Trifluorinated Tetralins via I(I)/I(III)-Catalysed Ring Expansion: Programming Conformation by [CH2 CH2 ] → [CF2 CHF] Isosterism.

Saturated, fluorinated carbocycles are emerging as important modules for contemporary drug discovery. To expand the current portfolio, the synthesis of novel trifluorinated tetralins has been achieved. Fluorinated methyleneindanes serve as convenient precursors and undergo efficient difluorinative ring expansion with in situ generated p-TolIF2 (>20 examples, up to >95 %). A range of diverse substituents are tolerated under standard catalysis conditions and this is interrogated by Hammett analysis. X-ray analysis indicates a preference for the CH-F bond to occupy a pseudo-axial orientation, consistent with stabilising σC-H →σC-F * interactions. The replacement of the symmetric [CH2 -CH2 ] motif by [CF2 -CHF] removes the conformational degeneracy intrinsic to the parent tetralin scaffold leading to a predictable half-chair. The conformational behavior of this novel structural balance has been investigated by computational analysis and is consistent with stereoelectronic theory.

Tau and other proteins found in Alzheimer's disease spinal fluid are linked to retromer-mediated endosomal traffic in mice and humans.

Endosomal trafficking has emerged as a defective biological pathway in Alzheimer's disease (AD), and the pathway is a source of cerebrospinal fluid (CSF) protein accumulation. Nevertheless, the identity of the CSF proteins that accumulate in the setting of defects in AD's endosomal trafficking pathway remains unknown. Here, we performed a CSF proteomic screen in mice with a neuronal-selective knockout of the core of the retromer complex VPS35, a master conductor of endosomal traffic that has been implicated in AD. We then validated three of the most relevant proteomic findings: the amino terminus of the transmembrane proteins APLP1 and CHL1, and the mid-domain of tau, which is known to be unconventionally secreted and elevated in AD. In patients with AD dementia, the concentration of amino-terminal APLP1 and CHL1 in the CSF correlated with tau and phosphorylated tau. Similar results were observed in healthy controls, where both proteins correlated with tau and phosphorylated tau and were elevated in about 70% of patients in the prodromal stages of AD. Collectively, the mouse-to-human studies suggest that retromer-dependent endosomal trafficking can regulate tau, APLP1, and CHL1 CSF concentration, informing on how AD's trafficking pathway might contribute to disease spread and how to identify its trafficking impairments in vivo.

Fluorohydration of alkynes via I(I)/I(III) catalysis.

Substrate specificity is ubiquitous in biological catalysis, but less pervasive in the realm of small-molecule catalysis. Herein, we disclose an intriguing example of substrate specificity that was observed whilst exploring catalysis-based routes to generate α-fluoroketones from terminal and internal alkynes under the auspices of I(I)/I(III) catalysis. Utilising p-TolI as an inexpensive organocatalyst with Selectfluor® and amine/HF mixtures, the formation of protected α-fluoroketones from simple alkynes was realised. Whilst the transient p-TolIF2 species generated in situ productively engaged with pentynyl benzoate scaffolds to generate the desired α-fluoroketone motif, augmentation or contraction of the linker suppressed catalysis. The prerequisite for this substructure was established by molecular editing and was complemented with a physical organic investigation of possible determinants.

Enantioselective Synthesis of 3-Fluorochromanes via Iodine(I)/Iodine(III) Catalysis.

The chromane nucleus is common to a plenum of bioactive small molecules where it is frequently oxidized at position 3. Motivated by the importance of this position in conferring efficacy, and the prominence of bioisosterism in drug discovery, an iodine(I)/iodine(III) catalysis strategy to access enantioenriched 3-fluorochromanes is disclosed (up to 7:93 e.r.). In situ generation of ArIF2 enables the direct fluorocyclization of allyl phenyl ethers to generate novel scaffolds that manifest the stereoelectronic gauche effect. Mechanistic interrogation using deuterated probes confirms a stereospecific process consistent with a type IIinv pathway.

Catalytic Geminal Difluorination of Styrenes for the Construction of Fluorine-rich Bioisosteres.

A geminal difluorination of alkenes based on I(I)/I(III) catalysis is disclosed, which is compatible with a range of electronically and substitutionally diverse styrenes (27 examples, up to 89% yield). Employing inexpensive p-TolI as the organocatalyst, turnover is enabled by Selectfluor-mediated oxidation to generate the ArIF2 species in situ. Extension to include α-substituted styrenes bearing fluorine-containing groups is disclosed and provides an expansive platform for the generation of fluorine-rich architectures.

An Alzheimer's Disease-Linked Loss-of-Function CLN5 Variant Impairs Cathepsin D Maturation, Consistent with a Retromer Trafficking Defect.

In a whole-exome sequencing study of multiplex Alzheimer's disease (AD) families, we investigated three neuronal ceroid lipofuscinosis genes that have been linked to retromer, an intracellular trafficking pathway associated with AD: ceroid lipofuscinosis 3 (CLN3), ceroid lipofuscinosis 5 (CLN5), and cathepsin D (CTSD). We identified a missense variant in CLN5 c.A959G (p.Asn320Ser) that segregated with AD. We find that this variant causes glycosylation defects in the expressed protein, which causes it to be retained in the endoplasmic reticulum with reduced delivery to the endolysosomal compartment, CLN5's normal cellular location. The AD-associated CLN5 variant is shown here to reduce the normal processing of cathepsin D and to decrease levels of full-length amyloid precursor protein (APP), suggestive of a defect in retromer-dependent trafficking.

Integrating Safety Plans for Suicidal Patients Into Patient Portals: Challenges and Opportunities.

Safety planning is an emerging evidence-based practice that is effective at decreasing suicidal behaviors. As electronic medical records and patient portals become more prevalent, patients and clinicians have recognized the value of using this technology in the safety planning process. This column describes the experience of one federally qualified health center, the Institute for Family Health, in integrating safety plans into the patient portal. The authors argue that incorporating safety plans into patient portals may unlock a new to way to expand safety planning efforts in health settings-a way that may ultimately save lives.

Synthesis of C2 Substituted Benzothiophenes via an Interrupted Pummerer/[3,3]-Sigmatropic/1,2-Migration Cascade of Benzothiophene S-Oxides.

Functionalized benzothiophenes are important scaffolds found in molecules with wide ranging biological activity and in organic materials. We describe an efficient, metal-free synthesis of C2 arylated, allylated, and propargylated benzothiophenes. The reaction utilizes synthetically unexplored yet readily accessible benzothiophene S-oxides and phenols, allyl-, or propargyl silanes in a unique cascade sequence. An interrupted Pummerer reaction between benzothiophene S-oxides and the coupling partners yields sulfonium salts that lack aromaticity and therefore allow facile [3,3]-sigmatropic rearrangement. The subsequently generated benzothiophenium salts undergo a previously unexplored 1,2-migration to access C2 functionalized benzothiophenes.