Phosphothreonine as a Catalytic Residue in Peptide‐Mediated Asymmetric Transfer Hydrogenations of 8‐Aminoquinolines

Phosphothreonine (pThr) was found to constitute a new class of chiral phosphoric acid (CPA) catalyst upon insertion into peptides. To demonstrate the potential of these phosphopeptides as asymmetric catalysts, enantioselective transfer hydrogenations of a previously underexplored substrate class for CPA‐catalyzed reductions were carried out. pThr‐containing peptides lead to the observation of enantioselectivities of up to 94:6 e.r. with 2‐substituted quinolines containing C8‐amino functionality. NMR studies indicate that hydrogen‐bonding interactions promote strong complexation between substrates and a rigid β‐turn catalyst.     

Catalytic Asymmetric Synthesis of 3,3′‐Diaryloxindoles as Triarylmethanes with a Chiral All‐Carbon Quaternary Center: Phase‐Transfer‐Catalyzed SNAr Reaction

Catalytic asymmetric synthesis of unsymmetrical triarylmethanes with a chiral all‐carbon quaternary center was achieved by using a chiral bifunctional quaternary phosphonium bromide catalyst in the S_NAr reaction of 3‐aryloxindoles under phase‐transfer conditions. The presence of a urea moiety in the chiral phase‐transfer catalyst was important for obtaining high enantioselectivity in this reaction.     

Quaternary β2,2‐Amino Acids: Catalytic Asymmetric Synthesis and Incorporation into Peptides by Fmoc‐Based Solid‐Phase Peptide Synthesis

β‐Amino acid incorporation has emerged as a promising approach to enhance the stability of parent peptides and to improve their biological activity. Owing to the lack of reliable access to β^2,2‐amino acids in a setting suitable for peptide synthesis, most contemporary research efforts focus on the use of β³‐ and certain β^2,3‐amino acids. Herein, we report the catalytic asymmetric synthesis of β^2,2‐amino acids and their incorporation into peptides by Fmoc‐based solid‐phase peptide synthesis (Fmoc‐SPPS). A quaternary carbon center was constructed by the palladium‐catalyzed decarboxylative allylation of 4‐substituted isoxazolidin‐5‐ones. The N?O bond in the products not only acts as a traceless protecting group for β‐amino acids but also undergoes amide formation with α‐ketoacids derived from Fmoc‐protected α‐amino acids, thus providing expeditious access to α‐β^2,2‐dipeptides ready for Fmoc‐SPPS.     

Tripeptides of the Type H‐D‐Pro‐Pro‐Xaa‐NH2 as Catalysts for Asymmetric 1,4‐Addition Reactions: Structural Requirements for High Catalytic Efficiency

Analysis of the structural and functional requirements within the asymmetric peptidic catalyst H‐D ‐Pro‐Pro‐Asp‐NH₂ led to the development of the closely related peptide H‐D ‐Pro‐Pro‐Glu‐NH₂ as an even more efficient catalyst for asymmetric conjugate addition reactions of aldehydes to nitroolefins. In the presence of as little as 1 mol % of H‐D ‐Pro‐Pro‐Glu‐NH₂, a broad range of aldehydes and nitroolefins react readily with each other. The resulting γ‐nitroaldehydes were obtained in excellent yields and stereoselectivities at room temperature. Within the structure of the peptidic catalysts, the D ‐Pro‐Pro motif is the major contributor to the high stereoselectivities. The C‐terminal amide and the spacer to the carboxylic acid in the side‐chain of the C‐terminal amino acid are responsible for the fine‐tuning of the stereoselectivity. The peptidic catalysts not only allow for highly effective asymmetric catalysis under mild conditions, but also function in the absence of additives.     

Bimetallic Gold(I)/Chiral N,N′‐Dioxide Nickel(II) Asymmetric Relay Catalysis: Chemo‐ and Enantioselective Synthesis of Spiroketals and Spiroaminals

A highly efficient asymmetric cascade reaction between keto esters and alkynyl alcohols and amides is reported. The success of the reaction was attributed to the combination of chiral Lewis acid N,N′‐dioxide nickel(II) catalysis with achiral π‐acid gold(I) catalysis working as an asymmetric relay catalytic system. The corresponding spiroketals and spiroaminals were synthesized in up to 99 % yield, 19:1 d.r., and more than 99 % ee under mild reaction conditions. Control experiments suggest that the N,N′‐dioxide ligand was essential for the formation of the spiro products.     

Optically Active Helical Poly[(S)‐3‐vinyl‐2,2′‐dihydroxy‐1,1′‐binaphthyl]: New Ligand for Asymmetric Addition of Diethylzinc to Aryl Aldehyde

Poly[(S)‐3‐vinyl‐2,2′‐dihydroxy‐1,1′‐binaphthyl] (L*) was obtained by taking off the protecting groups of poly[(S)‐3‐vinyl‐2,2′‐bis(methoxymethoxy)‐1,1′‐binaphthyl] (poly‐ 1 ). L* was proved to keep a stable helical conformation in solution. The application of helical L* in the asymmetric addition of diethylzinc to aldehydes has been studied. The catalytic system employing 10 mol% of L* and 150 mol% of Ti(OⁱPr)₄ was found to promote the addition of diethylzinc to a wide range of aromatic aldehydes, giving up to 99% enantiomeric excess (ee) and up to 93% yield of the corresponding secondary alcohol at 0°C. The chiral polymer can be easily recovered and reused without loss of catalytic activity as well as enantioselectivity.     

