Amyloid-β peptide 37, 38 and 40 individually and cooperatively inhibit amyloid-β 42 aggregation

The pathology of Alzheimer''s disease is connected to the aggregation of β-amyloid (Aβ) peptide, which in vivo exists as a number of length-variants. Truncations and extensions are found at both the N- and C-termini, relative to the most commonly studied 40- and 42-residue alloforms. Here, we investigate the aggregation of two physiologically abundant alloforms, Aβ₃₇ and Aβ₃₈, as pure peptides and in mixtures with Aβ₄₀ and Aβ₄₂. A variety of molar ratios were applied in quaternary mixtures to investigate whether a certain ratio is maximally inhibiting of the more toxic alloform Aβ₄₂. Through kinetic analysis, we show that both Aβ₃₇ and Aβ₃₈ self-assemble through an autocatalytic secondary nucleation reaction to form fibrillar β-sheet-rich aggregates, albeit on a longer timescale than Aβ₄₀ or Aβ₄₂. Additionally, we show that the shorter alloforms co-aggregate with Aβ₄₀, affecting both the kinetics of aggregation and the resulting fibrillar ultrastructure. In contrast, neither Aβ₃₇ nor Aβ₃₈ forms co-aggregates with Aβ₄₂; however, both short alloforms reduce the rate of Aβ₄₂ aggregation in a concentration-dependent manner. Finally, we show that the aggregation of Aβ₄₂ is more significantly impeded by a combination of Aβ₃₇, Aβ₃₈, and Aβ₄₀ than by any of these alloforms independently. These results demonstrate that the aggregation of any given Aβ alloform is significantly perturbed by the presence of other alloforms, particularly in heterogeneous mixtures, such as is found in the extracellular fluid of the brain.

The pathology of Alzheimer''s disease is connected to the aggregation of β-amyloid (Aβ) peptide, which in vivo exists as a number of length-variants. This study identifies the Aβ37/38/40 ratio that is maximally inhibitory to Aβ₄₂ aggregation.     

Multifunctional peptide-assembled micelles for simultaneously reducing amyloid-β and reactive oxygen species

The excessive production and deposition of amyloid-β (Aβ) is one of the most important etiologies of Alzheimer''s disease (AD). The interaction between Aβ and metal ions produces aberrant reactive oxygen species (ROS), which induce oxidative stress and accelerate the progression of AD. To reduce Aβ plaques and ROS to maintain their homeostasis is an emerging and ingenious strategy for effective treatment of AD. Herein, we report the rational design of multifunctional micelles (MPGLT) based on a polymer-grafted peptide to simultaneously clear Aβ and ROS for AD therapy. The MPGLT integrating three functional peptides as a ROS scavenger (tk-GSH), β-sheet breaker (LP) and an autophagy activator (TK) respectively, could capture and degrade Aβ. Meanwhile, the tk-GSH on the surface of MPGLT effectively scavenges the intracellular ROS. Consequently, MPGLT reduced the cytotoxicity of Aβ and ROS. In vivo animal studies using an AD mouse model further showed that MPGLT could transport across the blood–brain barrier for decreasing the Aβ plaque and eliminating ROS in vivo. This peptide micelle-based synergistic strategy may provide novel insight for AD therapy.

Multifunctional micelles based on a peptide–polymer for simultaneously targeting Aβ degradation and ROS scavenging for AD therapy.     

Phosphorylation of covalent organic framework nanospheres for inhibition of amyloid-β peptide fibrillation

