A practical synthesis of LFA-1 inhibitors utilizing CuCl-promoted intramolecular cyclization of thiohydantoins

An efficient and chromatography-free approach for synthesis of a new class of LFA-1 inhibitors was developed. A copper(I) chloride-promoted intramolecular cyclization of thiohydantoins 7a-b serves as a key step to highly functionalized bicyclic guanidines 5a-b, that were subsequently converted to 1H-imidazo[1,2-a]imidazol-2-one LFA-1 inhibitors. This process has been successfully implemented in the pilot plant to produce multikilogram quantities of LFA-1 inhibitors such as 1a-b.     

[3+2] Cycloaddition reactions: a simple entry to the 1-aza-2-oxo-3,4,5,6-tetrahydroxybicyclo[3.3.0]octane ring system

The [3+2] intramolecular nitrone cycloaddition (INC) reaction on appropriately designed olefinic nitrones derived from d-glucose, having the nitrone at C-1 and α,β-unsaturated ester functionalities at C-5 of the sugar backbone, afforded the isoxazolidine fused carbocycles 11-13, which were subsequently transformed into the chiral, tetrahydroxylated cis-azabicyclo[3.3.0]octanones 14-18 in good yields.     

Adaptive Catalysts for the Selective Hydrogenation of Bicyclic Heteroaromatics using Ruthenium Nanoparticles on a CO2-Responsive Support

Ruthenium nanoparticles (NPs) immobilized on an amine-functionalized polymer-grafted silica support act as adaptive catalysts for the hydrogenation of bicyclic heteroaromatics. Whereas full hydrogenation of benzofuran and quinoline derivatives is achieved under pure H₂, introducing CO₂ into the H₂ gas phase leads to an effective shutdown of the arene hydrogenation while preserving the activity for the hydrogenation of the heteroaromatic part. The selectivity switch originates from the generation of ammonium formate species on the surface of the materials by catalytic hydrogenation of CO₂. The CO₂ hydrogenation is fully reversible, resulting in a robust and rapid switch between the two states of the catalyst adapting its performance in response to the feed gas composition. A variety of benzofuran and quinoline derivatives were hydrogenated to fully or partially saturated products in high selectivity and yields simply by altering the composition of the feed gas from H₂ to H₂/CO₂. The adaptive catalytic system thus provides controlled access to valuable products using a single catalyst rather than two specific and distinct catalysts with static reactivity.     

Unprecedented single-pot protocol for the synthesis of N1, C6-linked bicyclic 3,4-dihydropyrimidinones via lithiation of Biginelli compounds

4-Aryl/alkyl-6-methyl-3,4-dihydropyrimidin-2(1H)-one ester derivatives readily undergo metalation at the C6 methyl (vinylogous ester) position along with two acidic NHs upon treatment with n-butyllithium at −10 °C. The trianion of DHPMs thus obtained react smoothly with various terminal dibromoalkanes to afford N1, C6-linked bicyclic DHPM derivatives, which represent key structural features of the medicinally potent marine alkaloids such as batzelladine A and crambescin A.     

Seebach’s oxazolidinone is a good catalyst for aldol reactions

Seebach’s proline-derived oxazolidinone 2d overcomes (S)-proline and is at least as efficient as (S)-5-(pyrrolidin-2-yl)tetrazole in several organocatalytic aldol reactions examined. A quick exchange takes place between 2d and carbonyl compounds that gives new bicyclic oxazolidinones, in equilibrium with the very minor active species (enamines). Maximum yields of the aldols (β-hydroxy ketones) were achieved after 1-4 h when, with proline, they are attained after 30-48 h.     

The intercalation of bicyclic and tricyclic carboxylates into layered double hydroxides

Twenty-four nanocomposites built from layered double hydroxides and bicyclic and tricyclic carboxylates have been synthesised for the first time. Eight carboxylates were successfully intercalated into [LiAl₂(OH)₆]Cl·yH₂O, [Ca₂Al(OH)₆]NO₃·yH₂O, and [Mg₂Al(OH)₆]NO₃·yH₂O, and the products fully characterised. Guest species incorporated include 1-adamantane carboxylate (1-AC) and 5-norbornene-2-endo-3-exo-dicarboxylate. In some cases, carbonate anions were co-intercalated with the organic guest, and in others poorly crystalline aluminium hydroxides formed as by-products. Sharper resonances were observed in the ¹³C solid-state NMR spectra of the 1-AC intercalates than in the spectrum of pure 1-AC, suggesting increased order in the arrangement of the cyclic cages in the intercalates. Where possible, time-resolved in situ X-ray diffraction was employed to study the nanoscopic steps involved in the intercalation reactions. These investigations showed that the reactions are one-step processes, proceeding directly to the fully exchanged intercalate with no intermediate phases. The intercalation processes were found to be nucleation controlled.     

Formation of polysubstituted chlorocyclopropanes from electrophilic olefins and activated trichloromethyl compounds

Chlorocyclopropanes and bicyclic chlorocyclopropanes are prepared in non basic conditions by electroreductive or Mg-promoted Barbier activation of PhCCl₃ or Cl₃CCO₂Me in the presence of acyclic or cyclic α,β-unsaturated carbonyl compounds.     

Functionalization of 2″‐C‐(Piperazinomethyl)‐2′,3′‐BcNA (Bicyclic Nucleic Acids) with Pyren‐1‐ylcarbonyl Units

Herein, we describe the incorporation of 2″‐C‐(piperazinomethyl)‐2′,3′‐BcNA (Bicyclic Nucleic Acids) into oligonucleotides via phosphoramidite chemistry and their subsequent solid‐phase functionalization with pyren‐1‐ylcarbonyl units after oligonucleotide synthesis. Thermal denaturation measurements showed that one modification led to increased thermal stability of the resulting duplex, and that two modifications could be incorporated in close proximity without decreasing the duplex stability (compared to the duplex stability of unmodified RNA). Fluorescence studies of the modified duplexes revealed that the structure and intensity of the fluorescence spectra were largely sequence‐dependent. Furthermore, molecular‐modeling studies showed that the pyrene moieties are placed in the major groove, and that the configuration at C(2″) is important for the thermal stability of the duplex.     

Phage selection of bicyclic peptides binding Her2

Aberrant expression of the epidermal growth factor receptor Her2 has been implicated in various malignancies including breast cancer. Monoclonal antibodies and an antibody–drug conjugate targeting Her2 have found wide clinical application. Herein, we aimed at developing Her2-specifc ligands based on peptides that have a 100-fold smaller molecular weight than antibodies. Such peptides could potentially offer advantages in the development of ligand–drug conjugates, such as ease of synthesis and conjugation, higher molecule-per-mass ratios, and better tumor penetration. Panning of large bicyclic peptide phage display libraries against Her2 yielded a range of Her2-specific ligands having different formats and binding motifs. Strong sequence similarities among several of the isolated peptides indicated that they interact with Her2 in a specific manner. The best bicyclic peptide obtained after affinity maturation bound Her2 with a K_D of 304 nM. The diverse peptide ligands may offer valuable starting points for the development of high-affinity Her2 binders with potential application for tumor imaging and therapy.     

Synthesis,characterization, and initial reaction study of two new bicyclic hypervalent iodine(III) reagents

The synthesis of two new bicyclic hypervalent iodine(III) reagents 5 and 6 is described along with their corresponding X-ray crystal structures for the first time. A detailed comparison in the bond lengths and bond angles of reported bicyclic hypervalent iodine(III) reagents is also presented. Furthermore, an initial study shows that these two hypervalent iodine(III) reagents could promote the dipeptide coupling reaction.