Design and synthesis of amidine-type peptide bond isosteres: application of nitrile oxide derivatives as active ester equivalents in peptide and peptidomimetics synthesis

Amidine-type peptide bond isosteres were designed based on the substitution of the peptide bond carbonyl (C=O) group with an imino (C=NH) group. The positively-charged property of the isosteric part resembles a reduced amide-type peptidomimetic. The peptidyl amidine units were synthesized by the reduction of a key amidoxime (N-hydroxyamidine) precursor, which was prepared from nitrile oxide components as an aminoacyl or peptidyl equivalent. This nitrile oxide-mediated C-N bond formation was also used for peptide macrocyclization, in which the amidoxime group was converted to peptide bonds under mild acidic conditions. Syntheses of the cyclic RGD peptide and a peptidomimetic using both approaches, and their inhibitory activity against integrin-mediated cell attachment, are presented.     

Analysis of plasma polymerization of allylamine by FTIR

The plasma polymerization of allylamine in an inductively coupled rf plasma reactor is analyzed by Fourier transform infrared spectroscopy. Comparison of the infrared spectra of the as-received monomer and the plasma polymerized film reveals a conversion of the primary amine in the monomer (? CH₂? NH₂) to an imine (? CH?NH) and a nitrile (C?N). Plasma polymerization of ethylenediamine yields the same results, suggesting that this polymerization scheme may be typical of primary amines. Increasing the plasma power seems to increase the proportion of nitrile groups in relation to the imine groups. The infrared spectra of the vapor phase polymerized monomer was similar to that of the substrate-grafted allylamine film implying a similar structure. Aging of this vapor phase polymer at 120°C for 1 h in vacuum and at 295°C for 15 min in an oxygen free environment reveals nitrile group reaction similar to that observed in polyacrylonitrile. Thermogravimetric analyses of the vapor phase polymers in a nitrogen atmosphere at 20°C/min demonstrated the thermal stability, with the polymer produced at a plasma power level of 50 W retaining 20% of its weight at 1000°C. This was better than the stability shown by the polymer produced at 150 W and is attributed to the ease of nitrile group polymerization in the former.     

Methyltransferase activity of an iridium center with methylpyridinium as methylene source

Hop on, hop off: An iridium center transfers a methyl group from pyridinium to an aryl unit, using exclusively the pyridine-bound methyl group as a mild methylene source. The reaction also involves cleavage of an unactivated C(aryl)?H bond and nitrile solvent activation. The process is reminiscent of DNA methylation and entails the formation of two new C(sp(2) )?C(sp(3) ) bonds within the metal coordination sphere.     

A new and general synthesis of chiral β-ketosulfoxides by reaction of (+)-(R)-methyl p-tolyl sulfoxide with nitriles

The nitrile functional group is efficiently transformed into the β-ketosulfoxide moiety by reaction with the anion formed from (+)-(R)-methyl p-tolyl sulfoxide and aqueous acidic work-up of the reaction.     

Asymmetric synthesis of β,β-difluoroamino acids via cross-coupling and Strecker reactions

β,β-Difluoroamino acids were synthesized from commercially available ethyl bromodifluoroacetate using cross-coupling and Strecker reactions as key steps. The coupling reaction of aryl iodides with ethyl bromodifluoroacetate gave the corresponding coupling products, which were transformed to 2-difluoromethyl-1,3-oxazolidines in two steps. Boron trifluoride etherate promoted Strecker reaction of 2-difluoromethyl-1,3-oxazolidines gave α-amino nitriles in good yields and diastereoselectivities. After removal of chiral auxiliary and hydrolysis of the nitrile group, β,β-difluorophenylalanine was obtained with 73% ee. Partial racemization occurred during the hydrolysis of nitrile group.     

