Stereolithography 3D-Printed Catalytically Active Devices in Organic Synthesis

This article describes the synthesis of stereolithography (SLA) 3D-printed catalyst-impregnated devices and their evaluation in the organocatalyzed Friedel\u2013Crafts alkylation of N\u2013Me\u2013indole with trans--nitrostyrene. Using a low-cost SLA 3D printer and freeware design software, dierent devices were designed and 3D-printed using a photopolymerizable resin containing a thiourea-based organocatalyst. The architectural control oered by the 3D-printing process allows a straightforward production of devices endowed with dierent shapes and surface areas, with high reproducibility. The 3D-printed organocatalytic materials promoted the formation of the desired product up to a 79% yield, although with longer reaction times compared to reactions under homogeneous conditions

Novel carbohydrate-based bifunctional organocatalysts for nucleophilic addition to nitroolefins and imines

Glucosamine has been selected as a cheap and readily available chiral scaffold for the synthesis of a series of novel enantiomerically pure bifunctional organocatalysts bearing a tertiary amino group in proximity to a (thio)urea group. The catalytic behaviour of these compounds, both as neutral and N-protonated species, was investigated using the addition of acetylacetone to \u3b2-nitrostyrene as a model reaction. Under optimized experimental conditions, chemical yields up to 93% and enantioselectivities up to 89% were obtained. Semiempirical (AM1) computational studies allowed to find a theoretical rationale for the chemical and stereochemical behaviour of the catalyst of choice. These catalysts were also preliminarily investigated as promoters in the addition of diethyl malonate to the N-Boc imine of benzaldehyde, affording the product in up to 81% ee

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Synthesis of Alpha-trifluoromethylthio Carbonyl Compounds : A Survey of the Methods for the Direct Introduction of the SCF3 Group on to Organic Molecules

The role of fluorine atoms in drug discovery has become of fundamental importance, due to their ability to confer unprecedented therapeutic profiles on a molecule. In this framework, the trifluoromethylthio group (SCF3) is attracting an increasing attention in pharmaceutical, agrochemical and material chemistry and it is commonly used to modulate lipophilicity, bioavailability and metabolic stability of newly designed molecules. Actually, several drugs whose biological activity is strictly related to the presence of a SCF3 residue in the molecular scaffold are already on the market. Despite trifluoromethylthiolated carbonyl derivatives present a high potential of application in medicinal chemistry, synthetic approaches to alpha-SCF3-substituted carbonyl compounds are still limited, and catalytic strategies to access optically active functionalized carbonyl compounds are almost unexplored. The present review will discuss the use of radical, nucleophilic and electrophilic trifluoromethylthiolating reagents, to synthesize decorated trifluoromethylthio carbonyl derivatives, with a particular attention on catalytic methodologies and stereoselective methods affording enantiomerically enriched molecules

Enantioselective Direct Aldol Reaction \u201con water\u201d Promoted by Chiral Organic Catalysts

1,1\ua2-Binaphthyl-2,2\ua2-diamine-based (S)-prolinamides in the presence of stearic acid were able to promote the direct aldol condensation of cyclohexanone and other ketones with different aldehydes in the presence of a massive amount of water in very good yields, high diastereoselectivity, and up to 99% ee. The behavior of both C2- and C1-symmetric catalysts in combination with different additives was investigated, and a preliminary experiment of recovering and recycling of the catalytic system was also attempted

