Regioselective Cleavage Research Articles

Oxygenation of Phenanthriporphyrin and Copper(III) Phenanthriporphyrin: An Efficient Route to Phenanthribilinones.

Photooxidation of copper(III) 5,6-dimethoxyphenathriporphyrin and copper(III) 5,6-dioxophenanthriporphyrin, which contain phenanthrene or dioxophenathrene moieties built into the macrocyclic frameworks, resulted in the regioselective cleavage that afforded organometallic copper(III) complexes of open-chain phenanthribilinone-type acyclic ligands terminated by carbonyl groups. The copper(III) coordinates two carbon atoms of phenantherene (dioxophenanthrene) and two nitrogen atoms of pyrrole and pyrrolone units, preserving the donor sets of the paternal complexes. The primary dioxygen attack is located at the meso carbon atom adjacent to the phenanthrene moiety. Demetalation of copper(III) 21-benzoyl-phenanthribilin-1-one and copper(III) 21-benzoyl-dioxophenanthribilin-1-one yielded mainly two diastereomers [15Z, 20E] and [15Z, 20Z], which differ in the configurations at two Cα-Cmeso double bonds. The regioselectivity of the cleavage, detected in the course of experimental studies, has been substantiated by DFT investigations. The regioselective cleavage of 5,6-dimethoxyphenanthriporphyrin in reaction with basic iron(III) acetate was detected, providing the synthetically efficient methodology to produce 21-benzoyl-dioxophenanthribilin-1-one.

Asymmetric Synthesis of Fluoro‐MLN4924 as a Selective NEDD8‐Activating Enzyme (NAE) Inhibitor

AbstractBased on bioisosteric rationale, fluorinated analogues of MLN4924, which is a selective NEDD8‐activating enzyme inhibitor, were designed and their asymmetric syntheses were accomplished via stereoselective reduction, regioselective isopropylidene cleavage and diethylaminosulfur trifluoride (DAST) fluorination as key steps.

Alcoholysis of Binor-S with Alcohols under the Action of Ionic Liquid

Inorganic ionic liquids are first shown to catalyze the alcoholysis of heptacyclo-[8.4.0.02,12.03,8.04,6.05,9.011,13]tetradecane (heptacyclic dimer of norbornadiene, binor-S) with primary and secondary alcohols. The reaction occurs at 65−100°C for 6−14 h via regioselective cleavage of the cyclopropane C4−C5 bond in binor-S to form 10-exo-alkoxyhexacyclo[9.2.1.02,7.03,5.04,8.09,13] tetradecanes in 85−90% yields.

Regioselective oxidative carbon-oxygen bond cleavage catalysed by copper(II) complexes: A relevant model study for lytic polysaccharides monooxygenases activity

Lytic polysaccharide monooxygenases (LPMOs) are copper-containing monooxygenase and catalyzing the oxidative cleavage of recalcitrant polysaccharides using dioxygen. The copper(II) complexes [Cu(L1)(H2O)ClO4]ClO41, [L1 = 4-methyl-1-[(pyridin-2-yl-methyl)]-1,4-diazepane]; [Cu(L2)(H2O)ClO4]ClO42, [L2 = 4-methyl-1-[(2-(pyridine-2-yl)ethyl]-1,4-diazepane] and [Cu(L3)(H2O)ClO4]ClO43, [L3 = 1-(4-methoxy-3,5-dimethyl-pyridin-2-yl)methyl)-4-methyl-1,4-diazepane] have been synthesized and characterized as the novel models for LPMOs. The molecular structures exhibit distorted square pyramidal geometry (τ, 0.183–0.388) as similar to LPMOs. The CuN (1.99–2.02 Å) bond distances of the model complexes are almost identical to those of native LPMOs enzyme (1.9–2.2 Å). The 1, 4-diazepane backbone and pyridine unit of complexes provide reasonable structural resemblances to ‘histidine brace’ and histidine residues of LPMOs respectively. The spectral, redox and kinetic studies were performed in water to mimic accurate enzymatic reaction conditions. The well-defined Cu(II)/Cu(I) reduction couples were observed around 8–112 mV versus NHE, which is lower than that of LPMOs. The electronic spectra of the complexes showed the d-d transitions around 600–635 nm and axial EPR parameter (g||, 2.28–2.29; A||, 160–168 × 10−4 cm−1), which are almost identical to that of LPMOs. The model complexes were catalyzed oxidative cleavage of model substrate p-nitrophenyl-β-D-glucopyranoside into p-nitrophenol and D-allose with a maximum yield up to 78.4% and TON, 300. The kinetics of reaction monitored by following the formation of an absorption band around at 400 nm corresponds to p-nitrophenol, showed the rate of 3.19–5.26 × 10−3 s−1. The oxidative cleavage reaction may occur via CuII-OOH intermediate, whose formation accompanied by an electronic spectral signature around 375 nm with the rate of 1.61–9.06 × 10−3 s−1. The CuII-OOH intermediate was characterized by spectral methods and its geometry was optimized by DFT calculations.

