Bulky N-Phosphino-Functionalized N-Heterocyclic Carbene Ligands: Synthesis, Ruthenium Coordination Chemistry, and Ruthenium Alkylidene Complexes for Olefin Metathesis.

Ruthenium chemistry and applications in catalytic olefin metathesis based on N-phosphino-functionalized N-heterocyclic carbene ligands (NHCPs) are presented. Alkyl NHCP Ru coordination chemistry is described, and access to several potential synthetic precursors for ruthenium alkylidene complexes is outlined, incorporating both trimethylsilyl and phenyl alkylidenes. The Ru alkylidene complexes are evaluated as potential olefin metathesis catalysts and were shown to behave in a latent fashion. They displayed catalytic activity at elevated temperatures for both ring closing metathesis and ring opening metathesis polymerization.

Acrylate formation from CO2 and ethylene: catalysis with palladium and mechanistic insight.

We report the first catalyst based on palladium for the reaction of CO2, alkene and a base to form sodium acrylate and derivatives. A mechanism similar to a previously reported Ni(0)-catalyst is proposed based on stoichiometric in situ NMR experiments, isolated intermediates and a parent palladalactone. Our palladium catalyst was applied to the coupling of CO2 with conjugated alkenes.

Nickel-catalyzed direct carboxylation of olefins with CO2 : one-pot synthesis of α,ß-unsaturated carboxylic acid salts.

The nickel-catalyzed direct carboxylation of alkenes with the cheap and abundantly available C1 building block carbon dioxide (CO2 ) in the presence of a base has been achieved. The one-pot reaction allows for the direct and selective synthesis of a wide range of α,ß-unsaturated carboxylates (TON>100, TOF up to 6 h(-1) , TON=turnover number, TOF=turnover frequency). Thus, it is possible, in one step, to synthesize sodium acrylate from ethylene, CO2 , and a sodium salt. Acrylates are industrially important products, the synthesis of which has hitherto required multiple steps.

Alcohol amination with ammonia catalyzed by an acridine-based ruthenium pincer complex: a mechanistic study.

The mechanistic course of the amination of alcohols with ammonia catalyzed by a structurally modified congener of Milstein's well-defined acridine-based PNP-pincer Ru complex has been investigated both experimentally and by DFT calculations. Several key Ru intermediates have been isolated and characterized. The detailed analysis of a series of possible catalytic pathways (e.g., with and without metal-ligand cooperation, inner- and outer-sphere mechanisms) leads us to conclude that the most favorable pathway for this catalyst does not require metal-ligand cooperation.

Ruthenium carbenes supported on mesoporous silicas as highly active and selective hybrid catalysts for olefin metathesis reactions under continuous flow.

In the search for a highly active and selective heterogenized metathesis catalyst, we systematically varied the pore geometry and size of various silica-based mesoporous (i.e., MCM-41, MCM-48, and SBA-15) and microporous (ZSM-5 and MWW) versus macroporous materials (D11-10 and Aerosil 200), besides other process parameters (temperature, dilution, and mean residence time). The activity and, especially, selectivity of such "linker-free" supports for ruthenium metathesis catalysts were evaluated in the cyclodimerization of cis-cyclooctene to form 1,9-cyclohexadecadiene, a valuable intermediate in the flavor and fragrance industry. The optimized material showed not only exceptionally high selectivity to the valuable product, but also turned out to be a truly heterogeneous catalyst with superior activity relative to the unsupported homogeneous complex.

Selective alkylation of amines with alcohols by Cp*-iridium(III) half-sandwich complexes.

[Cp*Ir(Pro)Cl] (Pro = prolinato) was identified among a series of Cp*-iridium half-sandwich complexes as a highly reactive and selective catalyst for the alkylation of amines with alcohols. It is active under mild conditions in either toluene or water without the need for base or other additives, tolerates a wide range of alcohols and amines, and gives secondary amines in good to excellent isolated yields.

Linker-free, silica-bound olefin-metathesis catalysts: applications in heterogeneous catalysis.

