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...
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.
Stereodivergent dual catalysis has emerged as a powerful tool to selectively prepare all four stereoisomers in molecules containing two chiral centers from common starting materials. Most processes involve the use of two substrates, and it remains challenging to use dual catalyst approaches to generate molecules having three newly formed stereocenters with high diastereo‐ and enantioselectivity. Here we report a multicomponent, stereodivergent method for the synthesis of targets containing three contiguous stereocenters by the combination of enantioselective Rh‐catalyzed conjugate addition and Ir‐catalyzed allylic alkylation methodologies. Both cyclic and acyclic α,β‐unsaturated ketones undergo β‐arylation using aryl boron reagents to form an enolate nucleophile that can be subsequently allylated at the α‐position. The reactions proceed often with >95 % ee and with >90 : 10 dr. Epimerization at the α‐carbonyl center enables the preparation of any of the eight possible stereoisomers from common starting materials, as demonstrated for cyclohexanone products.
The transition metal catalyzed hydrogenation of alkenes is a well-developed technology used on lab scale as well as on large scales in the chemical industry. Site-and chemoselective mono-hydrogenations of polarized conjugated dienes remain challenging. Instead, stoichiometric main-group hydrides are used rather than H 2 . As part of an effort to develop a scalable route to prepare geranylacetone, we discovered that Rh-(CO) 2 acac/xantphos based catalysts enable the selective mono-hydrogenation of electron-poor 1,3-dienes, enones, and other polyunsaturated substrates. D-labeling and DFT studies support a mechanism where a nucleophilic Rh I -hydride selectively adds to electronpoor alkenes and the resulting Rh-enolate undergoes subsequent inner-sphere protonation by alcohol solvent. The finding that (L n )Rh(H)(CO) type catalysts can enable selective mono-hydrogenation of electron-poor 1,3-dienes provides a valuable tool in the design of related chemoselective hydrogenation processes.
The transition metal catalyzed hydrogenation of alkenes is a well-developed technology used on a lab scale as well as on large scales in the chemical industry. Site- and chemoselective mono-hydrogenations of polarized conjugated dienes remain challenging. Instead, stoichiometric main-group hydrides are used rather than H2. As part of an effort to develop a scalable route to prepare geranylacetone, we discovered that Rh(CO)2acac/xantphos based catalysts enable the selective monohydrogenation of electron-poor 1,3-dienes, enones, and other polyunsaturated substrates. D-labeling and DFT studies support a mechanism where a nucleophilic Rh(I)-hydride selectively adds to electron-poor alkenes and the resulting Rh-enolate undergoes subsequent inner-sphere protonation by alcohol solvent. The finding that (Ln)Rh(H)(CO) type catalysts can enable selective mono-hydrogenation of electron-poor (poly)enes provides a valuable tool in the design of related chemoselective reduction processes of unsaturated substrates.
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