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A rare hetero-ene mechanism has been computationally elucidated to enable the activation of unactivated alkenes by moderately strong chiral N-triflylphosphoramide Brønsted acid catalysts.

Catalytic asymmetric aza-Michael represents one of the most convenient and atom-economical approaches for the rapid construction of biologically active chiral β-amino acid frameworks. However, the ...

Although C–N bonds are ubiquitous in natural products, pharmaceuticals and agrochemicals, biocatalysts forging these bonds with high atom-efficiency and enantioselectivity have been limited to a few select enzymes. In particular, ammonia lyases have emerged as powerful catalysts to access C–N bond formation via hydroamination. However, the use of ammonia lyases is rather restricted due to their narrow synthetic scope. Herein, we report the computational redesign of aspartase, a highly specific ammonia lyase, to yield C–N lyases with cross-compatibility of non-native nucleophiles and electrophiles. A wide range of non-canonical amino acids (ncAAs) are afforded with excellent conversion (up to 99%), regioselectivity >99% and enantioselectivity >99%. The process is scalable under industrially relevant protocols (exemplified in kilogram-scale synthesis) and can be facilely integrated in cascade reactions (demonstrated in the synthesis of β-lactams with N-1 and C-4 substitutions). This versatile and efficient C–N lyase platform supports the preparation of ncAAs and their derivatives, and will present opportunities in synthetic biology. Ammonia lyases are powerful catalysts to access C–N bond formation via hydroamination, but show a narrow synthetic scope. Now, by computational redesign of an aspartase, a C–N lyase is developed that shows cross-compatibility of non-native nucleophiles and electrophiles expanding the synthetic scope.

A copper-catalyzed hydroamination of styrenes using piv ZPhos as ligand is reported. Enantioselectivities up to 94% are achieved under optimized conditions with aryl and heteroaryl styrenes. A variety of electrophilic O-benzoylhydroxylamines are well tolerated.

International audience; The incorporation of a few chiral monomers (the “sergeants”) in a backbone composed of a majority of achiral monomers (the “soldiers”) is a well-established strategy to control the handedness of helical polymers. However, the implementation of this “sergeants-and-soldiers” effect in asymmetric catalysis is still at its infancy, with only limited examples for which the sergeant amount is actually in lower amount than the (metal) catalytic unit. Herein, supramolecular co-polymers composed of a benzene-1,3,5-tricarboxamide (BTA) phosphine soldier and a catalytically-inactive BTA sergeant were evaluated in the copper-catalysed hydroamination of styrene. Screening of various BTA ligands revealed the marked influence of substituents on the aryl group of the BTA phosphine ligand, the 3,5-bis-CF3-substituted ligand providing the highest rate and enantioselectivity. Thorough optimization of the reaction parameters led to a robust protocole for the generation of the amine product in high yield (82±4 %) and moderate e.e. (68±6 %). Addition of an achiral BTA additive was found to be beneficial for improving the yield (80-99%), enantioselectivity (up to 81% e.e.) and “sergeants-and-soldiers” effect displayed by the supramolecular helical catalyst. Consequently, an enantio-enriched product (75% e.e.) was afforded with as low as 0.51 mol% of sergeant in the catalytic mixture, i.e. one chiral molecule for 10 copper centers

Computational studies of chiral phosphoric acid (CPA)-catalyzed dynamic kinetic asymmetric hydroamination (DyKAH) of racemic allenes show that the reaction proceeds through a catalytic asymmetric model involving a highly reactive π-allylic carbocationic intermediate, generated from a racemic allene through an intermolecular proton transfer mediated by CPA, which also results in a high E/Z selectivity. Moreover, the distortion-interaction, atom in molecule, and electrostatic interaction analyses and space-filling models are employed on the basis of the DyKAH catalyzed by (S)-A5 (reaction 1) or (R)-A2 (reaction 2) to explain the high enantioselectivity and the controlling effects of SPINOL scaffolds on the signs of enantioselectivity. Our calculations indicate that the enantioselectivity of reactions 1 and 2 can be mainly ascribed to the favorable noncovalent interactions within the stronger chiral electrostatic environment created by the phosphoric acid in the preferential transition states. Finally, the effect of (S/R)-SPINOL-based CPAs on the signs of enantioselectivity can be explained by the different combination modes of substrates into the chiral binding pocket of the catalyst controlled by the chirality of SPINOL backbones. Overall, the new insights into the reaction rationalize the outcome and these key factors that affect the product enantioselectivity are important to guide the DyKAHs.

