A Deprotonation Approach to the Unprecedented Amino‐Trimethylenemethane Chemistry: Regio‐, Diastereo‐, and Enantioselective Synthesis of Complex Amino Cycles

The first realization of the amino‐trimethylenemethane chemistry is reported using a deprotonation strategy to simplify the synthesis of the amino‐trimethylenemethane donor in two steps from commercial and inexpensive materials. A broad scope of cycloaddition acceptors (seven different classes) participated in the chemistry, chemo‐, regio‐, diastereo‐, and enantioselectively generating various types of highly valuable complex amino cycles. Multiple derivatization reactions that further elaborated the initial amino cycles were performed without isolation of the crude product. Ultimately, we applied the amino‐trimethylenemethane chemistry to synthesize a potential pharmaceutical in 8 linear steps and 7.5 % overall yield, which previously was achieved in 18 linear steps and 0.6 % overall yield.     

Redox Stability Controls the Cellular Uptake and Activity of Ruthenium-Based Inhibitors of the Mitochondrial Calcium Uniporter (MCU)

The mitochondrial calcium uniporter (MCU) is the ion channel that mediates Ca²⁺ uptake in mitochondria. Inhibitors of the MCU are valuable as potential therapeutic agents and tools to study mitochondrial Ca²⁺. The best-known inhibitor of the MCU is the ruthenium compound Ru360. Although this compound is effective in permeabilized cells, it does not work in intact biological systems. We have recently reported the synthesis and characterization of Ru265, a complex that selectively inhibits the MCU in intact cells. Here, the physical and biological properties of Ru265 and Ru360 are described in detail. Using atomic absorption spectroscopy and X-ray fluorescence imaging, we show that Ru265 is transported by organic cation transporter 3 (OCT3) and taken up more effectively than Ru360. As an explanation for the poor cell uptake of Ru360, we show that Ru360 is deactivated by biological reductants. These data highlight how structural modifications in metal complexes can have profound effects on their biological activities.     

New insights into the interactions of serum proteins with bis(maltolato)oxovanadium(IV): transport and biotransformation of insulin-enhancing vanadium pharmaceuticals

Significant new insights into the interactions of the potent insulin-enhancing compound bis(maltolato)oxovanadium(IV) (BMOV) with the serum proteins, apo-transferrin and albumin, are presented. Identical reaction products are observed by electron paramagnetic resonance (EPR) with either BMOV or vanadyl sulfate (VOSO4) in solutions of human serum apo-transferrin. Further detailed study rules out the presence of a ternary ligand-vanadyl-transferrin complex proposed previously. By contrast, differences in reaction products are observed for the interactions of BMOV and VOSO4 with human serum albumin (HSA), wherein adduct formation between albumin and BMOV is detected. In BMOV-albumin solutions, vanadyl ions are bound in a unique manner not observed in comparable solutions of VOSO4 and albumin. Presentation of chelated vanadyl ions precludes binding at the numerous nonspecific sites and produces a unique EPR spectrum which is assigned to a BMOV-HSA adduct. The adduct species cannot be produced, however, from a solution of VOSO4 and HSA titrated with maltol. Addition of maltol to a VOSO4-HSA solution instead results in formation of a different end product which has been assigned as a ternary complex, VO(ma)(HSA). Furthermore, analysis of solution equilibria using a model system of BMOV with 1-methylimidazole (formation constant log K1 = 4.5(1), by difference electronic absorption spectroscopy) lends support to an adduct binding mode (VO(ma)2-HSA) proposed herein for BMOV and HSA. This detailed report of an in vitro reactivity difference between VOSO4 and BMOV may have bearing on the form of active vanadium metabolites delivered to target tissues. Albumin binding of vanadium chelates is seen to have a potentially dramatic effect on pharmacokinetics, transport, and efficacy of these antidiabetic chelates.     

