ABSTRACT
Twisted molecules: A modular approach for the synthesis of tetrasubstituted helical alkenes by a palladium-catalyzed norbornene-mediated domino reaction is presented. This intermolecular domino process allows the formation of three C-C bonds in one operation through a C-H activation/carbopalladation/C-H activation sequence.
Subject(s)
Alkenes/chemical synthesis , Palladium/chemistry , Alkenes/chemistry , Catalysis , Models, Molecular , StereoisomerismABSTRACT
A highly modular and stereoselective synthesis of tetrasubstituted helical alkenes is accomplished by a Pd-catalyzed norbornene-mediated domino reaction. This protocol features the rapid assembly of four C-C bonds via sequential C-H activations and carbopalladations along with efficient access to enantiopure bromoalkyl aryl alkyne precursors using homologative alkynylation as the key transformation. Three distinct elements of stereoselectivity were observed in the preparation of the chiral helical alkenes: retention of stereochemistry of the substrates, induced helical diastereoselectivity in the alkene formation, and the exclusive exo-facial selectivity of the norbornene incorporation.
Subject(s)
Alkenes/chemical synthesis , Palladium/chemistry , Alkenes/chemistry , Anhydrides/chemistry , Catalysis , Molecular Structure , Norbornanes/chemistry , StereoisomerismABSTRACT
Long-term use of estrogen supplements by women leads to an increased risk of breast and uterine cancers. Possible mechanisms include metabolism of estradiol and compounds related to tumor-initiating quinones, and ligand-induced activation of the estrogen receptors ERα and ERß which can cause cancer cell proliferation, depending on the ratio of receptors present. One therapeutic goal would be to create a spectrum of compounds of variable potency for ERα and ERß, which are resistant to quinone formation, and to determine an optimum point in this spectrum. We describe the synthesis, modeling, binding affinities, hormone potency, and a measure of quinone formation for a new family of A-CD estrogens, where the A-C bond is formed by ring coupling. Some substituents on the A-ring increase hormone potency, and one compound is much less quinone-forming than estradiol. These compounds span a wide range of receptor subtype selectivities and may be useful in hormone replacement therapy.
Subject(s)
Estradiol Congeners/chemical synthesis , Estradiol/chemistry , Estrogen Receptor alpha/agonists , Estrogen Receptor beta/agonists , Animals , Binding, Competitive , Cell Line , Estradiol Congeners/chemistry , Estradiol Congeners/pharmacology , Fluorine/chemistry , Hepatocytes/cytology , Hepatocytes/drug effects , Humans , Ligands , Male , Models, Molecular , Molecular Structure , Quinones/metabolism , Rats , Rats, Sprague-Dawley , Response Elements , Stereoisomerism , Structure-Activity Relationship , Thermodynamics , Transcriptional Activation/drug effectsABSTRACT
Estradiol and related estrogens have been widely used as supplements to relieve menopausal symptoms, but they lead to an increased risk of breast and endometrial cancer. Here we report the synthesis of a new family of compounds where we have removed the B-ring from the steroid ABCD structure, and functionalized the A-ring. These A-CD compounds show a preferential affinity for the estrogen receptor subtype ERbeta. Some show binding affinities which are greater than estradiol. The presence of electron-withdrawing substituents on the A-ring should reduce the tendency of these compounds to form carcinogenic metabolites, so they might lead to a safer approach to hormone replacement therapy.
