Tricycles by a new Ugi variation and Pictet-Spengler reaction in one pot.

Subsequent mild cyclization of aromatic substrates by Pictet-Spengler condensation stereoselectively gave new tricyclic compounds. Examples are described in decent yields over two steps in one pot, and a crystal structure is also presented to support the proposed structures.

Various cyclization scaffolds by a truly Ugi 4-CR.

Efficient access to a large chemical space based on new scaffolds with defined 3D conformations and highly variable in the side chains is needed to find novel functional materials. Four heterocyclic scaffolds based on a four component Ugi reaction of α-amino acids, oxo components, isocyanides and primary or secondary amines suitably functionalized are described. A handful of examples are described for each scaffold.

Bistable cucurbituril rotaxanes without stoppers.

Bistable rotaxanes are important design elements of molecular devices for a broad range of applications, such as controlled drug release, molecular rotary motors, and chemical sensors. The host-guest complexes of cucurbit[6]uril and 1,4-bis(alkylaminomethyl)benzene were found to exhibit two stable binding modes with an unexpectedly high barrier between them. Their structural and dynamic properties, kinetic and thermodynamic parameters, as well as different chemical reactivity towards the azide-alkyne [3+2] cycloaddition reaction (click chemistry), were discovered by NMR spectroscopy, X-ray crystallography, and isothermal titration microcalorimetry. The highly stable 2:1 complex, which is formed at room temperature, was found to be a kinetic product, which may be converted to the thermodynamic 1:1 complex upon prolonged heating to 100 °C. The latter is a very stable rotaxane despite the fact that it lacks bulky end groups.

Switchable cucurbituril-bipyridine beacons.

4-Aminobipyridine derivatives form strong inclusion complexes with cucurbit[6]uril, exhibiting remarkably large enhancements in fluorescence intensity and quantum yields. The remarkable complexation-induced pK(a) shift (DeltapK(a)=3.3) highlights the strong charge-dipole interaction upon binding. The reversible binding phenomenon can be used for the design of switchable beacons that can be incorporated into cascades of binding networks. This concept is demonstrated herein by three different applications: 1) a switchable fluorescent beacon for chemical sensing of transition metals and other ligands; 2) direct measurement of binding constants between cucurbit[6]uril and various nonfluorescent guest molecules; and 3) quantitative monitoring of biocatalytic reactions and determination of their kinetic parameters. The latter application is illustrated by the hydrolysis of an amide catalyzed by penicillin G acylase and by the elimination reaction of a beta-cabamoyloxy ketone catalyzed by aldolase antibody 38C2.

Repulsive interaction can be a key design element of molecular rotary motors.

Low-barrier molecular rotary motors having rotaxane architecture can be constructed using a cucurbituril host and a polyyne guest serving as stator and rotator, respectively. The repulsive interaction between these components is supported by molecular mechanics calculations with model systems and experimentally verified by X-ray crystallography with several synthetic host-guest complexes, all suggesting that the diyne rod floats at the center of the macrocyclic host with no apparent van der Waals contacts between them. Further support for these interactions is suggested by microcalorimetry measurements.

Synthesis and biocompatibility of a biodegradable and functionalizable thermo-sensitive hydrogel.

Injectable thermal gels are a useful tool for drug delivery and tissue engineering. However, most thermal gels do not solidify rapidly at body temperature (37°C). We addressed this by synthesizing a thermo-sensitive, rapidly biodegrading hydrogel. Our hydrogel, poly(ethylene glycol)-co-poly(propanol serinate hexamethylene urethane) (EPSHU), is an ABA block copolymer comprising A, methoxy poly ethylene glycol group and B, poly (propanol L-serinate hexamethylene urethane). EPSHU was characterized by gel permeation chromatography for molecular weight and (1)H NMR and Fourier transformed infrared for structure. Rheological studies measured the phase transition temperature. In vitro degradation in cholesterol esterase and in Dulbecco's phosphate buffered saline (DPBS) was tracked using the average molecular weight measured by gel permeation chromatography. LIVE/DEAD and resazurin reduction assays performed on NIH 3T3 fibroblasts exposed to EPSHU extracts demonstrated no cytotoxicity. Subcutaneous implantation into BALB/cJ mice indicated good biocompatibility in vivo. The biodegradability and biocompatibility of EPSHU together make it a promising candidate for drug delivery applications that demand carrier gel degradation within months.

Facile purification of rare cucurbiturils by affinity chromatography.

A practical method for the separation and purification of cucurbituril (CB) hexamers was developed on the basis of affinity chromatography using aminopentylaminomethylated polystyrene beads. This recyclable resin, which can be used repeatedly, facilitates the general preparation of cucurbituril derivatives and compensates for the usually moderate yields and mixed products that characterize the acid-catalyzed synthesis of CB derivatives. This technique allows convenient, rapid isolation of rare substituted cucurbiturils, including hexacyclohexanocucurbit[6]uril and dodecamethylcucurbit[6]uril. [reaction: see text]

Binary fluorous tagging enables the synthesis and separation of a 16-stereoisomer library of macrosphelides.

Fluorous mixture synthesis minimizes the effort to synthesize small-molecule libraries by labelling the molecules rather than the reaction vessels. Reactants are labelled with fluorinated tags and products can later be demixed based on the fluorine content. A limit in the number of available tags can be overcome by using binary encoding so that a total of four tags can label uniquely a library of 16 compounds. This strategy, however, means that separation based on fluorine content alone is not possible. Here, we solve this problem by selectively removing one tag after an initial demixing step; a second demixing provides each individual compound. The usefulness of this strategy is demonstrated by the synthesis of a library that contains all 16 diastereomers of the natural products macrosphelides A and E. Macrosphelide D was not in this library, and so its assigned structure was incorrect. We determined its constitution by using NMR spectroscopy and its configuration by synthesizing four candidate stereoisomers.

Total synthesis of 34-hydroxyasimicin and its photoactive derivative for affinity labeling of the mitochondrial complex I.

The asymmetric total synthesis of the 34-hydroxyasimicin and its 3-(4-benzoylphenyl)propionate ester was achieved by means of a convergent synthetic strategy. This ester, which contains eight asymmetric centers, represents the first photoaffinity-labeling agent that is derived from an Annonaceous acetogenin. The key transformations in the synthesis include the Sharpless asymmetric dihydroxylation reaction, the Wittig olefination reaction, an oxidative cyclization reaction with rhenium(vii) oxide, the Williamson etherification reaction, and a palladium-catalyzed cross-coupling reaction. Use of the target molecule for photoaffinity-labeling studies of bovine mitochondrial NADH-ubiquinone oxidoreductase (Complex I) may shed light on the structure/function of this intricate enzyme and on the origin of the high antitumor activity exhibited by the Annonaceous acetogenins.