Amination of Carbenium Ions Generated by Directed Protonolysis of Cyclopropane

Directed intramolecular protonolyis of the cyclopropane C-C bond is demonstrated as a strategy to generate carbenium ions. This intermediate can be subjected to amination with nitriles under Ritter reaction conditions. Directing groups such as carbamate, carboxamide, urea, ester, and ketone were found to be efficient for regioselective anti-Markovnikov cleavage of cyclopropane. Depending on the directing group, the amination provided orthogonally protected 1,4-diamine, ε-amino carboxylic, and ε-amino ketone derivatives.

Regio- and Chemoselective Deprotection of Primary Acetates by Zirconium Hydrides.

A combination of DIBAL-H and Cp2ZrCl2 is shown to promote the regioselective cleavage of primary acetates on a broad scope of substrates, ranging from carbohydrates to terpene derivatives, with a high tolerance toward protecting groups and numerous functionalities found in natural products and bioactive compounds. Apart from providing highly valuable building blocks in only two steps from biosourced raw materials, this selective de- O-acetylation should also be strongly helpful to solve selectivity issues in organic synthesis.

Aryldiazonium ion initiated C–N bond cleavage for the versatile, efficient and regioselective ring opening of aziridines

Aryldiazonium salts have been proved to initiate the regioselective cleavage of aziridines for the installation of varied functional groups.

Synthesis of the Deacetoxytubuvaline Fragment of Pretubulysin and its Lipophilic Analogues for Enhanced Permeability in Cancer Cell Lines

In the last two decades, tubulysins have emerged as alternatives to microtubule depolymerizing agents such as colchicine and vinblastine, which are well-established anticancer agents. However, the complex structure of tubulysins has always posed a challenge for synthetic chemists to scale up the production of these compounds. We report a new strategy for the practical gram-scale synthesis of a (4R)-4-[(tert-butoxycarbonyl)amino]-5-methylhexanoic acid through regioselective cleavage of a chiral aziridine ring with a vinyl Grignard reagent to afford tert-butyl [(1R)-1-isopropylbut-3-en-1-yl]carbamate, which was subjected to regioselective hydroboration–oxidation with 9-BBN. The resulting (4R)-4-[(tert-butoxycarbonyl)amino]-5-methylhexanoic acid was successfully transformed into the deacetoxytubuvaline fragment of pretubulysin or its highly lipophilic methyl-substituted thiazole and oxazole analogues for incorporation into pretubulysins. Increasing the lipophilicity of tubulysin or pretubulysin molecules should enhance their cell permeability and cytotoxicity in cancer cell lines.

Structural tuning and catalysis of tungsten carbides for the regioselective cleavage of C[sbnd]O bonds

Tungsten carbides exhibit excellent performance in many heterogeneous processes because of their distinctive catalytic properties. Preparation of tungsten carbides with controllable phase composition relevant to their catalytic behavior is essential yet challenging. In this study, tungsten carbides embedded in carbon spheres (WxC@CS) were fabricated through carburization of organic–inorganic hybrid precursors. W1.25C@CS with rational structure-tuning properties exhibits promising regioselectivity (reaching 91.5%) toward aryl CO bond cleavage, specifically during hydrogenolysis of guaiacol to phenol. A structure reconstruction strategy was adopted to elucidate structure–performance relationship by transforming commercially available bulk WC from inert phase to composition-dependent active catalysts. Combined catalytic and characteristic analyses illustrate that the catalyst performance is dependent on the C-defect structure. The intimate connection between the phenol space time yield and the C/W atomic ratio on the exterior interface of the catalyst was verified. The C/W atomic ratio of 7.2 leads to the optimal catalytic performance. Density functional theory calculations were performed to define the catalytic mechanism at the atomic level. The theoretical analysis suggests an appropriate configuration of surface W and C atoms for activation of hydrogen and guaiacol molecules, rendering the intrinsic active sites for phenol production. This work provides insights into controlling the surface compositions of tungsten carbides to develop efficient CO bond cleavage catalysts, which verifies the importance of hydrogenolysis catalysis in lignin-derived compounds involving complex O-containing guaiacols and phenolics.

