Search

In recent years, H2 activation at non-transition-metal centers has met with increasing attention. Here, a system in which H2 is activated and transferred to aldimines and ketimines using substoichiometric amounts of lithium bis(trimethylsilyl)amide is reported. Notably, the reaction tolerates the presence of acidic protons in the α-position. Mechanistic investigations indicated that the reaction proceeds via a lithium hydride intermediate as the actual reductant.

A synthesis of new NeoPHOX ligands derived from serine or threonine has been developed. The central intermediate is a NeoPHOX derivative bearing a methoxycarbonyl group at the stereogenic center next to the oxazoline N atom. The addition of methylmagnesium chloride leads to a tertiary alcohol, which can be acylated or silylated to produce NeoPHOX ligands with different sterical demand. The new NeoPHOX ligands were tested in the iridium-catalyzed asymmetric hydrogenation and palladium-catalyzed allylic substitution. In both reactions high enantioselectivities were achieved, that were comparable to the enantioselectivities obtained with the up to now best NeoPHOX ligand derived from expensive tert-leucine.

An efficient protocol for the evaluation of catalysts for the asymmetric Morita-Baylis-Hillman (MBH) reaction was developed. By mass spectrometric back-reaction screening of quasi-enantiomeric MBH products, an efficient bifunctional phosphine catalyst was identified that outperforms literature-known catalysts in the MBH reaction of methyl acrylate with aldehydes. The close match between the selectivities measured for the forward and back reaction and kinetic measurements provided strong evidence that the aldol step and not the subsequent proton transfer is rate- and enantioselectivity-determining.

In extension of a concept of Lloyd-Jones, based on the combination of a racemic catalyst with a scalemic substrate, we have recently developed a method for determining the enantioselectivity of a chiral catalyst from its racemic form by mass spectrometric screening of a non-equal mixture of two mass-labeled quasi-enantiomeric substrates. After an initial proof of principle using Pd-catalyzed allylic substitution as test reaction, we report now the successful application of this approach to the screening of chiral amines as catalysts for the enantioselective Michael addition to a,b-unsaturated aldehydes. The results confirm that our method allows fast and reliable evaluation of chiral racemic catalysts. This opens up new possibilities for investigating catalyst structures that are not easily available in enantiomerically pure form.

Enantioselective hydrogenation of furans and benzofurans remains a challenging task. We report the hydrogenation of 2- and 3-substituted furans by using iridium catalysts that bear bicyclic pyridine-phosphinite ligands. Excellent enantioselectivities and high conversions were obtained for monosubstituted furans with a 3-alkyl or 3-aryl group. Furans substituted at the 2-position and 2,4-disubstituted furans proved to be more difficult substrates. The best results (80-97% conversion, 65-82% enantiomeric excess) were obtained with monosubstituted 2-alkylfurans and 2-[4-(trifluoromethyl)phenyl]furan. Benzofurans with an alkyl substituent at the 2- or 3-position also gave high conversions and enantioselectivity, whereas 2-aryl derivatives showed essentially no reactivity. The asymmetric hydrogenation of a 3-methylbenzofuran derivative was used as a key step in the formal total synthesis of the cytotoxic naphthoquinone natural product (-)-thespesone.

Hydrogen isotope exchange (HIE) is one of the most attractive tools for the introduction of deuterium or tritium to an organic compound. Herein, iridium complexes with N,P-ligands, highly active catalysts for asymmetric double bond reductions, have been tested for their HIE capabilities. Electron-rich ligands, containing dicyclohexylphosphines or phosphinites, have been identified as excellent ligands for efficient deuterium incorporation. Substrates with strong directing groups, that is, pyridines, ketones, and amides, as well as weak ligating units, such as, nitro, sulfones, and sulfonamides, could be labeled efficiently. With the addition of tris(pentafluorophenyl) borane to the reaction mixture, also highly deactivating nitrile substituents were well tolerated in the reaction. Based on the excellent results obtained with the chiral ThrePhox ligand, a structurally simpler, achiral ligand was developed. The iridium complex containing this ligand, proved to be a powerful catalyst for HIE reactions.

Asymmetric hydrogenation of maleic and fumaric acid derivatives with iridium catalysts based on N,P ligands provides an efficient route to chiral enantioenriched succinates. A new catalyst derived from a 2,6-difluorophenyl-substituted pyridine-phosphinite ligand was developed and enables the conversion of a wide range of 2-alkyl and 2-arylmaleic acid diesters into the corresponding succinates in high enantiomeric purity. Mixtures of cis/trans substrates can be hydrogenated in an enantioconvergent fashion with high enantioselectivity, and further enhances the scope of this transformation. The products are valuable chiral building blocks with a structural motif found in many bioactive compounds, such as metalloproteinase inhibitors.