Exploiting the Pd- and Ru-catalyzed cycloisomerizations: enantioselective total synthesis of (+)-allocyathin B2

Pd- and Ru-catalyzed cycloisomerizations of 1,6-enynes are compared and contrasted. Such considerations led to the enantioselective synthesis of a cyathin terpenoid, (+)-allocyathin B(2) (1). The synthesis features a Pd-catalyzed asymmetric allylic alkylation (AAA) to install the initial quaternary center, a Ru-catalyzed diastereoselective cycloisomerization to construct the six-membered ring, and a diastereoselective hydroxylative Knoevenagel reaction to introduce the final hydroxyl group. We demonstrate for the first time a mechanism-based stereochemical divergence in Pd- and Ru-catalyzed cycloisomerization reactions as well as in creation of alkene geometry with alkynes bearing a carboalkoxy group. Mechanistic rationalization is proposed for these observations.     

Development of aliphatic alcohols as nucleophiles for palladium-catalyzed DYKAT reactions: total synthesis of (+)-hippospongic acid A

The ability to use aliphatic alcohols as competent nucleophiles in the palladium-catalyzed dynamic kinetic asymmetric transformation of Baylis-Hillman adducts is explored. High yield and enantioselectivity is obtained for both the kinetic transformation and dynamic kinetic transformation. The absolute stereochemistry of the products is used to explore the reactive conformation of 2-substituted pi-allyl complexes with DPPBA-based chiral ligands. The utility of this method is further demonstrated in the context of a concise total synthesis of the gastrulation inhibitor (+)-hippospongic acid A. The synthesis features three palladium-catalyzed allylic alkylation reactions to introduce three different bond types: C-S, C-H, and C-O.     

Efficient syntheses of rugulosin analogues

Oxidation of 3b or 14c,d with Pb(OAc)4 in AcOH for 20 min at 25 degrees C and 1 h at 75 degrees C gave flavoskyrin-type dimers 6b and 15c,d in 53-86% yield. Heating a solution of 6b or 15c,d in pyridine under air for 1 h at 75-80 degrees C and then for 1-2 h at 110 degrees C afforded rugulosin-type dimers 10b and 17c,d in 61-88% yield. This two-step sequence provides a practical route to this unusual natural product skeleton.     

Factors affecting the selection of products from a photochemically generated singlet biradical

The chemistries of a monoradical of the ultrafast "radical-clock" type and a structurally related singlet biradical, generated by Norrish type II photochemistry, are compared. The monoradical is found to undergo the characteristic ring-opening reaction of its class at about 10(10) s(-1) at room temperature. However, the singlet biradical shows no evidence of the analogous ring-opening reaction. The contrasting chemistry is traced not to a fundamental difference in electronic structure of the two intermediates, but rather to a steric interaction that the biradical alone would have to suffer during the ring opening. Although the magnitude of the steric hindrance is small (estimated 15-20 kJ mol(-1)), it is enough to shut down the reaction, because the biradical has other facile product-forming reactions available.     

Prediction of underwater sound levels from rain and wind

Wind and rain generated ambient sound from the ocean surface represents the background baseline of ocean noise. Understanding these ambient sounds under different conditions will facilitate other scientific studies. For example, measurement of the processes producing the sound, assessment of sonar performance, and helping to understand the influence of anthropogenic generated noise on marine mammals. About 90 buoy-months of ocean ambient sound data have been collected using Acoustic Rain Gauges in different open-ocean locations in the Tropical Pacific Ocean. Distinct ambient sound spectra for various rainfall rates and wind speeds are identified through a series of discrimination processes. Five divisions of the sound spectra associated with different sound generating mechanisms can be predicted using wind speed and rainfall rate as input variables. The ambient sound data collected from the Intertropical Convergence Zone are used to construct the prediction algorithms, and are tested on the data from the Western Pacific Warm Pool. This physically based semi-empirical model predicts the ambient sound spectra (0.5-50 kHz) at rainfall rates from 2-200 mm/h and wind speeds from 2 to 14 m/s.