Enantioselective Synthesis of Tropane Scaffolds by an Organocatalyzed 1,3-Dipolar Cycloaddition of 3-Oxidopyridinium Betaines and Dienamines.

Tropane alkaloids constitute a compound-class which is structurally defined by a central 8-azabicyclo[3.2.1]octane core. A diverse bioactivity profile combined with an unusual aza-bridged bicyclic framework has made tropanes molecules-of-interest within organic chemistry. Enantioselective examples of (5+2) cycloadditions between 3-oxidopyridinium betaines and olefins remain unexplored, despite 3-oxidopyridinium betaines being useful reagents in organic synthesis. The first asymmetric (5+2) cycloaddition of 3-oxidopyridinium betaines is reported, affording tropane derivatives in up to quantitative yield and with excellent control of peri-, regio-, diastereo-, and enantioselectivity. The reactivity is enabled by dienamine-activation of α,ß-unsaturated aldehydes combined with in situ formation of the pyridinium reaction-partner. A simple N-deprotection protocol allows for liberation of the tropane alkaloid motif, and synthetic elaborations of the cycloadducts demonstrate their synthetic utility to achieve highly diastereoselective modification around the bicyclic framework. DFT computations suggest a stepwise mechanism where regio- and stereoselectivity are defined during the first bond-forming step in which the pyridinium dipole exerts critical conformational control over its dienamine partner. In the second bond-forming step, a kinetic preference toward an initial (5+4) cycloadduct was identified; however, a lack of catalyst turn-over, reversibility, and thermodynamic bias favoring a (5+2) cycloadduct rendered the reaction fully periselective.

Ring-Opening 1,3-Sulfonylation-Fluorination of Donor-Acceptor Cyclopropanes: Three-Component Access to γ-Fluorosulfones.

A general method for 1,3-bisfunctionalization of donor-acceptor (D-A) cyclopropanes using sulfinate salts and electrophilic fluorination reagents is described. Utilizing Lewis acid catalysis, nucleophilic ring-opening by the sulfinate anion followed by trapping of electrophilic fluorine by the anionic intermediate leads to the formation of γ-fluorosulfones. To the best of our knowledge, this is the first direct one-step synthesis of sulfones fluorinated in the γ-position from a carbon backbone. A mechanistic proposal is presented based on experimental evidence.

C-H deuteration of organic compounds and potential drug candidates.

C-H deuteration has been intricately developed to satisfy the urgent need for site-selectively deuterated organic frameworks. Deuteration has been primarily used to study kinetic isotope effects of reactions but recently its significance in pharmaceutical chemistry has been discovered. Deuterium labelled compounds have stolen the limelight since the inception of the first FDA-approved deuterated drug, for the treatment of chorea-associated Huntington's disease, and their pharmacological importance was realised by chemists, although surprisingly very late. Various approaches were developed to carry out site-selective deuteration. However, the most common and efficient method is hydrogen isotope exchange (HIE). This review summarises deuteration methods of various organic motifs containing C(sp2)-H and C(sp3)-H bonds utilizing C-H bond functionalisation as a key step along with a variety of catalysts, and exemplifies their biological relevance.

Cycloadditions of Donor-Acceptor Cyclopropanes and -butanes using S=N-Containing Reagents: Access to Cyclic Sulfinamides, Sulfonamides, and Sulfinamidines.

We present (3+2)- and (4+2)-cycloadditions of donor-acceptor (D-A) cyclopropanes and cyclobutanes with N-sulfinylamines and a sulfur diimide, along with a one-pot, two-step strategy for the formal insertion of HNSO2 into D-A cyclopropanes. These are rare examples of cycloadditions with D-A cyclopropanes and cyclobutanes whereby the 2π component consists of two different heteroatoms, thus leading to five- and six-membered rings containing adjacent heteroatoms.

Chemistry Evolves, Terms Evolve, but Phenomena Do Not Evolve: From Chalcogen-Chalcogen Interactions to Chalcogen Bonding.

Chalcogen bonding is important in numerous aspects of chemistry, both in the solid state and in solution. Surveying the literature, it becomes clear that during its rebranding from chalcogen-chalcogen interactions, some parts of the community have somewhat neglected to recall its discovery and the initial studies referring to it in its previous guise. In this Viewpoint, we trace the path of research into this phenomenon, from its discovery, through its renaming, and to some of the varied and interesting chemistry it has led to so far, ranging from crystal engineering through supramolecular assembly to modern catalysis.

Sulfinamide Synthesis Using Organometallic Reagents, DABSO, and Amines.

We report the synthesis of sulfinamides using organometallic reagents, a sulfur dioxide reagent, and nitrogen based-nucleophiles. The addition of an organometallic reagent to the commercially available sulfur dioxide surrogate, DABSO, generates a metal sulfinate which is reacted with thionyl chloride to form a sulfinyl chloride intermediate. Trapping the sulfinyl chlorides in situ with a variety of nitrogen nucleophiles delivers sulfinamides in 32-83% yields. Each stage of the process is performed at room temperature, and the total reaction time is only 1.5 h.