ABSTRACT

Einfach selektiv: Die Monosubstitution von mehrfach funktionellen Molekülen ist ein generelles Problem in der Synthesechemie. Mit dem Katalysator [Cp*(PiPr₃)(H)₂RuSi(H)Ph⋅Et₂O][B(C₆F₅)₄] (Cp*=η⁵-C₅Me₅) kann die Alkylierung von Phenylsilanen PhSiH₃ mit einfachen Olefinen auf der Stufe des Monoalkylierungsprodukts PhSi(Alk)H₂ angehalten werden (siehe Schema, R=H, C₆H₅, C₄H₉).

One up in limiting reactivity: The monosubstitution of multifunctional molecules is a general problem in synthetic chemistry. The catalyst [Cp*(PiPr₃)(H)₂RuSi(H)Ph⋅Et₂O][B(C₆F₅)₄] (Cp*=η⁵-C₅Me₅) can be used for the alkylation of phenylsilane PhSiH₃ with simple olefins. The reaction stops at the monoalkylation level to give PhSi(Alk)H₂ (see scheme; R=H, C₆H₅, C₄H₉).

The methodology of enantioselective decarboxylation was applied to 2-aminomalonic acid derivatives in order to obtain enantio-enriched amino acid derivatives. Full conversion was achieved stirring racemic N-acetylated 2-aminomalonic hemiesters in THF at 70 °C with 10 mol % of a chiral base for 24 h. The catalyst may be recycled. Whereas the commercially available cinchona alkaloids gave poor results, benzamide and benzenesulfonamide derivatives of 9-amino(9-deoxy)epicinchonine turned out to be effective catalysts. The best result was obtained with 2-N-acetylamino-2-ethoxycarbonyl-3-phenylpropionic acid as the starting material and N-(9-deoxyepicinchonine-9-yl)-4-methoxybenzamide as the chiral base to give ethyl N-acetyl-L-phenylalaninate in 70% ee. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

The stereoselective Pd-catalyzed allylation of MBA [5-(2′-hex-3′-ynyl)-1-methylbarbituric acid] gives the commercial injection narcotic methohexital, which exists as four isomers: two diastereomeric pairs of enantiomers. The isomer composition produced depends on three stereochemical parameters: catalyst control, substrate control, and kinetic resolution. Judicious choice of these parameters allowed the synthesis of methohexital samples with greatly differing isomer compositions, and these samples were investigated with respect to their anaesthetic doses in rats. Some isomer compositions obtained were much more active than the commercially used drug and showed fewer side effects. As a consequence of the determination of the absolute configuration of the methohexital (S_bR_h) isomer, the unknown configuration of the trade product, the so-called α-racemate, can be established as (R_bS_h) and (S_bR_h). (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

Photodetection (PD) and photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA)–induced protoporphyrin IX (PPIX) accumulation are approaches to detect and treat dysplasia and early cancer in the gastrointestinal tract and in the urinary bladder. Because ALA-induced PPIX production is limited, we synthesized ALA ester hydrochlorides 3–22 and tested them in two different in vitro models (gastrointestinal tract: HT29–CCD18; urinary bladder: J82–UROTSA). PPIX accumulation after incubation with 0.12 mmol/L for 3 h and PPIX accumulation as a function of different incubation times were measured using flow cytometry. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays were performed to check cellular dark toxicity. Phototoxicity after irradiation was tested. ALA nonafluorohexylester hydrochloride 11, ALA thiohexylester hydrochloride 13 and ALA dibenzyldiester dihydrochloride 19 induced appreciably increased PPIX levels and showed improved phototoxicity compared with the references ALA hydrochloride 1, ALA hexylester hydrochloride 3 and ALA benzylester hydrochloride 4. Thus, the new compounds 11, 13 and 19 are promising compounds for PD and PDT.

