An expeditious route to sterically encumbered nonproteinogenic α-amino acid precursors using allylboronic acids

A diastereoselective allylation of N-tert-butane sulfinyl α-iminoesters using allylboronic acids is developed to obtain optically active non-proteinogenic α-amino acid precursors in good yields and diastereoselectivities. Gram-scale synthesis, broad tolerance of functional groups, excellent stereodivergence, post-synthetic modifications, and easy removal of the chiral auxiliary are some of the key highlights. The protocol is applicable to various amino acids and short peptides, resulting in the incorporation of these precursors at the N-terminal position.

A diastereoselective allylation of N-tert-butane sulfinyl α-iminoesters using allylboronic acids is developed to obtain optically active non-proteinogenic α-amino acid precursors in good yield and diastereoselectivities.     

Scalable synthesis and coupling of quaternary α-arylated amino acids: α-aryl substituents are tolerated in α-helical peptides

Quaternary amino acids are important tools for the modification and stabilisation of peptide secondary structures. Here we describe a practical and scalable synthesis applicable to quaternary alpha-arylated amino acids (Q4As), and the development of solid-phase synthesis conditions for their incorporation into peptides. Monomeric and dimeric α-helical peptides are synthesised with varying degrees of Q4A substitution and their structures examined using biophysical methods. Both enantiomers of the Q4As are tolerated in folded monomeric and oligomeric α-helical peptides, with the (R)-enantiomer slightly more so than the (S).

Both R and S enantiomers of Fmoc-protected amino acids bearing α-aryl substituents may be made on gram scale. Solid-phase synthesis leads to helical peptides unperturbed by the presence of these additional α-aryl groups.     

Enantioselective synthesis of α-amino ketones through palladium-catalyzed asymmetric arylation of α-keto imines

Chiral α-amino ketones are common structural motifs in natural products and pharmaceuticals, as well as important synthons in organic synthesis. Thus, establishing efficient methods for preparing compounds with these privileged scaffolds is an important endeavor in synthetic chemistry. Herein we disclose a new catalytic asymmetric approach for the synthesis of chiral α-amino ketones through a chiral palladium-catalyzed arylation reaction of in situ generated challenging α-keto imines from previously unreported C-acyl N-sulfonyl-N,O-aminals, with arylboronic acids. The current reaction offers a straightforward approach to the asymmetric synthesis of acyclic α-amino ketones in a practical and highly stereocontrolled manner. Meanwhile, the multiple roles of the chiral Pd(ii) complex catalyst in the reaction were also reported.

Chiral α-amino ketones are common structural motifs in natural products and pharmaceuticals, as well as important synthons in organic synthesis.     

Construction of a quaternary stereogenic center by asymmetric hydroformylation: a straightforward method to prepare chiral α-quaternary amino acids

The construction of chiral quaternary carbon stereocenters has been a long-standing challenge in organic chemistry. Particularly, α-quaternary amino acids that are of high importance in biochemistry still lack a straightforward synthetic method. We here reported a hydroformylation approach to access chiral quaternary stereogenic centers, which has been a long-standing challenge in transition metal catalysis. α,β-Unsaturated carboxylic acid derivatives undergo hydroformylation with a rhodium catalyst to generate an α-quaternary stereocenter under mild conditions. By using this method, a variety of chiral α-quaternary amino acids could be synthesized with satisfactory enantioselectivity. In-depth investigation revealed that the regioselectivity is dramatically influenced by the electronic properties of the substituents attached to the target C C bond. By applying NMR and DFT analyses, the chiral environment of a rhodium/Yanphos complex was depicted, based on which a substrate-catalyst interaction model was proposed.

A rhodium-catalyzed asymmetric hydroformylation reaction was reported to construct chiral α-quaternary amino acid derivatives. High chemo-, regio- and enantioselectivity were realized in one step.     