A Practical Method for Regioselective 5′-O-tert-Butyldimethylsilyl Deprotection of Persilylated Nucleosides by Methanolic Phosphomolybdic Acid

In nucleoside/nucleotide chemistry, the regioselective cleavage of 5′-O-TBS groups of persilylated nucleosides is a desired approach for structural functionalization at the 5′-position. However, efficient and practical methods for this purpose are still limited. In our research, we found that homogeneous methanolic phosphomolybdic acid (PMA) efficiently catalyzes the regioselective deprotection of 5′-O-TBS groups of a diversity of persilylated nucleoside substrates and can be applied in practical synthesis at scales of up to 15 g. 31P NMR results indicated that an anion cluster forms and the Lewis acidity of homogeneous PMA is organic-solvent dependent. The efficacy and pronounced regioselectivity of methanolic PMA occurs as a result of a lowering of the Lewis acid strength upon solvation of the molybdophosphate anions.

Reliably Regioselective Dialkyl Ether Cleavage with Mixed Boron Trihalides.

A protocol for the regioselective cleavage of unsymmetrical alkyl ethers to generate alkyl alcohol and alkyl bromide products is described. A mixture of trihaloboranes triggers this conversion and exhibits improved reactivity profiles (regioselectivity and yield) compared with BBr3 alone. Additionally, this procedure allows the efficient synthesis of (B-Cl) dialkyl boronate esters. There are limited methods to generate acyclic dialkoxyboryl chlorides, and these intermediates constitute important synthons in main-group chemistry.

Regioselective and Stereoselective Reductive Aziridinium Ring Cleavage Leading to Azabicyclodecane Architecture: Enantioselective Synthesis of (+)-Subincanadine F.

Enantioselective synthesis of cytotoxic indole alkaloid (+)-subincanadine F was accomplished starting from the corresponding ( S)-acetoxysuccinimide via aziridinium ring formation and its reductive ring expansion route. Regioselective and stereoselective reductive aziridinium carbon-nitrogen bond cleavage comprising ring expansions was a key step. The ( S)-OMOM protection of the hydroxyl moiety adjacent to a benzylic carbon of an in situ formed aziridinium system was necessary for lithium borohydride-induced reductive ring expansions, and it also served as a latent source of an essential ketone carbonyl group for the generation of an α,β-conjugated system.

Catalytic Transformation of Cellulose and Its Derivatives into Functionalized Organic Acids.

Cellulose is a promising renewable and abundant resource for the production of high-value chemicals, in particular, organic oxygenates, because of its high oxygen/carbon ratio. The sustainable production of hydroxycarboxylic acids and dicarboxylic acids, such as gluconic/glucaric acid, lactic acid, 2,5-furandicarboxylic acid, adipic acid, and terephthalic acid, most of which are monomers of key polymers, have attracted much attention in recent years. The synthesis of these organic acids from cellulose generally involves several tandem reaction steps, and thus, multifunctional catalysts that can catalyze the selective activation of specific C-O or C-C bonds hold the key. This review highlights recent advances in the development of efficient catalytic systems and new strategies for the selective conversion of cellulose or its derived carbohydrates into functionalized organic acids. The reaction mechanism is discussed to offer deep insights into the regioselective cleavage of C-O or C-C bonds.

Nanoporous Gold-Catalyzed Diboration of Methylenecyclopropanes via a Distal Bond Cleavage

We have demonstrated that nanoporous gold (AuNPore) is an efficient catalyst to promote the selective diboration of methylenecyclopropanes (MCPs) in a heterogeneous manner. Notably, the diboration takes place via a regioselective cleavage of the distal bond of the cyclopropane ring exclusively by AuNPore without using any additives. The experimental results and computational studies of the mechanism indicate that the present diboration proceeds through the formation of a relatively stable trimethylenemethane intermediate on the AuNPore surface with increased negative charges on trimethylene carbons, giving rise to the subsequent diboration selectively.

Diastereoselective Synthesis of (±)-epi-Subincanadine C

Starting from indolylmaleimide, concise and efficient total synthesis of (±)-epi-subincanadine C was described via stereoselective Wittig olefination, base-induced selective mono-prenylation, regioselective Grignard reaction, diastereoselective Pictet–Spengler cyclization, regioselective oxidative carbon–carbon double-bond cleavage, one-pot reductions, and intramolecular cyclization pathway. An attempted synthesis of (±)-subincanadine C via diastereoselective Grignard addition to the α,β-unsaturated γ-lactam or diastereoselective reduction of a carbon–carbon double bond also resulted in yet another route to (±)-epi-subincanadine C.

Noncanonical Radical SAM Enzyme Chemistry Learned from Diphthamide Biosynthesis.

