Asymmetric [3 + 2] photocycloadditions of cyclopropylamines with electron-rich and electron-neutral olefins

Radical addition to olefins is a common and useful chemical transformation. In the context of offering enantioenriched three-dimensional molecules via such a highly reactive process, chiral hydrogen-bonding (H-bonding) catalysis has been widely used to provide enantiocontrol. The current strategies for operating H-bonding induction are confined to following that are prevalent in ionic-type manifolds. Here, we report a novel protocol towards electron-rich olefins based on converting these species from acting as H-bonding donors to acceptors. It facilitates the first development of asymmetric [3 + 2] photocycloadditions with cyclopropylamines. The method is also effective for electron-neutral olefins, in which the successful construction of all-carbon quaternary stereocentres from 1,1-diaryl ethylenes that feature two structurally similar aryl substituents demonstrates the versatility of this new chiral H-bonding catalytic strategy. Furthermore, the importance of the obtained six kinds of products in pharmaceuticals and asymmetric catalysis underscores the practicability of this work.

Radical addition to olefins is a common and useful chemical transformation.     

Total synthesis of (+)-spiroindimicin A and congeners unveils their antiparasitic activity

The spiroindimicins are a unique class of chlorinated indole alkaloids characterized by three heteroaromatic rings structured around a congested spirocyclic stereocenter. Here, we report the first total synthesis of (+)-spiroindimicin A, which bears a challenging C-3′/C-5′′-linked spiroindolenine. We detail our initial efforts to effect a biomimetic oxidative spirocyclization from its proposed natural precursor, lynamicin D, and describe how these studies shaped our final abiotic 9-step solution to this complex alkaloid built around a key Pd-catalyzed asymmetric spirocyclization. Scalable access to spiroindimicins A, H, and their congeners has enabled discovery of their activity against several parasites relevant to human health, providing potential starting points for new therapeutics for the neglected tropical diseases leishmaniasis and African sleeping sickness.

Spiroindimicins A and H have been synthesized for the first time via a key palladium-catalyzed spirocyclization. Access to these alkaloids and several congeners has allowed the discovery of their antiparasitic properties.     

Regio- and diastereoselective dearomatizations of N-alkyl activated azaarenes: the maximization of the reactive sites

An unprecedented base-promoted multi-component one-pot dearomatization of N-alkyl activated azaarenes was developed, which enabled the synthesis of complex and diverse bridged cyclic polycycles with multiple stereocenters in a highly regio- and diastereoselective manner. Besides, we realized the step-controlled dearomative bi- and trifunctionalization of quinolinium salts. These transformations not only achieved the maximization of the reaction sites of pyridinium, quinolinium and isoquinolinium salts to enhance structural complexity and diversity, but also opened up a new reaction mode of these N-activated azaarenes. A unique feature of this strategy is the use of easily accessible and bench-stable N-alkyl activated azaarenes to provide maximum reactive sites for dearomative cascade cyclizations. In addition, the salient characteristics including high synthetic efficiency, short reaction time, mild conditions and simple operation made this strategy particularly attractive.

An unprecedented base-promoted multi-component one-pot dearomatization of N-alkyl activated azaarenes was developed to construct complex and diverse bridged cyclic polycycles with multiple stereocenters in a highly regio- and diastereoselective manner.     

Radical boron migration of allylboronic esters

A photocatalyzed 1,3-boron shift of allylboronic esters is reported. The boron atom migration through the allylic carbon skeleton proceeds via consecutive 1,2-boron migrations and Smiles-type rearrangement to furnish a variety of terminally functionalized alkyl boronates. Several types of migrating variations of heteronuclei radicals and dearomatization processes are also tolerated, allowing for further elaboration of highly functionalized boron-containing frameworks.

A photocatalyzed 1,3-boron shift of allylboronic esters is reported. The atom-switch acrobatics proceeds via cascade 1,2-boron migrations and Smiles type rearrangement to furnish a variety of terminally functionalized alkyl boronates.     

Decarboxylative 1,4-carbocyanation of 1,3-enynes to access tetra-substituted allenes via copper/photoredox dual catalysis

We disclose herein the first example of merging photoredox catalysis and copper catalysis for radical 1,4-carbocyanations of 1,3-enynes. Alkyl N-hydroxyphthalimide esters are utilized as radical precursors, and the reported mild and redox-neutral protocol has broad substrate scope and remarkable functional group tolerance. This strategy allows for the synthesis of diverse multi-substituted allenes with high chemo- and regio-selectivities, also permitting late stage allenylation of natural products and drug molecules.