The development and exploration of new nanostructural inhibitors against Alzheimer''s disease (AD)-associated amyloid-β (Aβ) fibrillation have attracted extensive attention and become a new frontier in nanomedicine. However, focusing on finding an effective nanostructure is one of the most challenging parts of the therapeutics task. Herein, nanoscale spherical covalent organic frameworks (COFs) via post-synthetic functionalization with sodium phosphate (SP) groups on the channel networks were found to efficiently inhibit Aβ fibrillation. The as-prepared uniform SP-COF nanospheres with high surface area, good crystallinity, and chemical stability were characterized by multifarious microscopic and spectroscopic techniques. Moreover, molecular dynamics simulation together with fibrillation kinetics and cytotoxicity assay experiments shows that there were restricted-access adsorption channels in the SP-COFs which were formed by the cavities with size and functional groups accommodated to the Aβ peptide sequence and significantly affected the fibrillation and cytotoxicity of Aβ. Transmission electron microscopy (TEM), dynamic light scattering (DLS) monitoring, isothermal titration calorimetry (ITC), Fourier transform infrared (FT-IR) and circular dichroism (CD) spectra measurements, and confocal imaging observation were performed to understand the inhibition mechanism and influencing factors of the SP-COFs. To our knowledge, our strategy is the first exploration of COF-based anti-amyloidogenic nanomaterials with high affinity and specific targeting, which are crucial for the inhibition of Aβ fibrillation for AD prevention and treatment.

Nanoscale spherical COFs via phosphorylation functionalization were found to efficiently inhibit fibrillation of the Alzheimer''s disease-associated Aβ peptide.     

3D-visualization of amyloid-β oligomer interactions with lipid membranes by cryo-electron tomography

Amyloid-β (Aβ) assemblies have been shown to bind to lipid bilayers. This can disrupt membrane integrity and cause a loss of cellular homeostasis, that triggers a cascade of events leading to Alzheimer''s disease. However, molecular mechanisms of Aβ cytotoxicity and how the different assembly forms interact with the membrane remain enigmatic. Here we use cryo-electron tomography (cryoET) to obtain three-dimensional nano-scale images of various Aβ assembly types and their interaction with liposomes. Aβ oligomers and curvilinear protofibrils bind extensively to the lipid vesicles, inserting and carpeting the upper-leaflet of the bilayer. Aβ oligomers concentrate at the interface of vesicles and form a network of Aβ-linked liposomes, while crucially, monomeric and fibrillar Aβ have relatively little impact on the membrane. Changes to lipid membrane composition highlight a significant role for GM1-ganglioside in promoting Aβ-membrane interactions. The different effects of Aβ assembly forms observed align with the highlighted cytotoxicity reported for Aβ oligomers. The wide-scale incorporation of Aβ oligomers and curvilinear protofibrils into the lipid bilayer suggests a mechanism by which membrane integrity is lost.

Cryo-electron tomography 3D imaging of amyloid-β oligomers carpeting the surface of lipid bilayers in near native conditions.     

Small molecule-mediated co-assembly of amyloid-β oligomers reduces neurotoxicity through promoting non-fibrillar aggregation

Amyloid-β (Aβ) oligomers, particularly low molecular weight (LMW) oligomers, rather than fibrils, contribute very significantly to the onset and progression of Alzheimer''s Disease (AD). However, due to the inherent heterogeneity and metastability of oligomers, most of the conventional anti-oligomer therapies have indirectly modulated oligomers'' toxicity through manipulating Aβ self-assembly to reduce oligomer levels, which are prone to suffering from the risk of regenerating toxic oligomers from the products of modulation. To circumvent this disadvantage, we demonstrate, for the first time, rational design of rigid pincer-like scaffold-based small molecules with blood–brain barrier permeability that specifically co-assemble with LMW Aβ oligomers through directly binding to the exposed hydrophobic regions of oligomers to form non-fibrillar, degradable, non-toxic co-aggregates. As a proof of concept, treatment with a europium complex (EC) in such a structural mode can rescue Aβ-mediated dysfunction in C. elegans models of AD in vivo. This small molecule-mediated oligomer co-assembly strategy offers an efficient approach for AD treatment.

A rational design of pincer-like scaffold-based small molecule with blood-brain barrier permeability that can specifically co-assemble with low molecular weight Aβ oligomers to form non-fibrillar, degradable, non-toxic co-aggregates.     