Molekulares Mobiliar: Halbsandwichkomplexe vom Typ [(Ar)MXY(NR*)] (siehe Strukturformel; X, Y=elektronegative Substituenten; M=Ru, Os, Rh, Ir) bilden im festen Zustand bevorzugt Inversionspaare, die durch kleine M⋅⋅⋅M-Abstände und CH⋅⋅⋅X/Y-Wasserstoffbrücken charakterisiert sind. Dabei bilden zwei Diastereomere mit gegebener Chiralität der NR*-Gruppe und unterschiedlichen Metallkonfigurationen mit ihren „racemischen Seiten“ ein Molekülpaar, was zu einer ungewöhnlich bevorzugten 1:1-Cokristallisation von Diastereomeren im selben Einkristall führt.

Half-sandwich complexes of the type [(Ar)MXY(NR*)] (see structure; X, Y=electronegative substituents; M=Ru, Os, Rh, Ir) tend to form inversion pairs in the solid state, which are characterized by short M⋅⋅⋅M separations and CH⋅⋅⋅X/Y hydrogen bonds between the pairs of molecules. As a consequence, two diastereomers with a given chirality in the Z substituent, usually an NR* substituent, and different metal configurations approach each other with their “racemic sides” resulting in an unusually preferred 1:1 diastereomer cocrystallization in the same single crystal.

The (+)-9-phenyldeltacyclanyl moiety as a chiral phosphorus substituent contains eight configurationally fixed asymmetric carbon atoms. It is easily obtained from the reaction of norbornadiene and phenylacetylene via a Co-catalyzed enantioselective homo-Diels−Alder reaction, to give (+)-8-phenyldeltacyclene. In the reaction of (+)-8-phenyldeltacyclene with 1,2-(H₂P)₂C₆H₄ the trisubstitution product P,P,P′-tris[(+)9-phenyldeltacyclan-8-yl)-1,2-bis(phosphanyl)benzene, (+)_δ-LH, is obtained, in which a single P−H bond at the stereogenic phosphorus atom is left. (+)_δ-LH crystallizes as a pure diastereomer, which isomerizes in solution with respect to the secondary phosphorus atom at −20 °C resulting in a 64:36 diastereomer mixture. Substitution of the P−H hydrogen atom in (+)_δ-LH by benzyl, 3-bromobenzyl, 6-bromo-n-hexyl and 3-(diphenylphosphanyl)phenyl gave the bis(tertiary) diphosphanes (+)_δ-LR¹−(+)_δ-LR⁴. NiBr₂, PdHal₂ (Hal = Cl, Br, I) and PtHal₂ (Hal = Cl, Br) complexes of (+)_δ-LH and (+)_δ-LR¹−(+)_δ-LR⁴have been synthesized. The complexes form two diastereomers differing in the configuration of the chiral P atom. X-ray structure analyses have been carried out with (+)_δ-LH, [(+)_δ-LR²]NiBr₂, [(+)_δ-LH]PdI₂ and [(+)_δ-LCl]PdI₂. Interestingly, for [(+)_δ-LH]PdI₂ both diastereomers are found in the same crystal lattice in a 1:1 ratio. In [(+)_δ-LH]PdI₂ and [(+)_δ-LCl]PdI₂the configuration at the secondary phosphorus atom is stable in solution at room temperature, whereas in the free ligand (+)_δ-LH it is configurationally labile. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

