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The first useful enantioselective Pd‐catalyzed asymmetric allylic alkylation of α‐fluoro‐β‐ketoesters has been achieved using the Trost family of chiral ligands yielding products in up to 92 % ee. This work provides new insights regarding the typically modest selectivities associated with acyclic α‐fluoroenolates and shows experimental evidence tha...
Citations
There are many fluorinated quaternary carbon structural units in pharmaceuticals and bioactive compounds. Organic chemists are interested in the stereoselective synthesis of fluorinated quaternary carbon structural units. Constructing a fluorinated quaternary carbon stereocenter can be achieved directly and efficiently by the asymmetric catalytic reaction of fluorinated compounds as substrates. This approach aims to construct fluorinated quaternary carbon stereocenters while diversifying the types of fluorinated compounds. This review introduces a series of reactions for synthesizing fluorinated quaternary carbon chiral centers through asymmetric organic catalysis and transition metal catalysis, including alkylation, arylation, Mannich, Michael addition, and allylation reactions. This work will contribute to the development of the synthesis of fluorinated quaternary carbon chiral center-containing compounds in the future.
Linearly fused polycyclic piperidines represent common substructures in natural products and biologically active small molecules. We have devised a Pd‐catalyzed annulation strategy to these compounds that converts readily available 2‐tetralones and indanones into these scaffolds with the potential for control of both enantio‐ and diastereoselectivity. Importantly, these compounds can be chemoselectively functionalized, providing an efficient and robust methodology to these important nitrogen‐containing molecules.
To facilitate the discovery and development of new pharmaceuticals, the demand for novel stereofunctionalised building blocks has never been greater. Whilst molecules bearing quaternary and tetrasubstituted stereogenic centres are ideally suited to explore untapped areas of chemical space, the asymmetric construction ofsterically congested carbon centres remains a longstanding challenge in organic synthesis. The enantioselective assembly of acyclic stereogenic centres is even more demanding due to the need to restrict a much wider range of geometries and conformations of the intermediates involved. In this context, the catalytic asymmetric allylicalkylation (AAA) of acyclic prochiral nucleophiles, namely enolates, has become an indispensable tool to access a range of linearα‐quaternary andα‐tetrasubstituted carbonyl compounds. However, unlike the AAA of cyclic enolates with a fixed enolate geometry, to achieve high levels of stereocontrol in the AAA of acyclic enolates, the stereoselectivity of enolisation must be considered. The aim of this review is to offer acomprehensivediscussion of catalytic AAA reactions of acyclic prochiral enolates and their analogues to generate congested quaternary and tetrasubstituted chiral centres using metal, non‐metal and dual catalysis, with particular focus given to the control of enolate geometry and its impact on the stereochemical outcome of the reaction.
A Pd-catalyzed formal [4 + 1] cycloaddition reaction of sulfur ylides and in situ-generated Pd-stabilized zwitterions offers a convenient route to a series of functionalized proline derivatives. The utility of this method is demonstrated by a gram-scale synthesis and chemoselective functionalization of a proline-based derivative.
A palladium-catalyzed enantioselective decarboxylative allylic alkylation of α-benzyl cyanoacetates with methylene cyclic carbamates has been successfully developed. An array of enantioenriched products bearing nitrile-containing acyclic quaternary carbon stereocenters were obtained...
Peptidomimetics are emerging as a promising class of potent and selective therapeutics. Among the current approaches to these compounds, the utilization of constrained lactams is a key element in enforcing the active peptide conformation, and the development of efficient and stereocontrolled methods for generating such lactam building blocks is an important objective. Current methods typically rely on the elaboration of existing α-amino acids, and in so doing, the side chain is sacrificed during the ring-forming process. We report a new asymmetric approach to lactam-constrained α-amino acid building blocks bearing a range of polar and hydrophobic side chains. The chemistry is amenable to rapidly generating di- and tripeptides, and the potential for these lactams to stabilize type II β-turns is demonstrated in the synthesis of the melanocyte-inhibiting factor peptidomimetic.
Comprehensive Summary
We developed a novel Pd‐catalyzed [4 + 4] cycloaddition of (benzo)furan‐derived azadienes with homo‐TMM all‐carbon 1,4‐dipoles in situ generated from α ‐allyl malonate derivatives, affording an array of benzofuro[3,2‐ b ]azocines and furo[3,2‐ b ]azocines with good to excellent yields (up to 96%) and exclusive regioselectivities. This methodology featured mild reaction conditions and good functional group tolerance. The synthetic utility was demonstrated by a gram‐scale reaction. Furthermore, the catalytic asymmetric [4 + 4] cycloaddition version has also been explored.
A palladium-catalyzed enantioselective α-allylation of deconjugated butenolides with aza-π-allylpalladium 1,4-diploes, in situ generated from palladium-mediated decarboxylation of cyclic carbamates and amide-substituted acyclic carbonates, has been successfully developed. An array of enantioenriched 2-piperidones bearing an all-carbon quaternary stereocenter were obtained in high yields with excellent enantioselectivities (up to 99% yield and 99% ee). The utility of this method was also showcased by a large-scale reaction and synthetic transformations of the product.