A Rh-catalyzed enantioselective hydroamination of allylamines using a chiral BIPHEP-type ligand is reported. Enantioenriched 1,2-diamines are formed in good yields and with excellent enantioselectivities. A diverse array of nucleophiles and amine directing groups are demonstrated, including deprotectable motifs. Finally, the methodology was demonstrated toward the rapid synthesis of 2-methyl-moclobemide.

A comprehensive mechanistic study on the title reaction by using DFT(B3LYP-D3) computational method is reported. Explicit consideration of mono- (m-xylylic) and dicarboxylic acid (phthalic) in the key transition states reveals active participation of the carboxylic acid, beginning with the generation of a monomeric Rh(I) active catalyst and in the ensuing catalytic steps. In the early catalytic event, uptake of alkyne is predicted to take place only after the oxidative addition of the Rh(I) active catalyst to the carboxylic acid. The hydrometalation of the alkyne bound to the Rh(III)-H intermediate then generates a Rh(III)-vinyl intermediate, which in turn converts to a Rh(III)-allyl species. The inclusion of m-xylylic acid results in a two-step pathway to Rh(III)-allyl species via Rh-allene intermediate. A number of weak noncovalent interactions (hydrogen bonding and C-H center dot center dot center dot pi) between the catalyst and the substrates and that involving m-xylylic acid are found to have a direct impact on the regiochemical preference toward the branched product and the enantiocontrolling hydroamination step involving C-N bond formation leading to the major enantiomer (S-allylic amine). The chiral induction is enabled by cumulative effect of noncovalent interactions, which is an insight that could aid future developments of chiral ligands for asymmetric hydroamination.

The design and synthesis of a new chiral monodentate spiro phosphoramidite ligand based on a hexamethyl-1,1'-spirobiindane scaffold has been accomplished. The ligand could serve as an elegant chiral monodentate ligand in the Pd-catalyzed asymmetric hydroamination/arylation of alkenes leading to chiral imidazolidin-2-ones with good enantioselectivities.

Although C-N bonds are ubiquitous in natural products, pharmaceuticals, and agrochemicals, biocatalysts that forge these bonds with high atom efficiency and enantioselectivity have primarily been limited to a few select enzymes. In particular, the use of ammonia lyases has emerged as a powerful strategy to access C-N bond formation through hydroamination reactions, which has no counterpart in traditional synthetic chemistry. However, the broad utility of ammonia lyases is rather restricted due to their narrow synthetic scope, and the conjugate addition of a matrix of nucleophilic donors to electrophilic acceptors remains a longstanding challenge. Herein, we report the computational redesign of aspartase, a highly specific ammonia lyase, to yield C-N lyases with unprecedented cross-compatibility of nonnative nucleophiles and electrophiles. A wide range of noncanonical amino acids (ncAAs) are afforded with excellent conversion (up to 99%), regioselectivity > 99%, and product enantiomeric excess > 99%, and the process is scalable under industrially relevant protocols (demonstrated in kilogram-scale synthesis). Furthermore, the redesigned enzymes can be facilely integrated in cascade reactions, as we demonstrated the synthesis of β-lactams with different substitution patterns at the N-1 and C-4 positions in a one-pot reaction. This versatile and efficient C-N lyase platform supports the preparation of diverse libraries of ncAAs and their derivatives and will present opportunities in medicinal chemistry and synthetic biology.