A long-standing challenge in synthetic chemistry is the development of the transamidation reaction. This process, which involves the conversion of one amide to another, is typically plagued by unfavourable kinetic and thermodynamic factors. Although some advances have been made with regard to the transamidation of primary amide substrates, secondary amide transamidation has remained elusive. Here we present a simple two-step approach that allows for the elusive overall transformation to take place using non-precious metal catalysis. The methodology proceeds under exceptionally mild reaction conditions and is tolerant of amino-acid-derived nucleophiles. In addition to overcoming the classic problem of secondary amide transamidation, our studies expand the growing repertoire of new transformations mediated by base metal catalysis.
Recent studies have demonstrated that amides can be used in nickel-catalyzed reactions that lead to cleavage of the amide C–N bond, with formation of a C–C or C–heteroatom bond. However, the general scope of these methodologies has been restricted to amides where the carbonyl is directly attached to an arene or heteroarene. We now report the nickel-catalyzed esterification of amides derived from aliphatic carboxylic acids. The transformation requires only a slight excess of the alcohol nucleophile and is tolerant of heterocycles, substrates with epimerizable stereocenters, and sterically congested coupling partners. Moreover, a series of amide competition experiments establish selectivity principles that will aid future synthetic design. These studies overcome a critical limitation of current Ni-catalyzed amide couplings and are expected to further stimulate the use of amides as synthetic building blocks in C–N bond cleavage processes.
An ongoing challenge in chemical research is to design catalysts that select the outcomes of the reactions of complex molecules. Chemists rely on organo- or transition metal catalysts to control stereo-, regio-, and periselectivity (selectivity among possible pericyclic reactions). Nature achieves these types of selectivity with a variety of enzymes such as the recently discovered pericyclases – a family of enzymes that catalyze pericyclic reactions. 1 To date, the majority of characterized enzymatic pericyclic reactions are cycloadditions and it has been difficult to rationalize how observed selectivities are achieved. 2 - 13 We report here the discovery of two homologous groups of pericyclases that catalyze distinct reactions: one group catalyzes an Alder-ene reaction, previously unknown in biology; the second catalyzes a stereoselective hetero-Diels–Alder reaction. Guided by computational studies, we rationalized the observed differences in reactivities and designed mutants that reverse periselectivities from Alder-ene to hetero-Diels–Alder and vice versa . A combination of in vitro biochemical characterizations, computational studies, enzyme co-crystal structures, and mutational studies provide a picture of how high regio- and periselectivities are achieved in nearly identical active sites.
Arynes, strained cyclic alkynes, and strained cyclic allenes were validated as plausible intermediates in the 1950s and 1960s. Despite initially being considered mere scientific curiosities, these transient and highly reactive species have now become valuable synthetic building blocks. This Perspective highlights recent advances in the field that have allowed access to structural and stereochemical complexity, including recent breakthroughs in asymmetric catalysis.
We report a facile method to synthesize stereodefined quaternary centers from reactions of arynes and related strained intermediates using β-ketoester-derived substrates. The conversion of β-ketoesters to chiral enamines is followed by reaction with in situ generated strained arynes or cyclic alkynes. Hydrolytic workup provides the arylated or alkenylated products in enantiomeric excesses as high as 96%. We also describe the one-pot conversion of a β-ketoester substrate to the corresponding enantioenriched α-arylated product. Computations show how chirality is transferred from the N-bound chiral auxiliary to the final products. These are the first theoretical studies of aryne trapping by chiral nucleophiles to set new stereocenters. Our approach provides a solution to the challenging problem of stereoselective β-ketoester arylation/alkenylation, with formation of a quaternary center.
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