Rational Development of Remote C−H Functionalization of Biphenyl: Experimental and Computational Studies

A simple and efficient nitrile‐directed meta‐C?H olefination, acetoxylation, and iodination of biaryl compounds is reported. Compared to the previous approach of installing a complex U‐shaped template to achieve a molecular U‐turn and assemble the large‐sized cyclophane transition state for the remote C?H activation, a synthetically useful phenyl nitrile functional group could also direct remote meta‐C?H activation. This reaction provides a useful method for the modification of biaryl compounds because the nitrile group can be readily converted to amines, acids, amides, or other heterocycles. Notably, the remote meta‐selectivity of biphenylnitriles could not be expected from previous results with a macrocyclophane nitrile template. DFT computational studies show that a ligand‐containing Pd–Ag heterodimeric transition state (TS) favors the desired remote meta‐selectivity. Control experiments demonstrate the directing effect of the nitrile group and exclude the possibility of non‐directed meta‐C?H activation. Substituted 2‐pyridone ligands were found to be key in assisting the cleavage of the meta‐C?H bond in the concerted metalation–deprotonation (CMD) process.     

Unprecedented stereoselective synthesis of 3-methylisoxazolidine-5-aryl-1,2,4-oxadiazoles via 1,3-dipolar cycloaddition and study of their in vitro antioxidant activity

The stereoselective 1,3-dipolar cycloaddition between allyl cyanide and a menthone-derived nitrone led to the desired isoxazolidine in good yield. Once the nitrile group transformed to an amidoxime group, the cyclocondensation of various aldehydes with chiral amidoxime led to unprecedented enantiopure 3-methylisoxazolidine-5-aryl-1,2,4-oxadiazoles. The menthone chiral auxiliary was then removed with acid hydrolysis. The new compounds were also screened for their in vitro antioxidant activity using DPPH and FRAP assays. Some of the compounds showed promising antioxidant activity.     

Inverse electron-demand 1,3-dipolar cycloaddition of nitrile oxide with common nitriles leading to 3-functionalized 1,2,4-oxadiazoles

A carbamoyl-substituted nitrile oxide was generated upon treatment of easily available 2-methyl-4-nitro-3-isoxazolin-5(2H)-one with THF (not dried); the reaction proceeded efficiently even in the absence of any special reagents and reaction conditions. The nitrile oxide caused 1,3-dipolar cycloaddition with common aliphatic nitriles or electron-rich aromatic nitriles to afford 3-functionalized 1,2,4-oxadiazoles, which are expected to serve as precursors for the preparation of a variety of functional materials by the chemical transformation of the carbamoyl group. While conventional preparative methods for 1,2,4-oxadiazoles involve the cycloaddition of an electron-rich nitrile oxide with an electron-deficient nitrile or a nitrile activated by a Lewis acid, our method employs the complementary combination of an electron-rich nitrile and an electron-deficient nitrile oxide- the inverse electron-demand 1,3-cycloaddition. The DFT calculations using B3LYP 6-31G* supported the abovementioned inverse reactivity, and also suggested the presence of an accelerating effect by the carbamoyl group as a result of hydrogen bond formation with a dipolarophilic nitrile.     

Competition and selectivity in the reaction of nitriles on ge(100)-2x1

We have experimentally investigated bonding of the nitrile functional group (R-Ctbd1;N:) on the Ge(100)-2x1 surface with multiple internal reflection infrared spectroscopy. Density functional theory calculations are used to help explain trends in the data. Several probe molecules, including acetonitrile, 2-propenenitrile, 3-butenenitrile, and 4-pentenenitrile, were studied to elucidate the factors controlling selectivity and competition on this surface. It is found that acetonitrile does not react on the Ge(100)-2x1 surface at room temperature, a result that can be understood with thermodynamic and kinetic arguments. A [4+2] cycloaddition product through the conjugated pi system and a [2+2] C=C cycloaddition product through the alkene are found to be the dominant surface adducts for the multifunctional molecule 2-propenenitrile. These two surface products are evidenced, respectively, by an extremely intense nu(C=C=N), or ketenimine stretch, at 1954 cm(-)(1) and the nu(Ctbd1;N) stretch near 2210 cm(-)(1). While the non-conjugated molecules 3-butenenitrile and 4-pentenenitrile are not expected to form a [4+2] cycloaddition product, both show vibrational modes near 1954 cm(-)(1). Additional investigation suggests that 3-butenenitrile can isomerize to 2-butenenitrile, a conjugated nitrile, before introduction into the vacuum chamber, explaining the presence of the vibrational modes near 1954 cm(-)(1). Pathways directly involving only the nitrile functional group are thermodynamically unfavorable at room temperature on Ge(100)-2x1, demonstrating that this functional group may prove useful as a vacuum-compatible protecting group.     

