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 syn- or anti-chromanone lactones with high stereoselectivities. The enantioselectivity-determining step varied with the use of B(OMe)3 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.

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.

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. Rh2 (esp)2 , a dicarboxylate-derived paddlewheel rhodium complex, is one of the most effective catalysts for nitrene chemistry. Its enormous success has led to preparing many analogous complexes. However, there has been little consideration for the conformational dynamics of the parent catalyst. Herein, we report a new ligand modification principle that prevents conformer interconversion. The resulting complex comprises two isolable conformers, whose structures have been determined by X-ray diffraction. Combined experimental and computational data has revealed similarities and dissimilarities between the conformationally confined and parent complexes. Three model cases have demonstrated the utility of conformational fixation in the development of stereoselective catalysts for nitrene transfer reactions. The design principle described in this study can be combined with other established modification strategies, serving as a springboard for further advancement of the chemistry of paddlewheel metal complexes.

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

A gram-scale syn-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. This methodology can be applied to a quinolone substrate, affording another type of heterocyclic scaffolds substituted with five-membered lactones. Computational studies support the role of ALB as a bifunctional catalyst in this reaction and provide insights into the origin of the observed stereoselectivity.

Less Is More: N(BOH)2 Configuration Exhibits Higher Reactivity than the B3NO2 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)2 compound as an amidation catalyst. The new catalyst outperforms the previously reported B3NO2 heterocycle catalyst, with respect to turnover frequency, albeit the former gradually decomposes upon exposure to amines. This work opens up an avenue for designing a better catalyst for direct amidation.

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. To bridge this gap, we report the stereoselective synthesis of remotely decorated, trisubstituted ß-prolines via Rh-catalyzed C-H amination. The transformation proceeds well in the presence of various functionalities with exclusive anti-selectivity. Carboxylic acids in the products serve as gateways for diverse downstream transformations. Furthermore, the combined experimental and computational study sheds lights on the origin of high diastereoselectivity.

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. Both syn and anti adducts can be accessed with excellent diastereo- and enantioselectivity by judicious choice of the chiral ligands. Our approach allowed for the efficient synthesis of (-)-blennolide B with precise stereochemical control, which provides a formal synthesis of secalonic acid A.

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

Isoxazolidin-5-ones have been regarded as ß-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. Asymmetric catalysis has proven effective for C-C bond formation at the carbonyl α-carbon. Catalytic asymmetric allylation and direct Mannich-type reactions have been developed. Further, the resulting products have been readily converted into the corresponding quaternary ß2,2-amino acids. Moreover, isoxazolidin-5-ones have been identified as alkyl nitrene precursors in the presence of a suitable metal catalyst. The generated metallonitrene undergoes either the electrophilic amination of the aromatic ring or aliphatic C-H insertion, affording a series of cyclic ß-amino acids. A remarkable difference in chemoselectivity between rhodium and copper alkyl nitrenes has also been demonstrated, highlighting the unique nature of the underexplored reactive intermediates. The various linear and cyclic ß-amino acids obtained through the study are likely to find great utility in a broad range of chemical sciences.

Ligand-Enabled, Copper-Catalyzed Electrophilic Amination for the Asymmetric Synthesis of ß-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. Copper catalysis promotes three classes of asymmetric transformations, namely, asymmetric desymmetrization, parallel kinetic resolution, and kinetic resolution, expanding the repertoire of alkyl nitrene transfer and providing various cyclic and linear ß-amino acids in their enantioenriched forms.

Generation and application of Cu-bound alkyl nitrenes for the catalyst-controlled synthesis of cyclic ß-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. The copper catalysis exclusively aminates aromatic C(sp2)-H bonds among other potentially reactive groups, offering a solution to the chemoselectivity problem that has been troublesome with rhodium catalysis. A combined experimental and computational study suggested that the active species in the current cyclic ß-amino acid synthesis is a dicopper alkyl nitrene, which follows a cyclisation pathway distinct from the analogous alkyl metallonitrene.

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

We introduce O-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 ß-Prolines and ß-Homoprolines by Rh-Catalyzed C-H Insertion.

