Jie-Sheng Huang

Selective functionalisation of saturated C–H bonds with metalloporphyrin catalysts

The recent surge of interest in metal-catalysed C-H bond functionalisation reactions reflects the importance of such reactions in biomimetic studies and organic synthesis. This critical review focuses on metalloporphyrin-catalysed saturated C-H bond functionalisation reported since the year 2000, including C-O, C-N and C-C bond formation via hydroxylation, amination and carbenoid insertion, respectively, together with a brief description of previous achievements in this area. Among the metalloporphyrin-catalysed reactions highlighted herein are the hydroxylation of steroids, cycloalkanes and benzylic hydrocarbons; intermolecular amination of steroids, cycloalkanes and benzylic or allylic hydrocarbons; intramolecular amination of sulfamate esters and organic azides; intermolecular carbenoid insertion into benzylic, allylic or alkane C-H bonds; and intramolecular carbenoid C-H insertion of tosylhydrazones. These metalloporphyrin-catalysed saturated C-H bond functionalisation reactions feature high regio-, diastereo- or enantioselectivity and/or high product turnover numbers. Mechanistic studies suggest the involvement of metal-oxo, -imido (or nitrene), and -carbene porphyrin complexes in the reactions. The reactivity of such metal-ligand multiple bonded species towards saturated C-H bonds, including mechanistic studies through both experimental and theoretical means, is also discussed (244 references).

Metal complexes of chiral binaphthyl Schiff-base ligands and their application in stereoselective organic transformations

Abstract Condensations of aromatic aldehydes with 2,2′-diamino-1,1′-binaphthyl or 2-amino-2′-hydroxy-1,1′-binaphthyl afford various chiral binaphthyl Schiff-base ligands, the most common of which are potentially tetradentate with a N2O2 donor set. The chiral binaphthyl Schiff-base ligands have been shown to form stable complexes with metal ions of Al(III), Ti(IV), Cr(III), Mn(II)/Mn(III), Fe(II)/Fe(III), Co(II)/Co(III), Ni(II), Cu(II), Zn(II), Y(III), Zr(IV), Ru(II), and Pd(II); some of such complexes have been characterized by X-ray crystallography. Catalytic studies reveal that these types of chiral metal complexes are active catalysts for stereoselective organic transformations including hydroxylation of styrene, aldol reactions, alkene epoxidation, trimethylsilylcyanation of aldehydes, desymmetrization of meso-N-sulfonylaziridine, Baeyer-Villiger oxidation of aryl cyclobutanone, Diels-Alder reactions of 1,2-dihydropyridine, and ring-opening polymerization of lactide.

Highly efficient oxidation of amines to imines by singlet oxygen and its application in ugi-type reactions

A variety of secondary benzylic amines were oxidized to imines in 90% to >99% yields by singlet oxygen generated from oxygen and a porphyrin photosensitizer. On the basis of these reactions, a protocol was developed for oxidative Ugi-type reactions with singlet oxygen as the oxidant. This protocol has been used to synthesize C1- and N-functionalized benzylic amines in up to 96% yields.

Metalloporphyrin-based oxidation systems: from biomimetic reactions to application in organic synthesis

The oxidation of organic substrates catalyzed by metalloporphyrins constitutes a major class of biomimetic oxidation reactions used in modern synthetic chemistry. Ruthenium porphyrins are among the most extensively studied metalloporphyrin oxidation catalysts. This article provides a brief outline of the metalloporphyrin-based oxidation systems and is focused on the oxidation reactions catalyzed by ruthenium porphyrins performed in the authors laboratory. A series of ruthenium porphyrin catalysts, including those immobilized onto insoluble supports and covalently attached to soluble supports, promote the oxidation of a wide variety of organic substrates such as styrenes, cycloalkenes, alpha,beta-unsaturated ketones, steroids, benzylic hydrocarbons and arenes with 2,6-dichloropyridine-N-oxide or air in up to >99% yields, with high regio-, chemo- and/or stereoselectivity, and with product turnovers of up to 3.0x10(4), demonstrating the potential application of ruthenium porphyrin-based oxidation systems in organic syntheses.

