Rh(III)-catalyzed Intra- and Intermolecular 3,4-Difunctionalization of 1,3-Dienes via Rh(III)-π-allyl Amidation with 1,4,2-Dioxazolones.

We herein report a modular strategy, which enables Rh(III)-catalyzed diastereoselective 3,4-amino oxygenation and diamination of 1,3-dienes using different O- and N-nucleophiles in combination with readily available 3-substituted 1,4,2-dioxazolones (78 examples, 37-91% yield). Previous attempts to functionalize the internal double bond rested on the use of plain alcoholic solvents as nucleophilic coupling partners thus dramatically limiting the scope of this transformation. We have now identified hexafluoroisopropanol as a non-nucleophilic solvent which allows the use of diverse nucleophiles and greatly expands the scope, including an unprecedented amino hydroxylation to selectively install valuable, unprotected ß-amino alcohols across 1,3-dienes. Moreover, various elaborate alcohols prove to be compatible providing unique access to complex organic molecules. Finally, this method is employed in a series of intramolecular reactions to deliver valuable nitrogen heterocycles as well as γ- and δ-lactones.

Diastereoselective Three-Component 3,4-Amino Oxygenation of 1,3-Dienes Catalyzed by a Cationic Heptamethylindenyl Rhodium(III) Complex.

The direct oxyamination of olefins is a compelling tool to rapidly access ß-amino alcohols-a privileged motif ubiquitous in natural products, pharmaceuticals and agrochemicals. Although a variety of expedient methods are established for simple alkenes, selective amino oxygenation of 1,3-dienes is less explored. Within this context, methods for the oxyamination of 1,3-dienes that are selective for the internal position remain unprecedented. We herein report a modular three-component approach to perform an internal and highly diastereoselective amino oxygenation of 1,3-dienes catalyzed by a cationic heptamethylindenyl (Ind*) Rh(III) complex.

Enantioselective Synthesis of Diaryl Sulfoxides Enabled by Molecular Recognition.

The enantioselective sulfoxidation of diaryl-type sulfides was accomplished using a chiral manganese porphyrin complex equipped with a remote molecular recognition site. Despite the marginal size difference between the two substituents at the prostereogenic sulfur center, hydrogen bonding enabled the formation of chiral sulfoxides with exquisite enantioselectivities (16 examples, up to 99% ee). Aside from the precise orientation of a distinct substrate, the quinolone lactam offers an excellent entry point for further derivatization.

Silver-Catalyzed Enantioselective Sulfimidation Mediated by Hydrogen Bonding Interactions.

An enantioselective sulfimidation of 3-thiosubstituted 2-quinolones and 2-pyridones was achieved with a stoichiometric nitrene source (PhI=NNs) and a silver-based catalyst system. Key to the success of the reaction is the use of a chiral phenanthroline ligand with a hydrogen bonding site. The enantioselectivity does not depend on the size of the two substituents at the sulfur atom but only on the binding properties of the heterocyclic lactams. A total of 21 chiral sulfimides were obtained in high yields (44-99 %) and with significant enantiomeric excess (70-99 % ee). The sulfimidation proceeds with high site-selectivity and can also be employed for the kinetic resolution of chiral sulfoxides. Mechanistic evidence suggests the intermediacy of a heteroleptic silver complex, in which the silver atom is bound to one molecule of the chiral ligand and one molecule of an achiral 1,10-phenanthroline. Support for the suggested reaction course was obtained by ESI mass spectrometry, DFT calculations, and a Hammett analysis.

Enantioselective oxygenation of exocyclic methylene groups by a manganese porphyrin catalyst with a chiral recognition site.

The natural enzyme cytochrome P450 is widely recognised for its unique ability to catalyse highly selective oxygen insertion reactions into unactivated C-H bonds under mild conditions. Its exceptional potential for organic synthesis served as an inspiration for the presented biomimetic hydroxylation approach. Via a remote hydrogen bonding motif a high enantioselectivity in the manganese-catalysed oxygenation of quinolone analogues (27 examples, 18-64% yield, 80-99% ee) was achieved. The site-selectivity was completely altered in favour of a less reactive but more accessible position.

Lactam Hydrogen Bonds as Control Elements in Enantioselective Transition-Metal-Catalyzed and Photochemical Reactions.

In the last two decades, hydrogen bonds have been established as useful interactions to control the selectivity of various chemical transformations. In this Perspective, the contributions by our group to this growing field of research are summarized and analyzed. In the first section, a chiral template is presented which displays a 1,5,7-trimethyl-3-azabicyclo[3.3.1]nonan-2-one skeleton with a lactam binding site and that has been used in superstoichiometric quantities in a variety of photochemical and radical reactions. Chiral catalysts with a related architecture evolved from the template by introducing a suitable chromophore for harvesting photons in the ultraviolet (benzophenone, xanthone) or visible region (thioxanthone). They act mainly by sensitization and allow for a high catalytic turnover in enantioselective [2 + 2] photocycloadditions and in deracemization reactions. Eventually, the concept of lactam hydrogen bonding was transferred to transition-metal catalysis, and catalysts have been developed which combine, in an enzyme-like fashion, a site for substrate binding and a catalytically active site. Substrate binding has been mainly achieved by a V-shaped ligand based on a tricyclic octahydro-1H-4,7-methanoisoindol-1-one scaffold with a lactam hydrogen-bonding site. The catalytically active metal (ruthenium, manganese, rhodium) is perfectly positioned to the substrate for a site- and enantioselective transfer of an oxygen atom (oxidation, oxygenation) or a nitrogen-based fragment (aziridination, amination).

A (+)-Larixol Congener with High Affinity and Subtype Selectivity toward TRPC6.

Natural products have many health benefits, and their application can improve the quality of life. Recently, the diterpene (+)-larixol and its acetylated congeners demonstrated selective inhibition of the second-messenger-gated cation channel transient receptor potential canonical 6 (TRPC6) over its close isoforms TRPC3 and TRPC7. Building on this knowledge, we expanded these findings by chemical diversification of (+)-larixol mostly at position C6. Implementing high-throughput Ca2+ FLIPR screening assays and electrophysiological patch-clamp recordings, we showcase larixyl N-methylcarbamate, termed SH045, as a compound with nanomolar affinity and 13-fold subtype selectivity over TRPC3 in stably expressing HEK293 cells. Expanding on this finding, TRPC6 inhibition was also observed in rat pulmonary smooth muscle cells. Furthermore, treatment of isolated perfused lung preparations with SH045 led to a decrease in lung ischemia-reperfusion edema (LIRE), a life-threatening condition associated with TRPC6 that may occur after organ transplantation. Taken together, and given the inexpensive, straightforward, and scalable preparation of SH045, we report a TRPC6 blocker that holds promise for the translational treatment of LIRE.

Site- and Enantioselective C-H Oxygenation Catalyzed by a Chiral Manganese Porphyrin Complex with a Remote Binding Site.

A chiral manganese porphyrin complex with a two-point hydrogen-bonding site was prepared and probed in catalytic C-H oxygenation reactions of 3,4-dihydroquinolones. The desired oxygenation occurred with perfect site selectivity at the C4 methylene group and with high enantioselectivity in favor of the respective 4S-configured secondary alcohols (12 examples, 29-97 % conversion, 19-68 % yield, 87-99 % ee). Mechanistic studies support the hypothesis that the reaction proceeds through a rate- and selectivity-determining attack of the reactive manganese oxo complex at the hydrogen-bound substrate and an oxygen transfer by a rebound mechanism.