Enantioselective Palladium-Catalyzed Carbene Insertion into the N-H Bonds of Aromatic Heterocycles.

C3-substituted indoles and carbazoles react with α-aryl-α-diazoesters under palladium catalysis to form α-(N-indolyl)-α-arylesters and α-(N-carbazolyl)-α-arylesters. The products result from insertion of a palladium-carbene ligand into the N-H bond of the aromatic N-heterocycles. Enantioselection was achieved using a chiral bis(oxazoline) ligand, in many cases with high enantioselectivity (up to 99 % ee). The method was applied to synthesize the core of a bioactive carbazole derivative in a concise manner.

Potent Antifungal Synergy of Phthalazinone and Isoquinolones with Azoles Against Candida albicans.

Four phthalazinones (CIDs 22334057, 22333974, 22334032, 22334012) and one isoquinolone (CID 5224943) were previously shown to be potent enhancers of antifungal activity of fluconazole against Candida albicans. Several even more potent analogues of these compounds were identified, some with EC50 as low as 1 nM, against C. albicans. The compounds exhibited pharmacological synergy (FIC < 0.5) with fluconazole. The compounds were also shown to enhance the antifungal activity of isavuconazole, a recently FDA approved azole antifungal. Isoquinolone 15 and phthalazinone 24 were shown to be active against several resistant clinical isolates of C. albicans.

Carbenylative Amination and Alkylation of Vinyl Iodides via Palladium Alkylidene Intermediates.

Most palladium-catalyzed reactions involving insertion of alkylidenes with α-hydrogens undergo ß-hydride elimination from alkylpalladium(II) intermediates to form alkenes. Vinyl iodides were shown to generate η(3)-allylpalladium intermediates that resist ß-hydride elimination, preserving the sp(3) center adjacent to the carbene moiety. Acyclic stereocontrol (syn/anti) for carbenylative amination and alkylation reactions was low, suggesting a lack of control in the migratory insertion step. Highly hindered carbene precursors inexplicably led to formation of Z-alkenes with high levels of stereocontrol.

Potent Synergy between Spirocyclic Pyrrolidinoindolinones and Fluconazole against Candida albicans.

A spiroindolinone, (1S,3R,3aR,6aS)-1-benzyl-6'-chloro-5-(4-fluorophenyl)-7'-methylspiro[1,2,3a,6a-tetrahydropyrrolo[3,4-c]pyrrole-3,3'-1H-indole]-2',4,6-trione, was previously reported to enhance the antifungal effect of fluconazole against Candida albicans. A diastereomer of this compound was synthesized, along with various analogues. Many of the compounds were shown to enhance the antifungal effect of fluconazole against C. albicans, some with exquisite potency. One spirocyclic piperazine derivative, which we have named synazo-1, was found to enhance the effect of fluconazole with an EC50 value of 300 pM against a susceptible strain of C. albicans and going as low as 2 nM against some resistant strains. Synazo-1 exhibits true synergy with fluconazole, with an FIC index below 0.5 in the strains tested. Synazo-1 exhibited low toxicity in mammalian cells relative to the concentrations required for antifungal synergy.

Pd-catalyzed bis-cyclization/dimerization reactions of ω-aminovinyl halides.

Palladium is shown to catalyze the dimerization and cyclization of vinyl halides to generate pyrrolidine and piperidine dimers connected by a trans-ethylene bridge. The reaction tolerates a variety of N-alkyl substituents, including adamantyl. This remarkable dimerization reaction generates the skeleton of the alkaloid hyalbidone in a single step. A crossover experiment with a vinyl halide and a vinyl bromide is consistent with a Michael-type addition to a vinylpalladium cation to generate a Pd(0) alkylidene intermediate.

Palladium-catalyzed Catellani aminocyclopropanation reactions with vinyl halides.

Palladium is shown to catalyze an intramolecular aminocyclopropanation of norbornenes with aliphatic vinyl halides in good yields. The reaction tolerates a variety of amine substituents and gives good results with a variety of carbocyclic and oxabicyclic [2.2.1] alkene acceptors. Notably, stabilized enolate nucleophiles were also employed in cyclopropanation reactions.