Ruthenium and osmium porphyrin carbene complexes: synthesis, structure, and connection to the metal-mediated cyclopropanation of alkenes

Abstract A series of monocarbene ruthenium/osmium porphyrins [M(Por)(CRR′)] (M=Ru, Os; RR′ in some cases) and two biscarbene osmium porphyrins [Os(Por)(CR 2 ) 2 ] have been prepared by several research groups from reactions of diazo compounds with ruthenium/osmium porphyrins [M(Por)] 2 , [M(Por)(CO)] (M=Ru, Os), [Ru(Por)], or [Os(Por)(CR 2 )], or from reactions of K 2 [Ru(Por)] with germinal dihalides. The structures of [Os(TTP)(CRR′)(THF)] (CRR′=C( p -C 6 H 4 CH 3 ) 2 , CHSiMe 3 ), [Ru(TPP)(C(CO 2 Et) 2 )(MeOH)], [Ru(Por*)(CRR′)] (CRR′CPh 2 , C(Ph)CO 2 CH 2 CHCH 2 ), [Os(TPFPP)(CPh 2 )(MeOH)], and [Os(TPFPP)(CPh 2 ) 2 ] have been determined by X-ray crystallography, which feature MC(carbene) bond lengths of 1.79(2)–1.870(2) A for the monocarbene complexes and 2.035(2), 2.027(3) A for the biscarbene complex. Reactions of [Os(TTP)(CHR)] (R=CO 2 Et, SiMe 3 ) with para -substituted pyridines 4-XC 5 H 4 N afford osmium porphyrin ylide complexes [Os(TTP)(CH(R)(4-XC 5 H 4 N))(4-XC 5 H 4 N)]. The complexes [Os(TTP)(CHCO 2 Et)], [Ru(TPP)(C(CO 2 Et) 2 )], and [Os(TPFPP)(CPh 2 ) 2 ] all undergo cyclopropanation reactions with styrene. The biscarbene complex [Os(TPFPP)(CPh 2 ) 2 ] also reacts with unfunctionalized alkenes such as cyclohexene to yield CH insertion products. A few ruthenium/osmium porphyrin carbene complexes, including [Os(TTP)(CHCO 2 Et)], [Ru(TPP)(CHCO 2 Et)], [Ru(Por*)(CHX)(L)] (X=CO 2 R, CO 2 CH 2 CHCR c R t ; L=a ligand with considerable trans effect such as CHX), and [Os(TPFPP)(CPh 2 ) 2 ], are proposed to be the active intermediates in the corresponding ruthenium/osmium porphyrin-catalyzed alkene cyclopropanations.

Modification of N-Terminal α-Amino Groups of Peptides and Proteins Using Ketenes

A method of highly selective N-terminal modification of proteins as well as peptides by an isolated ketene was developed. Modification of a library of unprotected peptides XSKFR (X varies over 20 natural amino acids) by an alkyne-functionalized ketene (1) at room temperature at pH 6.3 resulted in excellent N-terminal selectivity (modified α-amino group/modified ε-amino group = >99:1) for 13 out of the 20 peptides and moderate-to-high N-terminal selectivity (4:1 to 48:1) for 6 of the 7 remaining peptides. Using an alkyne-functionalized N-hydroxysuccinimide (NHS) ester (2) instead of 1, the modification of peptides XSKFR gave internal lysine-modified peptides for 5 out of the 20 peptides and moderate-to-low N-terminal selectivity (5:1 to 1:4) for 13 out of the 20 peptides. Proteins including insulin, lysozyme, RNaseA, and a therapeutic protein BCArg were selectively N-terminally modified at room temperature using ketene 1, in contrast to the formation of significant or major amounts of di-, tri-, or tetra-modified proteins in the modification by NHS ester 2. The 1-modified proteins were further functionalized by a dansyl azide compound through click chemistry without the need for prior treatment.

Highly selective metal catalysts for intermolecular carbenoid insertion into primary C-H bonds and enantioselective C-C bond formation.

Direct functionalization of C H bonds is an appealing strategy in organic synthesis but its practical application has so far been difficult to realize. The selective functionalization of primary C H bonds of alkanes that also contain secondary and/or tertiary C H bonds is a great challenge, as C H bond energy follows an order primary> secondary> tertiary. In seminal works by Bergman, Jones, and their respective co-workers, stoichiometric reactions of alkanes with [Cp*(Me3P)M] (Cp* = C5Me5; M = Rh, Ir) resulted in the formation of C M bonds by selective activation of primary C H bonds. Subsequent work by Hartwig and coworkers 2] demonstrated C B bond formation by stoichiometric and catalytic functionalization of primary C H bonds mediated by tungsten, rhodium, or ruthenium complexes. The high selectivity for primary C H bond functionalization in these C M or C B bond-formation reactions (Scheme S1 in the Supporting Information) is considered to result from kinetic factors or steric interaction between the metal complexes and alkanes. 3] A well-established process in C C bond formation by direct C H bond functionalization is the metal-catalyzed intraand intermolecular carbenoid insertion into C H bonds, with diazo compounds as the carbene source. 4] These catalytic C C bond-formation reactions generally feature lower selectivity for primary C H bonds than for secondary and tertiary C H bonds. For example, a selectivity order of primary< secondary< tertiary C H bonds has been observed for the extensively investigated carbene insertion catalyzed by rhodium complexes, 5] possibly because of the electron density order of primary< secondary< tertiary C H bonds, which renders primary C H bonds the least susceptible to attack by electrophilic rhodium–carbene intermediates. By manipulating the steric or electronic properties of the metal catalysts, a selectivity for primary C H bonds of alkanes comparable to that for secondary or tertiary C H bonds was observed, with the highest primary/secondary and primary/tertiary ratio per C H bond being 1.17:1.0 and 1.0:0.9, respectively. Herein we report a highly selective primary C H bond functionalization by metal-catalyzed carbenoid insertion into the C H bonds of alkanes (Scheme 1), which features a

