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Even though tuning electronic effect of chiral ligands has proven to be a promising method for designing efficient catalysts, the potential to achieve highly selective reactions by this strategy remains largely unexplored. Here, we report a palladium-catalyzed enantioselective ring-closing aminoalkylative amination of aminoenynes enabled by rationally tuning the remote electronic property of 1,1'-binaphthol-derived phosphoramidites. With a tailored 6,6'-CN-substituted 1,1'-binaphthol-derived phosphoramidite as a ligand, a broad range of aromatic amines are compatible with this reaction, allowing the efficient synthesis of a series of enantioenriched exocyclic allenylamines bearing saturated N-heterocycles with up to >99% enantiomeric excess. Remarkably, a one-pot aminoalkylative amination/hydroamination process for the rapid synthesis of chiral spirodiamines promoted by this catalytic system is also established. Detailed mechanistic studies provide solid evidence to support that the remote electronic character of these chiral ligands can efficiently tuning the enantioselectivity by altering the length of the allylic C-Pd bond of the key catalytic intermediate. The potential applications of remote electronic effect in Pd-catalyzed asymmetric transformations have remained largely unexplored. Here, the authors report a Pd-catalyzed enantioselective ring-closing aminoalkylative amination of aminoenynes enabled by rationally tuning the remote electronic property of BINOL-derived phosphoramidites. [ABSTRACT FROM AUTHOR]

Functionalization of Si‐bound methyl group provides an efficient access to diverse organosilanes. However, the asymmetric construction of silicon‐stereogenic architectures by functionalization of Si‐bound methyl group has not yet been described despite recent significant progress in producing chiral silicon. Herein, we disclosed the enantioselective silylmethyl functionalization involving the aryl to alkyl 1,5‐palladium migration to access diverse naphthalenes possessing an enantioenriched stereogenic silicon center, which are inaccessible before. It is worthy to note that the realization of asymmetric induction at the step of metal migration itself remains challenging. Our study constitutes the first enantioselective aryl to alkyl 1,5‐palladium migration reaction. The key to the success is the discovery and fine‐tuning of the different substituents of α,α,α,α‐tetraaryl‐1,3‐dioxolane‐4,5‐dimethanol (TADDOL)‐based phosphoramidites, which ensure the enantioselectivity and desired reactivity. [ABSTRACT FROM AUTHOR]

Functionalization of Si‐bound methyl group provides an efficient access to diverse organosilanes. However, the asymmetric construction of silicon‐stereogenic architectures by functionalization of Si‐bound methyl group has not yet been described despite recent significant progress in producing chiral silicon. Herein, we disclosed the enantioselective silylmethyl functionalization involving the aryl to alkyl 1,5‐palladium migration to access diverse naphthalenes possessing an enantioenriched stereogenic silicon center, which are inaccessible before. It is worthy to note that the realization of asymmetric induction at the step of metal migration itself remains challenging. Our study constitutes the first enantioselective aryl to alkyl 1,5‐palladium migration reaction. The key to the success is the discovery and fine‐tuning of the different substituents of α,α,α,α‐tetraaryl‐1,3‐dioxolane‐4,5‐dimethanol (TADDOL)‐based phosphoramidites, which ensure the enantioselectivity and desired reactivity. [ABSTRACT FROM AUTHOR]

A phthalimide or 3‐formylindole functionality was incorporated into a tris(hydroxymethyl)ethane (THME) scaffold, and the resulting compounds were subsequently transformed into phosphoramidites and solid supports. These building blocks were then used to synthesise oligonucleotides containing amine or aldehyde groups at various positions within their sequences. The resulting modified oligonucleotides were further conjugated through either amide bond formation or oxime ligation. These novel building blocks expand the repertoire of phosphoramidites and solid supports available for modifying oligonucleotides. [ABSTRACT FROM AUTHOR]

We recently reported the properties of RNA hairpins constrained by a dimethylene (DME) disulfide (S−S) linker incorporated between two adjacent nucleosides in the loop and showed that this linker locked the hairpin conformation thus disturbing the duplex/hairpin equilibrium. We have now investigated the influence of the length of the linker and synthesized oligoribonucleotides containing diethylene (DEE) and dipropylene (DPE) S−S bridges. This was achieved via the preparation of building blocks, namely 2′‐O‐acetylthioethyl (2′‐O‐AcSE) and 2′‐O‐acetylthiopropyl (2′‐O‐AcSP) uridine phosphoramidites, which were successfully incorporated into RNA sequences. Thermal denaturation analysis revealed that the DEE and DPE disulfide bridges destabilize RNA duplexes but do not disrupt the hairpin conformation. Furthermore, our investigation of the duplex/hairpin equilibrium indicated that sequences modified with DME and DEE S−S linkers predominantly lock the hairpin form, whereas the DPE S−S linker provides flexibility. These findings highlight the potential of S−S linkers to study RNA interactions. [ABSTRACT FROM AUTHOR]