Atomic force microscopic imaging of seeded fibril formation and fibril branching by the Alzheimer's disease amyloid-β protein

Background: Amyloid plaques composed of the fibrillar form of the amyloid-β protein (Aβ) are the defining neuropathological feature of Alzheimer's disease (AD). A detailed understanding of the time course of amyloid formation could define steps in disease progression and provide targets for therapeutic intervention. Amyloid fibrils, indistinguishable from those derived from an AD brain, can be produced in vitro using a seeded polymerization mechanism. In its simplest form, this mechanism involves a cooperative transition from monomeric Aβ to the amyloid fibril without the buildup of intermediates. Recently, however, a transient species, the Aβ amyloid protofibril, has been identified. Here, we report studies of Aβ amyloid protofibril and its seeded transition into amyloid fibrils using atomic force microscopy.Results: Seeding of the protofibril-to-fibril transition was observed. Preformed fibrils, but not protofibrils, effectively seeded this transition. The assembly state of Aβ influenced the rate of seeded growth, indicating that protofibrils are fibril assembly precursors. The handedness of the helical surface morphology of fibrils depended on the chirality of Aβ. Finally, branched and partially wound fibrils were observed.Conclusions: The temporal evolution of morphologies suggests that the protofibril-to-fibril transition is nucleation-dependent and that protofibril winding is involved in that transition. Fibril unwinding and branching may be essential for the post-nucleation growth process. The protofibrillar assembly intermediate is a potential target for AD therapeutics aimed at inhibiting amyloid formation and AD diagnostics aimed at detecting presymptomatic disease.     

Concurrent suppression of Aβ aggregation and NLRP3 inflammasome activation for treating Alzheimer's disease

Alzheimer''s disease (AD) is a neurodegenerative illness accompanied by severe memory loss, cognitive disorders and impaired behavioral ability. Amyloid β-peptide (Aβ) aggregation and nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome play crucial roles in the pathogenesis of AD. Aβ plaques not only induce oxidative stress and impair neurons, but also activate the NLRP3 inflammasome, which releases inflammatory cytokine IL-1β to trigger neuroinflammation. A bifunctional molecule, 2-[2-(benzo[d]thiazol-2-yl)phenylamino]benzoic acid (BPBA), with both Aβ-targeting and inflammasome-inhibiting capabilities was designed and synthesized. BPBA inhibited self- and Cu²⁺- or Zn²⁺-induced Aβ aggregation, disaggregated the already formed Aβ aggregates, and reduced the neurotoxicity of Aβ aggregates; it also inhibited the activation of the NLRP3 inflammasome and reduced the release of IL-1β in vitro and vivo. Moreover, BPBA decreased the production of reactive oxygen species (ROS) and alleviated Aβ-induced paralysis in transgenic C. elegans with the human Aβ₄₂ gene. BPBA exerts an anti-AD effect mainly through dissolving Aβ aggregates and inhibiting NLRP3 inflammasome activation synergistically.

Bifunctional molecule BPBA inhibits Aβ aggregation and NLRP3 inflammasome activation, thereby decreasing ROS and IL-1β in vitro and vivo; it synergistically prevents Alzheimer''s disease via alleviating Aβ neurotoxicity and reducing neuroinflammation.     

Molecular mechanism of secreted amyloid-β precursor protein in binding and modulating GABABR1a

A recent phenomenal study discovered that the extension domain of secreted amyloid-β precursor protein (sAPP) can bind to the intrinsically disordered sushi 1 domain of the γ-aminobutyric acid type B receptor subunit 1a (GABA_BR1a) and modulate its synaptic transmission. The work provided an important structural foundation for the modulation of GABA_BR1a; however, the detailed molecular interaction mechanism, crucial for future drug design, remains elusive. Here, we further investigated the dynamical interactions between sAPP peptides and the natively unstructured sushi 1 domain using all-atom molecular dynamics simulations, for both the 17-residue sAPP peptide (APP 17-mer) and its minimally active 9 residue segment (APP 9-mer). We then explored mutations of the APP 9-mer with rigorous free energy perturbation (FEP) calculations. Our in silico mutagenesis studies revealed key residues (D4, W6, and W7) responsible for the binding with the sushi 1 domain. More importantly, one double mutation based on different vertebrate APP sequences from evolution exhibited a stronger binding (ΔΔG = −1.91 ± 0.66 kcal mol⁻¹), indicating a potentially enhanced GABA_BR1a modulator. These large-scale simulations may provide new insights into the binding mechanism between sAPP and the sushi 1 domain, which could open new avenues in the development of future GABA_BR1a-specific therapeutics.

