Copper-catalyzed [3 + 1] cyclization of cyclopropenes/diazo compounds and bromodifluoroacetamides: facile synthesis of α,α-difluoro-β-lactam derivatives

We have developed a novel copper-catalyzed cyclization of cyclopropenes/diazo compounds and bromodifluoroacetamides, efficiently synthesizing a series of α,α-difluoro-β-lactams in moderate to excellent yields under mild reaction conditions. This reaction represents the first example of [3 + 1] cyclization for the synthesis of β-lactams utilizing a metal carbene intermediate as the C1 synthon.

A copper-catalyzed [3 + 1] cyclization of cyclopropenes and bromodifluoroacetamides/diazo compounds has been successfully developed, efficiently synthesizing a wide range of α,α-difluoro-β-lactams.     

Solvent directed chemically divergent synthesis of β-lactams and α-amino acid derivatives with chiral isothiourea

A protocol for the chemically divergent synthesis of β-lactams and α-amino acid derivatives with isothiourea (ITU) catalysis by switching solvents was developed. The stereospecific Mannich reaction occurring between imine and C(1)-ammonium enolate generated zwitterionic intermediates, which underwent intramolecular lactamization and afforded β-lactam derivatives when DCM and CH₃CN were used as solvents. However, when EtOH was used as the solvent, the intermediates underwent an intermolecular esterification reaction, and α-amino acid derivatives were produced. Detailed mechanistic experiments were conducted to prove that these two kinds of products came from the same intermediates. Furthermore, chemically diversified transformations of β-lactam and α-amino acid derivatives were achieved.

A protocol for the solvent directed chemically divergent synthesis of β-lactam and α-amino acid derivatives with chiral isothiourea was reported.     

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.     

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.     

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.     

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.     

Dynamic kinetic resolution of γ,γ-disubstituted indole 2-carboxaldehydes via NHC-Lewis acid cooperative catalysis for the synthesis of tetracyclic ε-lactones

The ubiquity of ε-lactones in various biologically active compounds inspired the development of efficient and enantioselective routes to these target compounds. Described herein is the enantioselective synthesis of indole-fused ε-lactones by the N-heterocyclic carbene (NHC)-Lewis acid cooperative catalyzed dynamic kinetic resolution (DKR) of in situ generated γ,γ-disubstituted indole 2-carboxaldehydes. The Bi(OTf)₃-catalyzed Friedel–Crafts reaction of indole-2-carboxaldehyde with 2-hydroxy phenyl p-quinone methides generates γ,γ-disubstituted indole 2-carboxaldehydes, which in the presence of NHC and Bi(OTf)₃ afforded the desired tetracyclic ε-lactones in up to 93% yield and >99 : 1 er. Moreover, preliminary studies on the mechanism of this formal [4 + 3] annulation are also provided.

NHC-Lewis acid cooperative catalyzed dynamic kinetic resolution (DKR) of transiently generated γ,γ-disubstituted indole 2-carboxaldehydes leading to the enantioselective synthesis of tetracyclic ε-lactones is reported.     

Stereoselective β-mannosylations and β-rhamnosylations from glycosyl hemiacetals mediated by lithium iodide

Stereoselective β-mannosylation is one of the most challenging problems in the synthesis of oligosaccharides. Herein, a highly selective synthesis of β-mannosides and β-rhamnosides from glycosyl hemi-acetals is reported, following a one-pot chlorination, iodination, glycosylation sequence employing cheap oxalyl chloride, phosphine oxide and LiI. The present protocol works excellently with a wide range of glycosyl acceptors and with armed glycosyl donors. The method doesn''t require conformationally restricted donors or directing groups; it is proposed that the high β-selectivities observed are achieved via an S_N2-type reaction of α-glycosyl iodide promoted by lithium iodide.

Breaking from the current paradigm, a highly selective synthesis of hard-to-make β-mannosides and β-rhamnosides from simple glycosyl hemi-acetals has been achieved without using conformational restrictions.     

Iridium-catalyzed α-selective deuteration of alcohols

The development of chemoselective C(sp³)-H deuteration is of particular interest in synthetic chemistry. We herein report the α-selective, iridium(iii)-bipyridonate-catalyzed hydrogen(H)/deuterium(D) isotope exchange of alcohols using deuterium oxide (D₂O) as the primary deuterium source. This method enables the direct, chemoselective deuteration of primary and secondary alcohols under basic or neutral conditions without being affected by coordinative functional groups such as imidazole and tetrazole. Successful substrates for deuterium labelling include the pharmaceuticals losartan potassium, rapidosept, guaifenesin, and diprophylline. The deuterated losartan potassium shows higher stability towards the metabolism by CYP2C9 than the protiated analogue. Kinetic and DFT studies indicate that the direct deuteration proceeds through dehydrogenation of alcohol to the carbonyl intermediate, conversion of [Ir^III–H] to [Ir^III−D] with D₂O, and deuteration of the carbonyl intermediate to give the α-deuterated product.

An α-selective, iridium(iii)-bipyridonate-catalyzed hydrogen isotope exchange of alcohols using D₂O has been developed for the direct, chemoselective deuteration of primary and secondary alcohols, thereby providing deuterated bioactive molecules.     

