In recent years, C 2-symmetric chiral bis(oxazoline) ligand-metal complexes have received a great deal of attention through their use in various catalytic process. 1c The bis(oxazoline) ligands are structurally related to C 2-symmetric semicorrins pioneered by Pfaltz and coworkers. 8a-c The inception of bis(oxazoline) ligands, however, added a new dimension in terms of flexibility in ligand design, convenient synthesis and availability of ligands in both enantiomeric forms. Since the early 1990s, many impressive enantioselective carbon-carbon bond forming reactions, aziridination reactions, hydrosilylations, oxidations and reductions have been recorded using bis(oxazoline)-metal complexes. The present review is intended to focus on the recent developments of bis(oxazoline) ligand-metal catalyzed asymmetric reactions and their applications in organic synthesis. The authors do not intend to provide an exhaustive review of this area since earlier developments have been reviewed by Pfaltz 8a-c and Bolm. 9 Applications of mono-and tris(oxazoline) ligand-metal complex catalyzed reactions are not included in this review. 2. C 2-Symmetric bis(oxazoline) ligands Chiral bis(oxazoline) ligands with a great deal of structural diversity have been introduced since 1989. Representative structural features of these novel ligands are shown in Fig. 1. In general, bis(oxazoline) ligands 1-10 with a one carbon spacer between the oxazoline rings are most frequently utilized. These ligands form a six membered metal chelate and the substituents on the ring are close to the metal center. These ligands were designed and applied for catalytic asymmetric allylic substitution (

Optimization of small-molecule probes or drugs is a lengthy, challenging and resource-intensive process. Lack of automation and reliance on skilled medicinal chemists is cumbersome in both academic and industrial settings. Here, we demonstrate a high-throughput hit-to-lead process based on the biocompatible SuFEx click chemistry. A modest high-throughput screening hit against a bacterial cysteine protease SpeB was modified with a SuFExable iminosulfur oxydifluoride [RN=S(O)F2] motif, rapidly diversified into 460 analogs in overnight reactions, and the products directly screened to yield drug-like inhibitors with 300-fold higher potency. We showed that the improved molecule is drug-like and biologically active in a bacteria-host coculture. Since these reactions can be performed on a picomole scale to conserve reagents, we anticipate our methodology can accelerate the development of robust biological probes and drug candidates. The introduction of high-throughput screening (HTS) robotics, liquid handler systems, and assay miniaturization have revolutionized screening of bioactive molecules. Relatively inexpensive HTS processes are now routinely used in cell-based and in vitro assays against biomedically relevant targets. Nevertheless, compound optimization is typically necessary to improve target specificity, potency, and stability. Lead optimization relies heavily on medicinal chemists, and extensive time and labor costs remain significant hurdles for probe and drug development. Click chemistry has found broad applications in materials chemistry, chemical biology, and drug development since the concept was first introduced in 1999 1-2. The sulfur(VI) fluoride exchange (SuFEx) represents the most recent set of ideal click chemistry transformations 3. Specifically, aryl fluorosulfates (ArOSO2F) and iminosulfur oxydifluorides (RN=S(O)F2) are readily synthesized using two connective oxyfluoride gases, sulfuryl fluoride (SO2F2) and thionyl tetrafluoride (O=SF4), respectively 4. These two S VI −F motifs have been successfully used as connective linkers in polymer synthesis and for construction of various functional molecules 5-7. Sulfonyl fluoride (RSO2F) and aryl fluorosulfate moieties have been successfully introduced into bioactive molecules in chemical biology and drug discovery 8-11 , especially as covalently binding warheads 12. However, the potential of SuFEx to unite diverse modules using an O=SF4 hub has not been explored in medicinal chemistry. While the copper(I)catalyzed azide-alkyne cycloaddition (CuAAC) reaction has been used in proof-of-concept studies on lead Statistical analysis was performed using one-way ANOVA with Dunnett's multiple comparisons test, *≤ 0.05. Supporting Information Additional texts, figures, and tables are provided. AUTHOR INFORMATION # Authors contributed equally.

The reaction of cyclopentadiene with various bidentate dienophiles in the presence of 4-10 mol% of copper(II)-bis(oxazoline) complexes afforded excellent endo/exo selectivity as well as endo enantioselectivity (95-99% ee) and isolated yields. On the other hand, Diels-Alder reaction with Mg(II)-complexes afforded a modest ( 61% ee) reversal in enantioselectivity.The enantioselective Diels-Alder reaction is of paramount interest in organic synthesis. 1 As a consequence, a number of effective enantioselective processes have been developed over the years. 2 Recent discoveries of various catalytic processes have added a new dimension to the enantioselective Diels-Alder reaction. 3,4 Of particular interest, C 2 -symmetric chiral bis(oxazoline)-metal complexes have shown exceptional promise as chiral catalysts for enantioselective Diels-Alder reactions. 5 As part of our interests in various ligand assisted asymmetric syntheses, 6 we have synthesized conformationally constrained chiral bis(oxazoline) ligands and investigated their effectiveness as chiral catalysts in asymmetric Diels-Alder reactions. Recent reports by Merck group 7 on the synthesis and application of (IS, 2R)-1-amino-2-indanol derived other bis(oxazoline) ligands in catalytic Diels-Alder reaction, prompted us to disclose our results in this area. Herein, we report that various metal-ligand complexes of conformationally constrained bis(oxazoline) ligands derived from phenylglycinol surrogates, cisI-amino-2-indanols 8 are indeed highly effective catalysts for the enantioselective Diels-Alder reaction. Among various metal complexes examined, bis(oxazoline)-copper(II) complex is particularly effective. Reaction of cyclopentadiene with various bidentate dienophiles 6 in the presence of 4-10 mol% of bis(oxazoline)-copper(II) complexes afforded excellent endo/exo selectivity as well as endo enantioselectivity and excellent isolated yields. Since either enantiomer of constrained bis(oxazoline) is readily prepared from commercially available 9 optically active cis-1-amino-2-indanols, the current methodology provides a convenient access to either enantiomer of various cyclopentadiene based Diels-Alder adducts in a stereopredictable fashion.Conformationally constrained ligand 4 was readily prepared on a multi gram scale according to the procedure of Lehn. 10 Treatment of malononitrile and ethanol in dioxane in the presence of anhydrous HCI afforded the amide enol ether hydrochloride salt 1 (Scheme I). Reaction of 1 with (IR, 2S)-1-amino-2-indanol 2 in DMF at 23°C provided the bis(oxazoline) 4 as a white solid (m.p.206-208°C; α D 23° + 352, c, 3.7, CHCl 3 ) after

Ring-closing olefin metathesis of acrylates derived from allylic and homo allylic alcohols in the presence of the Grubbs' catalyst (10-15 mol%) and titanium isopropoxide (0.3-3 equiv) provided ready access to α, β-unsaturated γand δ-lactones and an important dipeptide isostere intermediate.

Sulfur fluoride exchange (SuFEx), a next generation of click chemistry, opens an avenue for drug discovery. We report here the discovery and structure–activity relationship studies of a series of arylfluorosulfates, synthesized via SuFEx, as antibacterial agents. Arylfluorosulfates 3, 81, and 101 showed potency to overcome multidrug resistance and were not susceptible to the generation of resistance. They exhibited rapid bactericidal potency and selectively killed gram-positive bacterial strains. These compounds also exhibited the ability to disrupt established bacterial biofilm and kill persisters derived from biofilm. Furthermore, arylfluorosulfate 3 had a synergistic effect with streptomycin and gentamicin. In addition, their anti-MRSA potency was evaluated and determined by the Caenorhabditis elegans model.