Stille coupling of an aziridinyl stannatrane.

An aziridinyl stannatrane 8 couples with aryl or alkenyl halides RX under modified Stille conditions to afford substituted aziridines. Efficient coupling at room temperature is possible in the best examples in the presence of ((t)Bu3P)2Pd and CuOP(O)Ph2 (CuDPP).

Novel C-1 substituted cocaine analogs unlike cocaine or benztropine.

Despite a wealth of information on cocaine-like compounds, there is no information on cocaine analogs with substitutions at C-1. Here, we report on (R)-(-)-cocaine analogs with various C-1 substituents: methyl (2), ethyl (3), n-propyl (4), n-pentyl (5), and phenyl (6). Analog 2 was equipotent to cocaine as an inhibitor of the dopamine transporter (DAT), whereas 3 and 6 were 3- and 10-fold more potent, respectively. None of the analogs, however, stimulated mouse locomotor activity, in contrast to cocaine. Pharmacokinetic assays showed compound 2 occupied mouse brain rapidly, as cocaine itself; moreover, 2 and 6 were behaviorally active in mice in the forced-swim test model of depression and the conditioned place preference test. Analog 2 was a weaker inhibitor of voltage-dependent Na+ channels than cocaine, although 6 was more potent than cocaine, highlighting the need to assay future C-1 analogs for this activity. Receptorome screening indicated few significant binding targets other than the monoamine transporters. Benztropine-like "atypical" DAT inhibitors are known to display reduced cocaine-like locomotor stimulation, presumably by their propensity to interact with an inward-facing transporter conformation. However, 2 and 6, like cocaine, but unlike benztropine, exhibited preferential interaction with an outward-facing conformation upon docking in our DAT homology model. In summary, C-1 cocaine analogs are not cocaine-like in that they are not stimulatory in vivo. However, they are not benztropine-like in binding mechanism and seem to interact with the DAT similarly to cocaine. The present data warrant further consideration of these novel cocaine analogs for antidepressant or cocaine substitution potential.

Enantioselective synthesis of cocaine C-1 analogues using sulfinimines (N-sulfinyl imines).

The first examples of cocaine analogues having substituents (methyl, ethyl, n-propyl, n-pentyl, and phenyl) at the C-1 position of the cocaine tropane skeleton were prepared by heating sulfinimine-derived α,ß-unsaturated pyrrolidine nitrones. In the presence of the Lewis acid Al(O(t)Bu)(3) the nitrones undergo an intramolecular [3 + 2] cycloaddition to give tricyclic isoxazolidines that were transformed in three steps to the cocaine analogues. In the absence of the Lewis acid, lactams were formed resulting from rearrangement of the nitrone to an oxaziridine. A novel Pd- and base-promoted rearrangement of methanesulfonate salts of isoxazolidine to bridge bicyclic[4.2.1]isoxazolidines was discovered.

Asymmetric total synthesis of (S)-(+)-cocaine and the first synthesis of cocaine C-1 analogs from N-sulfinyl ß-amino ester ketals.

Sulfinimine-derived α,ß-unsaturated pyrrolidine nitrones, on heating with Al(O-t-Bu)(3), undergo a highly stereoselective intramolecular [3 + 2] cycloaddition to give tricyclic isoxazolidines, which are transformed in three-steps to give C-1 substituted cocaine analogs.

Asymmetric synthesis of cyclic cis-beta-amino acid derivatives using sulfinimines and prochiral Weinreb amide enolates.

Cyclic cis-beta-amino Weinreb amides, valuable building blocks for the asymmetric synthesis of cyclic beta-amino acids derivatives, are readily prepared via ring-closing metathesis of sulfinimine-derived N-sulfinyl beta-amino diene Weinreb amides. These unsaturated cyclic cis-beta-amino Weinreb amides are valuable building blocks for the asymmetric synthesis of cyclic beta-amino acid derivatives.

Asymmetric synthesis of substituted tropinones using the intramolecular mannich cyclization reaction and acyclic N-sulfinyl beta-amino ketone ketals.

Sulfinimine-derived, enantiopure N-sulfinyl beta-amino ketone ketals on hydrolysis give dehydropyrrolidine ketones that on treatment with (Boc)(2)O/DMAP afford substituted tropinones in good yield.

Selective peptide binding using facially amphiphilic dendrimers.

Amphiphilic dendrimers, which contain both hydrophobic and hydrophilic groups in every repeat unit, exhibit environment-dependent assemblies both in hydrophilic solvent, water, and in lipophilic solvent, toluene. Upon investigating the status of these assemblies in a mixture of immiscible solvents, these dendrimers were found to be kinetically trapped in the solvent in which they are initially assembled. This property has been exploited to selectively extract peptides from aqueous solution into an organic phase, where the peptides bind to the interior functionalities of the dendritic inverse micelles. While the corresponding small molecule surfactant does not exhibit any selective binding toward peptides, all dendrons (G1-G3) are capable of this selective binding. We show that the inverse micelle-type assembly itself is crucial for the binding event and that the assembly formed by the G1 dendron has a greater capability for binding compared to the G2 or G3 dendrons. We have also shown that the average apparent pKa of the carboxylic acid functionalities varies with generation, and this could be the reason for the observed differences in binding capacity.