Here we report the efficient synthetic access to 13C/15N‐labelled pseudouridine phosphoramidites, which were incorporated into a binary H/ACA box guide RNA/product complex comprising 77 nucleotides (nts) in total and into a 75 nt E. coli tRNAGly. The stable isotope (SI) labelled pseudouridines were produced via a highly efficient chemo‐enzymatic synthesis. 13C/15N labelled uracils were produced via chemical synthesis and enzymatically converted to pseudouridine 5′‐monophosphate (ΨMP) by using YeiN, a Ψ‐5′‐monophosphate C‐glycosidase. Removal of the 5′‐phosphate group yielded the desired pseudouridine nucleoside (Ψ), which was transformed into a phosphoramidite building suitable for RNA solid phase synthesis. A Ψ ‐building block carrying both a 13C and a 15N label was incorporated into a product RNA and the complex formation with a 63 nt H/ACA box RNA could be observed via NMR. Furthermore, the SI labelled pseudouridine building block was used to determine imino proton bulk water exchange rates of a 75 nt E. coli tRNAGly CCmnm5U, identifying the TΨC‐loop 5‐methyluridine as a modifier of the exchange rates. The efficient synthetic access to SI‐labelled Ψ building blocks will allow the solution and solid‐state NMR spectroscopic studies of Ψ containing RNAs and will facilitate the mass spectrometric analysis of Ψ‐modified nucleic acids. [ABSTRACT FROM AUTHOR]

Ribonucleic acids (RNAs) play a vital role in living organisms. Many of their cellular functions depend critically on chemical modification. Methods to modify RNA in a controlled manner—both in vitro and in vivo—are thus essential to evaluate and understand RNA biology at the molecular and mechanistic levels. The diversity of modifications, combined with the size and uniformity of RNA (made up of only 4 nucleotides) makes its site‐specific modification a challenging task that needs to be addressed by complementary approaches. One such approach is solid‐phase RNA synthesis. We discuss recent developments in this field, starting with new protection concepts in the ongoing effort to overcome current size limitations. We continue with selected modifications that have posed significant challenges for their incorporation into RNA. These include deazapurine bases required for atomic mutagenesis to elucidate mechanistic aspects of catalytic RNAs, and RNA containing xanthosine, N4‐acetylcytidine, 5‐hydroxymethylcytidine, 3‐methylcytidine, 2′‐OCF3, and 2′‐N3 ribose modifications. We also discuss the all‐chemical synthesis of 5′‐capped mRNAs and the enzymatic ligation of chemically synthesized oligoribonucleotides to obtain long RNA with multiple distinct modifications, such as those needed for single‐molecule FRET studies. Finally, we highlight promising developments in RNA‐catalyzed RNA modification using cofactors that transfer bioorthogonal functionalities. [ABSTRACT FROM AUTHOR]

Ribonucleic acids (RNAs) play a vital role in living organisms. Many of their cellular functions depend critically on chemical modification. Methods to modify RNA in a controlled manner—both in vitro and in vivo—are thus essential to evaluate and understand RNA biology at the molecular and mechanistic levels. The diversity of modifications, combined with the size and uniformity of RNA (made up of only 4 nucleotides) makes its site‐specific modification a challenging task that needs to be addressed by complementary approaches. One such approach is solid‐phase RNA synthesis. We discuss recent developments in this field, starting with new protection concepts in the ongoing effort to overcome current size limitations. We continue with selected modifications that have posed significant challenges for their incorporation into RNA. These include deazapurine bases required for atomic mutagenesis to elucidate mechanistic aspects of catalytic RNAs, and RNA containing xanthosine, N4‐acetylcytidine, 5‐hydroxymethylcytidine, 3‐methylcytidine, 2′‐OCF3, and 2′‐N3 ribose modifications. We also discuss the all‐chemical synthesis of 5′‐capped mRNAs and the enzymatic ligation of chemically synthesized oligoribonucleotides to obtain long RNA with multiple distinct modifications, such as those needed for single‐molecule FRET studies. Finally, we highlight promising developments in RNA‐catalyzed RNA modification using cofactors that transfer bioorthogonal functionalities. [ABSTRACT FROM AUTHOR]

This article discusses the development of a synthesis method for 3'-fluoro hexitol nucleic acids (FHNA) adenosine and guanosine phosphoramidites. The authors explain that antisense technology, which involves using oligonucleotides to downregulate gene expression, has shown promise in drug discovery. They describe the synthesis of FHNA pyrimidine nucleoside phosphoramidites and their properties, as well as the challenges faced in synthesizing FHNA purine nucleosides. The authors present two alternate routes for the synthesis of FHNA purine nucleosides and detail the steps involved in the synthesis process. They conclude that their synthetic method will facilitate the use of FHNA nucleic acids in genetic medicine and diagnostic applications. [Extracted from the article]

5′-18O labeled RNA oligos are important probes to investigate the mechanism of 2′-O-transphosphorylation reactions. Here we describe a general and efficient synthetic approach to the phosphoramidite derivatives of 5′-18O labeled nucleosides starting from the corresponding commercially available 5′-O-DMT protected nucleosides. Using this method, we prepared 5′-18O-guanosine phosphoramidite in 8 steps (13.2% overall yield), 5′-18O-adenosine phosphoramidite in 9 steps (10.1% overall yield) and 5′-18O-2′-deoxyguanosine phosphoramidite in 6 steps (12.8% overall yield). These 5′-18O labeled phosphoramidites can be incorporated into RNA oligos by solid phase synthesis for determination of heavy atom isotope effects in RNA 2′-O-transphosphorylation reactions. [ABSTRACT FROM AUTHOR]

