Matthias Westphal

Evaluation of tert-Butyl Isosteres: Case Studies of Physicochemical and Pharmacokinetic Properties, Efficacies, and Activities

The tert‐butyl group is a common motif in medicinal chemistry. Its incorporation into bioactive compounds is often accompanied by unwanted property modulation, such as increased lipophilicity and decreased metabolic stability. Several alternative substituents are available for the drug discovery process. Herein, physicochemical data of two series of drug analogues of bosentan and vercirnon are documented as part of a comparative study of tert‐butyl, pentafluorosulfanyl, trifluoromethyl, bicyclo[1.1.1]pentanyl, and cyclopropyl‐trifluoromethyl substituents.

Synthesis of Photoswitchable Δ9-Tetrahydrocannabinol Derivatives Enables Optical Control of Cannabinoid Receptor 1 Signaling

The cannabinoid receptor 1 (CB1) is an inhibitory G protein-coupled receptor abundantly expressed in the central nervous system. It has rich pharmacology and largely accounts for the recreational use of cannabis. We describe efficient asymmetric syntheses of four photoswitchable Δ9-tetrahydrocannabinol derivatives (azo-THCs) from a central building block 3-Br-THC. Using electrophysiology and a FRET-based cAMP assay, two compounds are identified as potent CB1 agonists that change their effect upon illumination. As such, azo-THCs enable CB1-mediated optical control of inwardly rectifying potassium channels, as well as adenylyl cyclase.

Selective Photoaffinity Probe That Enables Assessment of Cannabinoid CB2 Receptor Expression and Ligand Engagement in Human Cells

Chemical tools and methods that report on G protein-coupled receptor (GPCR) expression levels and receptor occupancy by small molecules are highly desirable. We report the development of LEI121 as a photoreactive probe to study the type 2 cannabinoid receptor (CB2R), a promising GPCR to treat tissue injury and inflammatory diseases. LEI121 is the first CB2R-selective bifunctional probe that covalently captures CB2R upon photoactivation. An incorporated alkyne serves as ligation handle for the introduction of reporter groups. LEI121 enables target engagement studies and visualization of endogenously expressed CB2R in HL-60 as well as primary human immune cells using flow cytometry. Our findings show that strategically functionalized probes allow monitoring of endogenous GPCR expression and engagement in human cells using tandem photoclick chemistry and hold promise as biomarkers in translational drug discovery.

Synthesis of (+)-N-Methylwelwitindolinone D Isonitrile

Significance: The welwitindolinones display interesting biological properties such as antifungal activity and microtubule depolymerization in human carcinoma cells. The challenging architecture of the target compound features an oxidized bicyclo[4.3.1]decane motif. The additional tetrahydrofuran ring was efficiently introduced by a double functionalization using air. Comment: A was converted into deuteriumcontaining indolinone C. As described earlier by the authors, exploitation of the isotope effect during nitrene insertion afforded E in good yield. Oxidation to F was affected using tetra-n-butylammonium fluoride (TBAF) and air. Since hydrolysis of F led to decomposition, H was prepared by a reduction–hydrolysis–oxidation sequence. Formylation and dehydration yielded the target. N Me O TBSO

Synthesis of (–)-Calyciphylline N

Significance: The authors report the first total synthesis of (–)-calyciphylline N. Although no biodata of this Daphniphyllum alkaloid was published, the complex architecture and potential activity render it an attractive target. Its structure contains six contiguous stereocenters (three of which are quaternary), a dihydropyrrole, and a bicyclo[2.2.2]octane as part of a decahydrocyclopentazulene system. Comment: An aluminum-catalyzed tethered Diels–Alder reaction of C afforded D as a 9:1 mixture of diastereomers. D was elaborated into J in 22 steps. Treatment with fluoroboric acid effected cyclization, deprotection, and substitution at silicon to give K. Conversion into diene M set the stage for chemoand diastereoselective iridiumcatalyzed hydrogenation to give O, which was carried on to the natural product. N CO2Me