The first enantioselective catalytic total synthesis of (–)-pyridovericin is reported. The key steps involve a modified HWE reaction under aqueous conditions and an asymmetric iridium-catalyzed hydrogenation. This resulted in a highly modular and stereoselective approach that delivered the target natural product in high yield and stereoselectivity.

Ir-phosphinomethyl-oxazoline complexes have been identified as efficient, highly enantioselective catalysts for the asymmetric hydrogenation of 3,3-disubstituted allylic alcohols and related homoallylic alcohols. In contrast to other N,P ligand complexes, which require weakly coordinating solvents, such as dichloromethane, these catalysts perform well in more ecofriendly THF or 2-MeTHF. Their synthetic potential was demonstrated with the formal total synthesis of four bisabolane sesquiterpenes.

Tetrasubstituted N-methylpyridinium salts bearing a free tertiary amino group have been synthesized by a straightforward procedure starting from inexpensive starting materials. The key feature of the synthesis is the use of a proton as a simple effective protecting group to achieve selective N-methylation of the pyridine ring without attacking the amino group.

Looking back: The asymmetric organocatalytic 1,4-addition of aldehydes to nitroolefins was studied by ESI-MS. Analysis of the back reaction starting from quasienantiomeric mass-labeled 1,4-adducts provided conclusive evidence for an enamine rather than an enol mechanism, and allowed identification of the enantioselectivity-determining step.

The dinuclear iridium hydride complexes [IrH(CH3CN)(L1)(μ-H)]2(BArF)2 (7; L1 = (S)-2-(2-((diphenylphosphanyl)oxy)propan-2-yl)-4-isopropyl-4,5-dihydrooxazole, BArF = tetrakis[3,5-bis(trifluoromethyl)phenyl]borate), [IrH(CH2Cl2)(L1)(μ-H)]2(BArF)2 (8), [IrH(L2)(μ-H)]2(BArF)2 (9a; L2 = (S)-1-[2-(2-adamantan-2-yl-4,5-dihydrooxazol-4-yl)-ethyl]-3-(2,6-diisopropylphenyl)-1,2-dihydroimidazol-2-ylidene), and [IrH(L3)(μ-H)]2(BArF)2 (9b; L3 = (S)-1-[2-(2-tert-butyl-4,5-dihydrooxazol-4-yl)-ethyl]-3-(2,6-diisopropylphenyl)-1,2-dihydroimidazol-2-ylidene) were prepared from the corresponding mononuclear [Ir(COD)(L)]BArF precursors by treatment with H2 and characterized by 2D NMR spectroscopy and X-ray diffraction. Conversion to a trinuclear iridium hydride complex, which is usually observed for N,P iridium hydride complexes, is inhibited by addition of 0.5 equiv of [H(OEt2)2]BArF or acetonitrile. Reactions with acetonitrile or 6,6′-bi-2-picoline afforded the mononuclear iridium dihydride complexes [Ir(H)2(CH3CN)2(L1)]BA...

Swapping N,P for C,N: Iridium complexes of bidentate pyridine-based C,N ligands with an N-heterocylic carbene (NHC) unit proved to be efficient and highly enantioselective hydrogenation catalysts. As a result of the lower acidity of iridium hydride intermediates produced from NHC-based complexes, these catalysts are much better suited than analogous N,P-ligand complexes for the hydrogenation of acid-sensitive substrates.

An efficient iridium-catalyzed asymmetric hydrogenation of substituted benzothiophene 1,1-dioxides is described. The use of iridium complexes with chiral pyridyl phosphinite ligands provides access to highly enantiomerically enriched sulfones with substituents at the 2- and 3-position. Sulfones of this type are of interest as core structures of agrochemicals and pharmaceuticals. Moreover, they can be further reduced to chiral 2,3-dihydrobenzothiophenes.

We have screened a diverse array of iridium complexes derived from chiral N,P ligands as catalysts for the asymmetric hydrogenation of vinylsilanes, a transformation for which generally applicable catalysts were lacking. Several catalysts emerged from this study that enabled the highly enantioselective hydrogenation of a wide range of vinylsilanes with trisubstituted or disubstituted terminal C=C bonds bearing aryl, alkyl, ethoxycarbonyl, or hydroxymethyl substituents. In addition to trimethylsilyl and dimethyl(phenyl) silyl derivatives, trialkoxysilyl- and silacyclobutyl-substituted alkenes were used as substrates.