Asymmetric Total Synthesis of (−)‐Erogorgiaene and Its C‐11 Epimer and Investigation of Their Antimycobacterial Activity

A short, nine‐step, highly enantioselective synthesis of (?)‐erogorgiaene and its C‐11 epimer is reported. The key stereochemistry controlling steps involve catalytic asymmetric crotylation, anionic oxy‐Cope rearrangement and cationic cyclisation. (?)‐Erogorgiaene exhibited promising antitubercular activity against multidrug‐resistant strains of Mycobacterium tuberculosis.     

Asymmetric γ‐Allylation of α,β‐Unsaturated Aldehydes by Combined Organocatalysis and Transition‐Metal Catalysis

The first asymmetric regio‐ and diastereodivergent γ‐allylation of cyclic α,β‐unsaturated aldehydes based on combined organocatalysis and transition‐metal catalysis is disclosed. By combining an aminocatalyst with an iridium catalyst, both diastereomers of branched allylated products can be achieved in moderate to good yields and excellent regio‐ and stereoselectivities. Furthermore, by replacing the iridium catalyst with a palladium catalyst, the linear allylated products are formed in good yields and excellent regio‐ and enantioselectivities. The developed method thus provides selective access to all six isomers of the γ‐allylated product in a divergent fashion by choosing the appropriate combination of organocatalyst, transition‐metal catalyst, and ligand.     

Two Energetic Salts based on 5,5′‐Bitetrazole‐1,1′‐diolate: Syntheses,Characterization, and Properties

Two salts based on 1H,1′H‐5,5′‐bitetrazole‐1,1′‐diolate (BTO) anion with pyrazole ( 1 ) and imidazole ( 2 ) cations were synthesized with metathesis reactions. Structural characterization was accomplished for them by using the element analysis, Fourier transform infrared spectroscopy (FT‐IR), NMR and mass spectrum, and X‐ray single crystal diffraction. Thermal analysis for the title salts were determined by means of differential scanning calorimetry (DSC) and thermogravimetry‐derivative thermogravimetry (TG‐DTG) as well as the calculation of non‐isothermal kinetic parameters. Consequently, both salts shown acceptable thermal stabilities as the decomposition temperatures were over 200 °C. The enthalpies of formation were calculated for these salts using the measured combustion energies with a result of 70.6 kJ · mol^–1 for 1 and –47.8 kJ · mol^–1 for 2 , respectively. Impact and friction sensitivities were also tested and the results indicated that these salts both have low sensitivities (>40 J, 120 N). The title energetic salts possess acceptable performance, they can therefore be applied in the field of energetic materials.     

Asymmetric Cyanation of Aldehydes,Ketones, Aldimines,and Ketimines Catalyzed by a Versatile Catalyst Generated from Cinchona Alkaloid,Achiral Substituted 2,2′‐Biphenol and Tetraisopropyl Titanate

Full investigation of cyanation of aldehydes, ketones, aldimines and ketimines with trimethylsilyl cyanide (TMSCN) or ethyl cyanoformate (CNCOOEt) as the cyanide source has been accomplished by employing an in situ generated catalyst from cinchona alkaloid, tetraisopropyl titanate [Ti(OiPr)₄] and an achiral modified biphenol. With TMSCN as the cyanide source, good to excellent results have been achieved for the Strecker reaction of N‐Ts (Ts=p‐toluenesulfonyl) aldimines and ketimines (up to >99 % yield and >99 % ee) as well as for the cyanation of ketones (up to 99 % yield and 98 % ee). By using CNCOOEt as the alternative cyanide source, cyanation of aldehyde was accomplished and various enantioenriched cyanohydrin carbonates were prepared in up to 99 % yield and 96 % ee. Noteworthy, CNCOOEt was successfully employed for the first time in the asymmetric Strecker reaction of aldimines and ketimines, affording various α‐amino nitriles with excellent yields and ee values (up to >99 % yield and >99 % ee). The merits of current protocol involved facile availability of ligand components, operational simplicity and mild reaction conditions, which made it convenient to prepare synthetically important chiral cyanohydrins and α‐amino nitriles. Furthermore, control experiments and NMR analyses were performed to shed light on the catalyst structure. It is indicated that all the hydroxyl groups in cinchona alkaloid and biphenol complex with Ti^IV, forming the catalyst with the structure of (biphenoxide)Ti(OR*)(OiPr). The absolute configuration adopted by biphenol 4 m in the catalyst was identified as S configuration according to the evidence from control experiments and NMR analyses. Moreover, the roles of the protonic additive (iPrOH) and the tertiary amine in the cinchona alkaloid were studied in detail, and the real cyanide reagent in the catalytic cycle was found to be hydrogen cyanide (HCN). Finally, two plausible catalytic cycles were proposed to elucidate the reaction mechanisms.     