5'‐O‐(2‐isopropoxyprop‐2‐yl) (IIP)‐protection was introduced to 5'‐OH function of nucleosides in high yields by an acid‐catalysed transacetalization with 2,2‐diisopropoxypropane. The applicability of this temporal 5'‐O‐protecting group was demonstrated in the liquid phase oligonucleotide synthesis (LPOS) using the corresponding phosphoramidite building blocks (dA, dG, dC and dT) and a tetrapodal precipitative soluble support. Standard protecting groups were used on nucleobases. Tetrazole as an activator, followed by oxidation using m‐chloroperbenzoic acid, was used for the coupling. The IIP was shown to be a capable choice to the 5'‐O protection in solution phase synthesis. It could be readily removed with formic acid (t1/2<10 s in 6 % HCOOH in dichloromethane/methanol (2/1) at RT), resulting in volatile byproducts (acetone and isopropanol). [ABSTRACT FROM AUTHOR]

P‐stereogenic compounds are widely used as ligands in asymmetric catalysis and are present in a myriad of bioactive compounds and pharmaceuticals. Yet, their stereocontrolled preparation remains challenging. Herein, we report a novel strategy towards versatile chiral‐at‐P alkenylphosphonamidates through a one‐pot Ni‐catalyzed C−P coupling/diastereoselective hydrolysis of readily available phosphoramidites and alkenyl halides. Remarkably, a chemo‐ and diastereodivergent behavior was observed upon subtle changes in the reaction conditions. Additionally, selective derivatizations of chiral alkenylphosphonamidates demonstrate their versatility as building blocks for the synthesis of structurally diverse P‐stereogenic compounds. [ABSTRACT FROM AUTHOR]

P‐stereogenic compounds are widely used as ligands in asymmetric catalysis and are present in a myriad of bioactive compounds and pharmaceuticals. Yet, their stereocontrolled preparation remains challenging. Herein, we report a novel strategy towards versatile chiral‐at‐P alkenylphosphonamidates through a one‐pot Ni‐catalyzed C−P coupling/diastereoselective hydrolysis of readily available phosphoramidites and alkenyl halides. Remarkably, a chemo‐ and diastereodivergent behavior was observed upon subtle changes in the reaction conditions. Additionally, selective derivatizations of chiral alkenylphosphonamidates demonstrate their versatility as building blocks for the synthesis of structurally diverse P‐stereogenic compounds. [ABSTRACT FROM AUTHOR]

Phosphorodiamidate morpholinos (PMOs) are known as premier gene knockdown tools in developmental biology. PMOs are usually 25 nucleo-base-long morpholino subunits with a neutral phosphorodiamidate linkage. PMOs work via a steric blocking mechanism and are stable towards nucleases' inside cells. PMOs are usually synthesized using phosphoramidate P(V) chemistry. In this review, we will discuss the synthesis of PMOs, phosphoroamidate morpholinos (MO), and thiophosphoramidate morpholinos (TMO). [ABSTRACT FROM AUTHOR]

The catalytic methodologies for the derivatization of aza‐QM have recently appeared in the literature and involve organocatalytic and organometallic approaches. This review aims at analyzing the diverse catalytic systems involving chiral NHC carbenes, phosphoric acids, phosphoramidites, phosphine and copper and palladium catalysis showing its applicability for the synthesis of a diverse away of N‐containing compounds which in many cases have biological activity. [ABSTRACT FROM AUTHOR]

As an important class of nucleoside triphosphate analogues, α‐P‐modified nucleoside triphosphates (NTPαXs) have long been recognized as versatile tools in molecular biology and medicinal chemistry. However, the available synthetic methods based on modified nucleoside monophosphate and cyclic PVPVPIII‐nucleoside intermediates are only low to moderate‐yielding. Inspired by recent progress on PV‐PIII coupling reactions, we attempted to access NTPαXs via the putative linear PVPVPIII‐nucleoside intermediates. The current research found that a specific type of nucleoside phosphoramidites, fluorenylmethyl (Fm) nucleosidyl‐phosphoromorpholidites, are highly reactive in coupling with nBu4NH3P2O7 even without acidic activators. In situ oxidation of linear PVPVPIII‐nucleosides with specific sulfurizing, boranylating, and selenylating reagents followed by deprotection of α‐P and nucleoside moieties afforded NTPαXs (X=S, Se, and BH3) in excellent isolated yields. By exploiting dicyanoimidazole (DCI)'s promoting effect on PV‐PIII coupling, the current linear PVPVPIII‐nucleoside‐based method was further developed into an efficient route to α‐P‐modified dinucleoside tetraphosphates. [ABSTRACT FROM AUTHOR]

A new representative of novel chiral P*, N-bidentate bicyclic phosphoramidite ligands was synthesized. Palladium catalysts based on this ligand were tested in the asymmetric allylic alkylation of (E)-1,3-diphenylallyl acetate with dimethyl malonate and in the amination of the same substrate with pyrrolidine and demonstrated high activity (up to 100% conversion) and enantioselectivity up to 40% ee. [ABSTRACT FROM AUTHOR]

