8 research outputs found
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Fluorinated Adenosine A2A Receptor Antagonists Inspired by Preladenant as Potential Cancer Immunotherapeutics
Antagonism of the adenosine A2A receptor on T cells blocks the hypoxia-adenosinergic pathway to promote tumor rejection. Using an in vivo immunoassay based on the Concanavalin A mouse model, a series of A2A antagonists were studied and identified preladenant as a potent lead compound for development. Molecular modeling was employed to assist drug design and subsequent synthesis of analogs and those of tozadenant, including fluorinated polyethylene glycol PEGylated derivatives. The efficacy of the analogs was evaluated using two in vitro functional bioassays, and compound 29, a fluorinated triethylene glycol derivative of preladenant, was confirmed as a potential immunotherapeutic agent
Three-Component [1 + 1 + 1] Cyclopropanation with Ruthenium(II)
We
report a one-step, Ru(II)-catalyzed cyclopropanation reaction that is
conceptually different from the previously reported protocols that include
Corey-Chaykovsky, Simmons-Smith, and metal catalyzed carbene attack on olefins.
Under the current protocol, various alcohols are transformed into sulfone
substituted cyclopropanes with excellent isolated yields and diastereoselectivities.
This new reaction forms highly congested cyclopropane products with three new
C–C bonds, three or two new chiral centers and one new quaternary carbon
center. 22 examples of isolated substrates are given. Previously reported
synthetic routes for similar substrates are all multi-step, linear routes that
proceed with overall low yields and poor control of stereochemistry.
Experimental mechanistic investigations suggest initial metal-catalyzed
dehydrogenation of the alcohol substrate and catalyst independent stepwise
attack of two equivalents of sulfone on the aldehyde under basic conditions.
While the Ru(II) is only responsible for the initial dehydrogenation step, the
rate of aldehyde formation is crucial to maintaining the right balance of
intermediates needed to afford the cyclopropane product
Three-Component [1+1+1] Cyclopropanation with Ruthenium(II)
We
report a one-step, Ru(II)-catalyzed cyclopropanation reaction that is
conceptually different from the previously reported protocols that include
Corey-Chaykovsky, Simmons-Smith, and metal catalyzed carbene attack on olefins.
Under the current protocol, various alcohols are transformed into sulfone
substituted cyclopropanes with excellent isolated yields and diastereoselectivities.
This new reaction forms highly congested cyclopropane products with three new
C–C bonds, three or two new chiral centers and one new quaternary carbon
center. 22 examples of isolated substrates are given. Previously reported
synthetic routes for similar substrates are all multi-step, linear routes that
proceed with overall low yields and poor control of stereochemistry.
Experimental mechanistic investigations suggest initial metal-catalyzed
dehydrogenation of the alcohol substrate and catalyst independent stepwise
attack of two equivalents of sulfone on the aldehyde under basic conditions.
While the Ru(II) is only responsible for the initial dehydrogenation step, the
rate of aldehyde formation is crucial to maintaining the right balance of
intermediates needed to afford the cyclopropane product
Shuttle HAT for mild alkene transfer hydrofunctionalization
Hydrogen atom transfer (HAT) from a metal-hydride is a reliable and powerful method for functionalizing unsaturated C–C bonds in organic synthesis. Cobalt hydrides (Co–H) have garnered significant attention in this field, where the weak Co–H bonds are most commonly generated in a catalytic fashion through a mixture of stoichiometric amounts of peroxide oxidant and silane reductant. Here we show that the reverse process of HAT to an alkene, i.e. hydrogen atom abstraction of a C–H adjacent to a radical, can be leveraged to generate catalytically active Co–H species in a new application of shuttle catalysis coined shuttle HAT. This method obviates the need for stoichiometric reductant/oxidant mixtures thereby greatly simplifying the generation of Co–H under exceedingly mild reaction conditions. This approach opens the door for the introduction of functional handles (e.g., iodides) that were previously inaccessible through other catalytic approaches, and paves the way for new reagent design which incorporates this shuttle HAT platform. To demonstrate the generality of this shuttle HAT platform, five different reaction manifolds are shown, including the late-stage C(sp3) iodination of structurally diverse FDA approved drugs
Nucleophilic 5-endo-trig cyclization of 2-(trifluoromethyl)allylic metal enolates and enamides: Synthesis of tetrahydrofurans and pyrrolidines bearing exo-difluoromethylene units
Ketones and imines bearing a 2-(trifluoromethyl)allylic moiety successfully underwent nucleophilic 5-endo-trig cyclization via their metal enolates and enamides. O- or N-Cyclization proceeded exclusively in each case to afford the corresponding five-membered heterocycles with both exo-difluoromethylene and exo-alkylidene units. On treatment with potassium hexamethyldisilazide (KHMDS) or lithium diisopropylamide (LDA), 2-(trifluoromethyl)allylic ketones or imines provided the corresponding tetrahydrofurans or pyrrolidines bearing a Z-alkylidene group with perfect or substantial stereoselectivity, respectively