Small molecules have been classically developed to inhibit enzyme activity; however, new classes of small molecules that endow new functions to enzymes via proximity-mediated effect are emerging. Phosphorylation (native or neo) of any given protein-of-interest can alter its structure and function, and we hypothesized that such modifications can be accomplished by small molecules that bring a kinase in proximity to the protein-of-interest. Herein, we describe phosphorylation-inducing chimeric small molecules (PHICS), which enable two example kinasesAMPK and PKCto phosphorylate target proteins that are not otherwise substrates for these kinases. PHICS are formed by linking small-molecule binders of the kinase and the target protein, and exhibit several features of a bifunctional molecule, including the hook-effect, turnover, isoform specificity, dose and temporal control of phosphorylation, and activity dependent on proximity (i.e., linker length). Using PHICS, we were able to induce native and neo-phosphorylations of BRD4 by AMPK or PKC. Furthermore, PHICS induced a signaling-relevant phosphorylation of the target protein Bruton’s tyrosine kinase in cells. We envision that PHICS-mediated native or neo-phosphorylations will find utility in basic research and medicine.

Chiral boronic esters are useful intermediates in asymmetric synthesis. We have previously shown that carbonyl-directed catalytic asymmetric hydroboration (CAHB) is an efficient approach to the synthesis of functionalized primary and secondary chiral boronic esters. We now report oxime-directed CAHB of alkyl-substituted methylidene and trisubstituted alkene substrates by pinacolborane (pinBH) affords oxime-containing chiral tertiary boronic esters with yields up to 87% and enantiomer ratios up to 96:4 er. The utility of the method is demonstrated by the formation of chiral diols and O-substituted hydroxylamines, the generation of quaternary carbon stereocenters via carbon-carbon coupling reactions, and the preparation of chiral 3,4,4-trisubstituted isoxazolines.

Regiocontrol in the rhodium-catalyzed boration of vinyl arenes is typically dominated by the presence of the conjugated aryl substituent. However,s mall differences in TADDOL-derived chiral monophosphite ligands can override this effect and direct rhodium-catalyzed hydroboration of baryl and b-heteroaryl methylidenes by pinacolborane to selectively produce either chiral primary or tertiary borated products.T he regiodivergent behavior is coupled with enantiodivergent addition of the borane.T he nature of the TADDOL backbone substituents and that of the phosphite moiety function synergistically to direct the sense and extent of regioselectivity and enantioinduction. Tw enty substrates are shown to undergo eachr eaction mode with regioselectivity values reaching greater than 20:1 and enantiomer ratios reaching up to 98:2. Avariety of subsequent transformations illustrate the potential utility of each product.Theenantioselectivepreparationofchiralboronicestersisof current interest due to the synthetic utility of these compounds in adiverse set of stereospecific transformations [1] and the growing appreciation that boronic acid derivatives may hold significant potential in medicinal chemistry. [2] Considerable progress has been realized in the development of regioselective asymmetric hydroboration [3,4] and asymmetric borometallation [5] reactions,m ost of which exploit substrate control through the use of activated alkenes or directing groups.C atalysts that override inherent substrate bias to selectively produce either of two regioisomers offer greater synthetic utility.I na ddition to several recent examples of non-stereocontrolled borylative difunctionalizations through regiodivergent borocupration, [6] the ligand-controlled regiodivergent palladium-catalyzed hydroboration of terminal alkynes serves to illustrate the potential of this approach. Ojiha and Prabhu [7] reported abulky N-heterocyclic carbene ligand promotes regioselective boropalladation to deliver boron to the terminus;p rotonolysis leads to 1 (Figure 1). In contrast, tricyclohexylphosphine effects delivery of boron to the internal position leading to the regioisomeric product 2.Examples of chiral-catalyst-controlled regiodivergent and enantioselective reactions are less common. [8,9] Herein, we report that relatively modest structural changes to ac hiral TADDOL-derived monophosphite ligand results in as witch in both regioselectivity and the sense of enantioselectivity in the catalytic asymmetric hydroboration (CAHB) of b-aryl methylidene substrates 3 by pinacolborane (pinBH). This method provides access to either rhodium-catalyzed g-boration at the unsubstituted terminus to give the primary organoboronic ester 4 (si-face addition favored), [10] or bboration to give the tertiary organoboronic ester 5 (re-face addition favored) [11] by using ligands (R,R)-T1 a or (R,R)-T2 b,r espectively.To probe the influence of structural changes in the ligand on the g-tob-boration ratio (4/5)and the levels of asymmetric induction (re/si-face addition), as eries o...

Phosphorylation-inducing chimeric small molecules (PHICS) can enable a kinase to act at a new cellular location or phosphorylate non-native substrates (neo-substrates)/ sites (neo-phosphorylations). [1,2] We report a modular design and high-yielding synthesis of such PHICS that endowed multiple new activities to protein kinase C (PKC). For example, while PKC is unable to downregulate the activity of a gain-of-function variant (S180A) of Bruton's tyrosine kinase that evokes B cell malignancy phenotype, PHICS enabled PKC to induce inhibitory neo-phosphorylations on this variant. Furthermore, while PKC typically phosphorylates its membrane-associated substrates, PKC with PHICS phosphorylated multiple cytosol-based neo-substrates (e.g., BCR-ABL). Finally, a PHICS for BCR-ABL induced death of chronic myeloid leukemia cell lines. These studies show the power of synthetic chemistry to expand the chemical and functional diversity of proteins in cells using bifunctional molecules.