Preparation of monodisperse functional poly(styrene-co-acrylamidoxime) microsphere with chelating amidoxime group

Monodisperse poly(styrene-co-acrylonitrile) microspheres were prepared by dispersion copolymerization of styrene (St) and acrylonitrile (AN) in ethanol (EtOH)/isopropanol medium. 2,2′-Azobis(isobutyronitrile) (AIBN) and poly(acrylic acid) (PAA) were utilized as initiator and steric stabilizer, respectively. The effects of PAA stabilizer, AIBN initiator, St/AN monomer ratio, and EtOH solvent on particle size and size distribution were investigated systematically. AN is a co-monomer with desired nitrile group (–CN); the functional P(St-co-acrylamidoxime) microsphere with chelating amidoxime group (–C(NH₂)=NOH) was derived by amidoximizing the nitrile group with hydroxylamine. The percentage of chemical modification was calculated to be 51.2% in this study.     

Addition de cyano-2 aziridines,ylures dázomethine potentiels aux isocyanates

The addition of azomethine ylids resulting from the thermal ring opening of the corresponding 2-cyanoaziridines on methyl and phenyl isocyanates occured exclusively at the CN double bond. Only one orientation of the addition was observed and a mixture or diastereoisomeric imidazolidones was obtained in each case. On the basis of X ray structure of one diastereoisomer the stereochemistry of the other imidazolidones was established by NMR considering the long range coupling constants values between H₂ and H₅ (J_cis < J_trans). The reaction of sodium methylate with the imidazolones led to imidates resulting from a nucleophilic addition on the nitrile fonction on the C₂ carbon atom of the heterocycles. These irnidates are easily hydrolyzed to the corresponding esters. If the reaction was carried out in the presence of oxygen the CHCN group was transformed into CO group via the oxidation of the C₂ carbanion.     

An unexpected two-group migration involving a sulfonynamide to nitrile rearrangement. Mechanistic studies of a thermal N --> C tosyl rearrangement

We report the discovery of the first double-barreled thermal rearrangement of a sulfonynamide and a methoxybenzyl to a nitrile and the first rearrangement of an SO(2) group from sulfonamide to ketoimine. The rearrangement occurs under surprisingly mild conditions (onset at 100 degrees C in the melt). [reaction: see text]     

Synthesis of fused ring 1,2,4-triazoles by intramolecular cycloaddition of nitrile imines to the nitrile function

Treatment of 1-chlorohydrazones (IIa-c) with triethylamine gave fused ring 1,2,4-triazoles arising from an intramolecular cycloaddition of the intermediate nitrile imines (IIIa-c). This reaction was not observed in the case of one compound (IId) bearing an unactivated nitrile group.     

Action du dicétène sur la benzoylcyanamide: La benzoylamino-2 méthyl-6 oxazine-1,3 one-4

Diketene and benzoylcyanamide give a 1,4 cycloaddition, in which the latter is involved only with the nitrile group. The reaction results in a 1,3-oxazin-4-one which is easily transformed by ring cleavage or rearrangement, both initiated by the high reactivity of the 2-carbon atom.     