The synthesis of seven dinuclear complexes [(+)_δ-LMHal]₂ (M = Ni, Pd, Pt; Hal = Cl, Br, I) is described, in which (+)_δ-L⁻ represents the deprotonated chiral chelate ligand P,P,P′tris[(+)-9-phenyldeltacyclan-8-yl]-1,2-bis(phosphanyl)benzene, easily accessible in a highly enantioselective homo-Diels−Alder reaction. All the dinuclear complexes are bent at the phosphido bridges which connect the two square-planar halves of the molecules. The phosphorus atoms of the phosphido bridges are stereogenic centers. For [(+)_δ-LNiBr]₂ and [(+)_δ-LPdCl]₂ both diastereomers with (S_P,S_P) and (R_P,R_P) configuration were observed, whereas for [(+)_δ-LPdBr]₂, [(+)_δ-LPdI]₂, and [(+)_δ-LPtCl]₂ only the (S_P,S_P) isomers could be obtained. Furthermore, the synthesis of eight trinuclear complexes [(+)_δ-L₂M₃Hal₄] (M = Pd, Pt; Hal = Cl, Br) is reported, which contain unusual three-square arrays. In the trinuclear complexes all the halogens are oriented to one side. Halogeno and phosphido bridges connect the three squares leading to chair configurations (opposite scaffold chirality possible) and boat configurations. For [(+)_δ-L₂Pd₃Cl₄], [(+)_δ-L₂Pd₃Br₄], and [(+)_δ-L₂Pt₃Cl₄] the two diastereomers with (S_P,S_P) and (R_P,R_P) configuration and for [(+)_δ-L₂Pt₃Br₄] the diastereomers with (S_P,S_P) and (S_P,R_P) configuration could be isolated. In addition, the dinuclear complex [(+)_δ-LPt₂Br₃(cod)] (cod = 1,5-cyclooctadiene) containing a single phosphido bridge was obtained. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

The synthesis of a series of 18-electron chiral-at-metal (cycloheptatrienyl)molybdenum complexes [(η⁷-C₇H₇)Mo(prophos)X] [prophos = (R)-1,2-bis(diphenylphosphanyl)propane; X = NCMeBF₄, Cl, I, CN, H, Me] is reported, which consist of diastereomers differing only in the metal configuration. Diastereomer enrichments have been achieved and the configurational stability of the compounds [(η⁷-C₇H₇)Mo(prophos)X] has been studied and compared with the isoelectronic ruthenium complexes [(η⁵-C₅H₅)Ru(prophos)X]. The stereochemistry of the substitution reactions has been investigated, and X-ray analysis and NMR spectroscopy were used to determine the absolute configuration of the complexes. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

The synthesis of a series of 18-electron chiral-at-metal (cycloheptatrienyl)molybdenum complexes [(η⁷-C₇H₇)Mo(prophos)X] [prophos = (R)-1,2-bis(diphenylphosphanyl)propane; X = NCMeBF₄, Cl, I, CN, H, Me] is reported, which consist of diastereomers differing only in the metal configuration. Diastereomer enrichments have been achieved and the configurational stability of the compounds [(η⁷-C₇H₇)Mo(prophos)X] has been studied and compared with the isoelectronic ruthenium complexes [(η⁵-C₅H₅)Ru(prophos)X]. The stereochemistry of the substitution reactions has been investigated, and X-ray analysis and NMR spectroscopy were used to determine the absolute configuration of the complexes. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Half-sandwich compounds with a three-legged piano-stool geometry are prominent examples of optically active chiral-at-metal complexes. In these compounds, the configuration at the metal atom may be stable or labile in solution. Configurationally stable compounds can be used for the elucidation of the stereochemical course of substitution reactions and for organic synthesis in ligand transformation reactions. With configurationally labile compounds, the rate of change of the metal configuration can be measured, which sets an upper limit with regard to the handling of the compounds in solution. Surprisingly, in a number of recent papers the lability of the metal configuration has been overlooked resulting in misinterpretations and wrong conclusions.