A recent phenomenal study discovered that the extension domain of secreted amyloid-β precursor protein (sAPP) can bind to the intrinsically disordered sushi 1 domain of the γ-aminobutyric acid type B receptor subunit 1a (GABA_BR1a) and modulate its synaptic transmission.     

Conformational Essentials Responsible for Neurotoxicity of Aβ42 Aggregates Revealed by Antibodies against Oligomeric Aβ42

Soluble aggregation of amyloid β-peptide 1-42 (Aβ42) and deposition of Aβ42 aggregates are the initial pathological hallmarks of Alzheimer’s disease (AD). The bipolar nature of Aβ42 molecule results in its ability to assemble into distinct oligomers and higher aggregates, which may drive some of the phenotypic heterogeneity observed in AD. Agents targeting Aβ42 or its aggregates, such as anti-Aβ42 antibodies, can inhibit the aggregation of Aβ42 and toxicity of Aβ42 aggregates to neural cells to a certain extent. However, the epitope specificity of an antibody affects its binding affinity for different Aβ42 species. Different antibodies target different sites on Aβ42 and thus elicit different neuroprotective or cytoprotective effects. In the present review, we summarize significant information reflected by anti-Aβ42 antibodies in different immunotherapies and propose an overview of the structure (conformation)−toxicity relationship of Aβ42 aggregates. This review aimed to provide a reference for the directional design of antibodies against the most pathogenic conformation of Aβ42 aggregates.     

Impact of sphingosine and acetylsphingosines on the aggregation and toxicity of metal-free and metal-treated amyloid-β

Pathophysiological shifts in the cerebral levels of sphingolipids in Alzheimer''s disease (AD) patients suggest a link between sphingolipid metabolism and the disease pathology. Sphingosine (SP), a structural backbone of sphingolipids, is an amphiphilic molecule that is able to undergo aggregation into micelles and micellar aggregates. Considering its structural properties and cellular localization, we hypothesized that SP potentially interacts with amyloid-β (Aβ) and metal ions that are found as pathological components in AD-affected brains, with manifesting its reactivity towards metal-free Aβ and metal-bound Aβ (metal–Aβ). Herein, we report, for the first time, that SP is capable of interacting with both Aβ and metal ions and consequently affects the aggregation of metal-free Aβ and metal–Aβ. Moreover, incubation of SP with Aβ in the absence and presence of metal ions results in the aggravation of toxicity induced by metal-free Aβ and metal–Aβ in living cells. As the simplest acyl derivatives of SP, N-acetylsphingosine and 3-O-acetylsphingosine also influence metal-free Aβ and metal–Aβ aggregation to different degrees, compared to SP. Such slight structural modifications of SP neutralize its ability to exacerbate the cytotoxicity triggered by metal-free Aβ and metal–Aβ. Notably, the reactivity of SP and the acetylsphingosines towards metal-free Aβ and metal–Aβ is determined to be dependent on their formation of micelles and micellar aggregates. Our overall studies demonstrate that SP and its derivatives could directly interact with pathological factors in AD and modify their pathogenic properties at concentrations below and above critical aggregation concentrations.

The reactivity of sphingosine and acetylsphingosines towards both metal-free and metal-treated amyloid-β is demonstrated showing a correlation of their micellization properties.     

