Algorithm-aided engineering of aliphatic halogenase WelO5* for the asymmetric late-stage functionalization of soraphens.

Late-stage functionalization of natural products offers an elegant route to create novel entities in a relevant biological target space. In this context, enzymes capable of halogenating sp carbons with high stereo- and regiocontrol under benign conditions have attracted particular attention. Enabled by a combination of smart library design and machine learning, we engineer the iron/α-ketoglutarate dependent halogenase WelO5* for the late-stage functionalization of the complex and chemically difficult to derivatize macrolides soraphen A and C, potent anti-fungal agents.

Chiral Atropisomeric Indenocorannulene Bowls: Critique of the Cahn-Ingold-Prelog Conception of Molecular Chirality.

Chiral corannulenes abound, but suffer generally from configurational lability associated with bowl-to-bowl inversion, thus obviating questions of stereogenicity and stereoelement construction. In contrast, peri-annulated corannulenes show greatly increased barriers for bowl-to-bowl inversion; specifically indenocorannulenes invert on a time scale too slow to observe by normal NMR methods and raise the possibility of creating chiral atropisomeric bowl-shaped aromatics. Two methods for preparing indenocorannulene from simple 2-haloarylcorannulenes-silyl cation C-F activation, and Pd-mediated C-Cl activation -enable the synthesis of an array of such chiral atropisomeric indenocorannulenes.

1,2,3- versus 1,2-Indeno Ring Fusions Influence Structure Property and Chirality of Corannulene Bowls.

Annulated corannulenes 3-5 form via distinct synthetic pathways: (i) Pd-catalyzed sp CH insertion, (ii) Pd-catalyzed aryl coupling, and (iii) silyl cation-promoted C-F activation/CH insertion. Crystal structure, redox, and photophysical studies elucidate the differing influence of 1,2,3- versus 1,2-indeno ring fusions. Mono and dianions of 3-5 are characterized.

Pauli Repulsion Versus van der Waals: Interaction of Indenocorannulene with a Cu(111) Surface.

Modification of metal electrode surfaces with functional organic molecules is an important step toward organic electronics. The interaction of the buckybowl indenocorannulene with a Cu(111) surface and the two-dimensional self-assembly on the same surface was studied by means of scanning tunneling microscopy and dispersion-enabled density functional theory. Based on the conjecture of maximizing van der Waals interaction with the surface one would expect the indeno group to be aligned parallel to the surface.

Key analogs of a uniquely potent synthetic vinblastine that contain modifications of the C20' ethyl substituent.

A key series of vinblastine analogs 7-13, which contain modifications to the C20' ethyl group, was prepared with use of two distinct synthetic approaches that provide modifications of the C20' side chain containing linear and cyclized alkyl groups or added functionalized substituents. Their examination revealed the unique nature of the improved properties of the synthetic vinblastine 6, offers insights into the origins of its increased tubulin binding affinity and 10-fold improved cell growth inhibition potency, and served to probe a small hydrophobic pocket anchoring the binding of vinblastine with tubulin. Especially noteworthy were the trends observed with substitution of the terminal carbon of the ethyl group that, with the exception of 9 (R=F vs H, equipotent), led to remarkably substantial reductions in activity (>10-fold): R=F (equipotent with H)>N, CN (10-fold)>Me (50-fold)>Et (100-fold)>OH (inactive).

Synthesis of a Potent Vinblastine: Rationally Designed Added Benign Complexity.

Many natural products, including vinblastine, have not been easily subjected to simplifications in their structures by synthetic means or modifications by late-stage semisynthetic derivatization in ways that enhance their biological potency. Herein, we detail a synthetic vinblastine that incorporates added benign complexity (ABC), which improves activity 10-fold, and is now accessible as a result of advances in the total synthesis of the natural product. The compound incorporates designed added molecular complexity but no new functional groups and maintains all existing structural and conformational features of the natural product.

Chiral conflict among different helicenes suppresses formation of one enantiomorph in 2D crystallization.

Diastereomeric interactions in 2D crystals formed at solid surfaces serve as excellent models for understanding molecular recognition in biomineralization. Adsorption of a pentahelicene racemate on a Au(111) surface leads to 2D conglomerate crystallization, i.e.

Catechol-O-methyltransferase in complex with substituted 3'-deoxyribose bisubstrate inhibitors.

The biological activity of catechol neurotransmitters such as dopamine in the synapse is modulated by transporters and enzymes. Catechol-O-methyltransferase (COMT; EC 2.1.

Proton-catalyzed, silane-fueled Friedel-Crafts coupling of fluoroarenes.

The venerable Friedel-Crafts reaction appends alkyl or acyl groups to aromatic rings through alkyl or acyl cation equivalents typically generated by Lewis acids. We show that phenyl cation equivalents, generated from otherwise unreactive aryl fluorides, allow extension of the Friedel-Crafts reaction to intramolecular aryl couplings. The enabling feature of this reaction is the exchange of carbon-fluorine for silicon-fluorine bond enthalpies; the reaction is activated by an intermediate silyl cation.