Photodynamic diagnosis (PDD) and photodynamic therapy (PDT) using 5-aminolevulinic acid (ALA)–induced protoporphyrin IX (PPIX) is an interesting approach to detect and treat dysplasia and early cancers in the gastrointestinal tract. Because of low lipophilicity resulting in poor penetration across cell membranes, high doses of ALA should be administered in order to reach clinically relevant levels of PPIX. One way of increasing PPIX accumulation is derivatization of ALA into a more lipophilic molecule. In our in vitro study, different esterifications of ALA were investigated to analyze the effects on PPIX accumulation in human adenocarcinoma cell lines. For systematic analysis of cell type–specific PPIX accumulation, three human adenocarcinoma cell lines (SW480, HT29 and CaCo₂) and a fibroblast cell line (CCD18) were tested. 3-(4,5-Dimethylthiazole-2-yl)-2,5-biphenyl tetrazolium bromide (MTT) assays were performed to ensure that the ALA esters showed no cellular dark toxicity. Different concentrations (ranging from 0.012 to 0.6 mmol/L, 3 h) and incubation times (5, 10, 30, 180 min; 0.12 mmol/L) were examined. PPIX accumulation was measured using flow cytometry. ALA esters, especially ALA-hexylester and ALA-benzylester, induced significant higher PPIX levels in adenocarcinoma cell lines when compared with ALA and may be promising candidates for PDT and PDD.

The narcotic drug methohexital 1 contains two asymmetric carbon atoms and, thus, consists of four isomers, two diastereomeric pairs of enantiomers. The commercial drug is the so-called α-racemate, one pair of diastereomers only. A method was developed to prepare differently enriched mixtures of methohexital isomers without resorting to lengthy and expensive optical resolutions. A model reaction for the synthesis of methohexital is the palladium-catalyzed allylation of 1,5-dimethyl-barbituric acid 3, which is optimized and checked by molecular modeling. Catalysts with the best ligands are used in the allylation of the methohexital precursor 7, which contains the C₆ sidechain at the tetrahedral center of the barbiturate skeleton. The product stereochemistry was determined by the contribution of the enantioselective Pd catalysts and by the fact that the allylation is a kinetic resolution. The methohexital isomer mixtures obtained were evaluated with the corneal stimulus test of rats. Methohexital compositions were found, which are superior to the commercially used α-racemate (Brevimytal®). Chirality 13:420–424, 2001. © 2001 Wiley-Liss, Inc.

Promoted by catalytic amounts of transition-metal complexes, the tertiary α-hydroxy ketones 1, 3, 5/6 undergo α-ketol rearrangements to afford equilibrium mixtures of isomers with a reorganization of the carbon skeleton. The range of metal complexes catalyzing the isomerizations is large; the best results were obtained with the catalyst systems NiCl₂/TMEDA, Ni(acac)₂, and Ni(acac)₂/TMEDA (TMEDA = N,N,N′,N′-tetramethyl-1,2-diaminoethane). The catalytic rearrangements were performed at 130 °C in the absence of solvent, with a Ni^II/ligand/substrate ratio of 1:2:100. The equilibrium composition of the model system 1/2 is 12.5:87:5. The conversion of the achiral substrates 1 and 3 into the chiral products 2 and 4 can be used for kinetic resolution. However, the reverse reactions 2 1 and 4 3 in the equilibrations narrow the window for asymmetric induction with enantioselective catalysts of the metal component/optically active ligand type. In system 1, the highest enantiomeric excess was achieved with the catalyst systems NiCl₂/pybox [18.9% (S)-2] and Ni(acac)₂/pybox [19.3% (R)-2] {pybox = 2,6-bis[(S)-4-isopropyl(oxazolin-2′-yl)]pyridine}. The α-ketol rearrangement of 3 with the Ni(acac)₂/pybox catalyst resulted in a maximum enantiomeric excess of 37.1% (S)-4.

