Convergent synthesis of thiodiazole dioxides from simple ketones and amines through an unusual nitrogen-migration mechanism.

We report the modular preparation of dihydro-1,2,5-thiodiazole dioxide heterocycles starting from methyl ketones and primary amines. This one-pot, three-component coupling employs 2,3-dimethylimidazole-1-sulfonyl azide triflate as a coupling reagent and oxidant. The transformation is scalable and various ketones and amines can be used, yielding thiodiazole dioxide products in up to 89% yield. In addition, 15N- and 13C-labeling studies suggest a mechanism involving a 1,2-nitrogen migration. Together with the mechanistic studies, DFT calculations provide insight into the reaction pathway and set the stage for further exploration of the mechanistic nuances of reactions that use sulfamoyl azides. In combination with the demonstrated modularity of the approach reported herein, the derivatization of the thiodiazole dioxide products highlights the potential of this methodology to rapidly access diverse chemical structures.

Skeletal Editing Approach to Bridge-Functionalized Bicyclo[1.1.1]pentanes from Azabicyclo[2.1.1]hexanes.

Azabicyclo[2.1.1]hexanes (aza-BCHs) and bicyclo[1.1.1]pentanes (BCPs) have emerged as attractive classes of sp3-rich cores for replacing flat, aromatic groups with metabolically resistant, three-dimensional frameworks in drug scaffolds. Strategies to directly convert, or "scaffold hop", between these bioisosteric subclasses through single-atom skeletal editing would enable efficient interpolation within this valuable chemical space. Herein, we describe a strategy to "scaffold hop" between aza-BCH and BCP cores through a nitrogen-deleting skeletal edit. Photochemical [2+2] cycloadditions, used to prepare multifunctionalized aza-BCH frameworks, are coupled with a subsequent deamination step to afford bridge-functionalized BCPs, for which few synthetic solutions currently exist. The modular sequence provides access to various privileged bridged bicycles of pharmaceutical relevance.

Control of Redox-Active Ester Reactivity Enables a General Cross-Electrophile Approach to Access Arylated Strained Rings.

Strained rings are increasingly important for the design of pharmaceutical candidates, but cross-coupling of strained rings remains challenging. An attractive, but underdeveloped, approach to diverse functionalized carbocyclic and heterocyclic frameworks containing all-carbon quaternary centers is the coupling of abundant strained-ring carboxylic acids with abundant aryl halides. Herein we disclose the development of a nickel-catalyzed cross-electrophile approach that couples a variety of strained ring N-hydroxyphthalimide (NHP) esters, derived from the carboxylic acid in one step, with various aryl and heteroaryl halides under reductive conditions. The chemistry is enabled by the discovery of methods to control NHP ester reactivity, by tuning the solvent or using modified NHP esters, and the discovery that t-Bu BpyCamCN , an L2X ligand, avoids problematic side reactions. This method can be run in flow and in 96-well plates.

Total synthesis and isolation of citrinalin and cyclopiamine congeners.

Many natural products that contain basic nitrogen atoms--for example alkaloids like morphine and quinine-have the potential to treat a broad range of human diseases. However, the presence of a nitrogen atom in a target molecule can complicate its chemical synthesis because of the basicity of nitrogen atoms and their susceptibility to oxidation. Obtaining such compounds by chemical synthesis can be further complicated by the presence of multiple nitrogen atoms, but it can be done by the selective introduction and removal of functional groups that mitigate basicity. Here we use such a strategy to complete the chemical syntheses of citrinalin B and cyclopiamine B. The chemical connections that have been realized as a result of these syntheses, in addition to the isolation of both 17-hydroxycitrinalin B and citrinalin C (which contains a bicyclo[2.2.2]diazaoctane structural unit) through carbon-13 feeding studies, support the existence of a common bicyclo[2.2.2]diazaoctane-containing biogenetic precursor to these compounds, as has been proposed previously.

New GABA/glutamate receptor target for [³H]isoxazoline insecticide.

The highly effective and selective isoxazoline insecticide A1443 is known to potently displace [(3)H]ethynylbicycloorthobenzoate ([(3)H]EBOB) binding to house fly head membranes with an IC50 of 0.2 nM in a manner characteristic of GABA-gated chloride channel antagonists. To further define its mode of action, we prepared phenyl-labeled [(3)H]A1443 as described with a specific activity of 14 Ci/mmol. This new radioligand with an apparent IC50 of about 0.4 nM is poorly displaced by most insecticides acting at the [(3)H]EBOB site. Interestingly, the isoxazoline binding site is directly coupled to the avermectin GABA/glutamate chloride channel activator site. These findings revive interest in the insect GABA/glutamate receptor as an insecticide target.

Biomimetic Synthesis of Cbz-(S)-Dolaphenine.

A new route to Cbz-(S)-dolaphenine, a recurring element in bioactive peptidic natural products, has been implemented, which closely parallels the biogenetic pathway. Cyclodehydration of 11 to yield thiazoline 2 allows for a Ni(0)-promoted decarbonylative aromatization to provide the thiazole framework with retention of stereochemistry.

Decarbonylative approach to the synthesis of enamides from amino acids: stereoselective synthesis of the (Z)-aminovinyl-D-cysteine unit of mersacidin.

The Pd- and Ni-promoted decarbonylation of amino acid thioesters proceeds smoothly to yield enamides. The synthesis of the (S)-(Z)-AviMeCys subunit of mersacidin, an MRSA-active lantibiotic, via this approach, is described.

A new total synthesis of patellamide A.

Patellamide A was efficiently synthesized from thiazole 2 via two complementary heterocyclization approaches to form the thiazole and oxazoline rings.