A set of heterogenized olefin-metathesis catalysts, which consisted of Ru complexes with the H(2)ITap ligand (1,3-bis(2',6'-dimethyl-4'dimethyl aminophenyl)-4,5-dihydroimidazol-2-ylidene) that had been adsorbed onto a silica support, has been prepared. These complexes showed strong binding to the solid support without the need for tethering groups on the complex or functionalized silica. The catalysts were tested in the ring-opening-ring-closing-metathesis (RO-RCM) of cyclooctene (COE) and the self-metathesis of methyl oleate under continuous-flow conditions. The best complexes showed a TON>4000, which surpasses the previously reported materials that were either based on the Grubbs-Hoveyda II complex on silica or on the classical heterogeneous Re(2)O(7)/B(2)O(3) catalyst.

The first catalytic synthesis of an acrylate from CO2 and an alkene-a rational approach.

For more than three decades the catalytic synthesis of acrylates from the cheap and abundantly available C(1) building block carbon dioxide and alkenes has been an unsolved problem in catalysis research, both in academia and industry. Herein, we describe a homogeneous catalyst based on nickel that permits the catalytic synthesis of the industrially highly relevant acrylate sodium acrylate from CO(2), ethylene, and a base, as demonstrated, at this stage, by a turnover number of greater than 10 with respect to the metal.

(Acetonitrile-κN)[2-(diphenylphosphan-yl)ethanamine-κN,P][(1,2,3,4,5-η)-1,2,3,4,5-pentamethylcyclopentadienyl]iron(II) hexafluoridophosphate tetrahydrofuran monosolvate.

In the title cationic Cp(*)Fe(II) complex, [Fe(C(10)H(15))(CH(3)CN)(C(14)H(16)NP)]PF(6)·C(4)H(8)O, the metal ion is coordinated by the η(5)-Cp* ring as well as the P and N atoms of the chelating 2-(diphenyl-phosphino)ethyl-amine ligand and an additional acetonitrile mol-ecule in a piano-chair conformation. The PF(6) (-) anion is disordered over two sets of sites with occupancies of 0.779 (7) and 0.221 (7).

Unsymmetrical Ru-NHC catalysts: a key for the selective tandem ring opening-ring closing alkene metathesis (RO-RCM) of cyclooctene.

Dissymmetry for selectivity: NHC ligand with two different pendant group allows the selective formation of cyclic oligomers in place of polymers opening new strategy to generate macrocycles.

µ(3)-Oxido-tris-{dichlorido[1,3-bis-(1,3,5-trimethyl-phen-yl)imidazol-2-yl-idene]gold(III)} bis-(trifluoro-methane-sulfon-yl)imide-[bis-(trifluoro-methane-sulfon-yl)imide]-silver(I) (1/2).

The unusual trinuclear Au(III) oxide title complex, [Au(3)Cl(6)O(C(21)H(24)N(2))(3)](C(2)F(6)NO(4)S(2))·2[Ag(C(2)F(6)NO(4)S(2))], is the side product of the reaction of [1,3-bis-(1,3,5-trimethyl-phen-yl)imidazol-2-yl-idene]dichloridophenyl-gold(III) with silver bis-(trifluoro-methane-sulfon-yl)imide in the presence of traces of water. In contrast to corresponding Au(I) complexes, the core structure of the title compound is planar. Two silver(I) bis-(trifluoro-methane-sulfon-yl)imide units are loosely bound to the complex cation. Here the silver atoms, disordered over two positions in a 0.870 (2):0.130 (2) ratio, inter-act either with the lone pairs of three chlorine ligands or two chlorine ligands and one edge of the mesityl π-system. The crystal under investigation was a partial racemic twin.

Facile synthesis of structurally diverse 5-oxopiperazine-2-carboxylates as dipeptide mimics and templates.

A sequence of Michael addition of a primary amine onto methyl 2-chloro-2-cyclopropylidene-acetate (1), acylation of the adduct with alpha-bromo acid chlorides under modified Schotten-Baumann conditions and ring-closing twofold nucleophilic substitution on the thus formed bishalides 3a-e with aliphatic or aromatic amines according to a very simple protocol with final acid/base extraction or filtration over silica gel for purification leads to the 3-spirocyclopropanated 5-oxopiperazine-2-carboxylates 2 or in two cases, after intermolecular transesterification of 2, to bicyclic oxopiperazines 6, with a remarkable variability of the substituents R1-R3 in 39-99% yields (20 examples). Starting with alpha-bromophenylacetic acid chloride, the trans-configured 6-phenyl-5-oxopiperazine-2-carboxylates are formed preferentially.

