Enantioselective Synthesis of 3,4-Dihydro-1,2-oxazepin-5(2<i>H</i>)‑ones and 2,3-Dihydropyridin-4(1<i>H</i>)‑ones from β‑Substituted β‑Hydroxyaminoaldehydes

The synthesis of 3,4-dihydro-1,2-oxazepin-5­(2<i>H</i>)-ones and 2,3-dihydropyridin-4­(1<i>H</i>)-ones from β-substituted β-hydroxyaminoaldehydes is reported. The β-hydroxyaminoaldehydes were prepared by enantioselective organocatalytic 1,4-addition of <i>N</i>-<i>tert</i>-butyl (<i>tert</i>-butyldimethylsilyl)­oxycarbamate to α,β-unsaturated aldehydes (MacMillan protocol). Alkyne addition to the aldehydes followed by alcohol oxidation furnished <i>N</i>-Boc <i>O-</i>TBS-protected β-aminoynones. Removal of the TBS protecting group initiated a 7<i>-endo-dig</i> cyclization to yield previously unknown 3,4-dihydro-1,2-oxazepin-5­(2<i>H</i>)-ones. Reductive cleavage of the N–O bond of the oxazepinones and Boc-deprotection provided 2-substituted 2,3-dihydropyridin-4­(1<i>H</i>)-ones via 6-<i>endo-trig</i> cyclization. 2,3-Dihydropyridin-4­(1<i>H</i>)-ones are versatile intermediates that have been used for the synthesis of many alkaloids. The new protocol allows the synthesis of 3-dihydropyridin-4­(1<i>H</i>)-ones carrying an array of substituents at C2 that cannot be prepared from commercial β-amino acids or by one-carbon homologation of proteinogenic amino acids. The use of readily available β-hydroxylaminoaldehydes expands the utility of our previously reported method to prepare 2,3-dihydropyridin-4­(1<i>H</i>)-ones from β-amino acids as the source of diversity and chirality. A broad substrate scope is possible because β-aminoaldehydes can be prepared from α,β-unsaturated aldehydes by an enantioselective organocatalytic process

Boron–Heck Reaction of Cyclic Enaminones: Regioselective Direct Arylation via Oxidative Palladium(II) Catalysis

An oxidative boron–Heck reaction of cyclic enaminones with arylboronic acids is reported. This protocol provides a regioselective arylation at the C6 position of cyclic enaminones. When an <i>N</i>-carbamylated cyclic enaminone was employed, a switch to a conjugate addition reaction occurred in the presence of acid

Boron–Heck Reaction of Cyclic Enaminones: Regioselective Direct Arylation via Oxidative Palladium(II) Catalysis

An oxidative boron–Heck reaction of cyclic enaminones with arylboronic acids is reported. This protocol provides a regioselective arylation at the C6 position of cyclic enaminones. When an <i>N</i>-carbamylated cyclic enaminone was employed, a switch to a conjugate addition reaction occurred in the presence of acid

Synthesis of Strained 1,3-Diene Macrocycles via Copper-Mediated Castro–Stephens Coupling/Alkyne Reduction Tandem Reactions

A copper-mediated macrocyclization involving the reaction of a vinyl iodide and a terminal alkyne followed by an in situ reduction of the enyne intermediate is reported. The reaction generates a conjugated <i>Z</i>-double bond within a strained medium-size lactone, lactam, or ether macrocycle. A variety of macrocyclic compounds bearing different ring sizes and functionalities were synthesized. A complementary stepwise procedure was also developed for less strained ring systems

Palladium-Catalyzed Direct C–H Arylation of Cyclic Enaminones with Aryl Iodides

A ligand-free method for the Pd-catalyzed direct arylation of cyclic enaminones using aryl iodides was developed. This method can be applied to a wide range of cyclic enaminones and aryl iodides with excellent C5-regioselectivity. Using widely available aryl iodides, the generality of this transformation provides easy access to a variety of 3-arylpiperidine structural motifs

Synthesis of Skeletally Diverse and Stereochemically Complex Library Templates Derived from Isosteviol and Steviol