New P,S-bidentate phosphoramidite ligands, including these having a stereogenic phosphorus atom in the 1,3,2-dioxaphosphepine ring, have been synthesized on the basis of (Ra)-BINOL and its adamantanyl derivatives. With their participation in the Pd-catalyzed asymmetric allylic alkylation of (E)-1,3-diphenylallyl acetate with dimethyl malonate and the amination with pyrrolidine involving these ligands have afforded selectivity up to 84 and 75% ee, respectively. [ABSTRACT FROM AUTHOR]

Oligonucleotides with an amino linker at the 3′-end are useful for the preparation of conjugated oligonucleotides. However, chemically modified nucleosides, which are unstable under basic conditions, cannot be incorporated into oligonucleotides using the conventional method entailing the preparation of oligonucleotides bearing a 3′-amino linker. Therefore, we designed Fmoc-protected phosphoramidites for the synthesis of base-labile oligonucleotides modified with a 3′-amino linker. The resultant phosphoramidites were then successfully incorporated into oligonucleotides bearing a 3′-amino linker. Various basic solutions were investigated for protecting group removal. All the protecting groups were removed by treating the oligonucleotides with 40% aqueous methylamine at room temperature for 2 h. Thus, the deprotection time and temperature were significantly reduced compared to the conventional conditions (28% NH3 aq., 55 °C, 17 h). In addition, the oligonucleotide protecting groups could be removed using a mild base (e.g., 50 mM potassium carbonate methanol solution). Furthermore, base-labile oligonucleotides bearing an amino linker at the 3′-end were successfully synthesized using the developed phosphoramidite reagents, highlighting the utility of our strategy. [ABSTRACT FROM AUTHOR]

Optically active cyclopropanes have been widely investigated especially from the views of pharmaceutical and agrochemical industries, and substituting one of the methylenes with the difluoromethylene unit should be promising for developing novel biologically relevant compounds and functional materials. In this paper, the copper‐catalyzed enantioselective hydrosilylation of gem‐difluorocyclopropenes to provide the corresponding chiral gem‐difluorocyclopropanes is presented. The use of copper(I) chloride, chiral ligands including bidentate BINAPs and monodentate phosphoramidites, and silylborane Me2PhSi‐Bpin accompanying sodium tert‐butoxide in methanol was appropriate for the enantioselective hydrosilylation of the strained C=C double bond, and the resultant chiral difluorinated three‐membered ring was unambiguously characterized. Subsequent activation of the silyl groups in enantio‐enriched gem‐difluorocyclopropanes showed substantial reduction of the enantiopurity, indicating cleavage of the distal C−C bond leading to the transient acyclic intermediates. [ABSTRACT FROM AUTHOR]

N,O‐Diacetyl tyrosine and 3‐(4‐hydroxy‐phenyl)‐propanoic acid were converted into phosphoramidite derivatives and introduced to the 5′‐end of oligonucleotides. The resulting oligonucleotides exhibiting a 4‐hydroxyphenyl alkyl group were conjugated with 4‐phenyl‐1,2,4‐triazoline‐3,5‐dione as a model of a Y‐click reaction. The reaction is fast (<1 h) and efficient (>90 %). A partial side reaction occurred at the C8 position of deoxyguanosine in single‐stranded oligonucleotides. This side reaction does not take place on the G quadruplex and double‐stranded oligonucleotides and when N2 position of guanine is protected. This Y‐click reaction could be applied to 1,2,4‐triazoline‐3,5‐dione derivatives displaying a fluorescent dye, a carbohydrate or orthogonal functions (alkyne, azide, ketone or maleimide) for the labelling of oligonucleotides. [ABSTRACT FROM AUTHOR]

Naturally occurring phospholipids, such as phosphatidyl glycerol (PG), are gaining interest due to the roles they play in disease mechanisms. To elucidate the metabolism of PG, an optically pure material is required, but this is unfortunately not commercially available. Our previous PG synthesis route utilized phosphoramidite methodology that addressed issues surrounding fatty acid substrate scope and glycerol backbone modifications prior to headgroup phosphorylation, but faltered in the reproducibility of the overall pathway due to purification challenges. Herein, we present a robust pathway to optically pure PG in fewer steps, utilizing H-phosphonates that features a chromatographically friendly and stable triethyl ammonium H-phosphonate salt. Our route is also amendable to the simultaneous installation of different acyl chains, either saturated or unsaturated, on the glycerol backbone. [ABSTRACT FROM AUTHOR]

Oligonucleotides containing cleavable linkers have emerged as versatile tools to achieve stimulus‐responsive and site‐specific cleavage of DNA. However, the limitations of previously reported cleavable linkers including photolabile and disulfide linkers have restricted their applications in vivo. Inspired by the cathepsin B‐sensitive dipeptide linkers in antibody–drug conjugates (ADCs) such as Adcetris, we have developed Val‐Ala‐02 and Val‐Ala‐Chalcone phosphoramidites for the automated synthesis of enzyme‐cleavable oligonucleotides. Cathepsin B digests Val‐Ala‐02 and Val‐Ala‐Chalcone linkers efficiently, enabling cleavage of oligonucleotides into two components or release of small‐molecule payloads. Based on the prior success of dipeptide linkers in ADCs, we believe that these dipeptide linker phosphoramidites will promote new clinical applications of therapeutic oligonucleotides. [ABSTRACT FROM AUTHOR]