A BINOL-phosphoric acid and metalloporphyrin derived chiral covalent organic framework for enantioselective α-benzylation of aldehydes

The catalytic asymmetric α-benzylation of aldehydes represents a highly valuable reaction for organic synthesis. For example, the generated α-heteroarylmethyl aldehydes, such as (R)-2-methyl-3-(pyridin-4-yl)propanal ((R)-MPP), are an important class of synthons to access bioactive drugs and natural products. We report herein a new and facile synthetic approach for the asymmetric intermolecular α-benzylation of aldehydes with less sterically hindered alkyl halides using a multifunctional chiral covalent framework (CCOF) catalyst in a heterogeneous way. The integration of chiral BINOL-phosphoric acid and Cu(ii)-porphyrin modules into a single COF framework endows the obtained (R)-CuTAPBP-COF with concomitant Brønsted and Lewis acidic sites, robust chiral confinement space, and visible-light induced photothermal conversion. These features allow it to highly promote the intermolecular asymmetric α-benzylation of aldehydes via visible-light induced photothermal conversion. Notably, this light-induced thermally driven reaction can effectively proceed under natural sunlight irradiation. In addition, this reaction can be easily extended to a gram-scale level, and its generality is ascertained by asymmetric α-benzylation reactions on various substituted aldehydes and alkyl bromides.

We report a new synthetic approach for the intermolecular α-alkylation of aldehydes with alkyl halides based on a BINOL-phosphate and Cu(ii)-porphyrin derived multifunctional CCOF catalyst via visible-light induced photothermal conversion.     

Direct access to tetrasubstituted cyclopentenyl scaffolds through a diastereoselective isocyanide-based multicomponent reaction

An efficient strategy combining the stereocontrol of organocatalysis with the diversity-generating character of multicomponent reactions is described to produce structurally unique, tetrasubstituted cyclopentenyl frameworks. An asymmetric Michael addition–hemiacetalization between α-cyanoketones and α,β-unsaturated aliphatic aldehydes was performed for constructing cyclic hemiacetals, which were next employed as chiral bifunctional substrates in a new diastereoselective intramolecular isocyanide-based multicomponent reaction. This approach furnished a diversity of structurally complex compounds – including peptidomimetics and natural product hybrids in high stereoselectivity (up to >99% ee and up to >99 : 1 dr) and in moderate to high yields.

Simple and available reagents are combined in this new three-component isocyanide-based multicomponent reaction providing an interesting and straightforward way to prepare complex and highly functionalized cyclopentenyl rings.     

Catalytic asymmetric transformations of racemic α-borylmethyl-(E)-crotylboronate via kinetic resolution or enantioconvergent reaction pathways

We report herein catalytic asymmetric transformations of racemic α-borylmethyl-(E)-crotylboronate. The Brønsted acid-catalyzed kinetic resolution–allylboration reaction sequence of the racemic reagent gave (Z)-δ-hydroxymethyl-anti-homoallylic alcohols with high Z-selectivities and enantioselectivities upon oxidative workup. In parallel, enantioconvergent pathways were utilized to synthesize chiral nonracemic 1,5-diols and α,β-unsaturated aldehydes with excellent optical purity.

We report herein catalytic asymmetric transformations of racemic α-borylmethyl-(E)-crotylboronate.     

Access to chiral β-sulfonyl carbonyl compounds via photoinduced organocatalytic asymmetric radical sulfonylation with sulfur dioxide

An organocatalytic enantioselective radical reaction of potassium alkyltrifluoroborates, DABCO·(SO₂)₂ and α,β-unsaturated carbonyl compounds under photoinduced conditions is developed, which provides an efficient pathway for the synthesis of chiral β-sulfonyl carbonyl compounds in good yields with excellent enantioselectivity (up to 96% ee). Aside from α,β-unsaturated carbonyl compounds with auxiliary groups, common chalcone substrates are also well compatible with this organocatalytic system. This method proceeds through an organocatalytic enantioselective radical sulfonylation under photoinduced conditions, and represents a rare example of asymmetric transformation involving sulfur dioxide insertion.