The chemistry of porphyrin a Position of the formyl group

Porphyrin a was transformed into the corresponding nitrile, which was oxidized with potassium permanganate. 3-Cyano-4-propionic-2,5-pyrroledicarboxylic acid was identified among the degradation products by chromatographic comparison with the same acid obtained by synthesis. This result shows that the formyl group is present in position 8.

A new synthesis of “cytopyrrolic acid” (III), a peculiar oxidation product of porphyrin a, is also described.     

Adsorption of acrylonitrile on diamond and silicon (001)-(2 x 1) surfaces: effects of dimer structure on reaction pathways and product distributions

Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS) are used to compare the reaction of acrylonitrile with Si(001) and C(001) (diamond) surfaces. Our results show that reaction with Si(001) and C(001) yield very different product distributions that result from fundamental differences in the ionic character of these surfaces. While acrylonitrile reacts with the C(001) surface via a [2 + 2] cycloaddition reaction in a manner similar to nonpolar molecules such as alkenes and disilenes, reaction with the Si(001) surface occurs largely through the nitrile group. This work represents the first experimental example of how differences in dimer structure lead to very different chemistry for C(001) compared to that for Si(001). The fact that Si(001) reacts with the strongly polar nitrile group of acrylonitrile indicates that the zwitterionic character of this surface controls its reactivity. C(001) dimers, on the other hand, behave more like a true molecular double bond, albeit a highly strained one. Consequently, while alternative strategies will be necessary for chemical modification of Si(001), traditional schemes from organic chemistry for functionalization of alkenes and disilenes may be available for building molecular layers on C(001).     

Biomimetic entry to the sarpagan family of indole alkaloids: total synthesis of +-geissoschizine and +-N-methylvellosimine

A concise synthesis of (+)-geissoschizine (1), a biosynthetic precursor of a variety of monoterpenoid indole alkaloids, from d-tryptophan (19) was performed as a critical prelude to achieving the first biomimetic, enantioselective synthesis of the sarpagine alkaloid (+)-N(a)-methylvellosimine (5). The approach to (+)-geissoschizine was designed to address the dual problems of stereocontrolled formation of the E-ethylidene moiety and the correct relative configuration at C(3) and C(15). Key steps in the synthesis involve a vinylogous Mannich reaction to prepare the carboline 22, which has the absolute stereochemistry at C(3) corresponding to that in 1 and 5, and an intramolecular Michael addition that leads to the tetracyclic corynantheane derivative 24, which possesses the correct stereochemical relationship between C(3) and C(15). Compound 24 was then transformed into 27, the pivotal intermediate in the syntheses of 1 and 5, by a sequence that allowed the stereospecific introduction of the E-ethylidene moiety. Selective reduction of the lactam in 27 followed by removal of the C(5) carboxyl group by radical decarbonylation gave deformylgeissoschizine (2) that was converted into (+)-geissoschizine (1) by formylation. The common intermediate 27 was then converted via a straightforward sequence of reactions into the alpha-amino nitrile 39. The derived silyl enol ether 40 underwent ionization upon exposure to BF(3).OEt(2) to give the intermediate iminium ion 41 that then cyclized in a biomimetically inspired intramolecular Mannich reaction to deliver (+)-N(a)-methylvellosimine (5). This transformation provides experimental support for the involvement of such a cyclization as one of the key steps in the biosynthesis of the sarpagine and ajmaline alkaloids.     