High yielding selective access to spirocyclopropanated 5-oxopiperazine-2-carboxylates and 1,4-diazepane-2,5-diones from methyl 2-chloro-2-cyclopropylideneacetate.

The 2-spirocyclopropanated methyl 5-oxopiperazine-2-carboxylate and the 3-spirocyclopropanated 6-chloro-1,4-diazepane-2,5-dione could both be prepared at choice in 93 and 88% yield, respectively, from methyl 2-chloro-2-cyclopropylideneacetate () in a sequence of Michael addition of 3-benzyloxypropylamine, peptide coupling with N-Boc-glycine, Boc-group removal and cyclization. Transformation of the benzyloxypropyl side chain, peptide coupling with N-Boc-(S)-asparagine, deprotection and repeated cyclization led to the octahydro[2H]pyrazino[1,2-a]pyrazinetrione scaffold containing a rigidified mimic of a tripeptide with a DGR motif. The overall yield of after deprotection of (a total of 13 steps in 8 distinct operations) was 30%.

Enzyme-catalyzed formation of beta-peptides: beta-peptidyl aminopeptidases BapA and DmpA acting as beta-peptide-synthesizing enzymes.

In recent studies, we discovered that the three beta-peptidyl aminopeptidases, BapA from Sphingosinicella xenopeptidilytica 3-2W4, BapA from S. microcystinivorans Y2, and DmpA from Ochrobactrum anthropi LMG7991, possess the unique feature of cleaving N-terminal beta-amino acid residues from beta- and alpha/beta-peptides. Herein, we investigated the use of the same three enzymes for the reverse reaction catalyzing the oligomerization of beta-amino acids and the synthesis of mixed peptides with N-terminal beta-amino acid residues. As substrates, we employed the beta-homoamino acid derivatives H-beta hGly-pNA, H-beta3 hAla-pNA, H-(R)-beta3 hAla-pNA, H-beta3 hPhe-pNA, H-(R)-beta3 hPhe-pNA, and H-beta3 hLeu-pNA. All three enzymes were capable of coupling the six beta-amino acids to oligomers with chain lengths of up to eight amino acid residues. With the enzyme DmpA as the catalyst, we observed very high conversion rates, which correspond to dimer yields of up to 76%. The beta-dipeptide H-beta3 hAla-beta3 hLeu-OH and the beta/alpha-dipeptide H-beta hGly-His-OH (carnosine) were formed with almost 50% conversion, when a five-fold excess of beta3-homoleucine or histidine was incubated with H-beta3 hAla-pNA and H-beta hGly-pNA, respectively, in the presence of the enzyme BapA from S. microcystinivorans Y2. BapA from S. xenopeptidilytica 3-2W4 turned out to be a versatile catalyst capable of coupling various beta-amino acid residues to the free N-termini of beta- and alpha-amino acids and even to an alpha-tripeptide. Thus, these aminopeptidases might be useful to introduce a beta-amino acid residue as an N-terminal protecting group into a 'natural' alpha-peptide, thereby stabilizing the peptide against degradation by other proteolytic enzymes.

Enzymatic degradation of beta- and mixed alpha,beta-oligopeptides.

