Enantioselective Total Synthesis of (-)-Finerenone Using Asymmetric Transfer Hydrogenation.

(-)-Finerenone is a nonsteroidal mineralocorticoid receptor antagonist currently in phase III clinical trials for the treatment of chronic kidney disease in type 2 diabetes. It contains an unusual dihydronaphthyridine core. We report a 6-step synthesis of (-)-finerenone, which features an enantioselective partial transfer hydrogenation of a naphthyridine using a chiral phosphoric acid catalyst with a Hantzsch ester. The process is complicated by the fact that the naphthyridine exists as a mixture of two atropisomers that react at different rates and with different selectivities. The intrinsic kinetic resolution was converted into a kinetic dynamic resolution at elevated temperature, which enabled us to obtain (-)-finerenone in both high yield and high enantioselectivity. DFT calculations have revealed the origin of selectivity.

Non-Directed Cross-Dehydrogenative (Hetero)arylation of Allylic C(sp3 )-H bonds enabled by C-H Activation.

Herein, we report the selective, non-directed and cross-dehydrogenative coupling of allylic C(sp3 )-H bonds with C(sp2 )-H bonds of (hetero)arenes. The methodology employs olefins and (hetero)arenes which are abundantly available chemical feedstocks, and could be applied in late-stage functionalization reactions of pharmaceuticals. Furthermore, the system exclusively delivers the allylic C-C coupling products highlighting the preservation of the olefin substitution pattern for further derivatization.

Efficient Synthesis of Arylated Furans by a Sequential Rh-Catalyzed Arylation and Cycloisomerization of Cyclopropenes.

A novel and efficient strategy for the synthesis of arylated furans was successfully developed by a RhIII -catalyzed coupling of N-phenoxyacetamides and cyclopropenyl esters. Mechanistic investigation reveals that the arylated furans are formed via arylation of the cyclopropenyl esters followed by cycloisomerization.

A General Cp*CoIII -Catalyzed Intramolecular C-H Activation Approach for the Efficient Total Syntheses of Aromathecin, Protoberberine, and Tylophora Alkaloids.

Herein, we report a Cp*CoIII -catalyzed C-H activation approach as the key step to create highly valuable isoquinolones and pyridones as building blocks that can readily be applied in the total syntheses of a variety of aromathecin, protoberberine, and tylophora alkaloids. This particular C-H activation/annulation reaction was achieved with several terminal as well as internal alkyne coupling partners delivering a broad scope with excellent functional group tolerance. The synthetic applicability of this protocol reported herein was demonstrated in the total syntheses of two Topo-I-Inhibitors and two 8-oxyprotoberberine cores that can be further elaborated into the tetrahydroprotoberberine and the protoberberine alkaloid core. Moreover these building blocks were also transformed to six different tylophora alkaloids in expedient fashion.

Cp*Rh(III)/Bicyclic Olefin Cocatalyzed C-H Bond Amidation by Intramolecular Amide Transfer.

A bicyclic olefin was discovered as a cocatalyst in a Cp*Rh(III)-catalyzed C-H bond amidation proceeding by an intramolecular amide transfer in N-phenoxyacetamide derivatives. Combining experimental and theoretical studies, we propose that the olefin promotes a Rh(III) intermediate to undergo oxidative addition into the O-N bond to form a Rh(V) nitrenoid species and subsequently direct the nitrenoid to add to the ortho position. The amide directing group plays a dual role as a cleavable coordinating moiety as well as an essential coupling partner for the C-H amidation. This methodology was successfully applied to the late-stage diversification of natural products and a marketed drug under mild conditions.

Mechanistic Studies on a Cooperative NHC Organocatalysis/Palladium Catalysis System: Uncovering Significant Lessons for Mixed Chiral Pd(NHC)(PR3) Catalyst Design.

A comprehensive investigation of the mechanism of the highly enantioselective Pd(PPh3)4/NHC-catalyzed annulation of vinyl benzoxazinanones and enals has been conducted. A study of reaction orders supports the postulated cooperative catalysis. Interestingly, a detailed investigation of the catalytically active palladium species pointed toward a dual role of the NHC acting as an organocatalyst and forming a novel mixed ligand Pd/NHC/phosphine complex. The catalytically active Pd/NHC/phosphine complex represents a new class of chiral palladium catalyst. Remarkably, phosphine plays a crucial role in this transformation. These complexes could be characterized by X-ray crystallographic analysis and employed as catalysts for the enantioselective [4 + 1] annulation reaction of vinyl benzoxazinones and sulfur ylides in good yields and good enantioselectivities.

Combination of Cp*RhIII -Catalyzed C-H Activation and a Wagner-Meerwein-Type Rearrangement.

A combination of Cp*RhIII -catalyzed C-H activation and Wagner-Meerwein-type rearrangement was successfully achieved for the first time. Thus, bridged polycyclic molecules that are not readily accessible by other means were accessed under mild conditions with high efficiency (as low as 0.5 mol % Rh catalyst) in the coupling of N-phenoxyacetamide with 7-azabenzonorbornadiene.

Unnatural Amino Acid Synthesis Enabled by the Regioselective Cobalt(III)-Catalyzed Intermolecular Carboamination of Alkenes.

Herein, we report an unprecedented regioselective and entirely atom-economic cobalt(III)-catalyzed method for the non-annulative, intermolecular carboamination of alkenes. The methodology enables the direct synthesis of unnatural amino acid derivatives and proceeds under redox-neutral conditions with a completely regioselective C-C bond and C-N bond formation. Furthermore, this reaction exemplifies the inherently different mechanistic behavior of the Cp*CoIII catalyst and its Cp*RhIII counterpart, especially towards ß-H-elimination.

A Comparative Investigation: Group 9 Cp*M(III)-Catalyzed Formal [4 + 2] Cycloaddition as an Atom-Economic Approach to Quinazolines.

A comparative study on the catalytic activity of different group 9 [Cp*M(III)] complexes in the formal [4 + 2] cycloaddition of arenes with rarely explored free imines and dioxazolones for the construction of multisubstituted quinazolines is reported herein. This investigation revealed that the cobalt catalyst is uniquely suited to this transformation due to its strong Lewis acidity and high sensitivity to steric hindrance.

Cobalt(III)-Catalyzed Redox-Neutral Synthesis of Unprotected Indoles Featuring an N-N Bond Cleavage.

A redox-neutral cobalt(III)-catalyzed synthetic approach for the direct synthesis of unprotected indoles showcasing an N-N bond cleavage is reported. The herein newly introduced Boc-protected hydrazines establish a beneficial addition to the limited portfolio of oxidizing directing groups for cobalt(III) catalysis. Moreover, the developed catalytic methodology tolerates a good variety of functional groups.

Catalytic Asymmetric Mannich Reactions with Fluorinated Aromatic Ketones: Efficient Access to Chiral ß-Fluoroamines.

Reported herein is a Zn/Prophenol-catalyzed Mannich reaction using fluorinated aromatic ketones as nucleophilic partners for the direct enantio- and diastereoselective construction of ß-fluoroamine motifs featuring a fluorinated tetrasubstituted carbon. The reaction can be run on a gram scale with a low catalyst loading without impacting its efficiency. Moreover, a related aldol reaction was also developed. Together, these reactions provide a new approach for the preparation of pharmaceutically relevant products possessing tetrasubstituted C-F centers.