Discovery of (4-Pyrazolyl)-2-aminopyrimidines as Potent and Selective Inhibitors of Cyclin-Dependent Kinase 2.

CDK2 is a critical regulator of the cell cycle. For a variety of human cancers, the dysregulation of CDK2/cyclin E1 can lead to tumor growth and proliferation. Historically, early efforts to develop CDK2 inhibitors with clinical applications proved unsuccessful due to challenges in achieving selectivity over off-target CDK isoforms with associated toxicity. In this report, we describe the discovery of (4-pyrazolyl)-2-aminopyrimidines as a potent class of CDK2 inhibitors that display selectivity over CDKs 1, 4, 6, 7, and 9. SAR studies led to the identification of compound 17, a kinase selective and highly potent CDK2 inhibitor (IC50 = 0.29 nM). The evaluation of 17 in CCNE1-amplified mouse models shows the pharmacodynamic inhibition of CDK2, measured by reduced Rb phosphorylation, and antitumor activity.

Benzylic Photobromination for the Synthesis of Belzutifan: Elucidation of Reaction Mechanisms Using In Situ LED-NMR.

A detailed mechanistic understanding of a benzylic photobromination en route to belzutifan (MK-6482, a small molecule for the treatment of renal cell carcinoma associated with von Hippel-Lindau syndrome) has been achieved using in situ LED-NMR spectroscopy in conjunction with kinetic analysis. Two distinct mechanisms of overbromination, namely, the ionic and radical pathways, have been revealed by this study. The behavior of the major reaction species, including reactants, intermediates, products, and side products, has been elucidated. Comprehensive understanding of both pathways informed and enabled mitigation of a major process risk: a sudden product decomposition. Detailed knowledge of the processes occurring during the reaction and their potential liabilities enabled the development of a robust photochemical continuous flow process implemented for commercial manufacturing.

Metal-Free Intermolecular Coupling of Arenes with Secondary Amides: Chemoselective Synthesis of Aromatic Ketimines and Ketones, and N-Deacylation of Secondary Amides.

The direct transformation of common secondary amides into aromatic ketimines and aromatic ketones with C-C bond formation is described. The reaction can also be used for N-deacylation of secondary amides to release amines. This method consists of in situ amide activation with triflic anhydride and intermolecular capture of the resulting highly electrophilic nitrilium intermediate with an arene. The reaction is applicable to various kinds of secondary amides (electrophiles), but only electron-rich and moderately electron-rich arenes can be used as nucleophiles. Thanks to the use of bench stable arenes instead of reactive and basic organometallics as nucleophiles, the reaction proceeded with high chemoselectivity at the secondary amido group in the presence of a series of sensitive functional groups such as aldehyde, ketone, ester, cyano, nitro, and tertiary amido groups. The reaction can be viewed as a Friedel-Crafts-type reaction using secondary amides as acylating agents or as an intermolecular version of the Bischler-Napieralski reaction.

Kinetic Resolution of Benzylamines via Palladium(II)-Catalyzed C-H Cross-Coupling.

A Pd(II)-catalyzed enantioselective C-H cross-coupling of benzylamines via kinetic resolution has been achieved using chiral mono-N-protected α-amino-O-methylhydroxamic acid (MPAHA) ligands. Both chiral benzylamines and ortho-arylated benzylamines are obtained in high enantiomeric purity. The use of a readily removable nosyl (Ns) protected amino group as the directing group is a crucial practical advantage. Moreover, the ortho-arylated benzylamine products could be further transformed into chiral 6-substituted 5,6-dihydrophenanthridines as important structural motifs in natural products and bioactive molecules.

Ligand-Enabled Arylation of γ-C-H Bonds.

Pd(II) -catalyzed arylation of γ-C(sp(3) )-H bonds of aliphatic acid-derived amides was developed by using quinoline-based ligands. Various γ-aryl-α-amino acids were prepared from natural amino acids using this method. The influence of ligand structure on reactivity was also systematically investigated.

Enantioselective C-H Olefination of α-Hydroxy and α-Amino Phenylacetic Acids by Kinetic Resolution.

Significant progress has been made in the past decade regarding the development of enantioselective C-H activation reactions by desymmetrization. However, the requirement for the presence of two chemically identical prochiral C-H bonds represents an inherent limitation in scope. Reported is the first example of kinetic resolution by a palladium(II)-catalyzed enantioselective C-H activation and C-C bond formation, thus significantly expanding the scope of enantioselective C-H activation reactions.

A general method for the one-pot reductive functionalization of secondary amides.

A one-pot reaction for the transformation of common secondary amides into amines with C-C bond formation is described. This method consists of in situ amide activation with Tf2O-partial reduction-addition of C-nucleophiles. The method is general in scope, which allows employing both hard nucleophiles (RMgX, RLi) and soft nucleophiles, as well as enolates. With the use of soft nucleophiles, the reaction proceeded with high chemoselectivity at a secondary amide in the presence of ester, cyano, nitro, and tertiary amide groups.

