Direct Catalytic Asymmetric Conjugate Addition of Benzofuran-3(2H)-Ones to α,β-Unsaturated Thioamides: Stereodivergent Synthesis of Rocaglaol.

Rocaglaol, a representative flavagline, has attracted significant attention because of its unique chemical structure and biological activities. This paper reports a mild and scalable copper-catalyzed enantioselective conjugate addition of benzofuran-3(2H)-ones to α,β-unsaturated thioamides. This method allows for the concise synthesis of all possible stereoisomers of a key intermediate of rocaglaol and its derivatives in a highly diastereo- and enantioselective manner using different chiral phosphine ligands.

Examining the effects of additives and precursors on the reactivity of rhodium alkyl nitrenes generated from substituted hydroxylamines.

In this study, the reactivity of the alkyl nitrenes, generated from the substituted hydroxylamine precursors, was determined using the same rhodium catalyst. The results revealed that in competitive C-H insertion experiments, the regioselectivity between benzylic and tertiary C-H bonds could be modulated by adding Brønsted acids or changing the substituents on oxygen. This study enhances our understanding of the metallonitrene structures and provides valuable insights for further development of selective N-heterocycle syntheses.

Catalytic Asymmetric Vinylogous Conjugate Addition of Butenolide to 2-Ester-Substituted Chromones: Access to Chiral Chromanone Lactones via Trapping of a Copper(I) Enolate by Trimethyl Borate.

A copper-catalyzed asymmetric vinylogous conjugate addition of butenolide to 2-ester-substituted chromones is described, and it delivers - or -chromanone lactones with high stereoselectivities. The enantioselectivity-determining step varied with the use of B(OMe) as an additive, resulting in enhanced stereoselectivities, as revealed by density functional theory calculations, which also provided theoretical insight into the origin of the ligand-dependent diastereodivergence.

Locking the Conformation of a Paddlewheel Rhodium Complex: Design, Synthesis, and Applications in Catalytic Nitrene Transfers.

The exponential proliferation of conformers makes it impossible to examine the entire population in most systems. Controlling conformational ensembles is thus pivotal in many areas of chemistry. Rh (esp) , a dicarboxylate-derived paddlewheel rhodium complex, is one of the most effective catalysts for nitrene chemistry.

Less Is More: N(BOH) Configuration Exhibits Higher Reactivity than the BNO Heterocycle in Catalytic Dehydrative Amide Formation.

Diboron substructures have emerged as a promising scaffold for the catalytic dehydrative amidation of carboxylic acids and amines. This Letter describes the design, synthesis, and evaluation of the first isolable N(BOH) compound as an amidation catalyst. The new catalyst outperforms the previously reported BNO heterocycle catalyst, with respect to turnover frequency, albeit the former gradually decomposes upon exposure to amines.

Asymmetric -Selective Vinylogous Addition of Butenolides to Chromones via Al-Li-BINOL Catalysis.

A gram-scale -selective asymmetric vinylogous addition of butenolides to chromones, catalyzed by an Al-Li-BINOL (ALB) complex, was developed in this study. For various combinations of substrates, the observed diastereoselectivity approached 20:1 with 84-98% ee. This protocol is complementary to previously reported ones and improves the selectivity for several chromones.

A Missing Link in Multisubstituted Pyrrolidines: Remote Stereocontrol Forged by Rhodium-Alkyl Nitrene.

Pyrrolidines are significant N-heterocycles in medicinal chemistry and are among the top ten ring systems found in drug molecules. While simple derivatives are commercially available, densely decorated derivatives with precise stereochemical arrangements remain difficult to obtain. Methods for synthesizing multisubstituted pyrrolidines with nonadjacent stereocenters are particularly scarce.

Concise and Stereodivergent Approach to Chromanone Lactones through Copper-Catalyzed Asymmetric Vinylogous Addition of Siloxyfurans to 2-Ester-Substituted Chromones.

Vicinal oxygen-containing tetra- and tri-substituted stereocenters exist widely in chromanone lactone and tetrahydroxanthone natural products. Their enantioselective construction in a single step remains elusive and poses a formidable challenge for chemical synthesis. Here, we report the first copper(I)-catalyzed asymmetric vinylogous additions of siloxyfurans to 2-ester-substituted chromones, which enable concise and enantioselective assembly of chromanone lactones.

Imbuing an Old Heterocycle with the Power of Modern Catalysis: An Isoxazolidin-5-one Story.