A series of monodentate neutral and anionic phosphorus ligands was synthesized and evaluated in the asymmetric rhodium-catalyzed hydrogenation of functionalized olefins by using either catalysts containing identical ligands or catalysts generated from mixtures of two different ligands. We expected that the combination of an anionic ligand with a neutral ligand would favor the formation of hetero over homo bis-ligand complexes due to charge repulsion. NMR spectroscopic studies confirmed that charge effects can indeed shift the equilibrium toward the hetero bis-ligand complexes. In several cases, the combination of a neutral phosphane with an anionic phosphane, one chiral and the other achiral, furnished significantly higher enantioselectivities than analogous mixtures of two neutral ligands. The best results were obtained with a mixture of an anionic phosphoramidite and a neutral phosphoric acid diester. It is supposed that in this case a hydrogen bond between the two ligands additionally stabilizes the hetero ligand combination.

A library of iridium and rhodium phosphine catalysts have been screened for the double-asymmetric hydrogenation of 2,6-di-(1-phenylethenyl)-4-methylaniline to produce the C2-symmetric aniline precursor of the N-heterocyclic carbenoid CuIPhEt. The best catalyst produced the desired enantiomer in 98.6% selectivity. This rare example of a highly selective hydrogenation of a 1,1-diaryl olefin enables a four-step asymmetric synthesis of the C2-symmetric phenylethyl imidazolium ion (IPhEt) from p-toluidine and phenylacetylene and its conversion to the hydrosilylation catalyst CuIPhEt.

Two new classes of proline-based P,O and P,N ligands were prepared and applied in the iridium-catalyzed asymmetric hydrogenation of alkenes. Both types of ligands induced high enantioselectivities in the hydrogenation of trisubstituted C[DOUBLE BOND]C bonds. Iridium complexes derived from P,O ligands bearing sterically demanding amide or urea groups at the pyrrolidine N-atom proved to be especially efficient catalysts for the conjugate reduction of α,β-unsaturated esters and ketones, whereas analogous P,N ligands led to better results with dialkyl-phenyl-substituted alkenes and an allylic alcohol as substrates.

A novel, highly stereocontrolled, and very flexible synthetic access to biologically relevant trideoxypropionate building blocks in optically pure form has been developed. On the basis of a three-step sequence comprising a thermal oxy-Cope rearrangement, an iridium-catalyzed hydrogenation, and an auxiliary-controlled enolate methylation, trideoxypropionates with easily adjustable relative configuration were synthesized in excellent yields. In addition, the functionalized end groups allow for chemoselective manipulations and further elongation of the chain. The underlying strategy constitutes the first noniterative process for the assembly of polydeoxypropionates and has further been applied in total syntheses of the pheromones (+)-vittatalactone and (+)-norvittatalactone, which had been isolated from the striped cucumber beetle Acalymma vittatum.

Enantioselective conjugate reduction of a wide range of α,β-unsaturated carboxylic esters was achieved using chiral Ir N,P complexes as hydrogenation catalysts. Depending on the substitution pattern of the substrate, different ligands perform best. α,β-Unsaturated carboxylic esters substituted at the α position are less problematic substrates than originally anticipated and in some cases α-substituted substrates actually reacted with higher enantioselectivity than their β-substituted analogues. The resulting saturated esters with a stereogenic center in the α or β position were obtained in high enantiomeric purity.

A new class of organocatalysts based on the structure of 2,3-dihydrobenzo[1,4]oxazine was prepared and applied in the enantioselective transfer-hydrogenation of α,β-unsaturated aldehydes with Hantzsch ester as hydride donor. These catalysts proved to be particularly effective for the conjugate reduction of β,β-diaryl-substituted acrylaldehydes leading to saturated aldehydes bearing a stereogenic center with two different aryl groups with enantioselectivities of up to 91% ee.

A series of serine-based phosphinooxazoline ligands was synthesized and the corresponding iridum complexes were successfully applied in the asymmetric hydrogenation of various unfunctionalized olefines and acetophenone-N-phenyl-imine. The results show that these new derivatives are useful substitutes for the standard tert-leucine-derived PHOX ligands.

Several zwitterionic iridium complexes based on chiral P,N-ligands with imidazoline or oxazoline donors and anionic tetraarylborate or aryltrifluoroborate substituents have been synthesized. The corresponding cationic analogues have also been prepared, to evaluate the effect of the covalent linkage between the anion and the cationic metal complex in catalytic reactions. The respective pairs of structurally analogous precatalysts have been compared for their efficacies in the asymmetric hydrogenation of unfunctionalized olefins. In most cases, the anionic derivatization has virtually no influence on the asymmetric induction of the iridium complex. This is in accordance with X-ray structural studies, which have shown that the chiral environment of the cationic metal center is not affected by the anionic substituent. Depending on the nature of the counterion employed, the zwitterionic catalysts proved to be significantly more reactive than their cationic counterparts in nonpolar solvents.

