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An enantioselective copper-catalyzed asymmetric conjugate addition of Me2Zn to (Z)-nitroalkenes led to the formation of all-carbon quaternary stereogenic centers with high stereoselectivity. The key features of the new method are the unprecedented use of [(MeCN)4Cu]PF6 in conjunction with the Hoveyda ligand L1 and the use of (Z)-nitroalkene substrates so that undesired nitroalkene isomerization is minimized and enantioselectivity is enhanced dramatically. We also describe a novel, practical, and highly (Z)-selective nitroalkene synthesis. [ABSTRACT FROM AUTHOR]

The development of synthetic routes to 4-[6-(morpholinomethyl) pyridin-3-yl]naphthalen-1-amine, the key intermediate of p38 MAP kinase inhibitor BIRB 1017, via (1) trialkylmagnesium ate complex mediated metalation and borylation followed by Suzuki coupling reactions and (2) pyridine-ring formation from a vinamidinium salt, is described. [ABSTRACT FROM AUTHOR]

This review article summarizes C-H functionalization-based synthesis of indoles and related structures (e.g. carbazoles and indolines) with an emphasis on literature after 2000. The discussion is organized into four broadly defined sections: a) via nitrene or carbene insertion into a C-H bond; b) via direct coupling of two sp2 carbon centers; c) via transition-metal catalyzed C-H amination and d) other strategies. [ABSTRACT FROM AUTHOR]

A mild and efficient synthesis of various 3-brominated azaindoles and diazaindoles was developed by regioselective halogenation of the parent systems. This practical and high-yielding transformation was achieved with copper(II) bromide in acetonitrile at room temperature. [ABSTRACT FROM AUTHOR]

A practical stereoselective synthesis is reported for an α-trifluoromethyl-α-alkyl epoxide (1), which is an important pharmaceutical intermediate. The key step involves a chiral auxiliary-controlled asymmetric trifluoromethylation reaction for the introduction of the unique trifluoromethyl-substituted tertiary alcohol stereogenic center in the target molecule. The fluoride-initiated CF3 addition to chiral keto ester 6a proceeded with a diastereoselectivity up to 86:14. The major diastereomer was readily obtained with a <99.5:0.5 dr through a simple crystallization of the crude product mixture. [ABSTRACT FROM AUTHOR]

Dilithiation of 3-amino-4-picoline (1) was achieved with sec-BuLi at room temperature. Condensation of the resulting dianion (2) with carboxylic esters afforded a wide range of 2-substituted 6-azaindoles in good yields. [ABSTRACT FROM AUTHOR]

(R)‐4‐((R)‐1‐((6‐(1‐[tert‐butyl]‐1H‐pyrazol‐4‐yl)‐2‐methyl‐2H‐pyrazolo[3,4‐d]pyridin‐4‐yl)oxy)ethyl)pyrrolidin‐2‐one (BI 894416, 1) and (R)‐4‐((R)‐1‐((6‐(1‐[tert‐butyl]‐1H‐pyrazol‐4‐yl)‐2,3‐dimethyl‐2H‐indazol‐4‐yl)oxy)ethyl)pyrrolidin‐2‐one (BI 1342561, 2) are two new potent and selective spleen tyrosine kinase inhibitors developed to treat severe asthma. Both compounds have similar structures and they differ only in the bicyclic moiety 2‐methyl‐2H‐pyrazolo[4,3‐c]pyridine in 1 versus 2,3‐dimethyl‐2H‐indazole in 2. In the carbon 14 synthesis, 1‐(1‐[tert‐butyl]‐1H‐pyrazol‐4‐yl)ethan‐1‐one‐1‐14C ([14C]‐8) was prepared from the cyanation of 4‐bromopyrazole using zinc [14C]cyanide followed by methyl lithium addition on the nitrile group. The enolate of [14C]‐8 was then used to access these two bicyclic moieties via pyrano‐pyrazoles [14C]‐11 and [14C]‐12, which were further transformed in few more steps to [14C]‐(1) and [14C]‐2. Both inhibitors contain a tert‐butyl group. Introducing tert‐butyl‐d9 will not only provide internal standards for bioanalytical studies, but it is also expected to slow down the metabolism of these two compounds. Most of the metabolites of compound 1, for example, are the result of tert‐butyl oxidation, like alcohol 3, acid 4, and the further N‐demethylation of 4 to 5. The detailed preparation of these deuterium‐labeled metabolites is also described. [ABSTRACT FROM AUTHOR]