Enantiomeric β-sheet peptides from Aβ form homochiral pleated β-sheets rather than heterochiral rippled β-sheets

In 1953, Pauling and Corey postulated “rippled” β-sheets, composed of a mixture of d- and l-peptide strands, as a hypothetical alternative to the now well-established structures of “pleated” β-sheets, which they proposed as a component of all-l-proteins. Growing interest in rippled β-sheets over the past decade has led to the development of mixtures of d- and l-peptides for biomedical applications, and a theory has emerged that mixtures of enantiomeric β-sheet peptides prefer to co-assemble in a heterochiral fashion to form rippled β-sheets. Intrigued by conflicting reports that enantiomeric β-sheet peptides prefer to self-assemble in a homochiral fashion to form pleated β-sheets, we set out address this controversy using two β-sheet peptides derived from Aβ_17–23 and Aβ_30–36, peptides 1a and 1b. Each of these peptides self-assembles to form tetramers comprising sandwiches of β-sheet dimers in aqueous solution. Through solution-phase NMR spectroscopy, we characterize the different species formed when peptides 1a and 1b are mixed with their respective d-enantiomers, peptides ent-1a and ent-1b. ¹H NMR, DOSY, and ¹H,¹⁵N-HSQC experiments reveal that mixing peptides 1a and ent-1a results in the predominant formation of homochiral tetramers, with a smaller fraction of a new heterochiral tetramer, and mixing peptides 1b and ent-1b does not result in any detectable heterochiral assembly. ¹⁵N-edited NOESY reveals that the heterochiral tetramer formed by peptides 1a and ent-1a is composed of two homochiral dimers. Collectively, these NMR studies of Aβ-derived peptides provide compelling evidence that enantiomeric β-sheet peptides prefer to self-assemble in a homochiral fashion in aqueous solution.

In aqueous solution, mixtures of l- and d- macrocyclic β-sheet peptides derived from Aβ self-assemble to form homochiral pleated β-sheets but do not co-assemble to form heterochiral rippled β-sheets.     

镍催化α,β-不饱和醛的选择性α,β-双芳基化反应

三组分双官能化反应是一种高效、简便构建C―C键、C―X键的方式. 双键广泛存在于众多有机化合物中, 对双键的双官能化反应研究有巨大的应用潜力. 本工作以Ni(COD)₂为催化剂, 以芳基溴化镁、芳基溴化物为芳基化试剂, 实现了3-芳基-2-丙烯醛亚胺中碳碳双键的双芳基化反应. 该反应建立了一个新的镍催化α,β-不饱和醛的α,β-双芳基化方法, 可以高度区域选择性地向底物分子中引入两个不同取代的芳环, 得到多种2,3,3-三芳基丙醛骨架的产物. 利用这一反应作为核心步骤实现了天然产物Quebecol的简便合成. 机理研究表明, 该反应可能经历了亲核加成、金属交换、还原消除的历程.     

An in situ protonation-activated supramolecular self-assembly for selective suppression of tumor growth

An in situ supramolecular self-assembly in the subcellular organelles could provide a new strategy to treat diseases. Herein, we report a protonation-activated in situ supramolecular self-assembly system in the lysosomes, which could destabilize the lysosome membrane, resulting in the selective suppression of cancer cells. In this system, pyridyl-functionalized tetraphenylethylene (TPE-Py) was protonated in the lysosomes of A549 lung cancer cells to form octahedron-like structures with cucurbit[8]uril (CB[8]), which impaired the integrity of the lysosome membrane, resulting in selective suppression of cancer cells. Moreover, its anticancer efficiency was also systematically evaluated in vivo, triggering the apoptosis of tumor tissues with ignorable effects on normal organs. Overall, the protonation-activated self-assembly in the lysosomes based on the host–guest complexation would provide a method for novel anti-cancer systems.

A protonation-activated supramolecular self-assembly through host–guest interaction was successfully constructed in lysosomes, which could selectively suppress the tumor growth.     