An efficient synthesis of multi-substituted allenes by metallaphotoredox-catalyzed decarboxylative 1,4-carbocyanation of 1,3-enynes is described.     

Enabling chemical protein (semi)synthesis via reducible solubilizing tags (RSTs)

Chemical synthesis of proteins with poor solubility presents a challenging task. The existing solubilizing tag strategies are not suitable for the expressed protein segment. To address this issue, we report herein that solubilizing tags could be introduced at the side chain of the peptide and C-terminal peptide salicylaldehyde esters via a disulfide linker. Such reducible solubilizing tags (RSTs) are compatible with peptide salicylaldehyde ester-mediated Ser/Thr ligation and Cys/Pen ligation for purifying and ligating peptides with poor solubility. This strategy features operational simplicity and readily accessible materials. Both the protein 2B4 cytoplasmic tail and FCER1G protein have been successfully synthesized via this strategy. Of particular note, the RST strategy could be used for solubilizing the expressed protein segment for protein semi-synthesis of the HMGB1 protein.

The reducible solubilizing tag strategy served as a simple and powerful method for the chemical synthesis and semi-synthesis via Ser/Thr ligation and Cys/Pen ligation of extensive self-assembly peptides, membrane proteins with poor solubility.     

An economical approach for peptide synthesis via regioselective C–N bond cleavage of lactams

An economical, solvent-free, and metal-free method for peptide synthesis via C–N bond cleavage using lactams has been developed. The method not only eliminates the need for condensation agents and their auxiliaries, which are essential for conventional peptide synthesis, but also exhibits high atom economy. The reaction is versatile because it can tolerate side chains bearing a range of functional groups, affording up to >99% yields of the corresponding peptides without racemisation or polymerisation. Moreover, the developed strategy enables peptide segment coupling, providing access to a hexapeptide that occurs as a repeat sequence in spider silk proteins.

An economical, solvent-free, and metal-free method for peptide synthesis via C–N bond cleavage using lactams has been developed.     

Nickel-catalyzed cross-electrophile allylation of vinyl bromides and the modification of anti-tumour natural medicine β-elemene

Herein, we present a facile and efficient allylation method via Ni-catalyzed cross-electrophile coupling of readily available allylic acetates with a variety of substituted alkenyl bromides using zinc as the terminal reductant. This Ni-catalyzed modular approach displays excellent functional group tolerance and a broad substrate scope, which the creation of a series of 1,4-dienes including several structurally complex natural products and pharmaceutical motifs. Moreover, the coupling strategy has the potential to realize enantiomeric control. The practicality of this transformation is demonstrated through the potent modification of the naturally antitumor active molecule β-elemene.

Herein, we present a facile and efficient allylation method via Ni-catalyzed cross-electrophile coupling of readily available allylic acetates with a variety of substituted alkenyl bromides using zinc as the terminal reductant.     

Me3SiSiMe2(OnBu): a disilane reagent for the synthesis of diverse silacycles via Brook- and retro-Brook-type rearrangement

Herein, a readily available disilane Me₃SiSiMe₂(OⁿBu) has been developed for the synthesis of diverse silacycles via Brook- and retro-Brook-type rearrangement. This protocol enables the incorporation of a silylene into different starting materials, including acrylamides, alkene-tethered 2-(2-iodophenyl)-1H-indoles, and 2-iodobiaryls, via the cleavage of Si–Si, Si–C, and Si–O bonds, leading to the formation of spirobenzosiloles, fused benzosiloles, and π-conjugated dibenzosiloles in moderate to good yields. Preliminary mechanistic studies indicate that this transformation is realized by successive palladium-catalyzed bis-silylation and Brook- and retro-Brook-type rearrangement of silane-tethered silanols.

A readily available disilane Me₃SiSiMe₂(OⁿBu) as a silylene source has been developed for the synthesis of diverse silacycles via Brook- and retro-Brook-type rearrangement.     