Isoxazolidin-5-ones have been regarded as β-amino acid surrogates owing to their labile N-O bond. While many efforts have been devoted to the catalytic enantioselective synthesis of the core of this heterocycle, its further transformation has been less explored, especially in the context of catalysis. This review summarizes the author's research on the development of catalytic reactions using isoxazolidin-5-ones as substrates.

Ligand-Enabled, Copper-Catalyzed Electrophilic Amination for the Asymmetric Synthesis of β-Amino Acids.

Catalytic asymmetric nitrene transfer has emerged as a reliable method for the synthesis of nitrogen-containing chiral compounds. Herein, we report the copper-catalyzed intramolecular asymmetric electrophilic amination of aromatic rings. The reactive intermediate is a copper-alkyl nitrene generated from isoxazolidin-5-ones.

Generation and application of Cu-bound alkyl nitrenes for the catalyst-controlled synthesis of cyclic β-amino acids.

The advent of saturated N-heterocycles as valuable building blocks in medicinal chemistry has led to the development of new methods to construct such nitrogen-containing cyclic frameworks. Despite the apparent strategic clarity, intramolecular C-H aminations with metallonitrenes have only sporadically been explored in this direction because of the intractability of the requisite alkyl nitrenes. Here, we report copper-catalysed intramolecular amination using an alkyl nitrene generated from substituted isoxazolidin-5-ones upon N-O bond cleavage.

-Benzoylhydroxylamines as Alkyl Nitrene Precursors: Synthesis of Saturated N-Heterocycles from Primary Amines.

We introduce -benzoylhydroxylamines as competent alkyl nitrene precursors. The combination of readily available, stable substrates and a proficient rhodium catalyst provides a straightforward means for the construction of various pyrrolidine rings from the corresponding primary amines. Preliminary mechanistic investigation suggests that the structure of the nitrene precursor plays a role in determining the nature of the resulting reactive intermediate.

On the Nitrogen Inversion of Isoxazolidin-5-ones.

The nitrogen inversion energies of a series of N-substituted isoxazolidin-5-ones were studied by density functional theory. The transition state energy was found to strongly correlate with the s-character of the lone pair of electrons on the nitrogen in the ground state. Although the activation energy trends for isxazolidin-5-ones and isoxazolidines are similar, their conformational equilibria are slightly different and the isoxazolidin-5-one inversion energies are generally higher.

Synthesis of Unprotected Spirocyclic β-Prolines and β-Homoprolines by Rh-Catalyzed C-H Insertion.

A series of unprotected spirocyclic β-prolines and β-homoprolines are prepared by Rh-catalyzed C-H insertion. The key intermediate, a Rh nitrenoid, is generated by the N-O bond cleavage of a substituted isoxazolidin-5-one. The reaction proceeds on a gram scale with a catalyst loading of as little as 0.

Lewis Base Assisted Lithium Brønsted Base Catalysis: A New Entry for Catalytic Asymmetric Synthesis of β-Amino Acids.

A new catalytic system comprising chiral Ag complex and Li aryloxide/bisphosphine oxide is developed for the synthesis of β-amino acids via direct asymmetric Mannich-type reaction of 4-subsituted isoxazolidin-5-ones. The Mannich adduct is a direct precursor of β-peptidic compounds otherwise difficult to obtain.

Traceless Electrophilic Amination for the Synthesis of Unprotected Cyclic β-Amino Acids.

Electrophilic aminations involve an umpolung of a nitrogen atom, providing an alternate, distinctive synthetic strategy. The recent advent of various designed O-substituted hydroxylamines has significantly advanced this research field. An underappreciated issue is atom economy of the transformations: The necessary activating group on the oxygen atom is left in coproduced waste.

All Non-Carbon B NO Exotic Heterocycles: Synthesis, Dynamics, and Catalysis.

The B NO six-membered heterocycle (1,3-dioxa-5-aza-2,4,6-triborinane=DATB), comprising three different non-carbon period 2 elements, has been recently demonstrated to be a powerful catalyst for dehydrative condensation of carboxylic acids and amines. The tedious synthesis of DATB, however, has significantly diminished its utility as a catalyst, and thus the inherent chemical properties of the ring system have remained virtually unexplored. Here, a general and facile synthetic strategy that harnesses a pyrimidine-containing scaffold for the reliable installation of boron atoms is disclosed, giving rise to a series of Pym-DATBs from inexpensive materials in a modular fashion.