A new catalytic method to synthesize the important anti-inflammatory agent naproxen [(S)-1] which has to be used as the (S) enantiomer, involves the enantioselective decarboxylation of the 6-methoxynaphth-2-yl derivative 2 of 2-cyanopropionic acid. Compound 2 was stirred in THF at 15 °C with catalytic amounts of chiral bases, which abstracted the carboxyl proton. After decarboxylation, reprotonation of the anion of 6 afforded the enantiomerically enriched naproxen nitrile 6, which may be hydrolyzed to naproxen. A variety of bases were screened, and cinchona alkaloids were found to give the best enantioselectivities. Thus, with quinidine 10, up to 34% ee was obtained for (S)-6. The enantiomeric excess could be increased by turning to amides of 9-amino-9-deoxyepicinchona alkaloids. The most successful 2-ethoxybenzamide 31a of 9-amino-9-deoxyepicinchonine 11 gave up to 71.9% ee (S)-6. Cyclic ethers like THF were suitable solvents, and at a temperature of 15 °C, conversion was quantitative within 24 h in most cases. For high enantioselectivities, 5−10 mol-% of chiral base was sufficient, and the catalyst could be fully recycled after decarboxylation. The model compound 2-cyano-2-phenylpropionic acid (40) was decarboxylated with base 31a to the (S) enantiomer of the corresponding nitrile 41 with 60% ee.

Allylation of 1-methyl-5-(1′-methylpent-2′-ynyl)barbituric acid (MBS) with allyl acetate using in situ catalysts of palladium(II) acetylacetonate and chiral phosphane imine ligands resulted in the enantioselective formation of 5-allyl-1-methyl-5-(1′-methylpent-2′-ynyl)barbituric acid (Methohexital), an important anesthetic drug. Both, MBS and Methohexital contain two stereogenic carbon atoms. In MBS, the asymmetric centre in the barbiturate system is labile due to enolization. The asymmetric centre in the hexyne side chain is stable and racemic. The two asymmetric centres of Methohexital are stable and give rise to four stereoisomers, two diastereomeric racemates. An analysis of the isomers of MBS and Methohexital was established on the basis of ¹H NMR and, in particular, GC including a base-line separation of the four stereoisomers of Methohexital. The stereoselectivity of the allylation is difficult to control, because the new quaternary asymmetric centre in the barbiturate ring of Methohexital is formed within the nucleophile, attacking the η³-allyl ligand of the catalyst from the side opposite to the palladium atom. Classical optically active ligands, such as diop or norphos, give only 2–6 % ee. Chiral phosphane imine ligands are a successful class of compounds, synthesized by Schiff base condensation of (2-formylphenyl)diphenylphosphane with optically active primary amines. The most efficient ligands have a hydroxymethyl and a bulky alkyl substituent at the asymmetric centre in the imine part, e.g. the L-iso-leucinol and the L-tert-leucinol derivatives 5 and 7. In the Pd-catalyzed allylation of MBS a kinetic resolution and the effect of the enantioselective catalyst interplay, the contributions of which are separated. For MBS the best stereoselectivity factor of the kinetic resolution s = k_R/k_S was 2.6 and 83 % “ee” were achieved. The corresponding values for Methohexital were s = 3.5 and 80 % ee in the α-dl pair. For 10 mixtures of Methohexital stereoisomers the anesthetic doses for rats were determined. With 9.1 mg/kg body weight of the animal the sample obtained from the catalysis with the D-α-phenylglycinol derivative 8 gave a much lower anesthetic dose than the widely used narcotic Brevimytal^®Natrium, the sodium salt of the α-dl racemate of Methohexital, with 13.0 mg/kg body weight.

Chirale Übergangsmetallatome treten nicht nur in Tris(chelat)komplexen [M(LL)₃]ⁿ⁺ auf, die bereits von Alfred Werner in die Enantiomere gespalten wurden, sondern auch in metallorganischen Halbsandwichkomplexen wie 1 mit Dreibein- oder Vierbein-Klavierstuhl-Struktur. Die Verbindungen haben sich bei der Aufklärung des räumlichen Ablaufs von Reaktionen und in der organischen Synthese bewährt. Anwendungen in der enantioselektiven Katalyse beginnen sich abzuzeichnen.