We have applied a diversity-oriented approach for the synthesis of skeletally diverse and stereochemically complex templates for small-molecule library production by performing Beckmann rearrangement and Beckmann fragmentation reactions on the bicyclo[3.2.1]octane rings of steviol and isosteviol, aglycones derived from the diterpene natural product stevioside. The optimization of these two reaction pathways is presented along with the successful application of a photo-Beckmann rearrangement. This work also led to the discovery of cyano-Prins-type and Thorpe–Ziegler-type cyclization reactions

Copper-Assisted Palladium(II)-Catalyzed Direct Arylation of Cyclic Enaminones with Arylboronic Acids

Described herein is a palladium­(II)-catalyzed direct arylation of cyclic enaminones with arylboronic acids. The versatility of this method is that both electron-rich and electron-poor boronic acids can be coupled in high yields. A mixture of two Cu­(II) additives was crucial for efficient cross-coupling. The role of each Cu­(II) reagent appears to be distinct and complementary serving to assist catalyst reoxidation and transmetalation through a putative arylcopper intermediate

Cyclin-Dependent Kinase Inhibitor Dinaciclib Interacts with the Acetyl-Lysine Recognition Site of Bromodomains

Bromodomain-containing proteins are considered atypical kinases, but their potential to interact with kinase inhibitors is unknown. Dinaciclib is a potent inhibitor of cyclin-dependent kinases (CDKs), which recently advanced to Phase III clinical trials for the treatment of leukemia. We determined the crystal structure of dinaciclib in complex with CDK2 at 1.7 Å resolution, revealing an elaborate network of binding interactions in the ATP site, which explains the extraordinary potency and selectivity of this inhibitor. Remarkably, dinaciclib also interacted with the acetyl-lysine recognition site of the bromodomain testis-specific protein BRDT, a member of the BET family of bromodomains. The binding mode of dinaciclib to BRDT at 2.0 Å resolution suggests that general kinase inhibitors (“hinge binders”) possess a previously unrecognized potential to act as protein–protein inhibitors of bromodomains. The findings may provide a new structural framework for the design of next-generation bromodomain inhibitors using the vast chemical space of kinase inhibitors

Design, Synthesis, and in Vitro and in Vivo Evaluation of Ouabain Analogues as Potent and Selective Na,K-ATPase α4 Isoform Inhibitors for Male Contraception

Na,K-ATPase α4 is a testis-specific plasma membrane Na⁺ and K⁺ transporter expressed in sperm flagellum. Deletion of Na,K-ATPase α4 in male mice results in complete infertility, making it an attractive target for male contraception. Na,K-ATPase α4 is characterized by a high affinity for the cardiac glycoside ouabain. With the goal of discovering selective inhibitors of the Na,K-ATPase α4 and of sperm function, ouabain derivatives were modified at the glycone (C3) and the lactone (C17) domains. Ouabagenin analogue <b>25</b>, carrying a benzyltriazole moiety at C17, is a picomolar inhibitor of Na,K-ATPase α4, with an outstanding α4 isoform selectivity profile. Moreover, compound <b>25</b> decreased sperm motility in vitro and in vivo and affected sperm membrane potential, intracellular Ca²⁺, pH, and hypermotility. These results proved that the new ouabagenin triazole analogue is an effective and selective inhibitor of Na,K-ATPase α4 and sperm function

Design, Synthesis, and in Vitro and in Vivo Evaluation of Ouabain Analogues as Potent and Selective Na,K-ATPase α4 Isoform Inhibitors for Male Contraception

Na,K-ATPase α4 is a testis-specific plasma membrane Na⁺ and K⁺ transporter expressed in sperm flagellum. Deletion of Na,K-ATPase α4 in male mice results in complete infertility, making it an attractive target for male contraception. Na,K-ATPase α4 is characterized by a high affinity for the cardiac glycoside ouabain. With the goal of discovering selective inhibitors of the Na,K-ATPase α4 and of sperm function, ouabain derivatives were modified at the glycone (C3) and the lactone (C17) domains. Ouabagenin analogue <b>25</b>, carrying a benzyltriazole moiety at C17, is a picomolar inhibitor of Na,K-ATPase α4, with an outstanding α4 isoform selectivity profile. Moreover, compound <b>25</b> decreased sperm motility in vitro and in vivo and affected sperm membrane potential, intracellular Ca²⁺, pH, and hypermotility. These results proved that the new ouabagenin triazole analogue is an effective and selective inhibitor of Na,K-ATPase α4 and sperm function