Late stage modification of peptides via CH activation reactions

Recently developed strategies for late stage modification of peptides through CH activation, an arena of contemporary interest in chemical biology and drug discovery, are discussed. Through this tactic, non-polar amino acids in peptides have been selectively functionalized and CH activation enabled new CC and CX bond formations (arylation, alkynylation, fluorination, hydroxylation, azidation, etc.) are documented. Significant advances have been made in Pd or Au-catalyzed, racemization-free, tryptophan specific modifications of large peptides via CH arylation and alkynylation reactions without any protecting group requirement. Development of a new biaryl stapling technique for complex peptides, 18F radiofluorine introduction and diversity oriented post synthetic applications on bio-active cyclopeptides like valinomycin and aureobasidin are additional highlights which underscores the vast potential of late stage CH activation reactions in peptide based therapeutics research.     

Perturbation par l''oxygene de l''oxydation anodique De l''anion complexe cr(co)5cn

OsCl₂(CFCl)(CO)(PPh₃)₂ results from reaction between OsCl₂(CCl₂)(CO)(PPh₃)₂ and Cd(CF₃)₂(DME). The CFCl ligand is converted into CFNMe₂ and CFSEt ligands through reaction with Me₂NH and NaSEt, respectively. The crystal structure of RuCl₂(CFOCH₂CMe₃)(CO)(PPh₃)₂ reveals the following dimensions about the carbene-carbon atom: RuC, 1.914(5)Å; CO, 1.303(7)Å; CF, 1.307(6)Å; RuCF, 127.1(4)°; RuCO, 125.5(4)°; FCO, 107.4(5)°.     

Iron-catalyzed CC bond activation/CO bond formation: Direct conversion of ketones to esters

The iron-catalyzed oxidative activation of the (O)CC bond in ketones has been developed. This method enables direct synthesis of esters by the reaction between ketones and alcohols via conversion of the (O)CC bond to the (O)CO bond. The reaction runs selectively: the (O)CC_Alkyl bond is activated, while the (O)CC_Aryl bond remains intact (i.e., iron-catalyzed intermolecular anti-Baeyer-Villiger activation of the (O)CC bond). The reaction conditions are carefully optimized and allow the production of esters with yields of up to 95%. The method is based on the inexpensive and commercially available catalyst (FeCl₃), oxidant ((NH₄)₂S₂O₈), and solvent (DCE) without using any ligands or additives.     

Metal- and solvent-free,iodine-catalyzed cyclocondensation and CH bond sulphenylation: A facile access to C-4 sulfenylated pyrazoles via a domino multicomponent reaction

We describe herein a green and efficient MCRs protocol to synthesize C-4 sulfenylated pyrazoles by iodine-catalyzed cyclocondensation and direct CH bond sulphenylation reactions. Through this protocol, two new CN bonds and one CS bond are constructed simultaneously in a single step. This method provides a straightforward and sustainable way to construct valuable sulfenylated pyrazoles under metal- and solvent-free conditions.     

Dithioester-enabled chemodivergent synthesis of acids,amides and isothiazoles via CC bond cleavage and CO/CN/CS bond formations under metal- and catalyst-free conditions

An operationally simple and user-friendly process to access privileged scaffolds such as acids, amides and isothiazoles has been devised employing β-ketodithioesters for the first time. Remarkably, the new protocol involves combination of CC bond cleavage and CO/CN/NS bond formations in one-pot. Aqueous ammonia led to the formation of skeletally distinct amide and isothiazole, whereas aqueous NaOH enabled the formation of aromatic acid near quantitative yield. This practical approach, which can dramatically streamline the synthesis of simple molecules, is highly chemoselective, cost-effective, amenable to gram scale, insensitive to moisture as well as bears high functional group compatibility.     

Palladium-catalysed cross-coupling as a key step in the synthesis of pyridyl-benzamides, -benzylamines and -sulfonamides

Novel N-, O- and S-substituted pyridyl-benzamides, -benzylamines and -sulfonamides were prepared by means of palladium-catalysed cross-coupling reactions. The synthetic approach, using Pd₂(dba)₃ as palladium source and rac-BINAP as supporting ligand, proved to be successful for CN, CO and CS cross-coupling reactions. One of the substrates underwent an unexpected nucleophilic aromatic substitution of fluorine, rather than the expected CN cross-coupling reaction.     

Regioselective preferential CH activation of sterically hindered 1,3-dienes over [4+2] cycloaddition

The study of Pd-catalyzed preferential CH activation of sterically hindered α, β-olefinic indoles onto alkenes beyond [4 + 2] cycloaddition has been described. The carbazole derivatives were readily synthesized via activation of vinylic CH bonds with excellent regioselectivity. Further, the one-pot strategy has been employed for the synthesis of tricyclic carbazoles. The double and triple CH activation followed by concomitant Michael addition provides an economical approach for the synthesis of N-protected carbazole. A wide range of alkenes at the α- and β-position are compatible with this reaction. The mechanistic and X-ray crystallographic studies supported the designed chemistry of CH activation.     