A series of unprotected spirocyclic ß-prolines and ß-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 0.1 mol %, affording spirocyclic ß-amino acids that are otherwise difficult to obtain. The building blocks prepared in this work will likely find applications in medicinal chemistry.

Lewis Base Assisted Lithium Brønsted Base Catalysis: A New Entry for Catalytic Asymmetric Synthesis of ß2,2-Amino Acids.

A new catalytic system comprising chiral Ag complex and Li aryloxide/bisphosphine oxide is developed for the synthesis of ß2,2-amino acids via direct asymmetric Mannich-type reaction of 4-subsituted isoxazolidin-5-ones. The Mannich adduct is a direct precursor of ß-peptidic compounds otherwise difficult to obtain.

Traceless Electrophilic Amination for the Synthesis of Unprotected Cyclic ß-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. Herein, we describe Rh-catalyzed electrophilic amination of substituted isoxazolidin-5-ones for the synthesis of unprotected, cyclic ß-amino acids featuring either benzo-fused or spirocyclic scaffolds. Using the cyclic hydroxylamines allows for retaining both nitrogen and oxygen functionalities in the product. The traceless, redox neutral process proceeds on a gram scale with as little as 0.1 mol % catalyst loading. In contrast to related electrophilic aminations in the literature, a series of mechanistic experiments suggests a unique pathway involving spirocyclization, followed by the skeletal rearrangement. The insights provided herein shed light on a nuanced reactivity of the active species, Rh-nitrenoid generated from the activated hydroxylamine, and extend the knowledge on electrophilic aromatic substitutions.

All Non-Carbon B3 NO2 Exotic Heterocycles: Synthesis, Dynamics, and Catalysis.

The B3 NO2 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. The identification of a soluble Pym-DATB derivative allowed for the investigation of the dynamic nature of the B3 NO2 ring system, revealing differential ring-closing and -opening behaviors depending on the medium. Readily accessible Pym-DATBs proved their utility as efficient catalysts for dehydrative amidation with broad substrate scope and functional-group tolerance, offering a general and practical catalytic alternative to reagent-driven amidation.

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. A generally high absorption coefficient and quantum yield were observed, including C4N4 derivatives that could fluoresce even in the solid state. The two amino groups at the 2,5-positions of the pyrimidine were essential for intense fluorescence with a large Stokes shift, which was corroborated by structural relaxation to a p-iminoquinone-like structure in the excited state. Besides live-cell imaging capabilities, fluorescent labeling of a protein involved in autophagy elucidated a new protein-protein interaction, supporting potential utility in bioimaging applications.

Neighboring Protonation Unveils Lewis Acidity in the B3NO2 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). The most active DATB catalyst has been shown to bear an azaborine ring in its structure, thus having four boron atoms in a single molecule. Three chemically distinct boron atoms in the catalyst framework have been shown to serve different roles in the catalytic cycle, depending on their innate Lewis acidity. More specifically, the most Lewis acidic boron interacts with the amine, whereas the two boron atoms in the B-N-B substructure acquire Lewis acidity only upon protonation of the center nitrogen atom. Furthermore, although the least acidic boron atom in the azaborine ring did not act as a Lewis acid, it still plays an important role in the catalytic cycle by forming a hydrogen bond between carboxylic acid and the B-OH moiety. The mechanistic insights obtained from this study not only extend the knowledge on catalytic direct amidation but also provide a guiding principle for the further exploration of multi-boron compounds.

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 ß-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 ß-amino-acid counterparts has been limited. This deficit has resulted in a short supply of ß2, 2 -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 ß2 -amino acid enolates in the direct catalytic diastereo- and enantioselective C-C bond-forming reactions, constructing two adjacent stereocenters in a highly stereoselective fashion. The obtained adducts were smoothly coupled with α-amino acid-derived α-ketoacids to afford α/ß2, 2 -hybrid dipeptides suitable for 9-fluorenylmethoxycarbonyl (Fmoc)-based solid-phase peptide synthesis. Moreover, the Mannich adducts obtained from isatin-derived imines were converted to spirocyclic ß-lactams, which have recently received increased attention due to their unique biological activities and conformational preferences.