Spin state dependent peroxidase activity of heme bound amyloid β peptides relevant to Alzheimer's disease

The colocalization of heme rich deposits in the senile plaque of Aβ in the cerebral cortex of the Alzheimer''s disease (AD) brain along with altered heme homeostasis and heme deficiency symptoms in AD patients has invoked the association of heme in AD pathology. Heme bound Aβ complexes, depending on the concentration of the complex or peptide to heme ratio, exhibit an equilibrium between a high-spin mono-His bound peroxidase-type active site and a low-spin bis-His bound cytochrome b type active site. The high-spin heme–Aβ complex shows higher peroxidase activity than free heme, where compound I is the reactive oxidant. It is also capable of oxidizing neurotransmitters like serotonin in the presence of peroxide, owing to the formation of compound I. The low-spin bis-His heme–Aβ complex on the other hand shows enhanced peroxidase activity relative to high-spin heme–Aβ. It reacts with H₂O₂ to produce two stable intermediates, compound 0 and compound I, which are characterized by absorption, EPR and resonance Raman spectroscopy. The stability of compound I of low-spin heme–Aβ is accountable for its enhanced peroxidase activity and oxidation of the neurotransmitter serotonin. The effect of the second sphere Tyr10 residue of Aβ on the formation and stability of the intermediates of low-spin heme–Aβ has also been investigated. The higher stability of compound I for low-spin heme–Aβ is likely due to H-bonding interactions involving Tyr10 in the distal pocket.

Low-spin heme-Aβ forms stable compound 0 and compound I in the presence of H₂O₂ where compound I is responsible for its substantial peroxidase activity. This compound I also oxidizes neurotransmitters which is a typical hallmark of Alzheimer''s disease.     

An explicitly designed paratope of amyloid-β prevents neuronal apoptosis in vitro and hippocampal damage in rat brain

Synthetic antibodies hold great promise in combating diseases, diagnosis, and a wide range of biomedical applications. However, designing a therapeutically amenable, synthetic antibody that can arrest the aggregation of amyloid-β (Aβ) remains challenging. Here, we report a flexible, hairpin-like synthetic paratope (SP1, ∼2 kDa), which prevents the aggregation of Aβ monomers and reverses the preformed amyloid fibril to a non-toxic species. Structural and biophysical studies further allowed dissecting the mode and affinity of molecular recognition events between SP1 and Aβ. Subsequently, SP1 reduces Aβ-induced neurotoxicity, neuronal apoptosis, and ROS-mediated oxidative damage in human neuroblastoma cells (SH-SY5Y). The non-toxic nature of SP1 and its ability to ameliorate hippocampal neurodegeneration in a rat model of AD demonstrate its therapeutic potential. This paratope engineering module could readily implement discoveries of cost-effective molecular probes to nurture the basic principles of protein misfolding, thus combating related diseases.

Herein, the therapeutic potentials of an explicitly designed peptide probe are systematically illuminated in vitro and in vivo against Aβ aggregation. The probe demonstrates remarkable potency for attenuating neurotoxicity and hippocampal damage.     

Catalyst-controlled selective borocarbonylation of benzylidenecyclopropanes: regiodivergent synthesis of γ-vinylboryl ketones and β-cyclopropylboryl ketones

Regioselective catalytic multi-functionalization reactions enable the rapid synthesis of complexed products from the same precursors. In this communication, we present a method for the regiodivergent borocarbonylation of benzylidenecyclopropanes with aryl iodides. Various γ-vinylboryl ketones and β-cyclopropylboryl ketones were produced in moderate to good yields with excellent regioselectivity from the same substrates. The choice of the catalyst is key for the regioselectivity control: γ-vinylboryl ketones were produced selectively with IPrCuCl and Pd(dppp)Cl₂ as the catalytic system, while the corresponding β-cyclopropylboryl ketones were obtained in high regioselectivity with Cu(dppp)Cl, [Pd(η³-cinnamyl)Cl]₂ and xantphos as the catalytic system. Moreover, γ-vinylboryl ketones and β-cyclopropylboryl ketones were successfully transformed into several other value-added products.

A novel procedure for regiodivergent borocarbonylation of benzylidenecyclopropanes has been developed. A variety of valuable γ-vinylboryl ketones and β-cyclopropylboryl ketones can be obtained selectively in excellent yields.     

