Rh(II)-Catalyzed Reactions of Diazoesters with Organozinc Reagents

Rh­(II)-catalyzed reactions of diazoesters with organozinc reagents are described. Diorganozinc reagents participate in reactions with diazo compounds by two distinct, catalyst-dependent mechanisms. With bulky diisopropylethyl acetate ligands, the reaction mechanism is proposed to involve initial formation of a Rh-carbene and subsequent carbozincation to give a zinc enolate. With Rh₂(OAc)₄, it is proposed that initial formation of an azine precedes 1,2-addition by an organozinc reagent. This straightforward route to the hydrazone products provides a useful method for preparing chiral quaternary α-aminoesters or pyrazoles via the Paul–Knorr condensation with 1,3-diketones. Crossover and deuterium labeling experiments provide evidence for the mechanisms proposed

Facially Selective Cu-Catalyzed Carbozincation of Cyclopropenes Using Arylzinc Reagents Formed by Sequential I/Mg/Zn Exchange

Described is a Cu-catalyzed directed carbozincation of cyclopropenes with organozinc reagents prepared by I/Mg/Zn exchange. This protocol broadens the scope with respect to functional group tolerance and enables use of aryl iodide precursors, rather than purified diorganozinc precursors. Critical to diastereoselectivity of the carbozincation step is the removal of magnesium halide salts after transmetalation with ZnCl₂

Rh(II)-Catalyzed Reactions of Diazoesters with Organozinc Reagents

Rh­(II)-catalyzed reactions of diazoesters with organozinc reagents are described. Diorganozinc reagents participate in reactions with diazo compounds by two distinct, catalyst-dependent mechanisms. With bulky diisopropylethyl acetate ligands, the reaction mechanism is proposed to involve initial formation of a Rh-carbene and subsequent carbozincation to give a zinc enolate. With Rh₂(OAc)₄, it is proposed that initial formation of an azine precedes 1,2-addition by an organozinc reagent. This straightforward route to the hydrazone products provides a useful method for preparing chiral quaternary α-aminoesters or pyrazoles via the Paul–Knorr condensation with 1,3-diketones. Crossover and deuterium labeling experiments provide evidence for the mechanisms proposed

Dehydrogenative Transformations of Imines Using a Heterogeneous Photocatalyst

Heterogeneous semiconductors are underexploited as photoredox catalysts in organic synthesis relative to their homogeneous, molecular counterparts. Here, we report the use of metal/TiO₂ particles as catalysts for light-induced dehydrogenative imine transformations. The highly oxophilic nature of the TiO₂ surface promotes the selective binding and dehydrogenation of alcohols in the presence of other oxidizable and Lewis basic functional groups. This feature enables the clean photogeneration of aldehyde equivalents that can be utilized in multicomponent couplings

Diels–Alder Cycloaddition for Fluorophore Targeting to Specific Proteins inside Living Cells

The inverse-electron-demand Diels–Alder cycloaddition between <i>trans</i>-cyclooctenes and tetrazines is biocompatible and exceptionally fast. We utilized this chemistry for site-specific fluorescence labeling of proteins on the cell surface and inside living mammalian cells by a two-step protocol. <i>Escherichia coli</i> lipoic acid ligase site-specifically ligates a <i>trans</i>-cyclooctene derivative onto a protein of interest in the first step, followed by chemoselective derivatization with a tetrazine–fluorophore conjugate in the second step. On the cell surface, this labeling was fluorogenic and highly sensitive. Inside the cell, we achieved specific labeling of cytoskeletal proteins with green and red fluorophores. By incorporating the Diels–Alder cycloaddition, we have broadened the panel of fluorophores that can be targeted by lipoic acid ligase

Improved Metabolic Stability for ¹⁸F PET Probes Rapidly Constructed via Tetrazine <i>trans</i>-Cyclooctene Ligation

The fast kinetics and bioorthogonal nature of the tetrazine <i>trans</i>-cyclooctene (TCO) ligation makes it a unique tool for PET probe construction. In this study, we report the development of an ¹⁸F-labeling system based on a CF₃-substituted diphenyl-<i>s</i>-tetrazine derivative with the aim of maintaining high reactivity while increasing in vivo stability. c­(RGDyK) was tagged by a CF₃-substituted diphenyl-<i>s</i>-tetrazine derivative via EDC-mediated coupling. The resulting tetrazine-RGD conjugate was combined with a ¹⁹F-labeled TCO derivative to give HPLC standards. The analogous ¹⁸F-labeled TCO derivative was combined with the diphenyl-<i>s</i>-tetrazine-RGD at μM concentration. The resulting tracer was subjected to in vivo metabolic stability assessment, and microPET studies in murine U87MG xenograft models. The diphenyl-<i>s</i>-tetrazine-RGD combines with an ¹⁸F-labeled TCO in high yields (>97% decay-corrected on the basis of TCO) using only 4 equiv of tetrazine-RGD relative to the ¹⁸F-labeled TCO (concentration calculated based on product’s specific activity). The radiochemical purity of the ¹⁸F-RGD peptides was >95% and the specific activity was 111 GBq/μmol. Noninvasive microPET experiments demonstrated that ¹⁸F-RGD had integrin-specific tumor uptake in subcutaneous U87MG glioma. In vivo metabolic stability of ¹⁸F-RGD in blood, urine, and major organs showed two major peaks: one corresponded to the Diels–Alder conjugate and the other was identified as the aromatized analog. A CF₃-substituted diphenyl-<i>s</i>-tetrazine displays excellent speed and efficiency in ¹⁸F-PET probe construction, providing nearly quantitative ¹⁸F labeling within minutes at low micromolar concentrations. The resulting conjugates display improved in vivo metabolic stability relative to our previously described system