Exporting Homogeneous Transition Metal Catalysts to Biological Habitats.

The possibility of performing designed transition-metal catalyzed reactions in biological and living contexts can open unprecedented opportunities to interrogate and interfere with biology. However, the task is far from obvious, in part because of the presumed incompatibly between organometallic chemistry and complex aqueous environments. Nonetheless, in the past decade there has been a steady progress in this research area, and several transition-metal (TM)-catalyzed bioorthogonal and biocompatible reactions have been developed. These reactions encompass a wide range of mechanistic profiles, which are very different from those used by natural metalloenzymes. Herein we present a summary of the latest progress in the field of TM-catalyzed bioorthogonal reactions, with a special focus on those triggered by activation of multiple carbon-carbon bonds.

Rhodium-Catalyzed Annulation of ortho-Alkenyl Anilides with Alkynes: Formation of Unexpected Naphthalene Adducts.

o-Alkenyl N-triflylanilides underwent rhodium(III)-catalyzed oxidative annulations with alkynes to produce different types of naphthylamides in a process which involves the cleavage of two C-H bonds. Remarkably, besides formal dehydrogenative (4C+2C) cycloadducts, the reaction also produces variable amounts of isomeric naphthylamides, whose formation requires a formal migration of the alkenyl moiety from the ortho to the meta position of the anilide. The annulation reaction can be efficiently carried out in the absence of external oxidants, such as Cu(OAc)2 .

Biomimetic Generation and Remodeling of Phospholipid Membranes by Dynamic Imine Chemistry.

Biomimetic liposomes have a wide array of applications in several areas, ranging from medicinal chemistry to synthetic biology. Due to their biocompatibility and biological relevance, there is particular interest in the formation of synthetic phospholipid vesicles and the development of methods to tune their properties in a controlled manner. However, while true biological membranes are capable of responding to environmental stimuli by enzymatically remodeling their composition, synthetic liposomes are typically static once formed. Herein we report the chemoselective reaction of the natural amine-containing lysosphingomyelin with a series of long-chain aldehydes to form imines. This transformation results in the formation of phospholipid liposomes that are in dynamic equilibrium with the aldehyde-amine form. The reversibility of the imine linkage is exploited in the synthesis of vesicles that are capable of responding to external stimuli such as temperature or the addition of small molecules.

Rhodium(III)-Catalyzed Annulation of 2-Alkenyl Anilides with Alkynes through C-H Activation: Direct Access to 2-Substituted Indolines.

A RhIII complex featuring an electron-deficient η5 -cyclopentadienyl ligand catalyzed an unusual annulation between alkynes and 2-alkenyl anilides to form synthetically appealing 2-substituted indolines. Formally, the process can be viewed as an allylic amination with concomitant hydrocarbonation of the alkyne. Mechanistic experiments indicate that this transformation involves an unusual rhodium migration with a concomitant 1,5-H shift.

Palladium-Catalyzed Formal (5 + 2) Annulation between ortho-Alkenylanilides and Allenes.

2-Alkenyltriflylanilides react with allenes upon treatment with catalytic amounts of Pd(OAc)2 and Cu(II) to give highly valuable 2,3-dihydro-1H-benzo[b]azepines, in good yields, and with very high regio- and diastereoselectivities. Density functional theory (DFT) calculations suggest that the C-H activation of the alkenylanilide involves a classical concerted metalation-deprotonation (CMD) mechanism.

Rhodium-catalyzed (5+1) annulations between 2-alkenylphenols and allenes: a practical entry to 2,2-disubstituted 2H-chromenes.

Readily available alkenylphenols react with allenes under rhodium catalysis to provide valuable 2,2-disubstituted 2H-chromenes. The whole process, which involves the cleavage of one C-H bond of the alkenyl moiety and the participation of the allene as a one-carbon cycloaddition partner, can be considered a simple, versatile, and atom-economical (5+1) heteroannulation. The reaction tolerates a broad range of substituents both in the alkenylphenol and in the allene, and most probably proceeds through a mechanism involving a rhodium-catalyzed C-C coupling followed by two sequential pericyclic processes.

Rhodium(III)-catalyzed dearomatizing (3 + 2) annulation of 2-alkenylphenols and alkynes.

Appropriately substituted 2-alkenylphenols undergo a mild formal [3C+2C] cycloaddition with alkynes when treated with a Rh(III) catalyst and an oxidant. The reaction, which involves the cleavage of the terminal C-H bond of the alkenyl moiety and the dearomatization of the phenol ring, provides a versatile and efficient approach to highly appealing spirocyclic skeletons and occurs with high selectivity.

Straightforward assembly of benzoxepines by means of a rhodium(III)-catalyzed C-H functionalization of o-vinylphenols.

Readily available o-vinylphenols undergo a formal (5 + 2) cycloaddition to alkynes when treated with catalytic amounts of [Cp*RhCl2]2 and Cu(OAc)2. The reaction, which involves the cleavage of the terminal C-H bond of the alkenyl moiety, generates highly valuable benzoxepine skeletons in a practical, versatile, and atom-economical manner. Using carbon monoxide instead of an alkyne as reaction partner leads to coumarin products which formally result from a (5 + 1) cycloaddition.