Room-temperature enantioselective C-H iodination via kinetic resolution.

Asymmetric carbon-hydrogen (C-H) activation reactions often rely on desymmetrization of prochiral C-H bonds on the same achiral molecule, using a chiral catalyst. Here, we report a kinetic resolution via palladium-catalyzed enantioselective C-H iodination in which one of the enantiomers of a racemic benzylic amine substrates undergoes faster aryl C-H insertion with the chiral catalysts than the other. The resulting enantioenriched C-H functionalization products would not be accessible through desymmetrization of prochiral C-H bonds. The exceedingly high relative rate ratio (k(fast)/k(slow) up to 244), coupled with the subsequent iodination of the remaining enantiomerically enriched starting material using a chiral ligand with the opposite configuration, enables conversion of both substrate enantiomers into enantiomerically pure iodinated products.

Tertiary amide-based Knoevenagel-type reactions: a direct, general, and chemoselective approach to enaminones.

We report one-pot and chemoselective Knoevenagel-type reactions using highly stable amides and lactams as the electrophilic substrates. The method is based on the in situ activation of amide carbonyl with triflic anhydride and a subsequent reaction with carbanions generated in situ from carbonyl compounds. The amide-based method is an alternative to the versatile thioamide-based Eschenmoser sulfide contraction.

Palladium(II)-catalyzed enantioselective C(sp³)-H activation using a chiral hydroxamic acid ligand.

An enantioselective method for Pd(II)-catalyzed cross-coupling of methylene ß-C(sp(3))-H bonds in cyclobutanecarboxylic acid derivatives with arylboron reagents is described. High yields and enantioselectivities were achieved through the development of chiral mono-N-protected α-amino-O-methylhydroxamic acid (MPAHA) ligands, which form a chiral complex with the Pd(II) center. This reaction provides an alternative approach to the enantioselective synthesis of cyclobutanecarboxylates containing α-chiral quaternary stereocenters. This new class of chiral catalysts also show promises for enantioselective ß-C(sp(3))-H activation of acyclic amides.

General one-pot reductive gem-bis-alkylation of tertiary lactams/amides: rapid construction of 1-azaspirocycles and formal total synthesis of (±)-cephalotaxine.

Amides are a class of highly stable and readily available compounds. The amide functional group constitutes a class of powerful directing/activating and protecting group for C-C bond formation. Tertiary tert-alkylamine, including 1-azaspirocycle is a key structural feature found in many bioactive natural products and pharmaceuticals. The transformation of amides into tert-alkylamines generally requires several steps. In this paper, we report the full details of the first general method for the direct transformation of tertiary lactams/amides into tert-alkylamines. The method is based on in situ activation of amide with triflic anhydride/2,6-di-tert-butyl-4-methylpyridine (DTBMP), followed by successive addition of two organometallic reagents of the same or different kinds to form two C-C bonds. Both alkyl and functionalized organometallic reagents and enolates can be used as the nucleophiles. The method displayed excellent 1,2- and good 1,3-asymmetric induction. Construction of 1-azaspirocycles from lactams required only two steps or even one-step by direct spiroannelation of lactams. The power of the method was demonstrated by a concise formal total synthesis of racemic cephalotaxine.

A direct and general method for the reductive alkylation of tertiary lactams/amides: application to the step economical synthesis of alkaloid (-)-morusimic acid D.

Full details of the direct and general method for the reductive alkylation of tertiary lactams and amides to give tertiary sec-alkylamines are presented. This one-pot method consists of in situ activation of a lactam or an amide with Tf2O/DTBMP, addition of a Grignard reagent, and reduction of the resulting iminium intermediates. Alkyl, benzyl, and aryl Grignard reagents and several reductants or reducing conditions (LiAlH4, NaBH4, Hantzsch ester, Bu3SnH, Pd(OH)2/C, H2) could be used effectively. Reductive alkylations of substituted lactams demonstrated good to excellent 1,3-asymmetric induction to provide the corresponding di- or trisubstituted pyrrolidine/piperidine in 6:1 (LiAlH4), 11:1 (Et3SiH), and 20:1 (catalytic hydrogenation) cis/trans diastereoselectivity, respectively. The versatility of this methodology was demonstrated by its application in the concise stereoselective synthesis of piperidine alkaloid (-)-morusimic acid.

Pd(II)-catalyzed phosphorylation of aryl C-H bonds.

A Pd(II)-catalyzed C-H phosphorylation reaction has been developed using heterocycle-directed ortho-palladation. Both H-phosphonates and diaryl phosphine oxides are suitable coupling partners for this reaction.