Oligonucleotides containing cleavable linkers have emerged as versatile tools to achieve stimulus‐responsive and site‐specific cleavage of DNA. However, the limitations of previously reported cleavable linkers including photolabile and disulfide linkers have restricted their applications in vivo. Inspired by the cathepsin B‐sensitive dipeptide linkers in antibody–drug conjugates (ADCs) such as Adcetris, we have developed Val‐Ala‐02 and Val‐Ala‐Chalcone phosphoramidites for the automated synthesis of enzyme‐cleavable oligonucleotides. Cathepsin B digests Val‐Ala‐02 and Val‐Ala‐Chalcone linkers efficiently, enabling cleavage of oligonucleotides into two components or release of small‐molecule payloads. Based on the prior success of dipeptide linkers in ADCs, we believe that these dipeptide linker phosphoramidites will promote new clinical applications of therapeutic oligonucleotides. [ABSTRACT FROM AUTHOR]

The weak noncovalent interactions and flexibility of ligands play a key role in enantioselective metal‐catalyzed reactions. In transition metal complexes and their catalytic applications, the experimental assessment and the design of key interactions is as difficult as the prediction of the enantioselectivities, especially for flexible, privileged ligands such as chiral phosphoramidites. Therefore, the interligand interactions in cis‐PdIIL2Cl2 phosphoramidite complexes were investigated by NMR spectroscopy and computations. We were able to induce a strong conformational preference by breaking the symmetry of the C2‐symmetric side chain of one of the ligands, and shift the equilibrium between hetero‐ and homocomplexes towards heterocomplexes because of interligand interactions in the cis‐complexes. The modulation of aryl substituents was exploited, along with the solvent effect. The combined CH–π and π–π interactions reveal design patterns for binding and folding of chiral ligands and catalysts. [ABSTRACT FROM AUTHOR]

The weak noncovalent interactions and flexibility of ligands play a key role in enantioselective metal‐catalyzed reactions. In transition metal complexes and their catalytic applications, the experimental assessment and the design of key interactions is as difficult as the prediction of the enantioselectivities, especially for flexible, privileged ligands such as chiral phosphoramidites. Therefore, the interligand interactions in cis‐PdIIL2Cl2 phosphoramidite complexes were investigated by NMR spectroscopy and computations. We were able to induce a strong conformational preference by breaking the symmetry of the C2‐symmetric side chain of one of the ligands, and shift the equilibrium between hetero‐ and homocomplexes towards heterocomplexes because of interligand interactions in the cis‐complexes. The modulation of aryl substituents was exploited, along with the solvent effect. The combined CH–π and π–π interactions reveal design patterns for binding and folding of chiral ligands and catalysts. [ABSTRACT FROM AUTHOR]

In solid-phase oligonucleotide synthesis, a single oligonucleotide is generally acquired from a column loaded with a specific solid support. Herein, we have developed new cleavable spacer (CS) derivatives for tandem synthesis of multiple oligonucleotides on a single column-. Four CS analogues were designed, synthesized, and inserted between two oligonucleotide sequences using an automated oligonucleotide synthesizer. The CS derivatives bearing a cyclic cis -1,2-diol exhibited efficient release of the two oligonucleotides under commonly employed basic conditions of aqueous ammonia. Among the CS analogues, it was found that CS with a robust structure can potentially be applied as a spacer molecule in the tandem synthesis of multiple oligonucleotides in a single sequence. [ABSTRACT FROM AUTHOR]

Amination reactions plays a paramount role as it finds wide applications in pharmaceuticals, production of natural compounds and in drug synthesis. Considering the wide tool chest of procedures, it is one of the key approaches to C−N bond construction. In recent years, substantial headway has been observed in reactions of these type and have progressed into vital assistance for building molecules in modern synthetic chemistry. Concerning the catalytic activity of Iridium complexes which are suitable for many organic transformations including amination reactions, studies on amination of allylic systems by Iridium catalysts are significant. This review concisely compiles information on Iridium‐catalyzed allylic amination, casing literature up to 2020. [ABSTRACT FROM AUTHOR]

A palladium‐catalysed carboborylation reaction for the synthesis of borylated indanes has been investigated. This reaction proceeds in good yields with an achiral catalyst, and is tolerant of substitution on the aryl ring, although sensitivity to the substitution of the alkene was observed. Initial studies towards an enantioselective version of this reaction were undertaken, identifying phosphoramidites as a promising ligand class. This allowed for the synthesis of chiral indane and indolone products with moderate levels of enantioselectivity. [ABSTRACT FROM AUTHOR]

The iridium‐catalysed enantioselective intramolecular allylic substitution of pyrimidine‐tethered allylic carbonates was developed. A wide range of chiral pyrimidine‐fused diazepinone derivatives were successfully constructed in 88–96% yields with 85–99% ees. This work further highlights the power of chiral‐bridged biphenyl phosphoramidites in asymmetric synthesis. [ABSTRACT FROM AUTHOR]

Joining peptides and oligonucleotides offers potential benefits, but current methods remain laborious. Here we present a novel approach towards enzymatic ligation of the two modalities through the development of tag phosphoramidites as adaptors that can be readily incorporated onto oligonucleotides. This simple and highly efficient approach paves the way towards streamlined development and production of peptide/protein–oligonucleotide conjugates. [ABSTRACT FROM AUTHOR]

