Steroidal ureas as enantioselective receptors for an N-acetyl alpha-amino carboxylate.

[reaction: see text] Cholic acid has been elaborated into three regioisomeric bis-carbamoylureas, which have been investigated as enantioselective receptors for N-acetyl phenylalanine. L/D selectivities, peaking at 5:1, have been determined by a sensitive and rapid MS-based extraction method that should be generalizable to related systems.

Substrate discrimination by cholapod anion receptors: geometric effects and the "affinity-selectivity principle".

Cholapod anion receptors can achieve high affinities while maintaining compatibility with nonpolar media. Previously they have been shown to transport anions across cell and vesicle membranes. In the present work, the scope of the architecture is expanded and structure-selectivity relationships are investigated. Eight new receptors have been synthesized, with up to six H-bond donor centers. Using Cram's extraction method, these compounds plus five known examples have been tested for binding to seven monovalent anions (tetraethylammonium salts, wet chloroform as solvent). Association constants in excess of 10(10) M(-1) have been measured for several pairings. Selectivities vary with receptor geometry, as expected. More remarkably, they also depend on receptor strength: more powerful receptors show a wider range of binding free energies, and therefore a greater spread of Ka(X-)/Ka(Y-). This "affinity-selectivity" effect can be derived from empirical relationships for H-bond strengths, and could prove widely operative in supramolecular chemistry.

Facilitated phospholipid flip-flop using synthetic steroid-derived translocases.

Cholate esters with phenylurea groups at the 7alpha- and 12alpha-positions are highly effective promoters of phosphatidylcholine translocation across vesicle and cell membranes. The urea groups are essential for strong binding of the highly polar phosphate portion of the phosphocholine headgroup and apparently cannot be replaced by simple amide, alcohol, or amine moieties. NMR and UV studies show that these synthetic translocases have very weak affinity for phosphatidylethanolamine and phosphatidylserine.

An extraction-based assay for neutral anionophores: the measurement of high binding constants to steroidal receptors in a nonpolar solvent.

The extraction-based protocol for measuring binding constants, developed by Cram and co-workers, has been extended for use with anionic substrates. The method is especially useful for high-affinity receptors, allowing very high binding constants to be measured in nonpolar solvents. Distribution constants K(d) between chloroform and water have been obtained for tetraethylammonium chloride and bromide, thus calibrating the method for these two substrates. Application to steroidal podands 5-9 has confirmed the ability of electron-withdrawing groups to enhance hydrogen-bond donor capabilities. Binding constants of approximately 3 x 10(7) M(-1) have been measured for the most powerful receptor 7. An X-ray crystal structure of 15, the methyl ester analogue of 7, reveals a well-defined binding site preorganised for anion recognition.

Differentially-protected steroidal triamines; scaffolds with potential for medicinal, supramolecular, and combinatorial chemistry.

Cholic acid 2a has been converted into two new orthogonally-protected triamino scaffolds, 13 and 14. The synthesis proceeds via the bis-Boc-NH-substituted azide 10, for which an improved preparation is described. After removal of the Boc groups, the two axial amines are differentiated through a novel monoprotection employing 1-(2-nitrobenzenesulfonyloxy)-benzotriazole 29. Regioselectivity of > or 50 : 1 is achieved, presumably reflecting an exceptional sensitivity to steric hindrance. Protection of the remaining amino group as Boc or Alloc gives the scaffolds in approximately 40% overall yield from cholic acid. Scaffold 13 has been sequentially deprotected and derivatised with N-carbamoyl amino acids, to give a model for tripodal peptide libraries.