(I) chloride.

A sterically demanding organo-superbase avoids decomposition of a naked trifluoromethyl carbanion directly generated from fluoroform.

A simple strategy avoiding the decomposition of a naked trifluoromethyl anion to difluorocarbene by a sterically very demanding organo-superbase without the help of a trifluoromethyl anion reservoir such as DMF is reported. The direct non-metallic trifluoromethylation of carbonyl compounds using fluoroform in the presence of t-Bu-P4 base afforded trifluoromethyl alcohols in high yields.

Regioselective 1,4-trifluoromethylation of α,ß-unsaturated ketones via a S-(trifluoromethyl)diphenylsulfonium salts/copper system.

Regioselective conjugate 1,4-trifluoromethylation of α,ß-unsaturated ketones by the use of shelf-stable electrophilic trifluoromethylating reagents, S-(trifluoromethyl)diphenylsulfonium salts and copper under mild conditions is described. A wide range of acyclic aryl-aryl-enones and aryl-alkyl-enones were converted into ß-trifluoromethylated ketones in low to moderate yields.

Agaritine derived from Agaricus blazei Murrill induces apoptosis via mitochondrial membrane depolarization in hematological tumor cell lines.

Objectives: Agaritine (AGT) is a hydrazine-containing compound derived from the mushroom Agaricus blazei Murill. We previously reported the antitumor effect of AGT on hematological tumor cell lines and suggested that AGT induces apoptosis in U937 cells via caspase activation. However, the antitumor mechanism of AGT has not been fully understood. Methods: Four hematological tumor cell lines (K562, HL60, THP-1, H929) were used in this study. The cells were incubated in the presence of 50 µM AGT for 24 h and analyzed for cell viability, annexin V positivity, caspase-3/7 activity, mitochondrial membrane depolarization, cell cycle, DNA fragmentation, and the expression of mitochondrial membrane-associated proteins (Bax and cytochrome c). Results: In HL60, K562, and H929 cells, AGT reduced cell viability and increased annexin V- and dead cell-positive rates; however, it did not affect THP-1 cells. In K562 and HL60 cells, caspase-3/7 activity, mitochondrial membrane depolarization, and expression of mitochondrial membrane proteins, Bax and cytochrome c, were all increased by AGT. Cell cycle analysis showed that only K562 exhibited an increase in the proportion of cells in G2/M phase after the addition of AGT. DNA fragmentation was also observed after the addition of AGT. Conclusions: These results indicate that AGT induces apoptosis in K562 and HL60 cells, like U937 reported previously, but showed no effect on THP-1 cells. It was suggested that AGT-induced apoptosis involves the expression of Bax and cytochrome c via mitochondrial membrane depolarization.

Organocatalytic asymmetric synthesis of trifluoromethyl-substituted diarylpyrrolines: enantioselective conjugate cyanation of ß-aryl-ß-trifluoromethyl-disubstituted enones.

Ether way: the cinchona-alkaloid-catalyzed title reaction was achieved in high yields with high to excellent ee values for the first time, and affords key intermediates for the biologically important 2 having a trifluoromethylated all-carbon quaternary chiral center. Ether-type catalysts (1) are more efficient in this transformation than the conventional hydroxy analogues.

Trifluoroethoxy-coating improves the axial ligand substitution of subphthalocyanine.

A novel trifluoroethoxy (TFEO)-coated SubPc (1) and various axially functionalised derivatives thereof (2) have been efficiently synthesised. The advantage of the TFEO-coating on SubPcs compared to conventional fluorine-coated or uncoated molecules has been clearly demonstrated, as axial derivatisation has been realised in very good yields. Among various SubPcs synthesised, formyl-SubPc 2f has been further used as a building block for the synthesis of donor-acceptor SubPc-C(60) hybrid 8, while iodo-SubPc 2e has been used for the synthesis of trifluoroethoxy-coated SubPc-Pc dyads 9 and 10. All of these compounds are highly soluble in all common organic solvents, which greatly facilitates their purification and characterisation. The SubPcs 2a-c incorporating oligoethylene glycol moieties are attractive from a biological point of view, while SubPcs 8-10 may prove useful for studies of intramolecular electron- and energy-transfer processes.

Synthesis and configurational stability of (S)- and (R)-deuteriothalidomides.

3'-Deuteriothalidomide was synthesized and found to be configurationally five times more stable than thalidomide toward racemization at physiological pH.

Current Contributions of Organofluorine Compounds to the Agrochemical Industry.

Currently, more than 1,200 agrochemicals are listed and many of these are regularly used by farmers to generate the food supply to support the expanding global population. However, resistance to pesticides is an ever more frequently occurring phenomenon, and thus, a continuous supply of novel agrochemicals with high efficiency, selectivity, and low toxicity is required. Moreover, the demand for a more sustainable society, by reducing the risk chemicals pose to human health and by minimizing their environmental footprint, renders the development of novel agrochemicals an ever more challenging undertaking. In the last two decades, fluoro-chemicals have been associated with significant advances in the agrochemical development process. We herein analyze the contribution that organofluorine compounds make to the agrochemical industry. Our database covers 424 fluoro-agrochemicals and is subdivided into several categories including chemotypes, mode of action, heterocycles, and chirality. This in-depth analysis reveals the unique relationship between fluorine and agrochemicals.

Gas/Liquid-Phase Micro-Flow Trifluoromethylation using Fluoroform: Trifluoromethylation of Aldehydes, Ketones, Chalcones, and N-Sulfinylimines.

Invited for this month's cover picture is the group of Norio Shibata at the Nagoya Institute of Technology (Japan). The cover picture shows an image related to the perpetual motion machine of the second kind in the eighteenth century, and "alchemy". Our biggest challenge on the path to the results presented in this paper was the creation of alchemy using fluorine chemistry. Read the full text of their Communication at 10.1002/open.201800286.