Organocatalytic asymmetric azidation of sulfoxonium ylides: mild synthesis of enantioenriched α-azido ketones bearing a labile tertiary stereocenter

Disclosed here is a catalytic asymmetric azidation reaction for the efficient synthesis of α-azido ketones bearing a labile tertiary stereocenter. With a superb chiral squaramide catalyst, a mild asymmetric formal H–N₃ insertion of α-carbonyl sulfoxonium ylides proceeded with excellent efficiency and enantioselectivity. This organocatalytic process not only complements the previous α-azidation approaches for the formation of quaternary stereocenters and mostly for 1,3-dicarbonyl compounds, but also has advantages over the well-known metal-catalyzed asymmetric carbene insertion chemistry using α-diazocarbonyl compounds. Detailed mechanistic studies via control reactions and NMR studies provided important insights into the reaction pathway, which features reversible protonation and dynamic kinetic resolution. The curiosity in mechanism also led to the development of a simplified alternative protocol with a cheaper HN₃ source.

An organocatalytic asymmetric H–N₃ insertion of α-carbonyl sulfoxonium ylides has been developed, providing efficient access to α-azido ketones bearing labile tertiary stereocenters and complementing the metal carbene insertion chemistry.     

Copper-catalyzed enantioselective carbonylation toward α-chiral secondary amides

Secondary amides are omnipresent structural motifs in peptides, natural products, pharmaceuticals, and agrochemicals. The copper-catalyzed enantioselective hydroaminocarbonylation of alkenes described in this study provides a direct and practical approach for the construction of α-chiral secondary amides. An electrophilic amine transfer reagent possessing a 4-(dimethylamino)benzoate group was the key to the success. This method also features broad functional group tolerance and proceeds under very mild conditions, affording a set of α-chiral secondary amides in high yields (up to 96% yield) with unprecedented levels of enantioselectivity (up to >99% ee). α,β-Unsaturated secondary amides can also be produced though the method by using alkynes as the substrate.

A copper-catalyzed regioselective and enantioselective intermolecular hydroaminocarbonylation of alkenes with electrophilic hydroxylamines has been developed.     

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).     

Organocatalytic asymmetric synthesis of α-amino esters from sulfoxonium ylides

Described here is the first organocatalytic asymmetric N–H insertion reaction of α-carbonyl sulfoxonium ylides. Without a metal catalyst, this reaction represents an attractive complement to the well-established carbene insertion reactions. As a stable surrogate of diazocarbonyl compounds, sulfoxonium ylides reacted with a range of aryl amines to provide efficient access to α-aryl glycines with excellent enantiocontrol in the presence of a suitable chiral phosphoric acid catalyst. The high stability and weak basicity of sulfoxonium ylides not only enable this protocol to be user-friendly and practically useful, but also preclude catalyst decomposition, which is crucial to the excellent amenability to electron-poor amine nucleophiles. Detailed mechanistic studies indicated that the initial protonation is reversible and the C–N bond formation is rate-determining.

An organocatalytic asymmetric N–H insertion reaction of α-carbonyl sulfoxonium ylides has been developed to provide efficient access to α-amino esters without involving a metal carbenoid intermediate.     

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.     

Copper catalyzed borocarbonylation of benzylidenecyclopropanes through selective proximal C–C bond cleavage: synthesis of γ-boryl-γ,δ-unsaturated carbonyl compounds

A copper catalyzed borocarbonylation of BCPs via proximal C–C bond cleavage for the synthesis of γ-boryl-γ,δ-unsaturated carbonyl compounds has been developed. Using substituted benzylidenecyclopropanes (BCPs) and chloroformates as starting material, a broad range of γ-boryl-γ,δ-unsaturated esters were prepared in moderate to excellent yields with excellent regio- and stereoselectivity. Besides, when aliphatic acid chlorides were used in this reaction, γ-boryl-γ,δ-unsaturated ketones could be produced in excellent yields. When substituted BCPs were used as substrates, the borocarbonylation occurred predominantly at the proximal C–C bond trans to the phenyl group in a regio- and stereoselective manner, which leads to the Z-isomers as the products. This efficient methodology involves the cleavage of a C–C bond and the formation of a C–C bond as well as a C–B bond, and provides a new method for the proximal C–C bond difunctionalization of BCPs.

A copper catalyzed borocarbonylation of benzylidenecyclopropanes (BCPs) via proximal C–C bond cleavage for the synthesis of γ-boryl-γ,δ-unsaturated carbonyl compounds has been developed.     

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.     

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.     

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.     

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.     

Deoxygenative α-alkylation and α-arylation of 1,2-dicarbonyls

Construction of C–C bonds at the α-carbon is a challenging but synthetically indispensable approach to α-branched carbonyl motifs that are widely represented among drugs, natural products, and synthetic intermediates. Here, we describe a simple approach to generation of boron enolates in the absence of strong bases that allows for introduction of both α-alkyl and α-aryl groups in a reaction of readily accessible 1,2-dicarbonyls and organoboranes. Obviation of unselective, strongly basic and nucleophilic reagents permits carrying out the reaction in the presence of electrophiles that intercept the intermediate boron enolates, resulting in two new α-C–C bonds in a tricomponent process.

α-Branched carboxylic acids and other carbonyls are readily accessed by a metal- and base-free deoxygenative α-alkylation and α-arylation of 1,2-dicarbonyls via boron enolates, resulting in a tricomponent coupling with unconventional electrophiles.