Folding a Molecular Strand into a Trefoil Knot of Single Handedness with Co(II)/Co(III) Chaperones.

We report the synthesis of a right-handed (Δ-stereochemistry of strand crossings) trefoil knot from a single molecular strand containing three pyrazine-2,5-dicarboxamide units adjacent to point-chiral centers and six pyridine moieties. The oligomeric ligand strand folds into an overhand (open-trefoil) knot through the assistance of coordinatively dynamic Co(II) "chaperones" that drive the formation of a three-metal-ion circular helicate. The entangled structure is kinetically locked by oxidation to Co(III) and covalently captured by ring-closing olefin metathesis to generate a trefoil knot of single topological handedness. The stereochemistry of the strand crossings in the metal-coordinated overhand knot is governed by the stereochemistry of the point-chiral carbon centers in the ligand strand. The overhand and trefoil knots were characterized by NMR spectroscopy, mass spectrometry, and X-ray crystallography. Removal of the metal ions from the knot, followed by hydrogenation of the alkene, yielded the wholly organic trefoil knot. The metal-free knot and parent ligand were investigated by circular dichroism (CD) spectroscopy. The CD spectra indicate that the topological stereochemistry of the knot has a greater effect on the asymmetry of the chromophore environment than do the point-chiral centers of the strand.

Self-Sorting Assembly of Molecular Trefoil Knots of Single Handedness.

We report on the stereoselective synthesis of trefoil knots of single topological handedness in up to 90% yield (over two steps) through the formation of trimeric circular helicates from ligand strands containing either imine or, unexpectedly, amide chelating units and metal ion templates of the appropriate coordination character (zinc(II) for imines; cobalt(III) for amides). The coordination stereochemistry of the octahedral metal complexes is determined by asymmetric carbon centers in the strands, ultimately translating into trefoil knots that are a single enantiomer, both physically and in terms of their fundamental topology. Both the imine-zinc and amide-cobalt systems display self-sorting behavior, with racemic ligands forming knots that individually contain only building blocks of the same chirality. The knots and the corresponding trimeric circular helicate intermediates (Zn(II)3 complex for the imine ligands; Co(III)3 complex for the amide ligands) were characterized by nuclear magnetic resonance spectroscopy, mass spectrometry, and X-ray crystallography. The latter confirms the trefoil knots as 84-membered macrocycles, with each of the metal ions sited at a crossing point for three regions of the strand. The stereochemistry of the octahedral coordination centers imparts alternating crossings of the same handedness within each circular helicate. The expression of chirality of the knotted molecules was probed by circular dichroism: The topological handedness of the demetalated knots was found to have a greater effect on the CD response than the Euclidean chirality of an individual chiral center.

Molecular Trefoil Knot from a Trimeric Circular Helicate.

We report the two-step synthesis of a molecular trefoil knot in 90% overall yield through the self-assembly of a 12-component trimeric circular zinc helicate followed by ring closing metathesis of six pendant alkene chains. Both the trimeric circular helicate intermediate and the resulting trefoil knot were characterized by NMR spectroscopy, mass spectrometry, and X-ray crystallography.

Organocatalytic and scalable synthesis of the anti-influenza drugs zanamivir, laninamivir, and CS-8958.

Zanamivir, laninamivir, and CS-8958 are three neuraminidase inhibitors that have been clinically used to combat influenza. We report herein a novel organocatalytic route for preparing these agents. Only 13 steps are needed for the assembly of zanamivir and laninamivir from inexpensive D-araboascorbic acid by this synthetic route, which relies heavily on a thiourea-catalyzed enantioselective Michael addition of acetone to tert-butyl (2-nitrovinyl)carbamate and an anti-selective Henry reaction of the resulting Michael adduct with an aldehyde prepared from D-araboascorbic acid. The synthetic procedures are scalable, as evident from the preparation of more than 3.5 g of zanamivir.