The generation of amyloid beta peptides that aggregate in the brain is believed to play a major role in Alzheimer's disease. In theory, the inhibition of beta‐site amyloid precursor protein‐cleaving enzyme 1 (BACE1), which catalyzes the initial rate‐limiting step in amyloid beta production, may slow or stop Alzheimer's disease. Herein, we report the preparation of two potent BACE1 inhibitors, BI 1147560 (1) and BI 1181181 (2), labeled with carbon‐14 and with deuterium. The use of advanced key chiral intermediates like 3 and 5 shortened the carbon‐14 syntheses of these two compounds to five and six steps, respectively, and helped in preparing them with very high chemical purity and enantiomeric excess without deviating from the process chemistry route. For the deuterium synthesis, oxetan‐3‐ylmethanamine [2H6]‐7 and 2‐fluoro‐2‐methylpropan‐1‐amine [2H6]‐9 were prepared then used with the chiral intermediate 5 to furnish deuterium labeled 1 and 2, respectively. [ABSTRACT FROM AUTHOR]

A new family of dihydrobenzoazaphosphosphole ligands was prepared and shown to enable modification of the phosphine electronic character by variation of the N-substituent. This new family of phosphines was shown to be highly active in the Pd-catalyzed Suzuki-Miyaura cross-coupling reaction with hindered coupling partners. [ABSTRACT FROM AUTHOR]

The Pd-catalyzed 3-arylation of 2-oxindoles with aryl bromides, chlorides and triflates is found to proceed using i-Pr-BI-DIME and Me2-BI-DIME ligands. The mono-arylation of 3-unsubstituted oxindoles is accomplished using a Pd2(dba)3/i-Pr-BI-DIME catalyst system, and gives good yields of 3-aryloxindoles from aryl bromides and chlorides. The arylation of 3-substituted oxindoles is also possible using this catalyst/ligand system. The asymmetric arylation of 3-substituted oxindoles is accomplished using Me2-BI-DIME to furnish oxindoles bearing a quaternary C-3 stereocenter in enantiomeric ratios of up to 93:7. [ABSTRACT FROM AUTHOR]

Novel bidentate phosphine ligands BABIPhos featuring a biaryl bis-dihydrobenzooxaphosphole core are presented. Their synthesis was achieved via Pd-catalyzed reductive homocoupling of dihydrobenzooxaphosphole aryl triflates. An efficient route toward various analogues was also established, giving access to phosphines with different electronic and steric properties. The newly obtained ligands demonstrated high efficiency and selectivity in Rh-catalyzed asymmetric hydrogenation of di- and trisubstituted enamides. This new class of ligands is complementary to previously described bidentate benzooxaphosphole ligands BIBOP. [ABSTRACT FROM AUTHOR]

Enantioselective synthesis of a-aryl and a-heteroaryl piperidines is reported. The key step is an iridium-catalyzed asymmetric hydrogenation of substituted N-benzylpyridinium salts. High levels of enantioselectivity up to 99.3:0.7 er were obtained for a range of a-heteroaryl piperidines. DFT calculations support an outersphere dissociative mechanism for the pyridinium reduction. Notably, initial protonation of the final enamine intermediate determines the stereochemical outcome of the transformation rather than hydride reduction of the resultant iminium intermediate. [ABSTRACT FROM AUTHOR]

P-Stereogenic chiral phosphine BI-BOP is employed for the first time as ligand to promote catalytic enantioselective synthesis of phosphoryl-substituted atropisomeric vinylarenes through a palladium−carbene pathway. This strategy utilizes 10 mol% palladium(II) acetate, 10 mol% phosphine ligand as well as a variety of N-tosylhydrazones and phosphoryl-substituted aryl bromides as the reaction partners. The desired axially chiral vinylarenes were isolated with up to 80% yield and 96:4 er, and can be further converted effectively and stereoselectively into dialkylphosphoryl-substituted atropisomeric arenes through a Grignard reaction. This protocol offers a general approach to synthesize phosphoryl-substituted atropisomeric vinylarenes with high enantiomeric purities. [ABSTRACT FROM AUTHOR]