A photoinduced organocatalytic enantioselective radical reaction is developed, affording chiral β-sulfonyl carbonyl compounds in good yields with excellent enantioselectivity (up to 96% ee).     

An umpolung-enabled copper-catalysed regioselective hydroamination approach to α-amino acids

A copper-catalysed regio- and stereoselective hydroamination of acrylates with hydrosilanes and hydroxylamines has been developed to afford the corresponding α-amino acids in good yields. The key to regioselectivity control is the use of hydroxylamine as an umpolung, electrophilic amination reagent. Additionally, a judicious choice of conditions involving the CsOPiv base and DTBM-dppbz ligand of remote steric hindrance enables the otherwise challenging C–N bond formation at the α position to the carbonyl. The point chirality at the β-position is successfully controlled by the Xyl-BINAP or DTBM-SEGPHOS chiral ligand with similarly remote steric bulkiness. The combination with the chiral auxiliary, (−)-8-phenylmenthol, also induces stereoselectivity at the α-position to form the optically active unnatural α-amino acids with two adjacent stereocentres.

A copper-catalysed regio- and enantioselective hydroamination of acrylates has been developed to afford the corresponding optically active unnatural α-amino acids.     

Enantioselective iodolactonization to prepare ε-lactone rings using hypervalent iodine

Despite the rapid growth of enantioselective halolactonization reactions in recent years, most are effective only when forming smaller (6,5,4-membered) rings. Seven-membered ε-lactones, are rarely formed with high selectivity, and never without conformational bias. We describe the first highly enantioselective 7-exo-trig iodolactonizations of conformationally unbiased ε-unsaturated carboxylic acids, effected by an unusual combination of a bifunctional BAM catalyst, I₂, and I(iii) reagent (PhI(OAc)₂:PIDA).

We describe the first highly enantioselective 7-exo-trig iodolactonizations of conformationally unbiased ε-unsaturated carboxylic acids, effected by an unusual combination of a bifunctional BAM catalyst, I₂, and I(iii) reagent (PhI(OAc)₂:PIDA).     

A step-economic and one-pot access to chiral Cα-tetrasubstituted α-amino acid derivatives via a bicyclic imidazole-catalyzed direct enantioselective C-acylation

C^α-Tetrasubstituted α-amino acids are ubiquitous and unique structural units in bioactive natural products and pharmaceutical compounds. The asymmetric synthesis of these molecules has attracted a lot of attention, but a more efficient method is still greatly desired. Here we describe the first sequential four-step acylation reaction for the efficient synthesis of chiral C^α-tetrasubstituted α-amino acid derivatives from simple N-acylated amino acids via an auto-tandem catalysis using a single nucleophilic catalyst. The synthetic efficiency is improved via a direct enantioselective C-acylation; the methodology affords the corresponding C^α-tetrasubstituted α-amino acid derivatives with excellent enantioselectivities (up to 99% ee). This step-economic, one-pot, and auto-tandem strategy provides facile access to important chiral building blocks, such as peptides, serines, and oxazolines, which are often used in medicinal and synthetic chemistry.

The first four-step sequential reaction for the synthesis of C^α-tetrasubstituted chiral α-amino acid derivatives via auto-tandem catalysis 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.     

Palladium-catalyzed asymmetric allylic alkylation (AAA) with alkyl sulfones as nucleophiles

An efficient palladium-catalyzed AAA reaction with a simple α-sulfonyl carbon anion as nucleophiles is presented for the first time. Allyl fluorides are used as superior precursors for the generation of π-allyl complexes that upon ionization liberate fluoride anions for activation of silylated nucleophiles. With the unique bidentate diamidophosphite ligand ligated palladium as catalyst, the in situ generated α-sulfonyl carbon anion was quickly captured by the allylic intermediates, affording a series of chiral homo-allylic sulfones with high efficiency and selectivity. This work provides a mild in situ desilylation strategy to reveal nucleophilic carbon centers that could be used to overcome the pK_a limitation of “hard” nucleophiles in enantioselective transformations.

