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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‐14C was converted to [14C]‐2 in three steps and then coupled to 3 to provide [14C]‐1a in 45% overall yield. In the second synthesis, [14C]‐3 was prepared in six radioactive steps and coupled to the acid 2 to furnish [14C]‐1b in 20% overall yield. Both synthetic routes provided [14C]‐1a and [14C]‐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 [14C]‐1. [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]

N-heterocyclic carbenes are found to be highly effective organocatalysts in activating TMSCN for facile cyanosilylation of carbonyl compounds. Cyano transfer from MSCN to aldehydes and ketones proceeds at room temperature in the presence of only 0.01-0.05 mol % of N-heterocyclic carbene leading to a range of trimethylsilylated cyanohydrins in very good to excellent yields.

Research has been conducted on (3S,5S)-3-[(tert-butyloxycarbonyl)methyl]-5-[(methanesulfonyloxy)methyl]-2-pyrrolidinone. The synthesis of this compound has been improved and the details are described.

A four-step synthetic route for an efficient synthesis of natural alkaloids fusaric acid and (S)-(+)-fusarinolic acid is described. The method is based on using 5-bromo-2-iodopyridine as a template to yield monoester without diester formation. Data show that the overall yields are 55% and 70% for fusaric acid and (S)-(+)-fusarinolic acid, respectively.

The article explains the various mechanisms involved in the enantio- and regioselective copper catalyzed asymmetric propargylation of aldehydes. The technique used for the propargylation is shown to exhibit broad functional tolerance and hence can be used for various other applications.

A wide range of stereoselective synthetic methods are used in the large-scale asymmetric synthesis of active pharmaceutical ingredients (APIs). Asymmetric catalysis, particularly asymmetric C-C bond-forming and dynamic kinetic resolution approaches are being incorporated into the large-scale synthesis of APIs because they are intrinsically more efficient than may stoichiometric protocols.

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]

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]

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]

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]

Extensive research has been conducted on stereospecific aldol reactions since 1978 because of their broad use in the synthesis of stereochemically complex polyketide natural products such as macrolides. However, anti-selective aldol reactions are hardly ever used in natural product synthesis as strategic bond-forming reactions. This issue is addressed through the development of a highly enantioselective anti-aldol reaction using the chiral E(O) enol borinate 1 generated from the chiral ester 2. Its application to synthesize two key fragments of miyakolide are discussed.

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]

An efficient continuous flow iron-catalyzed Kumada cross-coupling was developed for the coupling of 2-chloropyrazine and various aryl Grignard reagents in presence of low catalyst loadings (0.5 mol-%). Compared to batch mode, the continuous flow approach overcomes the exothermicity which enabled longer catalyst lifetime, facilitated scale-up and significantly improved the yield. To the best of our knowledge, this is the first example of flow iron-catalyzed Kumada cross-coupling reactions which addresses scale dependence issues which often plague Kumada reactions carried out in the traditional batch mode. [ABSTRACT FROM AUTHOR]

An efficient continuous flow iron-catalyzed Kumada cross-coupling was developed for the coupling of 2-chloropyrazine and various aryl Grignard reagents in presence of low catalyst loadings (0.5 mol-%). Compared to batch mode, the continuous flow approach overcomes the exothermicity which enabled longer catalyst lifetime, facilitated scale-up and significantly improved the yield. To the best of our knowledge, this is the first example of flow iron-catalyzed Kumada cross-coupling reactions which addresses scale dependence issues which often plague Kumada reactions carried out in the traditional batch mode. [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]

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]