The development of enantioselective carbon-carbon bond couplings catalyzed by nonprecious metals is highly desirable in terms of cost efficiency and sustainability. The first nickel-catalyzed enantioselective Mizoroki-Heck coupling is reported. This transformation is accomplished via mild reaction conditions, leveraging on QuinoxP* as a chiral ligand to afford oxindoles containing quaternary stereocenters. Good reactivity and selectivity are observed in the presence of various functional groups. Computational studies suggest that the oxidative addition assembles an atropisomeric intermediate responsible for the facial selectivity of the insertion step. [ABSTRACT FROM AUTHOR]

A general and efficient method for the synthesis of bulky and structurally diverse P-stereogenic chiral secondary phosphine oxides (SPOs) by using readily available chiral amino alcohol templates is described. These chiral SPOs could be used as chiral building blocks for the synthesis of difficult-to-access bulky P-stereogenic phosphine compounds or ligands for organic catalysis. [ABSTRACT FROM AUTHOR]

A convergent, robust, and concise synthesis of a developmental CCR1 antagonist is described using continuous flow technology. In the first approach, following an expeditious SNAr sequence for cyclopropane introduction, a safe, continuous flow Curtius rearrangement was developed for the synthesis of a p-methoxybenzyl (PMB) carbamate. Based on kinetic studies, a highly efficient and green process comprising three chemical transformations (azide formation, rearrangement, and isocyanate trapping) was developed with a relatively short residence time and high material throughput (0.8 kg h−1, complete E-factor = ∼9) and was successfully executed on 40 kg scale. Moreover, mechanistic studies enabled the execution of a semi-continuous, tandem Curtius rearrangement and acid–isocyanate coupling to directly afford the final drug candidate in a single, protecting group-free operation. The resulting API synthesis is further determined to be extremely green (RPG = 166%) relative to the industrial average for molecules of similar complexity. [ABSTRACT FROM AUTHOR]

Through a computer-guided approach, new series of monophosphine ligands were designed and developed for asymmetric Suzuki-Miyaura couplings of challenging heterocyclic substrates. Computer modeling pointed to a tunable, yet unexplored quadrant in BI-DIME, leading to the discovery of the 3′,5′-dimethyl-substituted ligand which improved the atropisomeric selectivity of the Suzuki-Miyaura reaction from the previously reported 5:1 dr to 15:1 dr for the synthesis of a challenging HIV integrase intermediate, and up to 24:1 dr with various other quinoline substrates. [ABSTRACT FROM AUTHOR]

The rhodium-catalyzed asymmetric allenylation of sulfonylimines is disclosed providing silyl homoallenylamide products in up to 99:1 er. Through subsequent activation of the C−N bond of the silyl homoallenyl sulfonamide, palladium-catalyzed stereospecific allylic allenylation could be achieved giving C−C bond formation with high chirality transfer. The synthetic utility of both the silyl homoallenyl sulfonamides and the silyl homoallenyl malonates as bis(nucleophiles) is demonstrated. [ABSTRACT FROM AUTHOR]

Two potent glucocorticoid receptor agonists were prepared labeled with carbon-14 and with stable isotopes to perform drug metabolism, pharmacokinetics, and bioanalytical studies. Carbon-14 labeled (1) was obtained from an enantiopure alkyne (5) via a Sonogashira coupling to a previously reported 5-amino-4-iodo-[2-14C]pyrimidine [14C]-(6), followed by a base-mediated cyclization (1) in 72% overall radiochemical yield. Carbon-14 labeled (2) was prepared in five steps employing a key benzoic acid intermediate [14C]-(13), which was synthesized in one pot from enolization of trifluoromethylketone (12), followed by bromine-magnesium exchange and then electrophile trapping reaction with [14C]-carbon dioxide. A chiral auxiliary ( S)-1-(4-methoxyphenyl)ethylamine was then coupled to this acid to give [14C]-(15). Propargylation and separation of diastereoisomers by crystallizations gave the desired diastereomer [14C]-(17) in 34% yield. Sonogashira coupling to iodopyridine (10) followed by cyclization to the azaindole [14C]-(18) and finally removal of the chiral auxiliary gave [14C]-(2) in 7% overall yield. For stable isotope syntheses, [13C6]-(1) was obtained in three steps using [13C4]-(6) and trimethylsilylacetylene-[13C2] in 26% yield, while [2H5]-(2) was obtained by first preparing the iodopyridine [2H5]-(10) in five steps. Then, Sonogashira coupling to chiral alkyne (24) and cyclization gave [2H5]-(2) in 42% overall yield. [ABSTRACT FROM AUTHOR]