A variety of “hard” α-sulfonyl carbanions of aryl, heteroaryl and alkyl sulfones were successfully employed as nucleophiles in palladium-catalyzed asymmetric allylic alkylation with excellent enantioselectivities.     

Formal oxo- and aza-[3 + 2] reactions of α-enaminones and quinones: a double divergent process and the roles of chiral phosphoric acid and molecular sieves

A double divergent process has been developed for the reaction of α-enaminones with quinones through facile manipulation of catalyst and additive, leading to structurally completely different products. The two divergent processes, which involve formal aza- and oxo-[3 + 2] cycloaddition reactions, are mediated by chiral phosphoric acid and molecular sieves, respectively. While inclusion of phosphoric acid in the reaction switched the reaction pathway to favor the efficient formation of a wide range of N-substituted indoles, addition of 4 Å molecular sieves to the reaction switched the reaction pathway again, leading to enantioselective synthesis of 2,3-dihydrobenzofurans in excellent yields and enantioselectivities under mild conditions. Studies in this work suggest that the chiral phosphoric acid acts to lower the transition state energy and promote the formation of amide intermediate for the formal aza-[3 + 2] cycloaddition and the molecular sieves serve to facilitate proton transfer for oxo-[3 + 2] cycloaddition. The reactivity of α-enaminones is also disclosed in this work.

A double divergent process for [3 + 2] cycloadditions of α-enaminones with quinones led to the formation of N-substituted indoles and 2,3-dihydrobenzofurans.     

Asymmetric β-arylation of cyclopropanols enabled by photoredox and nickel dual catalysis

The enantioselective functionalization and transformation of readily available cyclopropyl compounds are synthetically appealing yet challenging topics in organic synthesis. Here we report an asymmetric β-arylation of cyclopropanols with aryl bromides enabled by photoredox and nickel dual catalysis. This dual catalytic transformation features a broad substrate scope and good functional group tolerance at room temperature, providing facile access to a wide array of enantioenriched β-aryl ketones bearing a primary alcohol moiety in good yields with satisfactory enantioselectivities (39 examples, up to 83% yield and 90% ee). The synthetic value of this protocol was illustrated by the concise asymmetric construction of natural product calyxolane B analogues.

An asymmetric β-arylation of cyclopropanols with aryl bromides was enabled by enantioselective photoredox and nickel dual catalysis.     

Phosphine-catalyzed divergent domino processes between γ-substituted allenoates and carbonyl-activated alkenes

Highly enantioselective and chemodivergent domino reactions between γ-substituted allenoates and activated alkenes have been developed. In the presence of NUSIOC-Phos, triketone enone substrates smoothly reacted with γ-substituted allenoates to form bicyclic furofurans in good yields with high stereoselectivities. Alternatively, the reaction between diester-activated enone substrates and γ-substituted allenoates formed chiral conjugated 1,3-dienes in good yields with excellent enantioselectivities. Notably, by employing substrates with subtle structural difference, under virtually identical reaction conditions, we were able to access two types of chiral products, which are of biological relevance and synthetic importance.

Highly enantioselective and chemodivergent domino reactions between γ-substituted allenoates and activated alkenes have been developed.     

