Bridged [2.2.1] bicyclic phosphine oxide facilitates catalytic γ-umpolung addition-Wittig olefination.

A novel bridged [2.2.1] bicyclic phosphine oxide, devised to circumvent the waste generation and burdens of purification that are typical of reactions driven by the generation of phosphine oxides, has been prepared in three steps from commercially available cyclopent-3-ene-1-carboxylic acid. The performance of this novel phosphine oxide was superior to those of current best-in-class counterparts, as verified experimentally through kinetic analysis of its silane-mediated reduction. It has been applied successfully in halide-/base-free catalytic γ-umpolung addition-Wittig olefinations of allenoates and 2-amidobenzaldehydes to produce 1,2-dihydroquinolines with good efficiency. One of the 1,2-dihydroquinoline products was converted to known antitubercular furanoquinolines

Influence of paste thickness on the coated aggregates on properties of high-density sulphoaluminate cement concrete

An improved method for the densified mixture design algorithm and Fuller curve were used to design high-density sulphoaluminate cement concrete (HDSC). The performance of HDSC is significantly influenced by the paste thickness on the coated aggregates. Sulphoaluminate cement concrete mixtures containing aggregates coated with 3 different paste thickness of t=10μm, 20μm, and 30μm and water-binder ratios (W/B) of 0.25, 0.30 and 0.35 were prepared. The results of experiments show that paste thickness on the coated aggregates significantly influences the mechanical properties and durability of HDSC. With the increase of paste thickness, the compressive strength is increased, but the electrical resistivity is decreased, particularly at the early ages of 1 and 3 days. The sulfate corrosion resistance coefficients of HDSC are larger than 1.0, the total porosity can be less than 7%, and the micropore (i.e. with pore size less than 20nm) can be larger than 70%

Synthetic Studies toward Indole Alkaloids and Catalytic Asymmetric Staudinger–Aza-Wittig Reaction via Desymmetrization

In Chapter 1, we developed a catalytic asymmetric total synthesis of (–)-actinophyllic acid, with the key step being a chiral phosphine-catalyzed [3 + 2] annulation between an imine and an allenoate to form a pyrroline intermediate in 99% yield and 94% ee. The synthesis also features a CuI-catalyzed coupling between a ketoester and a 2-iodoindole to shape the tetrahydroazocine ring; intramolecular alkylative lactonization; SmI2-mediated intramolecular pinacol coupling between ketone and lactone subunits to assemble the complex skeleton of (–)-actinophyllic acid; and an unprecedented regioselective dehydroxylation.In Chapter 2, we applied our phosphine-catalyzed [4 + 2] annulation between an imine and an allenoate toward the synthetic studies on akuammiline indole alkaloids. We successfully constructed indole fused [3.3.1]azabicycles from [4 + 2] annulation precursor via Barbier reaction in high yields. We also developed a Lewis acid promoted dehydration to form the key indole–quinonemethide intermediate, which could generate a challenging quaternary carbon by trapping with a carbon nucleophile. By adopting this strategy, we proposed a pathway to finish formal total syntheses of aspidodasycarpine and lonicerine.In Chapter 3, we have successfully developed the catalytic asymmetric Staudinger–aza-Wittig reaction. Historically, both Staudinger and Wittig reactions need stoichiometric amounts of phosphine, which impede the development of catalytic asymmetric versions of these reactions. In 2006, Marsden and co-workers reported the first asymmetric Staudinger–aza-Wittig reaction with stoichiometric chiral phosphine, which was undesirable considering economic efficiency and environmental concerns. Based on our previous study, we found that the bridged [2.2.1]bicyclic phosphine oxide had higher efficiency than the known phosphine oxides during the reduction cycle in the presence of silane. In this project, after screening various Brønsted acids, we could realize the catalytic asymmetric Staudinger–aza-Wittig reaction at room temperature

Peptide Diversification through Addition Reaction of Free Carboxylic Acids to Ynamides