The use of chiral phosphinamides is relatively unexplored because of the lack of a general method for the synthesis. Reported herein is the development of a general, efficient, and highly enantioselective method for the synthesis of structurally diverse P-stereogenic phosphinamides. The method relies on nucleophilic substitution of a chiral phosphinate derived from the versatile chiral phosphinyl transfer agent 1,3,2-benzoxazaphosphinine-2-oxide. These chiral phosphinamides were utilized for the first synthesis of readily tunable P-stereogenic Lewis base organocatalysts, which were used successfully for highly enantioselective catalysis. [ABSTRACT FROM AUTHOR]

Air-stable P-chiral dihydrobenzooxaphosphole oxazoline ligands were designed and synthesized. When they were used in the iridium-catalyzed asymmetric hydrogenation of unfunctionalized 1-aryl-3,4-dihydronaphthalenes under one atmosphere pressure of H2, up to 99:1 e.r. was obtained. High enantioselectivities were also observed in the reduction of the exocyclic imine derivatives of 1-tetralones. [ABSTRACT FROM AUTHOR]

The development of a large scale synthesis of the glucocorticoid agonist BI 653048 BS H3PO4 (1⋅H3PO4) is presented. A key trifluoromethyl ketone intermediate 22 containing an N-(4-methoxyphenyl)ethyl amide was prepared by an enolization/bromine-magnesium exchange/electrophile trapping reaction. A nonselective propargylation of trifluoromethyl ketone 22 gave the desired diastereomer in 32% yield and with dr = 98:2 from a 1:1 diastereomeric mixture after crystallization. Subsequently, an asymmetric propargylation was developed which provided the desired diastereomer in 4:1 diastereoselectivity and 75% yield with dr = 99:1 after crystallization. The azaindole moiety was efficiently installed by a one-pot cross coupling/indolization reaction. An efficient deprotection of the 4-methoxyphenethyl group was developed using H3PO4/anisole to produce the anisole solvate of the API in high yield and purity. The final form, a phosphoric acid cocrystal, was produced in high yield and purity and with consistent control of particle size. [ABSTRACT FROM AUTHOR]

An efficient enantiospecific synthesis of the cell adhesion inhibitor BIRT-377 by self-regeneration of stereocenters has been achieved in 38% overall yield in eight steps. The key transformations involve the stereoselective formation of the trans imidazolidinone 7, subsequent alkylation, and the efficient hydrolysis of disubstituted imidazolidinone 9. The process is practical, robust, and cost-effective; it has been successfully implemented in the pilot plant to produce multikilogram quantities of the drug BIRT-377 1. [Copyright &y& Elsevier]

A practical and improved synthesis of (3S,5S)-3-[(tert-butyloxycarbonyl)methyl]-5-[(methanesulfonyloxy)-methyl] -2-pyrrolidinone (1) is described. The key transformations involve a highly efficient reaction sequence consisting of ethoxycarbonylation, alkylation, hydrolysis, and decarboxylation to produce compound 10. The process described herein is practical, robust, and cost-effective, and it has been successfully implemented in a pilot plant to produce a multikilogram quantity of mesylate 1. [ABSTRACT FROM AUTHOR]

The article discusses research on the discovery of a highly enantioselective and site selective copper alkoxide catalyzed propargylation of aldehydes with a propargyl borolane. It mentions that the sue of phospine ligands dramatically improves the site selectivity for the homopropargylic alcohol. It states that by utilizing disclosed air stable BIBOP ligands, an enantioselective reaction was achieved.

The first continuous flow iron-catalyzed Kumada cross-coupling is developed for the coupling of 2-chloropyrazine and various aryl Grignard reagents using low catalyst loadings (0.5 mol-%). [ABSTRACT FROM AUTHOR]

The article presents chemical equations related to the article "Synthesis of P-Chiral Dihydrobenzooxaphospholes Through Negishi Cross--Coupling" by J.D. Sieber and others, published in the periodical "Journal of Organic Chemistry" in 2016.