Main observation and conclusion: Asymmetric hydrogenation reaction is one of the most efficient synthetic methods to form useful chiral compounds for synthetic chemistry, medicinal chemistry and material chemistry. Generally, the enantioselectivity of many hydrogenation reactions is controlled by steric hindrance between the chiral ligand and substrate. Recently, Zhang group developed a highly asymmetric hydrogenation of 2‐aryl and 2‐alkyl acrylic acids catalyzed by a Rh(I) catalyst with a chiral Wudaphos ligand. The excellent enantioselectivity of this asymmetric reaction was proposed to be controlled by ion‐pair interaction between the substrate and chiral ligand. In this study, a systematic density functional theory study has been carried out to investigate the reaction mechanism and origin of the enantioselectivity. Our computational results suggest that this reaction follows the classic mechanism involving oxidative addition of H2, migratory insertion and reductive elimination. Different from the C=C coordination to the metal in the common oxidative addition step, our study found that the chelation of the carboxyl group of the substrate to the cationic Rh(I) metal is more favorable in this oxidative addition step. The high enantioselectivity is proposed to be dictated by a better catalyst/substrate geometric complementarity in the major pathway to have less distortion of the catalyst for a strong ion‐pair interaction. [ABSTRACT FROM AUTHOR]

Automated chemical synthesis of oligonucleotides is of fundamental importance for the production of primers for the polymerase chain reaction (PCR), for oligonucleotide-based drugs, and for numerous other medical and biotechnological applications. The highly optimised automised chemical oligonucleotide synthesis relies upon phosphoramidites as the phosphate precursors and one of the drawbacks of this technology is the poor bench stability of phosphoramidites. Here, we report on the development of an on-demand flow synthesis of phosphoramidites from their corresponding alcohols, which is accomplished with short reaction times, near-quantitative yields and without the need of purification before being submitted directly to automated oligonucleotide synthesis. Sterically hindered as well as redox unstable phosphoramidites are synthesised using this methodology and the subsequent couplings are near-quantitative for all substrates. The vision for this technology is direct integration into DNA synthesisers thereby omitting manual synthesis and storage of phosphoramidites. The poor bench stability of phosphoramidites is a drawback for fast automised chemical oligonucleotide synthesis. Here, the authors report a method for on-demand flow synthesis of phosphoramidites within short reaction times, in near-quantitative yields and sufficient purity for integration with DNA synthesizers. [ABSTRACT FROM AUTHOR]

Automated chemical synthesis of oligonucleotides is of fundamental importance for the production of primers for the polymerase chain reaction (PCR), for oligonucleotide-based drugs, and for numerous other medical and biotechnological applications. The highly optimised automised chemical oligonucleotide synthesis relies upon phosphoramidites as the phosphate precursors and one of the drawbacks of this technology is the poor bench stability of phosphoramidites. Here, we report on the development of an on-demand flow synthesis of phosphoramidites from their corresponding alcohols, which is accomplished with short reaction times, near-quantitative yields and without the need of purification before being submitted directly to automated oligonucleotide synthesis. Sterically hindered as well as redox unstable phosphoramidites are synthesised using this methodology and the subsequent couplings are near-quantitative for all substrates. The vision for this technology is direct integration into DNA synthesisers thereby omitting manual synthesis and storage of phosphoramidites. The poor bench stability of phosphoramidites is a drawback for fast automised chemical oligonucleotide synthesis. Here, the authors report a method for on-demand flow synthesis of phosphoramidites within short reaction times, in near-quantitative yields and sufficient purity for integration with DNA synthesizers. [ABSTRACT FROM AUTHOR]

Automated chemical synthesis of oligonucleotides is of fundamental importance for the production of primers for the polymerase chain reaction (PCR), for oligonucleotide-based drugs, and for numerous other medical and biotechnological applications. The highly optimised automised chemical oligonucleotide synthesis relies upon phosphoramidites as the phosphate precursors and one of the drawbacks of this technology is the poor bench stability of phosphoramidites. Here, we report on the development of an on-demand flow synthesis of phosphoramidites from their corresponding alcohols, which is accomplished with short reaction times, near-quantitative yields and without the need of purification before being submitted directly to automated oligonucleotide synthesis. Sterically hindered as well as redox unstable phosphoramidites are synthesised using this methodology and the subsequent couplings are near-quantitative for all substrates. The vision for this technology is direct integration into DNA synthesisers thereby omitting manual synthesis and storage of phosphoramidites. The poor bench stability of phosphoramidites is a drawback for fast automised chemical oligonucleotide synthesis. Here, the authors report a method for on-demand flow synthesis of phosphoramidites within short reaction times, in near-quantitative yields and sufficient purity for integration with DNA synthesizers. [ABSTRACT FROM AUTHOR]

An azido-derivative of a fluorescein bifluorophore was obtained and used for the synthesis of "molecular beacon"-type oligonucleotide fluorogenic probes for RT-PCR. Eight probe variants were synthesized based on an optimized sequence: with one or two quencher residues at the 3'-end, with a single or bifluorophore fluorescein label attached to 5'-end using modifying phosphoramidites (short linker) or "click reaction" (long linker). Comparison of probes in RT-PCR showed that probes with a doubled quencher (single fluorescein on a short linker) and doubled dye on a short linker (single dye) are somewhat superior in sensitivity to a standard probe (single quencher, single dye on a short linker) by the value of ΔCt = 1–2. [ABSTRACT FROM AUTHOR]

