Formic Acid Mediated Direct Z-Selective Reductive Coupling of Dienes and Aldehydes

We demonstrate that formic acid mediates the Rh-catalyzed, Z-selective coupling of dienes and aldehydes. The process is distinguished by broad tolerance towards reducible or electrophilic groups. Kinetic analysis suggests that generation of the catalytically active Rh-intermediate by ligand dissociation is the rate determining step. The rapid generation and trapping of Rh-allyl intermediates is key to preventing chain-walking isomerization events that plague related protocols. Insights gained through this study may have wider implications in selective metal-catalyzed hydrofunctionalization reactions.<br /

Enantio- and Z-Selective d-Hydroarylation of Aryldienes via Rh-Catalyzed Conjugate Addition

Metal-catalyzed enantioselective conjugate arylations of electron-poor alkenes are highly selective processes for C(sp2)–C(sp3) bond formation. d-Selective hydroarylations of electron-poor dienes are less well developed and reactions that deliver high enantioselectivity while giving single alkene isomer products are elusive. Here we report the Rh-catalyzed d-arylation of aryldienes that gives nearly exclusive Z-1,4-addition products (generally with >95:5 positional and geometrical selectivity). This remote functionalization provides access to chiral diarylated butenes from readily available precursors poised for further functionalization, including in the synthesis of bioactive molecules. Mechanistic studies suggest that protonolysis of a Rh-allyl intermediate generated by diene insertion into a Rh-aryl is the rate determining step and occurs by an inner-sphere proton transfer pathway

Enantioselective a,d-Difunctionalization of Dienes Initiated by Rh-Catalyzed Conjugate Addition

Metal-catalyzed enantioselective conjugate additions are highly reliable methods for stereoselective synthesis, however multi-component reactions that are initiated by conjugate arylation of acyclic p-systems are rare. These processes generally proceed with poor diastereoselectivity while requiring basic, moisture sensitive organometallic nucleophiles. Here we show that Rh-catalysts supported by a tetrafluorobenzobarrelene ligand (Ph-tfb) enable the enantio-, diastereo-, and Z-selective a,d-difunctionalization of electron-deficient 1,3-dienes with organoboronic acid nucleophiles and aldehyde electrophiles to generate Z-homoallylic alcohols with three stereocenters. The reaction accommodates diene substrates activated by ester, amide, ketone, or aromatic groups and can be used to couple aryl, alkenyl, or alkyl aldehydes. Diastereoselective functionalization of the Z-olefin unit in the addition products allow for the generation of compounds with five stereocenters in high dr and ee. Mechanistic studies suggest aldehyde allylrhodation is the rate determining step, and unlike reactions of analogous Rh-enolates, the Rh-allyl species generated by d-arylation undergoes aldehyde trapping rather than protonolysis, even when water is present as a co-solvent. These findings should have broader implications in the use of privileged metal-catalyzed conjugate addition reactions as entry points towards the preparation of acyclic molecules containing non-adjacent stereocenters

Fast Carbon Isotope Exchange of Carboxylic Acids Enabled by Organic Photoredox Catalysis

Carbazole/cyanobenzene photocatalysts promote the direct isotopic carboxylate exchange of C(sp3 )-acids with labelled CO2. Substrates that are not compatible with transition metal catalyzed degradation-reconstruction approaches or prone to thermally induced reversible decarboxylation undergo isotopic incorporation at room temperature in short reaction times. The radiolabelling of drug molecules and precursors with [11C]CO2 is demonstrated

Aldehyde-Catalyzed Carboxylate Exchange in a-Amino Acids with Isotopically Labeled CO2

a-Amino acids are among the essential chemical building blocks of life. These structures are embedded in many small molecule pharmaceuticals and are the primary components of peptide-based therapeutics and biologics. Isotopically labeled a-amino acids and their derivatives have widespread use in structural and mechanistic biochemistry, quantitative proteomics, absorption distribution metabolism and excretion (ADME) profiling, and as imaging agents in positron emission tomography (PET) techniques. The preparation of carbon-labeled a-amino acids remains difficult and time consuming, with established methods involving label incorporation at an early stage of synthesis. This explains the high cost and scarcity of C-labeled products and presents a major challenge in 11C applications (11C t1/2 = 20 min). Here we report that simple aldehydes catalyze the isotopic carboxylate exchange of native a-amino acids with *CO2 (* = 14, 13, 11). Proteinogenic a-amino acids and many non-natural variants containing diverse functional groups undergo labeling. The reaction likely proceeds via the trapping of *CO2 by imine-carboxylate intermediates to generate aminomalonates that are prone to monodecarboxylation. Tempering catalyst electrophilicity was key to preventing irreversible aldehyde consumption. The pre-generation of the imine carboxylate intermediate allows for the rapid and late-stage 11C-radiolabeling of a-amino acids in the presence of 11CO2