Regiodivergent sulfonylarylation of 1,3-enynes via nickel/photoredox dual catalysis

Catalytic difunctionalization of 1,3-enynes represents an efficient and versatile approach to rapidly assemble multifunctional propargylic compounds, allenes and 1,3-dienes. Controlling selectivity in such addition reactions has been a long-standing challenging task due to multiple reactive centers resulting from the conjugated structure of 1,3-enynes. Herein, we present a straightforward method for regiodivergent sulfonylarylation of 1,3-enynes via dual nickel and photoredox catalysis. Hinging on the nature of 1,3-enynes, diverse reaction pathways are feasible: synthesis of α-allenyl sulfones via 1,4-sulfonylarylation, or preparation of (E)-1,3-dienyl sulfones with high chemo-, regio- and stereoselectivity through 3,4-sulfonylarylation. Notably, this is the first example that nickel and photoredox catalysis are merged to achieve efficient and versatile difunctionalization of 1,3-enynes.

A mild reaction protocol for regiodivergent sulfonylarylation of 1,3-enynes via dual nickel and photoredox catalysis has been developed, which led to efficient synthesis of α-allenyl sulfones or 1,3-dienyl sulfones.     

Atroposelective synthesis of N-aryl peptoid atropisomers via a palladium(ii)-catalyzed asymmetric C–H alkynylation strategy

The introduction of chirality into peptoids is an important strategy to determine a discrete and robust secondary structure. However, the lack of an efficient strategy for the synthesis of structurally diverse chiral peptoids has hampered the studies. Herein, we report the efficient synthesis of a wide variety of N-aryl peptoid atropisomers in good yields with excellent enantioselectivities (up to 99% yield and 99% ee) by palladium-catalyzed asymmetric C–H alkynylation. The inexpensive and commercially available l-pyroglutamic acid was used as an efficient chiral ligand. The exceptional compatibility of the C–H alkynylation with various peptoid oligomers renders this procedure valuable for peptoid modifications. Computational studies suggested that the amino acid ligand distortion controls the enantioselectivity in the Pd/l-pGlu-catalyzed C–H bond activation step.

The introduction of chirality into peptoids is an important strategy to determine a discrete and robust secondary structure.     

Controllable access to trifluoromethyl-containing indoles and indolines: palladium-catalyzed regioselective functionalization of unactivated alkenes with trifluoroacetimidoyl chlorides

The synthesis of diverse products from the same starting materials is always attractive in organic chemistry. Here, a palladium-catalyzed substrate-controlled regioselective functionalization of unactivated alkenes with trifluoroacetimidoyl chlorides has been developed, which provides a direct but controllable access to a variety of structurally diverse trifluoromethyl-containing indoles and indolines. In more detail, with respect to γ,δ-alkenes, 1,1-geminal difunctionalization of unactivated alkenes with trifluoroacetimidoyl chloride enables the [4 + 1] annulation to produce indoles; as for β,γ-alkenes, a [3 + 2] heteroannulation with the hydrolysis product of trifluoroacetimidoyl chloride through 1,2-vicinal difunctionalization of alkenes occurs to deliver indoline products. The structure of alkene substrates differentiates the regioselectivity of the reaction.

A palladium-catalyzed dual functionalization of unactivated alkenes with trifluoroacetimidoyl chlorides toward the synthesis of structurally diverse trifluoromethyl-containing indoles and indolines has been developed.     

Catalyst-free arylation of sulfonamides via visible light-mediated deamination

A novel arylation of sulfonamides with boronic acids to afford numerous diaryl sulfones via a visible light-mediated N–S bond cleavage other than the typical transition-metal-catalyzed C(O)–N bond activation is described. This methodology, which represents the first catalyst-free protocol for the sulfonylation of boronic acids, is characterized by its simple reaction conditions, good functional group tolerance and high efficiency. Several successful examples for the late-stage functionalization of diverse sulfonamides indicate the high potential utility of this method in pharmaceutical science and organic synthesis.

The simple, catalyst-free sulfonylation of boronic acids with sulfonamides via a visible light-mediated N–S bond cleavage is described, affording diaryl sulfones with high efficiency. Late-stage functionalization of sulfonamide drugs was shown.     