Radical S-adenosylmethionine (SAM) enzymes are a superfamily of enzymes that use SAM and reduced [4Fe-4S] cluster to generate a 5'-deoxyadenosyl radical to catalyze numerous challenging reactions. We have reported a type of noncanonical radical SAM enzymes in the diphthamide biosynthesis pathway. These enzymes also use SAM and reduced [4Fe-4S] clusters, but generate a 3-amino-3-carboxypropyl (ACP) radical to modify the substrate protein, translation elongation factor 2. The regioselective cleavage of a different C-S bond of the sulfonium center of SAM in these enzymes comparing to canonical radical SAM enzymes is intriguing. Here, we highlight some recent findings in the mechanism of these types of enzymes, showing that the diphthamide biosynthetic radial SAM enzymes bound SAM with a distinct geometry. In this way, the unique iron of the [4Fe-4S] cluster in the enzyme can only attack the carbon on the ACP group to form an organometallic intermediate. The homolysis of the organometallic intermediate releases the ACP radical and generates the EF2 radial.

Copper-Catalyzed Regioselective Cleavage of C-X and C-H Bonds: A Strategy for Sulfur Dioxide Fixation.

The first example of direct fixation of sulfur dioxide between heteroaryls and aryl halides has been developed via copper-catalyzed regioselective cleavage of C-X and C-H bonds under base-free and ligand-free conditions by using DABSO (1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide)) as a solid and bench-stable sulfur dioxide surrogate. This mild protocol results in double C-S bond-forming reactions from simple precursors in the absence of prefunctionalized organometallic reagents, arenediazonium salts, and iodonium salts which extends the still limited number of sulfur dioxide fixation strategies.

Total synthesis of myxol and deoxymyxol stereoisomers and their application to determining the absolute configurations of the natural products

The total synthesis of myxol stereoisomers 1a,b and deoxymyxol (plectaniaxanthin) stereoisomers 2a,b was accomplished by Wittig reaction of (S)- and (R)-C10-phosphonium salts 8a,b bearing a silyl-protected 1,2-dihydroxy-ψ end group with C30-apocarotenals 6 and 7. The phosphonium salts 8a,b were derived from aldehydes 11a,b possessing a cyclopentylidene ketal moiety, prepared via Sharpless asymmetric epoxidation of allylic alcohol 12 followed by regioselective cleavage of the oxirane ring. We established an analytical HPLC method using a chiral column to separate stereoisomers 1a,b and 2a,b and thus determined the absolute configurations of the natural products. The HPLC analyses established that both myxol and deoxymyxol isolated from bacteria have the 2′S-configuration.

Regioselective ester cleavage of di-(2-ethylhexyl) trimellitates by porcine liver esterase

In a comparative study the ester hydrolysis of the plasticizers di-(2-ethylhexyl) phthalate (DEHP) and tri-(2-ethylhexyl) trimellitate (TEHTM) as well as of the diester isomers 1,2-di-(2-ethylhexyl) trimellitate (1,2-DEHTM), 1,4-di-(2-ethylhexyl) trimellitate (1,4-DEHTM) and 2,4-di-(2-ethylhexyl) trimellitate (2,4-DEHTM) was investigated by a newly developed in vitro experimental design using porcine liver esterase (PLE). The substrates were incubated with PLE for 48h at 25°C in borate buffer and samples were taken at predetermined intervals during the experiment. The samples were processed using liquid-liquid extraction and analyzed using LC-MS/MS. The results demonstrated a rapid and extensive hydrolysis of the diester DEHP to the monoester mono-(2-ethylhexyl) phthalate (MEHP) during the incubation with PLE. The isomers of DEHTM were also hydrolyzed by PLE to a high extent, whereas TEHTM showed a high stability against enzymatic hydrolysis. The regioselective analysis revealed that the monoester isomers 1-MEHTM and 2-MEHTM were predominantly produced during the degradation of DEHTM isomers, indicating a preferred hydrolysis at the para-position. These findings are eminent for planning further investigations on the human TEHTM metabolism, as the extent, rate and route of metabolism are of crucial importance for a toxicological assessment.

Mn(OAc)3-Promoted Oxidative Csp3-P Bond Formation through Csp2-Csp2 and P-H Bond Cleavage: Access to β-Ketophosphonates.

The Mn(OAc)3-promoted oxidative phosphonylation of N,N-dimethylenaminones with H-phosphonates, involving a chemo- and regioselective Csp2-Csp2 bond cleavage and Csp3-P bond formation in one step, provided successfully functionalized β-ketophosphonates under mild reaction conditions. Oxidative Csp3-H/P-H cross-coupling reactions via Csp3-C(C═O) bond cleavage and mechanistic studies are conducted preliminarily, and a possible mechanism is proposed. This novel method proceeds in good to excellent yields, shows operational simplicity, broad substrate scope, and large-scale preparation.