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.
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 ERβ 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 ERβ, 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.
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.
Nach einem modularen Ansatz wurden tetrasubstituierte helicale Alkene hergestellt. Dabei ermöglicht eine intermolekulare, Pd‐katalysierte und Norbornen‐vermittelte Dominoreaktion die Bildung dreier C‐C‐Bindungen in einem einzigen Arbeitsschritt über eine Sequenz aus C‐H‐Aktivierung, Carbopalladierung und erneuter C‐H‐Aktivierung.
Expeditious Synthesis of Tetrasubstituted Helical Alkenes by a Cascade of Palladium-Catalyzed C-H Activations. -A highly effective synthesis of sterically crowded target compounds is developed through a Pd-catalyzed norbornene-mediated reaction of alkyne substrates with iodoarenes. Optically pure alkynes give products with high induction of helical chirality. -(LIU, H.; EL-SALFITI, M.; LAUTENS*, M.; Angew. Chem., Int. Ed. 51 (2012) 39, 9846-9850, http://dx.doi.org/10.1002/anie.201204226 ; Dep. Chem., Univ. Toronto, Toronto, Ont. M5S 3H6, Can.; Eng.) -Mais 09-106
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