Computational study of Rh(I)-Catalyzed Cycloaddition–Fragmentation of N-cyclopropylacrylamides

Rh-catalyzed cycloaddition–fragmentation of N-cyclopropylacrylamides is an effective method to directly obtain substituted azocanes. In this transformation, the challenging step is insertion of CO and alkene into the more hindered proximal cyclopropane CC bond while avoiding competitive less hindered proximal CC activation. Given the importance of this novel strategy, we performed a density functional theory study to clarify the catalytic mechanism. The calculations confirm that cleavage of the more hindered bond is more favorable than cleavage of the less hindered bond for Rh-catalyzed (7 + 1) cycloaddition of N-cyclopropylacrylamides. Comparison between Rh-catalyzed (3 + 1 + 2) and (7 + 1) cycloaddition shows that the coordination mode with different ligand plays a crucial role in enabling different CC cleavage. The main factors responsible for the occurrence of β-hydride elimination rather than CC reductive elimination are also discussed. The kinetic preference for β-hydride elimination can be attributed to the transition state of CC reductive elimination being more distorted and forming in a much more concerted fashion than that of β-hydride elimination. Additionally, C4H elimination is disfavored owing to weaker interaction energy compared with C7H elimination by analyzing using the distortion/interaction model.     

A scaling theoretical analysis of vibrational relaxation experiments: rotational effects and long-range collisions

Expressions for the quantum number scaling of vibration—translation (VT) and vibration—vibration (VV) rates are derived. The derivation uses the recently developed scaling theory of non-reactive processes and invokes the assumption of rotational equilibrium. However, the VV and VT scaling relationships include rotational effects through the rotational energy gaps and the rotational distributions. The variables in this theory are a fundamental set of rates and the average collision range, l_c, for the particular inelastic process. The physically transparent meaning of these variables, combined with the a priori nature of the scaling coefficients, allows one to investigate actual dynamical effects and not just merely fit data. A detailed analysis of VV energy transfer in the COCO system is presented. Three conclusions are drawn: (1) rotational effects are crucially important in the scaling of the rates; (2) the process is predominantly long-range with l_c = 5.5 ± 0.5 au; and, (3) the available experimental data is consistent with single quanta vibrational changes in the VV rates.     

Iodine-catalysed regioselective synthesis of β-hydroxysulfides

A metal-free, and environment benign iodine-catalysed protocol has been developed for the regioselective synthesis of β-hydroxysulfides in good to excellent yields from easily accessible styrenes and thiophenols. The reaction involves single step CS and CO bonds construction.     

The Crystal and Molecular Structure of Bis(cyclopentadienyldicarbonylchromium) (CrCr)

The crystal structure of bis(cyclopentadienyldicarbonyl-chromium) has been determined by x-ray diffraction. The compound crystalizes in the triclinic system, space group P1¯(C¹_i, No. 2) with unit cell parameters: a, 7.829(3); b, 14.543(6); c, 6.588(2)Å; α, 94.67(3), β, 110.70(3); γ, 104.04°(3); V, 699.1(4)ų; z=2. There are two independent molecules per unit cell located at the inversion centers at O,O,O and O, 1/2, O. The CrCr bond distances are, respectively 2.200(3) and 2.230(3), thus supporting their formulation as triple bonds. The CpCrCr angles in the two molecules are 165.0° and 158.7°, respectively. The structural features are compared with those of Cp₂Mo₂(CO)₄, which has a linear CpMoMoCp axis; and the differences rationalized in terms of electronic interactions of the Cp-ligand with the orbitals of the M₂ unit. The differences observed in the structures of the two independent molecules are also related to the proposed bonding model and to packing considerations.     

Palladium-catalyzed direct C2-arylation of free (NH) indoles via norbornene-mediated regioselective CH activation

A palladium-catalyzed direct C2-arylation reaction of free (NH) indoles has been developed. This reaction relies on a norbornene-mediated CH activation process on the indole ring, which features high regioselectivity and excellent functional group tolerance.     

Iron catalyzed CN bond formation

Diversely functionalized nitrogen-containing heteroaromatic building blocks, fine chemicals and active pharmaceutical or agrochemical ingredients are conveniently prepared via CN bond formation as the key step. Since beginning of the last decade, there has been a flurry of intense research in forging CN bonds using iron catalysts due to their low cost, high natural abundance and non-toxic nature. The present review offers an overview of CN bond forming reactions involving aryl, allyl, propargyl and unactivated alkyl electrophilic substrates with nitrogen nucleophiles via the regular cross coupling reactions catalyzed by iron. In the miscellaneous section, a set of novel transformations facilitated by iron are included as well.     