Retrosynthesis, the strategy of devising laboratory pathways by working backwards from the target compound, is crucial yet challenging. Enhancing retrosynthetic efficiency requires overcoming the vast complexity of chemical space, the limited known interconversions between molecules, and the challenges posed by limited experimental datasets. This study introduces generative machine learning methods for retrosynthetic planning. The approach features three innovations: generating reaction templates instead of reactants or synthons to create novel chemical transformations, allowing user selection of specific bonds to change for human-influenced synthesis, and employing a conditional kernel-elastic autoencoder (CKAE) to measure the similarity between generated and known reactions for chemical viability insights. These features form a coherent retrosynthetic framework, validated experimentally by designing a 3-step synthetic pathway for a challenging small molecule, demonstrating a significant improvement over previous 5-9 step approaches. This work highlights the utility and robustness of generative machine learning in addressing complex challenges in chemical synthesis., (© 2024. The Author(s).)

Carbon 14 labeled Iclepertin (BI 425809, 1) and its major metabolites were needed for ADME and several other studies necessary for the advancement of this drug candidate in clinical trials. Iclepertin is composed of two main chemical blocks, (R)-5-(methylsulfonyl)-2-([1,1,1-trifluoropropan-2-yl]oxy)benzoic acid (2), and 3-[(1R,5R)-3-azabicyclo[3.1.0]hexan-5-yl]-5-(trifluoromethyl)isoxazole (3) linked to each other via an amide bond. In the first synthesis of carbon 14 labeled 1, 2-fluorobenzoic acid, carboxyl- 14 C was converted to [ 14 C]-2 in three steps and then coupled to 3 to provide [ 14 C]-1a in 45% overall yield. In the second synthesis, [ 14 C]-3 was prepared in six radioactive steps and coupled to the acid 2 to furnish [ 14 C]-1b in 20% overall yield. Both synthetic routes provided [ 14 C]-1a and [ 14 C]-1b with specific activities higher than 53 mCi/mmol and radiochemical, chemical, and enantiomeric purities above 98%. Two major metabolites of 1, BI 761036 and BI 758790, were also prepared labeled with carbon 14 using intermediates already available from the synthesis of [ 14 C]-1., (© 2023 John Wiley & Sons Ltd.)

Density functional theory (DFT) is a powerful tool to model transition state (TS) energies to predict selectivity in chemical synthesis. However, a successful multistep synthesis campaign must navigate energetically narrow differences in pathways that create some limits to rapid and unambiguous application of DFT to these problems. While powerful data science techniques may provide a complementary approach to overcome this problem, doing so with the relatively small data sets that are widespread in organic synthesis presents a significant challenge. Herein, we show that a small data set can be labeled with features from DFT TS calculations to train a feed-forward neural network for predicting enantioselectivity of a Negishi cross-coupling reaction with P -chiral hindered phosphines. This approach to modeling enantioselectivity is compared with conventional approaches, including exclusive use of DFT energies and data science approaches, using features from ligands or ground states with neural network architectures., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Selective carbon-carbon (C-C) bond formation in chemical synthesis generally requires prefunctionalized building blocks. However, the requisite prefunctionalization steps undermine the overall efficiency of synthetic sequences that rely on such reactions, which is particularly problematic in large-scale applications, such as in the commercial production of pharmaceuticals. Herein, we describe a selective and catalytic method for synthesizing 1,3-enynes without prefunctionalized building blocks. In this transformation several classes of unactivated internal acceptor alkynes can be coupled with terminal donor alkynes to deliver 1,3-enynes in a highly regio- and stereoselective manner. The scope of compatible acceptor alkynes includes propargyl alcohols, (homo)propargyl amine derivatives, and (homo)propargyl carboxamides. This method is facilitated by a tailored P,N-ligand that enables regioselective addition and suppresses secondary E / Z -isomerization of the product. The reaction is scalable and can operate effectively with as low as 0.5 mol % catalyst loading. The products are versatile intermediates that can participate in various downstream transformations. We also present preliminary mechanistic experiments that are consistent with a redox-neutral Pd(II) catalytic cycle.