Overcoming peri- and ortho-selectivity in C–H methylation of 1-naphthaldehydes by a tunable transient ligand strategy

Methyl groups widely exist in bioactive molecules, and site-specific methylation has become a valuable strategy for their structural functionalization. Aiming to introduce this smallest alkyl handle, a highly regioselective peri- and ortho-C–H methylation of 1-naphthaldehyde by using a transient ligand strategy has been developed. A series of methyl-substituted naphthalene frameworks have been prepared in moderate to excellent yields. Mechanistic studies demonstrate that peri-methylation is controlled by the higher electronic density of the peri-position of 1-naphthaldehyde as well as the formation of intermediary 5,6-fused bicyclic palladacycles, whereas experimental studies and theoretical calculations inferred that a 5-membered iridacycle at the ortho-position of 1-naphthaldehyde leads to energetically favorable ortho-methylation via an interconversion between the peri-iridacycle and ortho-iridacycle. Importantly, to demonstrate the synthetic utility of this method, we show that this strategy can serve as a platform for the synthesis of multi-substituted naphthalene-based bioactive molecules and natural products.

This work provides a highly regioselective peri- and ortho-C–H methylation of 1-naphthaldehyde by using a transient ligand strategy, enabling practical synthesis of multi-substituted naphthalene-based bioactive molecules and natural products.     

Primary trifluoroborate-iminiums enable facile access to chiral α-aminoboronic acids via Ru-catalyzed asymmetric hydrogenation and simple hydrolysis of the trifluoroborate moiety

This work describes the first preparation and application of primary trifluoroborate-iminiums (pTIMs) as a new, easily accessible and valuable class of organoboron derivatives. An array of structurally diverse pTIMs was prepared from potassium acyltrifluoroborates in excellent yields. Highly efficient and enantioselective [(R,R)-TethTsDpen-RuCl] complex-catalyzed hydrogenation of pTIMs provided direct access to chiral primary trifluoroborate-ammoniums (pTAMs). Moreover, facile synthesis of a series of structurally diverse chiral α-aminoboronic acids from chiral pTAMs was accomplished through novel, operationally simple and efficient conversion using hexamethyldisiloxane/aqueous HCl. Using no chromatography at any point, this work allowed easy access to chiral α-aminoboronic acids, as exemplified by the synthesis of optically pure anti-cancer drugs bortezomib and ixazomib.

Starting with potassium acyltrifluoroborates (KATs), N-unprotected chiral α-aminoboronic acids are prepared in three simple steps without chromatography. This facile methodology will tap the broad potential of these valuable compounds.     

By-design molecular architectures via alkyne metathesis

Shape-persistent purely organic molecular architectures have attracted tremendous research interest in the past few decades. Dynamic Covalent Chemistry (DCvC), which deals with reversible covalent bond formation reactions, has emerged as an efficient synthetic approach for constructing these well-defined molecular architectures. Among various dynamic linkages, the formation of ethynylene linkages through dynamic alkyne metathesis is of particular interest due to their high chemical stability, linearity, and rigidity. In this review, we focus on the synthetic strategies of discrete molecular architectures (e.g., macrocycles, molecular cages) containing ethynylene linkages using alkyne metathesis as the key step, and their applications. We will introduce the history and challenges in the synthesis of those architectures via alkyne metathesis, the development of alkyne metathesis catalysts, the reported novel macrocycle structures, molecular cage structures, and their applications. In the end, we offer an outlook of this field and remaining challenges.

The recent synthesis of novel shape-persistent 2D and 3D molecular architectures via alkyne metathesis is reviewed and the critical role of catalysts is also highlighted.     

Catalytic asymmetric hydrometallation of cyclobutenes with salicylaldehydes

Chiral, substituted cyclobutanes are common motifs in bioactive compounds and intermediates in organic synthesis but few asymmetric routes for their synthesis are known. Herein we report the Rh-catalyzed asymmetric hydrometallation of a range of meso-cyclobutenes with salicylaldehydes. The ortho-phenolic group promotes hydroacylation and can be used as a handle for subsequent transformations. The reaction proceeds via asymmetric hydrometallation of the weakly activated cyclobutene, followed by a C–C bond forming reductive elimination. A prochiral, spirocyclic cyclobutene undergoes a highly regioselective hydroacylation. This report will likely inspire the development of other asymmetric addition reactions to cyclobutenes via hydrometallation pathways.

Chiral, substituted cyclobutanes are common motifs in bioactive compounds and intermediates in organic synthesis but few asymmetric routes for their synthesis are known.     