The enantioselectivity of a chiral catalyst can be determined from its racemic form by mass spectrometric screening of a nonequal mixture of two mass-labeled quasienantiomeric substrates. The presented method opens up new possibilities for evaluating catalyst structures that are not readily available in enantiomerically pure form.

Aryl−iridium(III) hydride complexes with a P-coordinated phosphinate were formed from [Ir(cod)Cl]2 and secondary phosphine oxide−oxazoline ligands under basic conditions. The structure of these complexes, whose formation involved C−P cleavage, was assigned by X-ray analysis and NMR spectroscopy.

Enantiomerically pure 2-[2-(diphenylphosphino)aryl]oxazolines are readily prepared from 2-bromobenzonitrile by transmetalation with BuLi, subsequent reaction with chloro-diphenylphosphine and conversion of the resulting phosphinoaryl nitrile to the oxazoline by treatment with a chiral amino alcohol in the presence of ZnCl2. An alternative synthesis is based on the orthometalation of 2-aryloxazolines followed by reaction with chlorodiphenylphosphine.

Chiral C2-symmetric semicorrins, a class of bidentate nitrogen ligands, are readily prepared in enantiomerically pure form starting either from D- or L-pyroglutamic acid. They possess a number of features that make them attractive ligands for enantioselective control of metal-catalyzed reactions. (Semicorrinato)copper complexes have been used as efficient catalysts for the enantioselective cyclopropanation of olefins with diazo compounds. Using (semicorrinato)cobalt complexes as catalysts, α,β-unsaturated carboxylic esters and amides can be enantioselectively reduced with sodium borohydride, giving the corresponding saturated esters and amides with enantiomeric excesses up to 98%.

A short enantioselective and protecting group free access to the novel antibiotic platensimycin is reported. The crucial stereogenic information is provided by iridium catalyzed asymmetric hydrogenation.

The bis(2-methoxymethyl pyrrolidine)phosphine moiety is shown to be a very effective chiral auxiliary for the ortho- and diastereoselective lithiation of ferrocene, thereby allowing the highly selective attachment of various electrophiles to the cyclopentadienyl ring of ferrocene. The potential of the methodology is demonstrated by the synthesis of Kephos, a new family of ferrocenyl diphosphines and of OH-Taniaphos derivatives.

We have evaluated a wide range of iridium complexes derived from chiral oxazoline-based N,P ligands for the asymmetric hydrogenation of imines and identified three efficient catalysts. These catalysts are readily synthesized by straightforward convenient routes and are air and moisture stable. In the reduction of acetophenone N-arylimines and related acyclic substrates, excellent enantioselectivities (up to 96 % ee) were obtained by using 0.1-0.5 mol % of catalyst at -20 degrees C and 5-50 bar hydrogen pressure.

Chiral indolines substituted at C-2 or C-3 can be prepared in high yield and excellent enantioselectivity by asymmetric hydrogenation of N-protected indoles by using Ir catalysts with chiral N,P ligands. With less reactive substrates, the reaction had to be carried out at elevated temperature, but even at 60–110 °C very high enantiomeric excesses of up to 98–99 % could be obtained.

Shortcut to chiral catalysts: An efficient combinatorial strategy based on back reaction screening by ESI-MS allows rapid evaluation of organocatalysts for the asymmetric Michael addition to α,β-unsaturated aldehydes (see scheme). An unexpected nonlinear effect has been observed in this reaction, resulting from a double nucleophilic–electrophilic activation mechanism involving two catalyst molecules.

Racemic secondary alcohols were resolved by enzymatic esterification using Candida antarctica lipase B (CAL B). After derivatization of the unreacted enantiomer with phthalic anhydride, the resulting phthalic acid monoesters could be easily separated from the corresponding acetates by precipitation and filtration or distillation, thus avoiding laborious column chromatography, which is a major obstacle for large-scale reactions. This method has been successfully applied to the multigram synthesis of enantiopure pyridyl alcohols.

Optically active tertiary amines are readily prepared by iridium-catalyzed asymmetric hydrogenation of unfunctionalized enamines (see scheme). The best enantioselectivities with >90 % ee were obtained with N-aryl- and N-benzyl-substituted enamines with a terminal double bond. The hydrogenation of enamines derived from cyclic ketones, which has not been reported yet with other catalysts, gave enantiomeric excesses of up to 87 %.