α-Diimine synthesis via titanium-mediated multicomponent diimination of alkynes with C-nitrosos

α-Diimines are commonly used as supporting ligands for a variety of transition metal-catalyzed processes, most notably in α-olefin polymerization. They are also precursors to valuable synthetic targets, such as chiral 1,2-diamines. Their synthesis is usually performed through acid-catalyzed condensation of amines with α-diketones. Despite the simplicity of this approach, accessing unsymmetrical α-diimines is challenging. Herein, we report the Ti-mediated intermolecular diimination of alkynes to afford a variety of symmetrical and unsymmetrical α-diimines through the reaction of diazatitanacyclohexadiene intermediates with C-nitrosos. These diazatitanacycles can be readily accessed in situ via the multicomponent coupling of Ti NR imidos with alkynes and nitriles. The formation of α-diimines is achieved through formal [4 + 2]-cycloaddition of the C-nitroso to the Ti and γ-carbon of the diazatitanacyclohexadiene followed by two subsequent cycloreversion steps to eliminate nitrile and afford the α-diimine and a Ti oxo.

Alkyne diimination to unsymmetric α-diimines can be achieved via multicomponent reaction of Ti imidos and C-nitrosos. C-nitroso [4 + 2] cycloaddition across a diazatitanacyclohexadiene initiates cascading retrocycloadditions, liberating the α-diimine.     

Harnessing α-l-fucosidase for in vivo cellular senescence imaging

Precise detection of cellular senescence may allow its role in biological systems to be evaluated more effectively, while supporting studies of therapeutic candidates designed to evade its detrimental effect on physical function. We report here studies of α-l-fucosidase (α-fuc) as a biomarker for cellular senescence and the development of an α-fuc-responsive aggregation induced emission (AIE) probe, termed QM-NHαfuc designed to complement more conventional probes based on β-galactosidase (β-gal). Using QM-NHαfuc, the onset of replicative-, reactive oxygen species (ROS)-, ultraviolet A (UVA)-, and drug-induced senescence could be probed effectively. QM-NHαfuc also proved capable of identifying senescent cells lacking β-gal expression. The non-invasive real-time senescence tracking provided by QM-NHαfuc was validated in an in vivo senescence model. The results presented in this study lead us to suggest that the QM-NHαfuc could emerge as a useful tool for investigating senescence processes in biological systems.

Evidence of close association of α-fuc with senescence induction highlights the potential of α-fuc as a novel biomarker for cellular senescence. Here, an α-fuc-responsive AIE probe (QM-NHαfuc) allows for the identification of senescent cell in vivo.     

Sulfur(iv)-mediated umpolung α-heterofunctionalization of 2-oxazolines

The α-umpolung of carbonyl compounds significantly expands the boundaries of traditional carbonyl chemistry. Despite various umpolung methods available today, reversing the inherent reactivity of carbonyls still remains a substantial challenge. In this article, we report the first use of sulfonium salts, in lieu of well-established hypervalent iodines, for the carbonyl umpolung event. The protocol enables the incorporation of a wide variety of heteroatom nucleophiles into the α-carbon of 2-oxazolines. The success of this investigation hinges on the following factors: (1) the use of sulfoxides, which are abundant, structurally diverse and tunable, and easily accessible, ensures the identification of a superior oxidant namely phenoxathiin sulfoxide for the umpolung reaction; (2) the “assembly/deprotonation” protocol previously developed for rearrangement reactions in our laboratory was successfully applied here for the construction of α-umpoled 2-oxazolines.

Aryl sulfonium salts serving as a new type of carbonyl umpolung reagent enable direct α-heterofunctionalization of 2-oxazolines.     

Stereodivergent entry to β-branched β-trifluoromethyl α-amino acid derivatives by sequential catalytic asymmetric reactions

Currently, conventional reductive catalytic methodologies do not guarantee general access to enantioenriched β-branched β-trifluoromethyl α-amino acid derivatives. Herein, a one-pot approach to these important α-amino acids, grounded on the reduction – ring opening of Erlenmeyer–Plöchl azlactones, is presented. The configurations of the two chirality centers of the products are established during each of the two catalytic steps, enabling a stereodivergent process.

A one-pot approach to β-branched β-trifluoromethyl α-amino acids, grounded on the reduction – ring opening of Erlenmeyer–Plöchl azlactones, and complementary to conventional catalytic asymmetric hydrogenation, is presented.