An Imidazoline–Aminophenol (IAP) Nickel Catalyst: Structure and Catalytic Activity in the Enantioselective 1,4‐Addition of 3′‐Indolyl‐3‐Oxindoles to Nitroethylene

The structure of a nickel complex of imidazoline–aminophenol (IAP) prepared from IAP with Ni(OAc)₂ was elucidated as cis‐bis(imidazolineaminophenoxide) [Ni(IAP)₂]. The [Ni(IAP)₂] complex smoothly promoted catalytic asymmetric 1,4‐addition of 3′‐indolyl‐3‐oxindole to nitroethylene to provide chiral mixed 3,3′‐bisindoles with high enantioselectivities. Mechanistic studies using ESI‐MS analyses suggest that one IAP ligand dissociated from [Ni(IAP)₂] to generate the Ni–enolate of 3′‐indolyl‐3‐oxindole. From the optically active 3,3′‐mixed indole adduct, biologically important 3′‐indolyl‐3‐pyrrolidinoindoline was successfully synthesized in a three‐step reaction sequence.     

Asymmetric Hetero‐Diels–Alder Reaction of Danishefsky’s Diene with α‐Ketoesters and Isatins Catalyzed by a Chiral N,N′‐Dioxide/Magnesium(II) Complex

A highly enantioselective hetero‐Diels–Alder reaction of Danishefsky’s diene with α‐ketoesters and isatins has been realized by using a chiral N,N′‐dioxide/Mg^II complex. In the presence of only 0.1–0.5 mol % catalyst, a series of substrates were transformed into the corresponding tetrasubstituted 2,3‐dihydropyran‐4‐ones in up to 99 % yield and more than 99 % ee in two hours.     

Palladium‐Catalyzed Enantioselective Heck Carbonylation with a Monodentate Phosphoramidite Ligand: Asymmetric Synthesis of (+)‐Physostigmine, (+)‐Physovenine,and (+)‐Folicanthine

Reported herein is the development of the first enantioselective monodentate ligand assisted Pd‐catalyzed domino Heck carbonylation reaction with CO. The highly enantioselective domino Heck carbonylation of N‐aryl acrylamides and various nucleophiles, including arylboronic acids, anilines, and alcohols, in the presence of CO was achieved. A novel monodentate phosphoramidite ligand, Xida‐Phos, has been developed for this reaction and it displays excellent reactivity and enantioselectivity. The reaction employs readily available starting materials, tolerates a wide range of functional groups, and provides straightforward access to a diverse array of enantioenriched oxindoles having β‐carbonyl‐substituted all‐carbon quaternary stereocenters, thus providing a facile and complementary method for the asymmetric synthesis of bioactive hexahydropyrroloindole and its dimeric alkaloids.     

Chiral DMAP‐N‐oxides as Acyl Transfer Catalysts: Design,Synthesis, and Application in Asymmetric Steglich Rearrangement

A DMAP‐N‐oxide, featuring an α‐amino acid as the chiral source, was developed, synthesized and applied in asymmetric Steglich rearrangement. A series of O‐acylated azlactones afforded C‐acylated azlactones possessing a quaternary stereocenter in high yields (up to 97 % yield) and excellent enantioselectivities (up to 97 % ee). Compared to the widespread use of pyridine nitrogen, which serves as the nucleophilic site in the asymmetric acyl transfer reaction, we discovered that chiral DMAP‐N‐oxides, in which the oxygen now acts as the nucleophilic site, are efficient acyl transfer catalysts. Our finding might open a new door for the development of chiral DMAP‐N‐oxides for asymmetric acyl transfer reactions.     

Syntheses of 5′‐Nucleoside Monophosphate Derivatives with Unique Aminal,Hemiaminal, and Hemithioaminal Functionalities: A New Class of 5′‐Peptidyl Nucleotides

A number of synthetically useful transformations have been developed to generate novel 5′‐peptidyl nucleoside monophosphate analogues that incorporate sensitive phosphoaminal, ‐hemiaminal or ‐hemithioaminal functionalities. The strategies adopted entailed the coupling between dipeptides, which enclose a reactive Cα‐functionalized glycine residue and phosphate or phosphorothioate moieties. These developments led to potentially powerful and general methodologies for the preparation of α‐phosphorylated pseudopeptides as well as nucleoside monophosphate mimics. The resulting conjugates are of interest for a variety of important applications, which range from drug development to synthetic biology, as pronucleotides or artificial building blocks for the enzymatic synthesis of xenobiotic information systems. The potential of all dipeptide‐TMP conjugates as pyrophosphate mimics in the DNA polymerization reaction was tested, and the influence of the nature of the linker was evaluated by in vitro chain elongation assay in the presence of wild‐type microbial DNA polymerases.