STEREOSELECTIVITY OF INTRAMOLECULAR NITRILE OXIDE CYCLOADDITIONS TO Z-CHIRAL ALKENE AND E-CHIRAL ALKENES

Intramolecular nitrile oxide cycloaddition (INOC) reactions on chiral alkenes were studied in order to evaluate the influence of the double bond configuration on the stereochemical outcome of the process. Oximes 11-16 were prepared, starting from aldehydes 1-4, via Wittig reaction, isomerization of the double bond for the E derivatives, Swern oxidation, and reaction with hydroxylamine. Treatment of oximes 11-16 with sodium hypochlorite gave the nitrile oxides, which were trapped in situ by intramolecular cycloaddition to give the corresponding isoxazolines 17-22 as mixtures of diastereoisomers (Table I). From (2)-alkenyl oximes C-4/C-5 syn products and from (E)-alkenyl oximes C-4/C-5 anti products were obtained, while the relative stereochemistry at C-5/C-5\u2018 of the predominant isomers was found to be anti in all cases. The assignment of relative stereochemistry was based on \u2018H and 13C NMR spectroscopic evidence and on chemical correlations. With Houk\u2018s approach, MM2 calculations were performed to evaluate the relative energies of the transition structures. The CNO-ethylene fragment was frozen in the ab initio HCNO-ethylene transition structure model geometry, and the substituents were fully optimized by MM2. With the (2)-alkenes, the \u201csmall\u201d group of the allylic stereocenter prefers the inside position, the \u201cmedium\u201d the anti, and the \u201clarge\u201d the outside, with respect to the forming C-0 bond, and the factors controlling the stereoselectivity are mainly steric. On the contrary, with the (E)-alkenes the \u201cmedium\u201d group will be inside, the \u201clarge\u201d anti, and the \u201csmall\u201d outside. In the case of allyl ethers this model is mainly ruled by electronic factors. Quite good stereoselectivities were achieved in the INOC reactions using the allyl ethers derived from glyceraldehyde. A rationale for this result has been proposed

In-flow synthesis of advanced precursors of Chiral APIs

In the field of APIs (Active Pharmaceutical Ingredients), the industry is gradually progressing towards enantiopure formulations. In this context, chiral amines are unanimously considered a class of paramount importance, due to their widespread diffusion in a plethora of compounds.1 The diastereoselective and metal free, trichlorosilane-mediate reduction of imines, bearing different and removable chiral auxiliaries, in combination either with achiral bases or catalytic amounts of chiral Lewis bases, represents a feasible approach to afford immediate precursors of chiral APIs.2 In the present work, the carbon-nitrogen double bond reduction was successfully performed in batch and in flow mode, in high yields and almost complete stereocontrol.3 By this metal-free approach, the formal synthesis of Rasagiline and Tamsulosin was successfully accomplished in micro(meso) flow reactors, under continuous flow conditions. Chiral primary amines were obtained, either by a continuous flow hydrogenolysis, or directly out from the flow reactor after an in-line aqueous work up, depending on the chiral auxiliary group at the amine nitrogen atom. References 1. Chiral Amine Synthesis: Methods, Developments and Applications (Ed.: T. C. Nugent), Wiley-VCH, Weinheim, 2010. 2. D. Brenna, M. Benaglia, R. Porta, S. D. Fernandes, A. J. Burke, Eur. J. Org. Chem, 2016, doi:10.1002/ejoc.201601268. 3. D. Brenna, M. Pirola, L. Raimondi, A.J. Burke, M. Benaglia, Bioorg. & Med. Chem., 2017, doi: http://dx.doi.org/10.1016/j.bmc.2017.01.02

Surface Free Energy of Bare and Fluorinated Siloxanes: Comparing Experimental Evaluation and Dipole Moments Calculations

The surface free energy (SFE) is a key parameter in evaluating the physico-chemical features of solid surfaces. Studies on the composition, structure and interfacial phenomena of a surface layer of materials are of special importance. Its assessment allows the interpretation of several phenomena, such as adsorption mechanisms and surface wettability behaviors, occurring at solid-liquid and solid-gas interfaces; hence the knowledge of such properties is fundamental for both technological and more fundamental point of view. Here, the surface free energy of three non-fluorinated and three fluorinated siloxanes is evaluated. All siloxanes were synthesized and deposited in thick films onto a glass substrate by spin coating. Experimental static contact angle data elaborated by empirical models (Zisman, EOS, OWRK), together with theoretical dipole moment calculations and wetting envelope (WE) elaborations allow us to predict the wetting behaviors towards the most common solvents. The effect of the addition of fluorinated -CF3 end-groups in imposing the final wetting features of the siloxane films is fully investigated on the grounds of the above mentioned experimental and theoretical investigations

Localisation in the Human Genome of th Mariner Transposable Element Ccmar1: its Possible Role in Genomic Instability.

A DNA transposon belonging to the Tigger family has been localized in the human genome. Implications for human genome insatbility are discussed