A C4N4 Diaminopyrimidine Fluorophore.

A new scaffold for producing efficient organic fluorescent materials was identified: 2,5-diamino-4,6-diarylpyrimidine featuring a C4N4 elemental composition. Single-step installation of two aryl groups at the 4,6-positions of the pyrimidine core delivered fluorescent organic materials in a modular fashion. A range of fluorescent compounds with distinct absorption/emission properties was readily accessed by changing the aromatic attachments.

Neighboring Protonation Unveils Lewis Acidity in the BNO Heterocycle.

Boron serves a distinctive role in a broad range of chemistry disciplines. The utility of the element lies in its Lewis acidity, and thus, it is crucial to understand the properties of the boron atom in chemically different contexts. Herein, a combination of experiments and computations reveals the nuanced nature of boron in direct amidation reactions catalyzed by recently disclosed 1,3-dioxa-5-aza-2,4,6-triborinanes (DATBs).

A fluorogenic C4N4 probe for azide-based labelling.

The design, synthesis and photophysical properties of a new fluorogenic probe are described. The structure is based on the recently identified 2,5-diaminopyrimidine (C4N4) fluorophore. The strain-promoted [3 + 2] cycloaddition of the azido-C4N4 probe furnished a triazole that exhibited more than 30-fold enhancement in fluorescence intensity as compared to the azide.

Exploiting β-Amino Acid Enolates in Direct Catalytic Diastereo- and Enantioselective C-C Bond-Forming Reactions.

In contrast to the widespread use of α-amino acid-equivalent enolates for the preparation of non-natural amino acids, the utilization of β-amino-acid counterparts has been limited. This deficit has resulted in a short supply of β -amino acids bearing two substituents at the α-carbon, especially for peptide synthesis. Herein, racemic 4-substituted isoxazolidin-5-ones were used as precursors of β -amino acid enolates in the direct catalytic diastereo- and enantioselective C-C bond-forming reactions, constructing two adjacent stereocenters in a highly stereoselective fashion.

Synthetic fermentation of β-peptide macrocycles by thiadiazole-forming ring-closing reactions.

Macrocyclic β-peptides were efficiently prepared using a thiadiazole-forming cyclization reaction between an α-ketoacid and a thiohydrazide. The linear β-peptide precursors were assembled from isoxazolidine monomers by α-ketoacid-hydroxylamine (KAHA) ligations with a bifunctional initiator - a process we have termed 'synthetic fermentation' due to the analogy of producing natural product-like molecules from simpler building blocks. The linear synthetic fermentation products underwent Boc-deprotection/thiadiazole-forming macrocyclization under aqueous, acidic conditions to provide the cyclic products in a one-pot process.

Catalytic Oligopeptide Synthesis.

Waste-free catalytic assembly of α-amino acids is fueled by a multiboron catalyst that features a characteristic BNO heterocycle, providing a versatile catalytic protocol wherein functionalized natural α-amino acid units are accommodated and commonly used protecting groups are tolerated. The facile dehydrative conditions eliminate the use of engineered peptide coupling reagents, exemplifying a greener catalytic alternative for peptide coupling. The catalysis is sufficiently robust to enable pentapeptide synthesis, constructing all four amide bond linkages in a catalytic fashion.

Quaternary β -Amino Acids: Catalytic Asymmetric Synthesis and Incorporation into Peptides by Fmoc-Based Solid-Phase Peptide Synthesis.

β-Amino acid incorporation has emerged as a promising approach to enhance the stability of parent peptides and to improve their biological activity. Owing to the lack of reliable access to β -amino acids in a setting suitable for peptide synthesis, most contemporary research efforts focus on the use of β - and certain β -amino acids. Herein, we report the catalytic asymmetric synthesis of β -amino acids and their incorporation into peptides by Fmoc-based solid-phase peptide synthesis (Fmoc-SPPS).

Direct Catalytic Asymmetric Aldol Addition of an α-CF Amide to Arylglyoxal Hydrates.

Direct asymmetric aldol addition of an α-CF amide to arylglyoxal hydrates was promoted by a chiral catalyst comprising a soft Lewis acidic Cu(I), a chiral bisphosphine ligand, and DBU. The 7-azaindoline moiety of the amide facilitates its enolization and stabilizes the thus-generated Cu enolate, furnishing enantioenriched aldol adducts.