Carbazole/cyanobenzene photocatalysts promote the direct isotopic carboxylate exchange of C(sp 3 )-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 [ 11 C]CO2 is demonstrated.The synthesis of isotopically labelled molecules is essential to drug development and nuclear medicine. As drug candidates move towards clinical research and human trials, absorption, distribution, metabolism, and excretion (ADME) studies require compounds enriched with long-lived radioisotopes like 3 H and 14 C. 1 Positron emission tomography (PET) techniques that probe the advance of disease states and can determine the efficacy of drug treatment require molecular targets radiolabelled with short-lived positron-emitting isotopes such as 11 C or 18 F. 2 The limited availability and high cost of isotopically enriched precursors make the preparation of complex targets challenging. For PET studies, compounds must be synthesized and purified within a few half-lives of the radiolabel ( 11 C t1/2 = 20.3 minutes). Approaches that selectively introduce isotopic labels from feedstock sources with compatibility towards common structural motifs found in clinical candidates will have a positive impact on both drug discovery efforts and medical imaging.Metal-catalyzed 1 H/ 3 H exchange is widely used in drug development to introduce long-lived radiolabels into target molecules. [3][4][5][6][7][8][9] The loss of 3 H labels through (bio)chemical reactions and metabolic shifting due to primary kinetic isotope effects are liabilities of 3 H-labelling approachs. 10-11 ADME tracer compounds with greater stability can be obtained by using 14 C radiolabels. 12 Similarly, 11 C-isotopologues of native bioactive molecules enable PET probe generation without changes to their biological or pharmacological properties. 13 The incorporation of 14 C, 13 C or 11 C (*C) units into drug molecules or precursors by the formation of a *C-C bond is challenging and often requires revised synthetic pathways to introduce the label from *CO, 14-18 *CH3I, [19][20] or other small molecules derived by reduction of *CO2. [21][22][23][24][25] The direct exchange of carboxylate groups with CO2 offers the potential for simple and cost-effective syntheses of C-labelled small molecules, particularly as CO2 (or BaCO3) is the feedstock for all radiolabelled carbon-based precursors. 26 The easy conversion of carboxylic acids into other common functionalities (esters, amides, ketones, alcohols) makes this an attractive tactic for isotope incorporation.The use of redox active hydroxyphthalimide ester substrates in combination with Ni-based mediators and stoichiometric metal reductants enables carboxylate groups to undergo net exchange with CO2 (Fig 1A ). [27][28] These reactions are limited to primary alkyl or cyclic secondary a...
Methods for the addition of unsaturated nucleophiles to carbonyls to generate Z-olefin products remain rare and often require either alkylb orane or zinc reductants, limiting their utility.D emonstrated here is that formic acid mediates the Rh-catalyzed, Z-selective coupling of dienes and aldehydes.T he process is distinguished by broad tolerance towards reducible or electrophilic groups.K inetic 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 mayhave wider implications in selective metal-catalyzed hydrofunctionalization reactions.
Metal-catalyzed enantioselective conjugate additions are highly reliable methods for stereoselective synthesis; however, multicomponent reactions that are initiated by conjugate arylation of acyclic π-systems are rare. These reactions 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 α,δ-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 allows 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 δ-arylation undergoes aldehyde trapping rather than protonolysis, even when water is present as a cosolvent. These findings should have broader implications in the use of privileged metal-catalyzed conjugate addition reactions as entry points toward the preparation of acyclic molecules containing nonadjacent stereocenters.
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.
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