During continuing studies with a novel oxidative gold oxyarylation reaction, arylsilanes were found to be competent coupling partners, providing further evidence for an intramolecular electrophilic aromatic substitution mechanism. While providing complementary yields to the previously described boronic acid methods, the use of trimethylsilanes reduces the observation of homocoupling byproducts and allows for facile intramolecular coupling reactions.With the development of transition metal-catalyzed cross-coupling reactions, significant effort has been expended in the development of inexpensive and reliable organometallic reagents as coupling partners. 1 In this context, organosilanes present an attractive solution; however, there have been relatively few reports of transition metal-catalyzed reactions with the readily accessible aryltrimethylsilanes. Moreover, a stoichiometric additive such as fluoride or hydroxide is typically employed to activate the relatively unreactive silicon center for transmetallation. 2 Alternatively, a variety of reactive silicon reagents have been designed and utilized in transition metal catalyzed cross-coupling reactions on milder conditions. 3 During our recent examination of the Selectfluor mediated gold-catalyzed amino-and oxyarylation of terminal olefins with boronic acids, 4 mechanistic experimentation and computational analysis provided evidence against transmetallation to the gold center. Instead, studies suggested a bimolecular reductive elimination reminiscent of an electrophilic aromatic substitution. While unactivated trimethylarylsilanes do not typically directly engage in cross-couplings, 5 they can readily react as nucleophiles in aromatic substitution reactions. 6 We therefore hypothesized that arylsilanes might be utilized as the terminating nucleophile in oxidative gold-catalyzed coupling with alkenes.On the basis of this hypothesis, we were delighted to find that when olefin 1 was reacted with phenyltrimethylsilane under the previously described reaction conditions, the desired intermolecular oxyarylation product (2) was observed in 50% yield (Table 1, entry 1). No exogenous base or fluoride is required for silicon activation, and a wide variety of readily available silanes, silanols, and siloxanes are capable oxyarylation coupling partners. In attempting to identify the optimal silicon coupling regent, we found silanediols and -triols provided excellent yields (entries 5, 8), though rapid oligomerization lead to concerns regarding reproducibility. The more bench stable trisiloxane derivatives 7 unfortunately fdtoste@berkeley.edu.

The discovery of complementary methods for enantioselective transition-metal-catalyzed cyclization with silyloxyenynes has been accomplished using chiral phosphine ligands. Under palladium catalysis, 1,6-silyloxyenynes bearing a terminal alkyne led to the desired 5-membered ring with high enantioselectivities (up to 91% ee). As for reactions under cationic gold catalysis, 1,6- and 1,5-silyloxyenynes bearing an internal alkyne furnished the chiral cyclopentane derivatives with excellent enantiomeric excess (up to 94% ee). Modification of the substrate by incorporating an α,β-unsaturation led to the discovery of a tandem cyclization. Remarkably, using silyloxy-1,3-dien-7-ynes under gold catalysis conditions provided the bicyclic derivatives with excellent diastereo- and enantioselectivities (up to >20:1 dr and 99% ee).

A platform to accelerate optimization of proteolysis targeting chimeras (PROTACs) has been developed using a direct-to-biology (D2B) approach with a focus on linker effects. A large number of linker analogs—with varying length, polarity, and rigidity—were rapidly prepared and characterized in four cell-based assays by streamlining time-consuming steps in synthesis and purification. The expansive dataset informs on linker structure–activity relationships (SAR) for in-cell E3 ligase target engagement, degradation, permeability, and cell toxicity. Unexpected aspects of linker SAR was discovered, consistent with literature reports on “linkerology”, and the method dramatically speeds up empirical optimization. Physicochemical property trends emerged, and the platform has the potential to rapidly expand training sets for more complex prediction models. In-depth validation studies were carried out and confirm the D2B platform is a valuable tool to accelerate PROTAC design–make–test cycles.

The present application claims a series of triazolopyrimidine analogues that inhibit the stress response of general control nonderepressible 2 kinase (GCN2) and that may be useful as chemotherapeutic drugs for the treatment of cancer.

The structure-activity study of a bioactive natural product containing polypropionate subunits requires that its stereoisomers also be evaluated. Therefore, a general approach to synthesize these motifs is necessary. We describe herein the synthesis of the C1-C13 polypropionate subunit of zincophorin and isomers thereof using a two-reaction sequence: an aldol reaction using a mixture of tetrasubstituted enoxysilanes and a hydrogen-transfer reaction, both under Lewis acid control. Selection of the appropriate Lewis acid dictates the stereochemical outcome of these reactions. From a tactical standpoint, this study shows how a polypropionate sequence can be read and constructed in two directions, either the east-west or the west-east approaches. The choice of the optimal route is influenced by the number of complexation sites that can interfere in the aldol step under bidentate Lewis acid control.