Herein we report the synthesis of a new P‐chirogenic triazole‐based phosphine according to the ephedrine methodology. Upon reaction with late transition‐metal derivatives, RhI and PdII, phosphine‐triazole forms complexes with bidentate P,N coordination, as demonstrated by spectroscopic and X‐ray crystallographic analyses. First experiments in asymmetric catalysis showed the catalytic potential of this new chiral P,N‐type ligand. [ABSTRACT FROM AUTHOR]

The first example of a chiral osmium catalyst is reported in which the overall chirality originates exclusively from a stereogenic metal center (metal-centered chirality) with all coordinating ligands being achiral. The non-C2-symmetric chiral-at-metal complex contains two cyclometalated 7-methyl-1,7-phenanthrolinium heterocycles which can be described as two chelating pyridylidene remote N-heterocyclic carbene (rNHC) ligands. The octahedral coordination sphere is completed with one CO and one acetonitrile ligand. A monodentate chiral oxazoline ligand is used as a chiral auxiliary ligand to obtain enantiomerically pure chiral-at-osmium complexes (>99 : 1 e.r.). Finally, it is demonstrated that the developed chiral-at-osmium complex is suitable for ring-closing enantioselective C(sp3)–H aminations, including the first example of catalytic enantioselective cyclizations of azidoformates to chiral 2-oxazolidinones. [ABSTRACT FROM AUTHOR]

A highly enantioselective hydrogenation of α,β‐unsaturated boronate esters catalyzed by Rh‐(S)‐DTBM‐Segphos complex has been developed. Both (Z)‐α,β‐ and β,β‐disubstituted substrates can be successfully hydrogenated to afford chiral boronates with excellent enantioselectivities, up to 98 % ee. Furthermore, the obtained chiral boronate esters, as important versatile synthetic intermediates are successfully transformed to the corresponding chiral alcohols, amines and other important derivatives with maintained enantioselectivities. [ABSTRACT FROM AUTHOR]

1,2‐Bisphosphines have been identified as one class of important and powerful chiral ligands in asymmetric catalysis with transition metals. Herein, a copper(I)‐catalyzed asymmetric hydrophosphination of α,β‐unsaturated phosphine sulfides was developed with the assistance of "soft–soft" interaction between copper(I)‐catalyst and the phosphine sulfide moiety, which afforded 1,2‐bisphosphine derivatives with diversified electronic nature and steric hindrance in high to excellent yields with high to excellent enantioselectivity. Moreover, the challenging catalytic asymmetric hydrophosphination/protonation reaction was achieved with excellent enantioselectivity. Strikingly, the dynamic kinetic resolution of racemic diarylphosphines was also successfully carried out with high to excellent diastereo‐ and enantioselectivities. Interestingly, the nucleophilic copper(I)‐diphenylphosphide species was characterized by 31P NMR spectrum and mass spectrum. At last, three products were transformed to chiral 1,2‐bisphosphines, which were employed as ligands in Rh‐catalyzed asymmetric hydrogenation of α‐amino‐α,β‐unsaturated ester. The α‐amino acid derivative was produced in high enantioselectivity, which demonstrated the utility of the present methodology. [ABSTRACT FROM AUTHOR]

1,2‐Bisphosphines have been identified as one class of important and powerful chiral ligands in asymmetric catalysis with transition metals. Herein, a copper(I)‐catalyzed asymmetric hydrophosphination of α,β‐unsaturated phosphine sulfides was developed with the assistance of "soft–soft" interaction between copper(I)‐catalyst and the phosphine sulfide moiety, which afforded 1,2‐bisphosphine derivatives with diversified electronic nature and steric hindrance in high to excellent yields with high to excellent enantioselectivity. Moreover, the challenging catalytic asymmetric hydrophosphination/protonation reaction was achieved with excellent enantioselectivity. Strikingly, the dynamic kinetic resolution of racemic diarylphosphines was also successfully carried out with high to excellent diastereo‐ and enantioselectivities. Interestingly, the nucleophilic copper(I)‐diphenylphosphide species was characterized by 31P NMR spectrum and mass spectrum. At last, three products were transformed to chiral 1,2‐bisphosphines, which were employed as ligands in Rh‐catalyzed asymmetric hydrogenation of α‐amino‐α,β‐unsaturated ester. The α‐amino acid derivative was produced in high enantioselectivity, which demonstrated the utility of the present methodology. [ABSTRACT FROM AUTHOR]

Modifying the surface of metal catalyst is a crucial subject for improving the heterogeneous metal catalysts. It is still a great challenge to understand the structure‐activity relationship (SAR) between the surface supporting groups and the metal particles. Herein, Rh NPs supported on the magnetic silica sphere with various functional groups (−NH2, −SH, −SO3H, −N=CH2, −Cl, −NHCOCH3 and −NHCH2Ph) have been prepared for catalytic hydrogenation of nitroarenes under atmospheric pressure at room temperature. We discover that the chemical state of Rh NPs depends on the supporting groups significantly. The electron‐donating functionalities can effectively elevate the Rh0/Rh3+ ratio, which increase the catalytic performance both in conversion and selectivity. The amino group decorated catalyst has such a good selectivity that no dechlorination reaction is observable in the hydrogenation of 2‐chloro‐3‐nitropyridine. What's more, by introducing magnetic Fe3O4 nuclei and mesoporous silica encapsulating layer, the catalyst can be recovered conveniently by an external magnet, and can be reused 10 cycles without any loss of activity. [ABSTRACT FROM AUTHOR]

