Dynamic and Persistent Cyclochirality in Hydrogen-Bonded Derivatives of Medium-Ring Triamines.

Cyclic triureas derived from 1,4,7-triazacyclononane (TACN) were synthesized; X-ray crystallography showed a chiral bowl-like conformation with each urea hydrogen-bonded to its neighbor with uniform directionality, forming a "cyclochiral" closed loop of hydrogen bonds. Variable-temperature 1H NMR, 1H-1H exchange spectroscopy, Eyring analysis, computational modeling, and studies in various solvents revealed that cyclochirality is dynamic (ΔG‡25°C = 63-71 kJ mol-1 in noncoordinating solvents), exchanging between enantiomers by two mechanisms: bowl inversion and directionality reversal, with the former subject to a slightly smaller enantiomerization barrier. The enantiomerization rate substantially increased in the presence of hydrogen-bonding solvents. Population of only one of the two cyclochiral hydrogen-bond directionalities could be induced by annulating one ethylene bridge with a trans-cyclohexane. Alternatively, enantiomerization could be inhibited by annulating one ethylene bridge with a cis-cyclohexane (preventing bowl inversion) and replacing one urea function with a formamide (preventing directionality reversal). Combining these structural modifications resulted in an enantiomerization barrier of ΔG‡25°C = 93 kJ mol-1, furnishing a planar-chiral, atropisomeric bowl-shaped structure whose stereochemical stability arises solely from its hydrogen-bonding network.

Sequence-Selective Decapeptide Synthesis by the Parallel Operation of Two Artificial Molecular Machines.

We report on the preparation of a decapeptide through the parallel operation of two rotaxane-based molecular machines. The synthesis proceeds in four stages: (1) simultaneous operation of two molecular peptide synthesizers in the same reaction vessel; (2) selective residue activation of short-oligomer intermediates; (3) ligation; (4) product release. Key features of the machine design include the following: (a) selective transformation of a thioproline building block to a cysteine (once it has been incorporated into a hexapeptide intermediate by one molecular machine); (b) a macrocycle-peptide hydrazine linkage (as part of the second machine) to differentiate the intermediates and enable their directional ligation; and (c) incorporation of a Glu residue in the assembly module of one machine to enable release of the final product while simultaneously removing part of the assembly machinery from the product. The two molecular machines participate in the synthesis of a product that is beyond the capability of individual small-molecule machines, in a manner reminiscent of the ligation and post-translational modification of proteins in biology.

Dynamic Control of Chiral Space Through Local Symmetry Breaking in a Rotaxane Organocatalyst.

We report on a switchable rotaxane molecular shuttle that features a pseudo-meso 2,5-disubstituted pyrrolidine catalytic unit on the axle whose local symmetry is broken according to the position of a threaded benzylic amide macrocycle. The macrocycle can be selectively switched (with light in one direction; with catalytic acid in the other) with high fidelity between binding sites located to either side of the pyrrolidine unit. The position of the macrocycle dictates the facial bias of the rotaxane-catalyzed conjugate addition of aldehydes to vinyl sulfones. The pseudo-meso non-interlocked thread does not afford significant selectivity as a catalyst (2-14 % ee), whereas the rotaxane affords selectivities of up to 40 % ee with switching of the position of the macrocycle changing the handedness of the product formed (up to 60 % Δee).

Minimizing the Entropy Penalty for Ligand Binding: Lessons from the Molecular Recognition of the Histo Blood-Group Antigens by Human Galectin-3.

Ligand conformational entropy plays an important role in carbohydrate recognition events. Glycans are characterized by intrinsic flexibility around the glycosidic linkages, thus in most cases, loss of conformational entropy of the sugar upon complex formation strongly affects the entropy of the binding process. By employing a multidisciplinary approach combining structural, conformational, binding energy, and kinetic information, we investigated the role of conformational entropy in the recognition of the histo blood-group antigens A and B by human galectin-3, a lectin of biomedical interest. We show that these rigid natural antigens are pre-organized ligands for hGal-3, and that restriction of the conformational flexibility by the branched fucose (Fuc) residue modulates the thermodynamics and kinetics of the binding process. These results highlight the importance of glycan flexibility and provide inspiration for the design of high-affinity ligands as antagonists for lectins.

Ni-Catalyzed Borylation of Aryl Fluorides via C-F Cleavage.

A Ni-catalyzed borylation via C-F activation is described. This protocol is distinguished by a wide scope, including unactivated fluoroarenes, without compromising its efficiency and scalability, thus representing a significant step-forward toward the implementation of C-F activation protocols.

Active template rotaxane synthesis through the Ni-catalyzed cross-coupling of alkylzinc reagents with redox-active esters.

The synthesis of unsymmetrical axle [2]rotaxanes through a recently developed Ni-catalyzed C(sp3)-C(sp3) cross-coupling of redox-active esters (formed directly from carboxylic acids) and organozinc reagents (derived from alkyl bromides) is reported. The method also furnishes, as a minor product, the symmetrical axle [2]rotaxanes resulting from the homo-coupling of the organozinc half-thread. The rotaxanes are formed in up to 56% yield with the ratio of unsymmetrical rotaxane increasing with the cavity size of the macrocycle. In the absence of the redox-active ester neither rotaxane is formed, even though the homo-coupling rotaxane product does not incorporate the redox-active ester building block. A Ni(iii) intermediate is consistent with these observations, providing support for the previously postulated mechanism of the Ni-catalyzed cross-coupling reaction.

RhI/RhIII catalyst-controlled divergent aryl/heteroaryl C-H bond functionalization of picolinamides with alkynes.

The ability to establish switchable site-selectivity through catalyst control in the direct functionalization of molecules that contain distinct C-H bonds remains a demanding challenge that would enable the construction of diverse scaffolds from the same starting materials. Herein we describe the realization of this goal, namely a divergent heteroaryl/aryl C-H functionalization of aromatic picolinamide derivatives, targeting two distinct C-H sites, either at the pyridine ring or at the arene unit, to afford isoquinoline or ortho-olefinated benzylamine (or phenethylamine) derivatives. This complementary reactivity has been achieved on the basis of a RhIII/RhI switch in the catalyst, resulting in different mechanistic outcomes. Notably, a series of experimental and DFT mechanistic studies revealed important insights about the mechanism of the reaction and reasons behind the divergent regiochemical outcome.