One of the main and most astonishing characteristics of peptides comprised of beta-amino acids with proteinogenic side chains is their extraordinarily high stability towards enzymatic degradation. So far, only certain microbial enzymes have been shown to cleave N-terminal beta(3)-homoamino acid residues from peptides. In this work, the L-aminopeptidase-D-amidase/esterase (DmpA) from Ochrobactrum anthropi LMG7991 is compared to two closely related beta-peptidyl aminopeptidases (BapA), which originate from Sphingosinicella strains, and to microsomal leucine aminopeptidase (LAP) as a reference. All four enzymes are aminopeptidases cleaving N-terminal amino acids from small peptides. Degradation experiments reveal that DmpA and both BapA enzymes exhibit unique, but clearly distinct substrate specificities and preferences. DmpA also cleaves beta- and mixed alpha,beta-peptides and amides, but a short side chain of the N-terminal beta-amino acid residue seems to be a prerequisite, since only peptides carrying N-terminal betahGly and beta(3)hAla are hydrolyzed with good efficiencies. Both beta-peptidyl aminopeptidases cleave beta-amino acids from a variety of beta-peptides and mixed alpha,beta-peptides, but they do not accept alpha-amino acids in the N-terminal position. Astonishingly, DmpA exhibited much higher catalytical rates for the mixed dipeptide carnosine (H-betahGly-His-OH) than for any other substrate described until now.

5-(pyrrolidin-2-yl)-1H-tetrazole and 5-[(pyrrolidin-2-yl)methyl]-1H-tetrazole: proline surrogates with increased potential in asymmetric catalysis.

Catalytic enantioselective methodology has dramatically been enriched by the re-discovery of the simple amino acid proline as a chiral catalyst in the year 2000. Although no catalyst offers such a simple and broad access to quite complex reaction products, as does proline, its synthetic potential is not unrestricted, what is especially connected to its poor solubility in organic media. Exchange of the carboxylic moiety by a tetrazole unit leads to proline surrogates, that by far outperform proline with respect to yield, enantioselectivity, reaction time, substrate and solvent scope, catalyst loading, and stoichiometry of the compounds used in excess. These factors are discussed and critically compared with selected representative proline-catalyzed reactions.

Bacterial beta-peptidyl aminopeptidases with unique substrate specificities for beta-oligopeptides and mixed beta,alpha-oligopeptides.

We previously discovered that BapA, a bacterial beta-peptidyl aminopeptidase, is able to hydrolyze two otherwise metabolically inert beta-peptides [Geueke B, Namoto K, Seebach D and Kohler H-PE (2005) J Bacteriol 187, 5910-5917]. Here, we describe the purification and characterization of two distinct bacterial beta-peptidyl aminopeptidases that originated from different environmental isolates. Both bapA genes encode a preprotein with a signal sequence and were flanked by ORFs that code for enzymes with similar predicted functions. To form the active enzymes, which had an (alphabeta)(4) quaternary structure, the preproteins needed to be cleaved into two subunits. The two beta-peptidyl aminopeptidases had 86% amino acid sequence identity, hydrolyzed a variety of beta-peptides and mixed beta/alpha-peptides, and exhibited unique substrate specificities. The prerequisite for peptides being accepted as substrates was the presence of a beta-amino acid at the N-terminus; peptide substrates with an N-terminal alpha-amino acid were not hydrolyzed at all. Both enzymes cleaved the peptide bond between the N-terminal beta-amino acid and the amino acid at the second position of tripeptidic substrates of the general structure H-betahXaa-Ile-betahTyr-OH according to the following preferences with regard to the side chain of the N-terminal beta-amino acid: aliphatic and aromatic > OH-containing > hydrogen, basic and polar. Experiments with the tripeptides H-d-betahVal-Ile-betahTyr-OH and H-betahVal-Ile-betahTyr-OH demonstrated that the two BapA enzymes preferred the peptide with the l-configuration of the N-terminal beta-homovaline residue as a substrate.

'Five at one stroke': proline and small peptides in the stereoselective de novo synthesis and enantiotopic functionalization of carbohydrates.

Asymmetric catalysis with the simple amino acid proline (so called 'enamine catalysis') arrested big attention in the last few years since the re-discovery of the Hajos-Parrish-Eder-Sauer-Wiechert reaction. After basic mechanistic studies, probing scope and limitations of the catalyst and the corresponding reactions, this concept has now emerged to a state where it is applied to the assembly of up to five stereogenic centers of carbohydrates, not really 'at one stroke', but in only two simple synthetic operations. Beyond, it is not only possible to build up complicated natural products elegantly, but also to address selectively the similar functional groups of carbohydrates by small peptidic catalysts. This short review covers the recent developments of organocatalysis in both fields, with special emphasis on the asymmetric assembly and selective derivatization of carbohydrates.