Stereodivergent synthesis of enantioenriched azepino[3,4,5-cd]-indoles via cooperative Cu/Ir-catalyzed asymmetric allylic alkylation and intramolecular Friedel–Crafts reaction

The development of enantioselective annulation reactions using readily available substrates for the construction of structurally and stereochemically diverse heterocycles is a compelling topic in diversity-oriented synthesis. Herein, we report efficient catalytic asymmetric formal 1,3-dipolar (3 + 4) cycloadditions of azomethine ylides with 4-indolyl allylic carbonates for the construction of azepino[3,4,5-cd]-indoles fused with a challenging seven-membered N-heterocycle, a frequently occurring tricyclic indole scaffold in bioactive compounds and pharmaceuticals. Through cooperative Cu/Ir-catalyzed asymmetric allylic alkylation followed by intramolecular Friedel–Crafts reaction, an array of azepino[3,4,5-cd]-indoles were obtained in good yields with excellent diastereo-/enantioselective control. More importantly, the full stereodivergence of this transformation was established via synergistic catalysis followed by acid-promoted epimerization, and up to eight stereoisomers of the cycloadducts bearing three stereogenic centers could be predictably achieved from the same set of starting materials for the first time. Quantum mechanical computations established a plausible mechanism for the synergistic Cu/Ir catalysis to stereodivergently introduce two vicinal stereocenters whose stereochemical information is remotely delivered across the fused azepine ring to control the third chiral center. Epimerization of the last center involves protonation-enabled reversal of the thermodynamically controlled relative configuration.

A stereodivergent synthesis of azepino[3,4,5-cd]-indoles bearing three stereogenic centers was established via synergistic dual-metal catalysis followed by acid-promoted epimerization, and up to all eight stereoisomers could be predictably achieved.     

Variable control of the electronic states of a silver nanocluster via protonation/deprotonation of polyoxometalate ligands

The properties of metal nanoclusters depend on both their structures and electronic states. However, in contrast to the significant advances achieved in the synthesis of structurally well-defined metal nanoclusters, systematic control of their electronic states is still challenging. In particular, stimuli-responsive and reversible control of the electronic states of metal nanoclusters is attractive from the viewpoint of their practical applications. Recently, we developed a synthesis method for atomically precise Ag nanoclusters using polyoxometalates (POMs) as inorganic ligands. Herein, we exploited the acid/base nature of POMs to reversibly change the electronic states of an atomically precise {Ag₂₇} nanocluster via protonation/deprotonation of the surrounding POM ligands. We succeeded in systematically controlling the electronic states of the {Ag₂₇} nanocluster by adding an acid or a base (0–6 equivalents), which was accompanied by drastic changes in the ultraviolet-visible absorption spectra of the nanocluster solutions. These results demonstrate the great potential of Ag nanoclusters for unprecedented applications in various fields such as sensing, biolabeling, electronics, and catalysis.

The electronic states of Ag nanoclusters were reversibly controlled driven by protonation/deprotonation of polyoxometalate ligands.     

Generation of organo-alkaline earth metal complexes from non-polar unsaturated molecules and their synthetic applications

Organomagnesium compounds, represented by the Grignard reagents, are one of the most classical yet versatile carbanion species which have widely been utilized in synthetic chemistry. These reagents are typically prepared via oxidative addition of organic halides to magnesium metals, via halogen–magnesium exchange between halo(hetero)arenes and organomagnesium reagents or via deprotonative magnesiation of prefunctionalized (hetero)arenes. On the other hand, recent studies have demonstrated that the organo-alkaline earth metal complexes including those based on heavier alkaline earth metals such as calcium, strontium and barium could be generated from readily available non-polar unsaturated molecules such as alkenes, alkynes, 1,3-enynes and arenes through unique metallation processes. Nonetheless, the resulting organo-alkaline earth metal complexes could be further functionalized with a variety of electrophiles in various reaction modes. In particular, organocalcium, strontium and barium species have shown unprecedented reactivity in the downstream functionalization, which could not be observed in the reactivity of organomagnesium complexes. This perspective will focus on the newly emerging protocols for the generation of organo-alkaline earth metal complexes from non-polar unsaturated molecules and their applications in chemical synthesis and catalysis.

In this perspective, we highlight the recent development of metallation protocols of non-polar unsaturated molecules for the generation of organo-alkaline earth metal compounds and their applications in chemical synthesis and catalysis.