Discrete, Chiral Polymer-Insulin Conjugates.

Polymer conjugation has been widely used to improve the stability and pharmacokinetics of therapeutic biomacromolecules; however, conventional methods to generate such conjugates often use disperse and/or achiral polymers with limited functionality. The heterogeneity of such conjugates may lead to manufacturing variability, poorly controlled biological performance, and limited ability to optimize structure-property relationships. Here, using insulin as a model therapeutic polypeptide, we introduce a strategy for the synthesis of polymer-protein conjugates based on discrete, chiral polymers synthesized through iterative exponential growth (IEG). These conjugates eliminate manufacturing variables originating from polymer dispersity and poorly controlled absolute configuration. Moreover, they offer tunable molecular features, such as conformational rigidity, that can be modulated to impact protein function, enabling faster or longer-lasting blood glucose responses in diabetic mice when compared to PEGylated insulin and the commercial insulin variant Lantus. Furthermore, IEG-insulin conjugates showed no signs of decreased activity, immunogenicity, or toxicity following repeat dosing. This work represents a significant step toward the synthesis of precise synthetic polymer-biopolymer conjugates and reveals that fine tuning of synthetic polymer structure may be used to optimize such conjugates in the future.

Nickel-catalyzed, regio- and stereoselective hydroalkynylation of methylenecyclopropanes with retention of the cyclopropane ring, leading to the synthesis of 1-methyl-1-alkynylcyclopropanes.

The C-H bond of triisopropylsilylacetylene adds to the C=C bond of substituted methylenecyclopropanes in a regio- and stereoselective manner at room temperature in the presence of nickel catalysts bearing PMePh(2). The C-C bond formation takes place at the internal sp(2) carbon atom with high regioselectivity from the pi face opposite the substituents located in the three-membered rings.

Nickel-catalyzed regioselective hydroalkynylation of styrenes: improved catalyst system, reaction scope, and mechanism.

Addition of the sp-C-H bond of triisopropylsilylacetylene to the carbon-carbon double bonds of styrenes bearing functional groups proceeded efficiently at room temperature in the presence of 3 mol % of Ni(cod)(2) with a PMePh(2) ligand. Use of 2-deuteriotriisopropylsilylacetylene in the hydroalkynylation of styrenes resulted in regioselective incorporation of deuterium into the beta-positions of recovered styrenes, along with its regioselective introduction into the product's methyl group.

Nickel-catalyzed addition of C-H bonds of terminal alkynes to 1,3-dienes and styrenes.

The C-H bond of a terminal alkyne adds to a carbon-carbon double bond of 1,3-dienes, styrenes, and norbornene at room temperature in the presence of a nickel catalyst in regio- and stereoselective manners. Reaction of triisopropylsilylacetylene with 1-substituted 1,3-butadiene derivatives afforded hydroalkynylation products via introduction of a hydrogen atom and a triisopropylsilylethynyl group to 4- and 3-positions of the dienes, respectively. Likewise, 1-triisopropylsiloxy-1,3-butadiene, 1,3-pentadiene, 1-cyclohexen-1-yl-1,3-butadiene, and 1,3-cyclohexadiene underwent the hydroalkynylation reaction, giving the corresponding 1,4-enyne derivatives in good yields at room temperature. Reaction of p-substituted styrene with triisopropylsilylacetylene also proceeded in the presence of the nickel catalyst, giving the branched hydroalkynylation products in good yields. Norbornene gave a exo-addition product in good yield under the same reaction conditions.

Easy access to esters with a benzylic quaternary carbon center from diallyl malonates by palladium-catalyzed decarboxylative allylation.

Diallyl 2-alkyl-2-arylmalonates underwent palladium-catalyzed decarboxylative allylation quickly under mild conditions. In contrast, no reaction took place with diallyl 2,2-dialkylmalonates under the same conditions. Electron-donating phosphine ligands were found to be vital for this reaction. Most of the solvents used did not affect the catalytic cycle. Catalysis in [bmim][BF4], a well-known ionic liquid, was inhibited as a result of formation of a hydrogen bond between a carboxylate anion and a [bmim]+ cation; however, the reaction in [bdmim][BF4], in which the acidic proton of [bmim][BF4] was replaced with a methyl group, proceeded smoothly. The catalytic mechanism was investigated using a tetradeuterated substrate and an enzymatically synthesized enantio-enriched allyl methyl 2-methyl-2-phenylmalonate. Even the electron-deficient phosphite ligand was found to be active for catalysis of diallyl 2-methyl-2-(2- or 4-nitrophenyl)malonates.

Nickel-catalyzed addition of alkynylboranes to alkynes.

Alkynylboration has been achieved in the reaction of alkynyl(pinacol)boranes with alkynes in the presence of nickel catalysts, giving cis-1-borylbut-1-en-3-yne derivatives. 1-Aryl-1-alkynes underwent the alkynylboration regioselectively with the selective introduction of the alkynyl groups at their 1-positions, where the aryl groups were attached. The boryl-substituted enynes were reacted with sp2 halides under the Suzuki-Miyaura coupling conditions, giving highly conjugated enynes in high yields.