The first synthesis of the natural product (+)-mutisianthol was accomplished in 11 steps and in 21% overall yield from 2-methylanisole. The synthesis of its enantiomer was also performed in a similar overall yield. The absolute configuration of the sesquiterpene (+)-mutisianthol was assigned as (1S,3R). Key steps in the route are the asymmetric hydrogenation of a nonfunctionalized olefin using chiral iridium catalysts and the ring contraction of 1,2-dihydronaphthalenes using thallium(III) or iodine(III). The target molecules show moderate activity against the human tumor cell lines SF-295, HCT-8, and MDA-MB-435.

Iridium complexes of chiral oxazoline-based P,N-ligands provedto be efficient catalysts for the enantioselective hydrogenationof 2-aryl- and 2-alkyl-4 H-chromenes.The best results were obtained with a ligand derived from threonine(ThrePHOX), which induced ee values of 95% to >99% inthe hydrogenation of 2-methyl-, 2-cyclohexyl- and various 2-aryl-substitutedchromenes.

Anionic boron-bridged bisoxazolines (borabox ligands) have been synthesized and characterized in their protonated forms. The ligands are tuneable over a wide range, allowing either alkyl or aryl substituents at the oxazoline rings and the central bridging boron atom. The structural parameters of this new ligand type have been investigated by X-ray analyses of palladium and copper complexes. Electronic properties have been studied by 13C NMR spectroscopy and by DFT calculations on palladium allyl complexes and compared to those of analogous bisoxazoline (box) complexes. Borabox complexes are more electron-rich at the metal center than their neutral box congeners, and as a consequence of the longer bonds between the bridging atom and the oxazoline rings, their bite angles are larger. Palladium(II) complexes bearing an unsubstituted allyl ligand and homoleptic copper(II) complexes each possess an almost flat chelate ring. NMR analysis of a (1,3-diphenylallyl)(borabox)palladium complex showed a 92:8 mixture of (syn,syn) and (anti,syn) allyl isomers, in contrast with a previously reported box analogue that existed exclusively in the (syn,syn) form. Comparison of the corresponding crystal structures revealed that the distance between the bisoxazoline and the allyl ligand in the borabox complex is shorter. In the copper-catalyzed allylic oxidation of cyclohexene and cyclopentene with tert-butyl perbenzoate, borabox ligands gave results similar - and in some cases superior - to those obtained with analogous box ligands.

N-Arylation or N-alkylation of chiral 1,2-diamines followed by ring closure with phosphorus trichloride (PCl 3 ) and subsequent coupling with an oxazoline alcohol resulted in a new class of N,P ligands. The corresponding iridium tetrakis[3,5-bis(tri-fluormethyl)phenyl]borate (BAr F ) complexes were found to be efficient catalysts for the enantioselective hydrogenation of unfunctionalized olefins and a,(3-unsaturated carboxylic esters.

Metal complexes of boron-bridged bisoxazolines (borabox ligands) were evaluated as catalysts for the Henry reaction. Copper(II) complexes induced high enantio- and diastereoselectivity in reactions with nitroethane and nitropropane. The amount of base added had a strong influence on the formation of the chiral complex and the enantioselectivity. Comparison with the corresponding dimethylmethylene-bridged bisoxazoline and other privileged ligands showed that borabox was the most suitable ligand system for the enantio- and diastereoselective formation of nitroalcohols derived from nitropropane and aliphatic aldehydes.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Four iridium complexes with achiral phosphino-oxazoline (PHOX) ligands were readily prepared in two steps starting from commercially available phenyloxazolines. The air-stable complexes with tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (BArF) as counterion showed high reactivity in the hydrogenation of a range of tri- and tetrasubstituted olefins. The best results were obtained with an iridium complex (11) derived from a dicyclohexylphosphino-oxazoline ligand bearing no additional substituents in the oxazoline ring. With several substrates, which gave only low conversion with the Crabtree catalyst, [Ir(Py)(PCy3)(COD)]PF6, full conversion was observed. The productivity of the Crabtree catalyst could be strongly increased by replacing the hexafluorophosphate anion with tetrakis[3,5-bis(trifluoromethyl)phenyl]borate. In one case, in the hydrogenation of a tetraalkyl-substituted CC bond, [Ir(Py)(PCy3)(COD)]BArF gave higher conversion than catalyst 11. However, with several other substrates complex 11 proved to be superior.

Mono- and bifunctional fluorinated borate building blocks were prepared in three to five steps with good to excellent overall yields. Compounds with both nucleophilic and electrophilic functionalities are presented, which can be used for the anionic derivatization of neutral molecules.