Peptide modification has emerged as an important topic in the academic community and pharmaceutical industry. However, they are primarily focused on the diversification of amines, thiols, and alcohols. Direct and chemoselective modification of acid residues in peptides is relatively underdeveloped. In this context, we report a novel and efficient method for the direct functionalization of acid residues in peptides. By using ynamides as reaction partners, the adducts are rapidly obtained in moderate to excellent yields at room temperature in water. This approach shows excellent chemoselectivity and a broad scope including dipeptides bearing unprotected Trp or Tyr residue and free Ser or Gln residue

Modular Chemical Synthesis of Streptogramin and Lankacidin Antibiotics

Continued, rapid development of antimicrobial resistance has become worldwide health crisis and a burden on the global economy. Decisive and comprehensive action is required to slow down the spread of antibiotic resistance, including increased investment in antibiotic discovery, sustainable policies that provide returns on investment for newly launched antibiotics, and public education to reduce the overusage of antibiotics, especially in livestock and agriculture. Without significant changes in the current antibiotic pipeline, we are in danger of entering a post-antibiotic era.In this Account, we summarize our recent efforts to develop next-generation streptogramin and lankacidin antibiotics that overcome bacterial resistance by means of modular chemical synthesis. First, we describe our highly modular, scalable route to four natural group A streptogramins antibiotics in 6-8 steps from seven simple chemical building blocks. We next describe the application of this route to the synthesis of a novel library of streptogramin antibiotics informed by in vitro and in vivo biological evaluation and high-resolution cryo-electron microscopy. One lead compound showed excellent inhibitory activity in vitro and in vivo against a longstanding streptogramin-resistance mechanism, virginiamycin acetyltransferase. Our results demonstrate that the combination of rational design and modular chemical synthesis can revitalize classes of antibiotics that are limited by naturally arising resistance mechanisms.Second, we recount our modular approaches toward lankacidin antibiotics. Lankacidins are a group of polyketide natural products with activity against several strains of Gram-positive bacteria but have not been deployed as therapeutics due to their chemical instability. We describe a route to several diastereomers of 2,18-seco-lankacidinol B in a linear sequence of ≤8 steps from simple building blocks, resulting in a revision of the C4 stereochemistry. We next detail our modular synthesis of several diastereoisomers of iso-lankacidinol that resulted in the structural reassignment of this natural product. These structural revisions raise interesting questions about the biosynthetic origin of lankacidins, all of which possessed uniform stereochemistry prior to these findings. Finally, we summarize the ability of several iso- and seco-lankacidins to inhibit the growth of bacteria and to inhibit translation in vitro, providing important insights into structure-function relationships for the class

Synthesis, Structural Reassignment, and Antibacterial Evaluation of 2,18‐Seco‐Lankacidinol B

Lankacidins are a group of polyketide natural products with activity against several strains of Gram-positive bacteria. We developed a route to stereochemically diverse variants of 2,18-seco-lankacidinol B and found that the stereochemical assignment at C4 requires revision. This has interesting implications for the biosynthesis of natural products of the lankacidin class, all of which possessed uniform stereochemistry prior to this finding. We have evaluated 2,18-seco-lankacidinol B and three stereochemical derivatives against a panel of pathogenic Gram-positive and Gram-negative bacteria

Phosphine-Catalyzed α-Umpolung-Aldol Reaction for the Synthesis of Benzo[ b]azapin-3-ones.

A novel phosphine-catalyzed intermolecular cyclization between 2-sulfonamidobenzaldehyes and ynones is reported. This methodology serves as a conduit for the construction of benzo[ b]azepin-3-ones in good to excellent yields under mild conditions. The resulting 2-benzylidene moieties are formed exclusively in the E-configuration. Mechanistically, this unusual annulation occurs through a phosphine-catalyzed α-umpolung addition, followed by an aldol reaction. One of the benzo[ b]azepin-3-one products was converted to the core structure of 3-amino-[ a]benzazepin-2-one-1-alkanoic acids, many of which function as angiotensin-converting enzyme inhibitors