RESUMEN
The ring strain present in azetidines can lead to undesired stability issues. Herein, we described a series of N-substituted azetidines which undergo an acid-mediated intramolecular ring-opening decomposition via nucleophilic attack of a pendant amide group. Studies were conducted to understand the decomposition mechanism enabling the design of stable analogues.
RESUMEN
Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules that simultaneously bind to a target protein and an E3 ligase, thereby leading to ubiquitination and subsequent degradation of the target. They present an exciting opportunity to modulate proteins in a manner independent of enzymatic or signaling activity. As such, they have recently emerged as an attractive mechanism to explore previously "undruggable" targets. Despite this interest, fundamental questions remain regarding the parameters most critical for achieving potency and selectivity. Here we employ a series of biochemical and cellular techniques to investigate requirements for efficient knockdown of Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase essential for B cell maturation. Members of an 11-compound PROTAC library were investigated for their ability to form binary and ternary complexes with BTK and cereblon (CRBN, an E3 ligase component). Results were extended to measure effects on BTK-CRBN cooperative interactions as well as in vitro and in vivo BTK degradation. Our data show that alleviation of steric clashes between BTK and CRBN by modulating PROTAC linker length within this chemical series allows potent BTK degradation in the absence of thermodynamic cooperativity.
Asunto(s)
Proteínas Tirosina Quinasas/metabolismo , Proteolisis , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinación , Agammaglobulinemia Tirosina Quinasa , Animales , Células Cultivadas , Ligandos , Poliubiquitina/metabolismo , Ratas , TermodinámicaRESUMEN
A new and highly selective method for the synthesis of hydroxyl-substituted tetrahydropyrans is described. This method utilizes titanium(IV) isopropoxide and diethyl tartrate to perform a diastereoselective epoxidation followed by in situ epoxide activation and highly selective endo-cyclization to form the desired tetrahydropyran ring. The HIJ ring fragment of the marine ladder polyether yessotoxin was synthesized using this two-stage tactic that proceeds with high efficiency and excellent regioselectivity.
Asunto(s)
Compuestos Epoxi/síntesis química , Éteres/síntesis química , Compuestos Organometálicos/química , Piranos/síntesis química , Tartratos/química , Ciclización , Compuestos Epoxi/química , Éteres/química , Estructura Molecular , Piranos/química , EstereoisomerismoRESUMEN
The coordination of transition metals to organic fragments can yield complexes with fascinating and unexpected binding patterns. The study of metal-benzyl complexes has demonstrated the feasibility of η(3)-coordination, which results in a dearomatized ring. These complexes also offer insight into reaction mechanisms as proposed intermediates in catalytic cycles. In this Review we discuss the synthesis and characterization of these complexes with late transition metals and the subsequent development of catalytic benzylic functionalization methods, including asymmetric variants.
RESUMEN
Asymmetric benzylation of prochiral azlactone nucleophiles enables the catalytic introduction of a benzyl group towards the synthesis of α,α-disubstituted amino acids. Herein, we report an enantioselective palladium-catalyzed process using chiral bis(diphenylphosphinobenzoyl)diamine (dppba) ligands. Naphthalene- and heterocycle-based methyl carbonates react with a number of azlactones derived from both natural and unnatural amino acids. Monocyclic benzylic electrophiles, for which the barrier to ionization is higher, must employ a phosphate leaving group in order to react. Reaction conditions for electron-rich and -neutral benzylic electrophiles have been developed, and the scope of the reaction has been explored with respect to both reaction partners. The high levels of asymmetric induction, as well as the reactivity pattern of the electrophiles, suggest an η(3)-benzyl intermediate that arises through two distinct pathways.
RESUMEN
Palladium-catalyzed asymmetric benzylation has been demonstrated with azlactones as prochiral nucleophiles in the presence of chiral bisphosphine ligands. Benzylic electrophiles are utilized under two sets of reaction conditions to construct a new tetrasubstituted stereocenter. Electron density of the phenyl ring dictates the reaction conditions, including the leaving group. The reported methodology represents a novel asymmetric carbon-carbon bond formation in an amino acid precursor.
RESUMEN
Herein we report palladium-catalyzed asymmetric benzylic alkylation with 3-aryl oxindoles as prochiral nucleophiles. Proceeding analogously to asymmetric allylic alkylation, asymmetric benzylation occurs in high yield and enantioselectivity for a variety of unprotected 3-aryl oxindoles and benzylic methyl carbonates using chiral bisphosphine ligands. This methodology represents a novel asymmetric carbon-carbon bond formation between a benzyl group and a prochiral nucleophile to generate a quaternary center.