Spectroscopic and computational studies of nitrile hydratase: insights into geometric and electronic structure and the mechanism of amide synthesis

Nitrile hydratases (NHases) are mononuclear nonheme enzymes that catalyze the hydration of nitriles to amides. NHase is unusual in that it utilizes a low-spin (LS) Fe^III center and a unique ligand set comprised of two deprotonated backbone amides, cysteine-based sulfenic acid (RSO(H)) and sulfinic acid (RSO₂^–), and an unmodified cysteine trans to an exogenous ligand site. Electron paramagnetic resonance (EPR), magnetic circular dichroism (MCD) and low-temperature absorption (LT-Abs) spectroscopies are used to determine the geometric and electronic structures of butyrate-bound (NHaseBA) and active (NHaseAq) NHase. These data calibrate DFT models, which are then extended to explore the mechanism of nitrile hydration by NHase. In particular, the nitrile is activated by coordination to the LS Fe^III and the sulfenate group is found to be deprotonated and a significantly better nucleophile than water that can attack the coordinated nitrile to form a cyclic species. Attack at the sulfenate S atom of the cyclic species is favorable and leads to a lower kinetic barrier than attack by water on coordinated, uncyclized nitrile, while attack at the C of the cyclic species is unfavorable. The roles of the unique ligand set and low-spin nature of the NHase active site in function are also explored. It is found that the oxidized thiolate ligands are crucial to maintaining the LS state, which is important in the binding and activation of nitrile susbtrates. The dominant role of the backbone amidate ligands appears to be as a chelate in keeping the sulfenate properly oriented for nucleophilic attack on the coordinated substrate.     

Nitrile biotransformations for the synthesis of highly enantioenriched beta-hydroxy and beta-amino acid and amide derivatives: a general and simple but powerful and efficient benzyl protection strategy to increase enantioselectivity of the amidase

Biotransformations of a number of racemic beta-hydroxy and beta-amino nitrile derivatives were studied using Rhodococcus erythropolis AJ270, the nitrile hydratase and amidase-containing microbial whole cell catalyst, under very mild conditions. The overall enantioselectivity of nitrile biotransformations was governed predominantly by the amidase whose enantioselectivity was switched on remarkably by an O- and a N-benzyl protection group of the substrates. While biotransformations of beta-hydroxy and beta-amino alkanenitriles gave low yields of amide and acid products of very low enantiomeric purity, introduction of a simple benzyl protection group on the beta-hydroxy and beta-amino of nitrile substrates led to the formation of highly enantioenriched beta-benzyloxy and beta-benzylamino amides and acids in almost quantitative yield. The easy protection and deprotection operations, high chemical yield, and excellent enantioselectivity render the nitrile biotransformation a useful protocol in the synthesis of enantiopure beta-hydroxy and beta-amino acids.     

A Unified Mechanism to Account for Manganese- or Ruthenium-Catalyzed Nitrile α-Olefinations by Primary or Secondary Alcohols: A DFT Mechanistic Study

Acceptorless dehydrogenative coupling (ADC) reactions generally involve a nucleophile (e.g., amine) as a coupling partner. Intriguingly, it has been reported that nitriles could also act as nucleophiles in ADC reactions, achieving the α-olefination of nitriles with primary or secondary alcohols by employing a manganese or ruthenium pincer complex as the catalyst, respectively. Although different mechanisms have been postulated for the two catalytic systems, the results of our DFT mechanistic study, reported herein, have allowed us to propose a unified mechanism to account for both nitrile α-olefinations. The reactions take place in four stages, namely alcohol dehydrogenation, nitrile activation to generate a nucleophilic metal species, coupling of an aldehyde or ketone with the metal species to form a C−C bond and to transfer a nitrile (C^α−)H atom to the carbonyl group, and dehydration by transferring the protonic (N−)H to the hydroxy group. A notable feature of the coupling stage is the activation of water or alcohol to give an intermediate featuring an OH⁻- or OR⁻-like group that activates a nitrile C^α−H bond. Moreover, the mechanism can even be applied to the base (KOtBu, modeled by the (KOtBu)₄ cluster)-catalyzed Knoevenagel condensation of nitriles with ketones, which further indicates the generality of the mechanism and the resemblance of the metal pincer complexes to the (KOtBu)₄ base. We expect these in-depth mechanistic insights and the finding of the resemblance of the metal pincer complexes to the (KOtBu)₄ cluster could assist the development of new ADC reactions.