Chiral transition metal atoms are not only present in tris-chelate complexes [M(LL)₃]ⁿ⁺, which were already resolved into the enantiomers by Alfred Werner, but also in organometallic half-sandwich complexes such as 1 with three- or four-legged piano-stool structure. These complexes have been tools in the elucidation of the spatial course of reactions and in organic syntheses. Applications in enantioselective catalysis are beginning to show up.

The bond lengths Co–C(CO), Co–N(NO) and angles L–Co–C(CO), L–Co–N(NO) in six tetrahedral complexes, determined by X-ray crystallography, were analysed and compared with the calculated compound Co(CO)₂(NO)PH₃. Distinct differences were found which allow a differentiation of the two similar ligands CO and NO. These differences are used to assign CO and NO ligands in cases where this has not been possible before including a structure in which the two independent molecules in the unit cell are diastereomers. The relationship seems to hold not only for tetrahedral compounds but also for other polyhedral coordination types.

Condensation of (R)-2-aminobutanol with salicylaldehyde and 2-pyrrolecarbaldehyde gave the chiral chelate ligands HLL₁* and HLL₂*, respectively. The diastereomeric complexes (R_Ru,R_C)- and (S_Ru,R_C)-[(η⁶-arene)Ru(LL₁*)Cl], η⁶-arene = p-cymene (1a/1b), η⁶-arene = benzene (2a/2b), and (R_Ru,R_C)- and (S_Ru,R_C)-[(η⁶-arene)Ru(LL₂*)Cl], η⁶-arene = p-cymene (3a/3b), η⁶-arene = benzene (4a/4b), which only differ in the ruthenium configuration, were prepared by the reaction of [(η⁶-arene)RuCl₂]₂ with the anion of the corresponding ligand HLL*. X-ray analyses of 1a/1b and 3a/3b showed a structural peculiarity. The unit cell of these complexes contained diastereomers with the same configuration at the carbon atoms but opposite configuration at the metal centers in a 1:1 ratio. Weak intramolecular O–H···Cl hydrogen bridges were formed in all the complexes. ¹H-NMR studies demonstrated the configurational lability at the Ru center. The iodo complexes (R_Ru,R_C)- and (S_Ru,R_C)-[(η⁶-p-cymene)Ru(LL*)I], LL* = LL₁* (5a/5b) and LL* = LL₂* (6a/6b), were synthesized by halogen exchange.

Novel 2-(4,4′-bipyridin-2-yl)oxazolines, bearing a chiral oxazoline moiety, were synthesised starting from 4,4′-bipyridine and selectively monomethylated in the N′-position. After coordination to rhodium these electron-poor ligands are supposed to exhibit charge-transfer effects with electron-donating substrates in the Rh(I)-catalysed enantioselective hydrosilylation (see next publication). Similar effects were expected from 4,4′-bipyridine- and pyrazine-bisoxazolines after complexation with rhodium. For comparison 2-(4-phenylpyridin-2-yl)oxazoline ligands were synthesised. Rh(I)-complexes of selected ligands were prepared and characterised, including an X-ray structure analysis.

Novel N′-methylated 2-(oxazolin-2-yl)-4,4′-bipyridinium salts, bearing a chiral oxazoline moiety, were tested in the Rh(I)-catalysed enantioselective hydrosilylation. After coordination to rhodium these electron-attracting ligands are supposed to exhibit charge-transfer effects with electron-donating substrates. Therefore, a new catalytic hydrosilylation reaction with 2,5-dimethoxyacetophenone as an electron-rich substrate was developed. The results were compared with those of the non-methylated 2-(oxazolin-2-yl)-4,4′-bipyridine and related ligands. In addition, the new ligands and Rh(I)-complexes were tested in the hydrosilylation of acetophenone.

The two hydride ligands in [Cp₂MoH₂] and [Cp₂WH₂] are directed towards the coordination center in silver(I) halide complexes such as 1. X-ray crystal structure analyses of several of these complexes with the [Cp₂MoH₂] ligand illustrate the diverse range of structures available.