Mild Strategy for the Preparation of Alkyl Sulfonyl Fluorides from Alkyl Bromides and Alcohols Using Photoredox Catalysis and Flow Chemistry.

Facile access to sp3-rich scaffolds containing a sulfonyl fluoride group is still limited. Herein, we describe a mild and scalable strategy for the preparation of alkyl sulfonyl fluorides from readily available alkyl bromides and alcohols using photoredox catalysis. This approach is based on halogen atom transfer (XAT), followed by SO2 capture and fluorination. The method features mild conditions enabling fast access to high-value derivatives and has been scaled up to 5 g using a continuous stirred tank reactor cascade.

Rapid PROTAC Discovery Platform: Nanomole-Scale Array Synthesis and Direct Screening of Reaction Mixtures.

Precise length, shape, and linker attachment points are all integral components to designing efficacious proteolysis targeting chimeras (PROTACs). Due to the synthetic complexity of these heterobifunctional degraders and the difficulty of computational modeling to aid PROTAC design, the exploration of structure-activity relationships remains mostly empirical, which requires a significant investment of time and resources. To facilitate rapid hit finding, we developed capabilities for PROTAC parallel synthesis and purification by harnessing an array of preformed E3-ligand-linker intermediates. In the next iteration of this approach, we developed a rapid, nanomole-scale PROTAC synthesis methodology using amide coupling that enables direct screening of nonpurified reaction mixtures in cell-based degradation assays, as well as logD and EPSA measurements. This approach greatly expands and accelerates PROTAC SAR exploration (5 days instead of several weeks) as well as avoids laborious and solvent-demanding purification of the reaction mixtures, thus making it an economical and more sustainable methodology for PROTAC hit finding.

Single-Scan Selective Excitation of Individual NMR Signals in Overlapping Multiplets.

2D NMR is an immensely powerful structural tool but it is time-consuming. Targeting individual chemical groups by selective excitation in a 1D experiment can give the information required far more quickly. A major problem, however, is that proton NMR spectra are often extensively overlapped, so that in practice only a minority of sites can be selectively excited. Here we overcome that problem using a fast, single-scan method that allows selective excitation of the signals of a single proton multiplet even where it is severely overlapped by other multiplets. The advantages of the method are illustrated in a selective 1D NOESY experiment, the most efficient way to determine relative configuration unambiguously by NMR. The new approach presented here has the potential to broaden significantly the applicability of selective excitation and unlock its real potential for many other experiments.

Samarium(II) folding cascades involving hydrogen atom transfer for the synthesis of complex polycycles.

The expedient assembly of complex, natural product-like small molecules can deliver new chemical entities with the potential to interact with biological systems and inspire the development of new drugs and probes for biology. Diversity-oriented synthesis is a particularly attractive strategy for the delivery of complex molecules in which the 3-dimensional architecture varies across the collection. Here we describe a folding cascade approach to complex polycyclic systems bearing multiple stereocentres mediated by reductive single electron transfer (SET) from SmI2. Simple, linear substrates undergo three different folding pathways triggered by reductive SET. Two of the radical cascade pathways involve the activation and functionalization of otherwise inert secondary alkyl and benzylic groups by 1,5-hydrogen atom transfer (HAT). Combination of SmI2, a privileged reagent for cascade reactions, and 1,5-HAT can lead to complexity-generating radical sequences that unlock access to diverse structures not readily accessible by other means.

Enantioselective cyclizations and cyclization cascades of samarium ketyl radicals.

The rapid generation of molecular complexity from simple starting materials is a key challenge in synthesis. Enantioselective radical cyclization cascades have the potential to deliver complex, densely packed, polycyclic architectures, with control of three-dimensional shape, in one step. Unfortunately, carrying out reactions with radicals in an enantiocontrolled fashion remains challenging due to their high reactivity. This is particularly the case for reactions of radicals generated using the classical reagent, SmI2. Here, we demonstrate that enantioselective SmI2-mediated radical cyclizations and cascades that exploit a simple, recyclable chiral ligand can convert symmetrical ketoesters to complex carbocyclic products bearing multiple stereocentres with high enantio- and diastereocontrol. A computational study has been used to probe the origin of the enantioselectivity. Our studies suggest that many processes that rely on SmI2 can be rendered enantioselective by the design of suitable ligands.

Synthesis and preliminary biological assay of uridine glycoconjugate derivatives containing amide and/or 1,2,3-triazole linkers.

A series of UDP-sugar analogues was synthesized and their preliminary biological activity was evaluated. Glycoconjugates of uridine 1 and 2 were synthesized by condensation of uridine-5'-carboxylic acid and 1-amino sugars derivatives of d-glucose and d-galactose, glycoconjugates 3 and 4 were synthesized by azide-alkyne 1,3-dipolar cycloaddition (CuAAC) of 1-azido sugars and propargylamide derivatives of uridine while glycoconjugates 5 and 6 were synthesized by CuAAC of propargyl ß-O-glycosides and 5'-azido uridine. Evaluation of inhibitory activity of compounds 1-6 against commercially available ß-1,4-galactosyltransferase I (ß4GalT) show that compound 5 inhibited the enzyme in µmolar range. Additionally, the antitumor activity of the obtained glycoconjugates 1-6 were tested using MTT assay.

SmCpR2-mediated cross-coupling of allyl and propargyl ethers with ketoesters and a telescoped approach to complex cycloheptanols.

A highly regio- and diastereoselective cross-coupling of allyl/propargyl ethers and δ-ketoesters, mediated by SmCpR2 reagents, delivers decorated δ-lactones. Screening of the Cp ligands on Sm(ii) was employed to achieve high regio and diastereocontrol in some cases. Crucially, SmI2 gave unsatisfactory results in the transformation. The process has been exploited in a telescoped approach to complex cycloheptanols in which two Sm(ii) reagents act in turn on the simple starting materials.

Intravascular lymphoma mimicking multiple sclerosis.

Diagnosis of relapsing-remitting multiple sclerosis requires demonstration disseminated symptoms in time and space on the basis of neurological assessment or magnetic resonance imaging findings. In addition, the diagnosis is conditioned by ruling out other conditions that may explain the clinical symptoms. We describe the patient presenting in the initial stage of the disease neurological symptoms and magnetic resonance imaging lesions, that met criteria for relapsing-remitting multiple sclerosis diagnosis. The patient was administered immunomodulatory treatment. However, the subsequent course of the disease tended to verify the diagnosis. Finally, the patient was diagnosed with intravascular B-cell lymphoma. Intravascular lymphoma is a rare form of lymphoma characterized by the development of cancerous cells in the lumen of small and medium-sized blood vessels. Due to the lack of characteristic biomarkers in laboratory tests and neuroimaging, the diagnosis is based on histopathological examination of the sample of the affected organ taken by biopsy. It should be consider in all cases of central nervous system damage of unknown, undiagnosed etiology.