Efficient synthesis of aryl-substituted carbazoles via tandem double or triple suzuki coupling and cadogan cyclization

An efficient one-step method to prepare aryl-substituted carbazoles via tandem double or triple CC bond formations by multiple Suzuki couplings and CN bond formation by Cadogan cyclization has been developed. The developed method employs commercially available or easily preparable polybromonitrobenzenes and arylboronic acids as starting materials, tolerates various functional groups, and provides good yields.     

Insight into hydrogen bonding of terephthalamides with amino acids: Synthesis,structural and spectroscopic investigations

Several bis-terephthalamides based on methyl esters of amino acids including glycine (1), β-alanine (2), γ-aminobutyric acid (3) and ε-aminocaproic acid (4), X(CH₂)_nHNOCC₆H₄CONH(CH₂)_nX (XCO₂CH_3,n = 1, 2, 3 and 5), have been synthesized and characterized by single-crystal X-ray diffraction and spectroscopic methods: FT-IR, polarized FT-IR, Raman, ¹H NMR and ¹³C NMR. The four structures assemble via classical NH?O hydrogen bonds between amide functionalities linking the molecules into chains parallel to the short axis. The analysis of polarized IR spectra of pure and deuterated compounds reveals that a weak interchain (“through-space”) exciton coupling involves two closely-spaced hydrogen bonds belonging to two different adjacent chains. The exciton coupling magnitude decreases with the addition of methylene groups to the terephthalamide system. Isotope effects in terephthalamides show that the distribution of protons and deuterons in the crystalline lattice depends on the strength of the exciton couplings involving hydrogen bonds.     

Divalent tin-mediated synthesis: a very simple,stereoselective route to terminal conjugated (E) dienes and trienes.

The conversion of aldehydes RCHO into terminal conjugated dienes RCHCHCHCH₂ with (E) stereochemistry was carried out at room temperature with 1-bromo-3-iodopropene in the presence of SnCl₂. Starting from an unsaturated aldehyde, a terminal conjugated triene was obtained in the same conditions.     

Mechanism of rhodium(III)-catalyzed formal C(sp3)H activation/spiroannulation of α-arylidene pyrazolones with alkynes: A computational study

DFT calculations were performed to investigate the rhodium-catalyzed formal C(sp³)-H activation/ spiroannulation of α-arylidene pyrazolones with alkynes. The calculations indicate that the spiroannulation through the proposed C-C reductive elimination is kinetically unfeasible. Instead, the C-C coupling from the eight-membered rhodacycle was proposed to account for the experimental results     

Preparation of γ,δ-unsaturated-β-ketoesters: Lewis acid-catalysed CH insertion of ethyl diazoacetate into α,β-unsaturated aldehydes

The synthesis of γ,δ-unsaturated-β-keto esters was achieved by the Lewis acid-catalysed direct CH insertion of an α-diazoester into various α,β-substituted-unsaturated aldehydes. CH insertion of ethyl diazoacetate into alkyl- and aryl-substituted α,β-unsaturated aldehydes was performed under mild conditions to afford the corresponding γ,δ-unsaturated-β-keto esters in moderate to high yields as a mixture of keto/enol tautomers.     

A 1-hydroxy-2,3,1-benzodiazaborine-containing π-conjugated system: Synthesis,optical properties and solvent-dependent response toward anions

Our interest in the functionalization of OH-substituted azaborines prompted us to synthesize a 1-hydroxy-2,3,1-benzodiazaborine conjugated with 1,8-naphthalimide 1. Its fluorescence was dramatically affected by the nature of the solvent. In particular, the use of DMSO, which has a relatively high donor number (DN = 29.8), led to a remarkable decrease in the fluorescence intensity (Φ_F = 0.0014), possibly due to intermolecular hydrogen-bonding interactions (Me₂SO?HOB). The presence of the hydroxyl group on boron led to a solvent-driven colorimetric response towards anions; high selectivity for F^? over other anions in DMSO, and responded to AcO^? and F^? in THF, as shown by UV/vis titrations, NMR, and mass spectroscopic analysis. The nucleus-independent chemical shift (NICS) indices suggested that hydrogen bonding interactions between Me₂SO and HOB reduced the aromaticity of the benzodiazaborine macrocycle, causing an increase in the negative character of the boron. The increase in the polarity of the BN bond may prevent acetate-binding of 1 in DMSO.     

Acetylene diethers: Dineopentyloxyethyne

Dineopentyloxyethyne has been synthesized fromtrans-2,3-dichloro-1,4-dioxane according to a general procedure already described. In contrast with alkyl neopentyloxyacetylenes, RC=COCH₂Bu^t, which only polymerize when are strongly heated (150°), dineopentyloxyethyne is a kinetically unstable acetylene diether that polymerizes readily at room temperature. However, the compound has been trapped with Co₂(CO)₈ to give either the corresponding hexacarbonyl complex, m.p. 74–75°, or the cyclic trimer, m.p. 205–206°, depending upon the experimental conditions.