Anatomy and formation mechanisms of early amyloid-β oligomers with lateral branching: graph network analysis on large-scale simulations

Oligomeric amyloid-β aggregates (AβOs) effectively trigger Alzheimer''s disease-related toxicity, generating great interest in understanding their structures and formation mechanisms. However, AβOs are heterogeneous and transient, making their structure and formation difficult to study. Here, we performed graph network analysis of tens of microsecond massive simulations of early amyloid-β (Aβ) aggregations at near-atomic resolution to characterize AβO structures with sizes up to 20-mers. We found that AβOs exhibit highly curvilinear, irregular shapes with occasional lateral branches, consistent with recent cryo-electron tomography experiments. We also found that Aβ40 oligomers were more likely to develop branches than Aβ42 oligomers, explaining an experimental observation that only Aβ40 was trapped in network-like aggregates and exhibited slower fibrillization kinetics. Moreover, AβO architecture dissection revealed that their curvilinear appearance is related to the local packing geometries of neighboring peptides and that Aβ40''s greater branching ability originates from specific C-terminal interactions at branching interfaces. Finally, we demonstrate that whether Aβ oligomerization causes oligomers to elongate or to branch depends on the sizes and shapes of colliding aggregates. Collectively, this study provides bottom-up structural information for understanding early Aβ aggregation and AβO toxicity.

Graph network analysis on large-scale simulations uncovers the differential branching behaviours of large Aβ40 and Aβ42 oligomers.     

Redox deracemization of β,γ-alkynyl α-amino esters

The first non-enzymatic redox deracemization method using molecular oxygen as the terminal oxidant has been described. The one-pot deracemization of β,γ-alkynyl α-amino esters consisted of a copper-catalyzed aerobic oxidation and chiral phosphoric acid-catalyzed asymmetric transfer hydrogenation with excellent functional group compatibility. By using benzothiazoline as the reducing reagent, an exclusive chemoselectivity at the C N bond over the C C bond was achieved, allowing for efficient deracemization of a series of α-amino esters bearing diverse α-alkynyl substituent patterns. The origins of chemo- and enantio-selectivities were elucidated by experimental and computational mechanistic investigation. The generality of the strategy is further demonstrated by efficient deracemization of β,γ-alkenyl α-amino esters.

A one-pot deracemization of β,γ-alkynyl α-amino esters consisting of an aerobic oxidation and chiral phosphoric acid-catalyzed asymmetric transfer hydrogenation has been described.     

Trityl Cation-Catalyzed Hosomi-Sakurai Reaction of Allylsilane with β,γ-Unsaturated α-Ketoester to Form γ,γ-Disubstituted α-Ketoesters

(Ph₃C)[BPh(^F)₄]-catalyzed Hosomi-Sakurai allylation of allylsilanes with β,γ-unsaturated α-ketoesters has been developed to give γ,γ-disubstituted α-ketoesters in high yields with excellent chemoselectivity. Preliminary mechanistic studies suggest that trityl cation dominates the catalysis, while the silyl cation plays a minor role.     

anti-Selective synthesis of β-boryl-α-amino acid derivatives by Cu-catalysed borylamination of α,β-unsaturated esters

A copper-catalysed regio- and diastereoselective borylamination of α,β-unsaturated esters with B₂pin₂ and hydroxylamines has been developed to deliver acyclic β-boryl-α-amino acid derivatives with high anti-diastereoselectivity (up to >99 : 1), which is difficult to obtain by the established methods. A chiral phosphoramidite ligand also successfully induces the enantioselectivity, giving the optically active β-borylated α-amino acids. The products can be stereospecifically transformed into β-functionalised α-amino acids, which are of potent interest in medicinal chemistry.

A Cu-catalysed regio-, diastereo-, and enantioselective borylamination of α,β-unsaturated esters with B₂pin₂ and hydroxylamines has been developed. The products can be converted into functionalised α-amino acids with two adjacent stereocentres.