A series of 1,1′‐spirobiindane‐7,7′‐diol (SPINOL) analogues bearing a 2,2′‐dimethyl‐, cyclopentyl‐, or cyclohexyl‐fused ring were synthesized, and their distinct structural features were elucidated by X‐ray crystallography. On the basis of these scaffolds, chiral monophosphoramidite ligands 6 a–m were synthesized, which demonstrated excellent enantioselectivity in RhI‐catalyzed asymmetric hydrogenation of a dehydro amino acid methyl ester. Ligands 6 a–m were also successfully applied in the RhI‐catalyzed enantioselective [4+2] cycloaddition of α,β‐unsaturated imines with isocyanates, which afforded the corresponding pyrimidinones in good yields (60–92 %) with high enantioselectivities (75–92 % ee). [ABSTRACT FROM AUTHOR]

A highly enantioselective organocatalytic Michael addition‐acetalation/oxa‐Michael reaction involving aldehydes and dioxopyrrolidines has been discovered. The asymmetric reaction is mediated by modularly designed organocatalysts (MDOs) self‐assembled from cinchona alkaloid derivatives and amino acids providing a range of optically active tricyclic hexahydro‐2H‐pyrano[3′,2′:5,6]pyrano[2,3‐c]pyrrol derivatives in high yields (up to 99%) with good to excellent enantioselectivities (up to 99% ee) under mild reaction conditions. [ABSTRACT FROM AUTHOR]

Morpholinos are six‐membered rings that may provide higher conformational rigidity when incorporated into an oligonucleotide (ODN) backbone. Phosphorodiamidate morpholinos are chemically modified ODNs containing morpholinos in place of 2'‐deoxyribose moieties throughout their backbone and have garnered much interest in recent years due to their ability to function as highly effective steric blockers in exon skipping therapy. To further explore the biophysical and biological properties of ODNs derived from morpholino nucleosides, we have replaced the 2'‐deoxyribonucleotides of phosphodiester DNA with morpholinonucleotides to generate phosphoramidate ODNs. Here, we evaluate the mechanistic pathways observed during the solution‐phase synthesis of morpholinonucleoside phosphoramidites, solid‐phase synthesis of morpholinonucleotide phosphoramidates of mA, mG, mC and mT (prefix 'm' represents morpholino) and our first attempts directed at the solid‐phase synthesis of chimeric DNA‐phosphoramidate ODNs, as well as fully modified 22‐mer phosphoramidate ODNs. [ABSTRACT FROM AUTHOR]

A novel chiral phosphoramidite ligand, (Sa)-2-[N-ethyl-N-(1-naphthylmethyl)amino]-dinaphtho[2,1-d:1´,2´-f][1,3,2]dioxaphosphepane, was obtained and tested in Ir-catalyzed asymmetric hydrogenation of a series of 4-R-1,3-dihydro-2H-1,5-benzodiazepin-2-ones, wherein up to 74% ee was achieved. The structure of the resulting compounds was determined based on one- and two-dimensional NMR (1H, 13C, 31P, 1H—1H COSY, 1H—1H ROESY, 1H—13C HSQC and 1H—13C HMBC) spectroscopy data. [ABSTRACT FROM AUTHOR]

Rh/bisphosphine - thiourea ligand (Zhao-Phos)-catalyzed asymmetric hydrogenation of (Z)-β-substituted-β-boryl-α,β-unsaturated esters was successfully developed, furnishing a variety of chiral β-borylated carboxylic esters with high yields and excellent enantioselectivities (up to 99% yield and >99% ee). The gram-scale asymmetric hydrogenation was performed efficiently in the presence of only 0.05 mol% (S/C=2 000) catalyst loading with full conversion, 99% yield and 99% ee. Moreover, the hydrogenation product was easily converted to other versatile synthetic intermediates, such as methyl (S)-3-hydroxy-3-phenylpropanoate and methyl (S)-3-(furan-2-yl)-3-phenylpropanoate. [ABSTRACT FROM AUTHOR]

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Copyright of Angewandte Chemie is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copper complexes of monodentate phosphoramidites efficiently promote asymmetric arylation of N‐azaaryl aldimines with arylboroxines. DFT calculations and experiments support an elementary step of 1,4‐insertion in the reaction pathway, a step in which an aryl‐copper species adds directly across four atoms of C=N−C=N in the N‐azaaryl aldimines. Copper complexes of monodentate phosphoramidites efficiently promote asymmetric arylation of N‐azaaryl aldimines with arylboroxines. The N‐heterocyclic nitrogen center of aldimines is directly involved in 1,4‐insertion of an aryl‐copper species across four atoms of C=N−C=N in the N‐azaaryl aldimines. [ABSTRACT FROM AUTHOR]