A Water-Soluble Ruthenium Glycosylated Porphyrin Catalyst for Carbenoid Transfer Reactions in Aqueous Media with Applications in Bioconjugation Reactions

Water-soluble [Ru(II)(4-Glc-TPP)(CO)] (1, 4-Glc-TPP = meso-tetrakis(4-(beta-D-glucosyl)phenyl)porphyrinato dianion) is an active catalyst for the following carbenoid transfer reactions in aqueous media with good selectivities and up to 100% conversions: intermolecular cyclopropanation of styrenes (up to 76% yield), intramolecular cyclopropanation of an allylic diazoacetate (68% yield), intramolecular ammonium/sulfonium ylide formation/[2,3]-sigmatroptic rearrangement reactions (up to 91% yield), and intermolecular carbenoid insertion into N-H bonds of primary arylamines (up to 83% yield). This ruthenium glycosylated porphyrin complex can selectively catalyze alkylation of the N-terminus of peptides (8 examples) and mediate N-terminal modification of proteins (four examples) using a fluorescent-tethered diazo compound (15). A fluorescent group was conjugated to ubiquitin via 1-catalyzed alkene cyclopropanation with 15 in aqueous solution in two steps: (1) incorporation of an alkenic group by the reaction of N-hydroxysuccinimide ester 19 with ubiquitin and (2) cyclopropanation of the alkene-tethered Lys(6) ubiquitin (23) with the fluorescent-labeled diazoacetate 15 in the presence of a catalytic amount of 1. The corresponding cyclopropanation product (24) was obtained with approximately 55% conversion based on MALDI-TOF mass spectrometry. The products 23, 24, and the N-terminal modified peptides and proteins were characterized by LC-MS/MS and/or SDS-PAGE analyses.

Highly Selective Intramolecular Carbene Insertion into Primary C–H Bond of α-Diazoacetamides Mediated by a (p-Cymene)ruthenium(II) Carboxylate Complex

Complex [(p-cymene)Ru(η(1)-O(2)CCF(3))(2)(OH(2))] mediated transformation of α-diazoacetamides ArCH(2)N(C(CH(3))(3))C(O)CHN(2) to result in carbene insertion into the primary C-H bond exclusively, with the γ-lactam products being isolated in up to 98% yield. This unexpected reaction is striking in view of the presence of usually more reactive sites such as secondary C-H bonds in the substrates. DFT calculations based on proposed Ru-carbene species provide insight into this unique selectivity.

Nonheme Iron Mediated Oxidation of Light Alkanes with Oxone: Characterization of Reactive Oxoiron(IV) Ligand Cation Radical Intermediates by Spectroscopic Studies and DFT Calculations†

The oxidation of light alkanes that is catalyzed by heme and nonheme iron enzymes is widely proposed to involve highly reactive {Fe(V)=O} species or {Fe(IV)=O} ligand cation radicals. The identification of these high-valent iron species and the development of an iron-catalyzed oxidation of light alkanes under mild conditions are of vital importance. Herein, a combination of tridentate and bidentate ligands was used for the generation of highly reactive nonheme {Fe=O} species. A method that employs [Fe(III)(Me3tacn)(Cl-acac)Cl](+) as a catalyst in the presence of oxone was developed for the oxidation of hydrocarbons, including cyclohexane, propane, and ethane (Me3tacn=1,4,7-trimethyl-1,4,7-triazacyclononane; Cl-acac=3-chloro-acetylacetonate). The complex [Fe(III)(Tp)2](+) and oxone enabled stoichiometric oxidation of propane and ethane. ESI-MS, EPR and UV/Vis spectroscopy, (18)O labeling experiments, and DFT studies point to [Fe(IV)(Me3tacn)({Cl-acac}(.+))(O)](2+) as the catalytically active species.