A machine-learning tool to predict substrate-adaptive conditions for Pd-catalyzed C-N couplings.

Machine-learning methods have great potential to accelerate the identification of reaction conditions for chemical transformations. A tool that gives substrate-adaptive conditions for palladium (Pd)-catalyzed carbon-nitrogen (C-N) couplings is presented. The design and construction of this tool required the generation of an experimental dataset that explores a diverse network of reactant pairings across a set of reaction conditions. A large scope of C-N couplings was actively learned by neural network models by using a systematic process to design experiments. The models showed good performance in experimental validation: Ten products were isolated in more than 85% yield from a range of couplings with out-of-sample reactants designed to challenge the models. Importantly, the developed workflow continually improves the prediction capability of the tool as the corpus of data grows.

Second-Generation Atroposelective Synthesis of KRAS G12C Covalent Inhibitor GDC-6036.

A chromatography-free asymmetric synthesis of GDC-6036 (1) was achieved via a highly atroposelective Negishi coupling of aminopyridine 5 and quinazoline 6b catalyzed by 0.5 mol % [Pd(cin)Cl]2 and 1 mol % (R,R)-Chiraphite to afford the key intermediate (Ra)-3. An alkoxylation of (Ra)-3 with (S)-N-methylprolinol (4) and a global deprotection generates the penultimate heterobiaryl intermediate 2. A controlled acrylamide installation by stepwise acylation/sulfone elimination and final adipate salt formation and crystallization delivered high-purity GDC-6036 (1).

Asymmetric Hydrogenation of Unfunctionalized Tetrasubstituted Acyclic Olefins.

Asymmetric hydrogenation has evolved as one of the most powerful tools to construct stereocenters. However, the asymmetric hydrogenation of unfunctionalized tetrasubstituted acyclic olefins remains the pinnacle of asymmetric synthesis and an unsolved challenge. We report herein the discovery of an iridium catalyst for the first, generally applicable, highly enantio- and diastereoselective hydrogenation of such olefins and the mechanistic insights of the reaction. The power of this chemistry is demonstrated by the successful hydrogenation of a wide variety of electronically and sterically diverse olefins in excellent yield and high enantio- and diastereoselectivity.

Enantiospecific Synthesis of ortho-Substituted 1,1-Diarylalkanes by a 1,2-Metalate Rearrangement/anti-SN 2' Elimination/Rearomatizing Allylic Suzuki-Miyaura Reaction Sequence.

The one-pot sequential coupling of benzylamines, boronic esters, and aryl iodides has been investigated. In the presence of an N-activator, the boronate complex formed from an ortho-lithiated benzylamine and a boronic ester undergoes stereospecific 1,2-metalate rearrangement/anti-SN 2' elimination to form a dearomatized tertiary boronic ester. Treatment with an aryl iodide under palladium catalysis leads to rearomatizing γ-selective allylic Suzuki-Miyaura cross-coupling to generate 1,1-diarylalkanes. When enantioenriched α-substituted benzylamines are employed, the corresponding 1,1-diarylalkanes are formed with high stereospecificity.

ortho-Directing Chromium Arene Complexes as Efficient Mediators for Enantiospecific C(sp2 )-C(sp3 ) Cross-Coupling Reactions.

A new strategy for the coupling of a broad scope of electronically diverse aromatics to boronic esters is reported. The coupling sequence, which relies on the directed ortho-lithiation of chromium arene complexes followed by boronate formation and oxidation, occurs with complete ortho-selectivity and enantiospecificity to give the coupling products in excellent yields and with high functional group tolerance. An intermediate chromium arene boronate complex was characterized by X-ray, NMR, and IR experiments to elucidate the reaction mechanism.

Enantiospecific Synthesis of ortho-Substituted Benzylic Boronic Esters by a 1,2-Metalate Rearrangement/1,3-Borotropic Shift Sequence.

Coupling reactions between benzylamines and boronic esters have been investigated. ortho-Lithiated benzylamines react with boronic esters and a N-activator to afford ortho-substituted benzylic boronic esters with formal 1,1'-benzylidene insertion into the C-B bond. The reaction occurs by a SN2' elimination and 1,2-metalate rearrangement of the N-activated boronate complex to afford a dearomatized intermediate, which undergoes a Lewis-acid catalyzed 1,3-borotropic shift to afford the boronic ester products in high yield and with excellent enantiospecificity. The use of enantioenriched α-substituted benzylamines gave the corresponding secondary boronic esters with high ee.

Highly enantioselective transfer hydrogenation of ketones with chiral (NH)2 P2 macrocyclic iron(II) complexes.

Bis(isonitrile) iron(II) complexes bearing a C2 -symmetric diamino (NH)2 P2 macrocyclic ligand efficiently catalyze the hydrogenation of polar bonds of a broad scope of substrates (ketones, enones, and imines) in high yield (up to 99.5 %), excellent enantioselectivity (up to 99 % ee), and with low catalyst loading (generally 0.1 mol %). The catalyst can be easily tuned by modifying the substituents of the isonitrile ligand.

Isonitrile iron(II) complexes with chiral N2P2 macrocycles in the enantioselective transfer hydrogenation of ketones.

Bis(isonitrile) iron(II) complexes bearing a C2-symmetric N2P2 macrocyclic ligand, which are easily prepared from the corresponding bis(acetonitrile) analogue, catalyze the asymmetric transfer hydrogenation (ATH) of a broad scope of ketones in excellent yields (up to 98%) and with high enantioselectivity (up to 91% ee).