Prochiral Substrates Research Articles

The Hydrovinylation Reaction: A New Highly Selective Protocol Amenable to Asymmetric Catalysis

Carbon-carbon bond forming reaction is arguably the most important type of bond construction in organic chemistry; yet, paucity of methods for the stereoselective incorporation of abundantly available carbon feedstocks such as CO, CO2, HCN, or simple olefins to prochiral substrates is one of the major limitations in this area.1 One potentially important class of such reactions is the cationic [Ni-H]+-catalyzed olefin dimerization reaction.2,3 There had been only limited success in finding an enantioselective variation of this reaction partly because of the competing oligomerization of starting olefins and isomerization of the primary products (eq 1). In this paper we report our initial

Enzymatic condensation and polycondensation reactions in organic solvents

AbstractLipases in organic solvents catalyse lactonisation or polymerisation of ω‐hydroxyesters. Under these conditions the enzymes exhibit both enantioselectivity and prochiral selectivity. This approach was used to develop the synthesis of chiral γ‐lactones and A‐B type polyesters from racemic or prochiral hydroxyester substrate.

２，４‐ペンタンジオールをキラル連結架橋に用いる立体区別反応：簡便で確実な不斉反応の開発

The diastereodifferentiating reactions between a prochiral substrate and a reagent connected with optically active 2, 4-pentanediol were studied. The reactions based on this simple design were found to give products of over 99% diastereomeric excess during carbenoid addition, mata-arene-olefin photocycloaddition, oxidative couplings, and epoxidation, and after removal of the chiral auxiliary from the products, optically pure compounds were obtained in good yields. By using the obtained asymmetric reaction, total synthesis of (+) -africanol was achieved in 16 steps. Newly found highly effective and diastereodifferentiating radical abstraction was applied for total syntheses of (+) -ipomeamarone and (-) -ngaione.

Influence of a remote hydroxy group in the ligand on the reactivity of a chiral hydrogenation catalyst

A kinetic study concerning the asymmetric hydrogenation of prochiral olefins by chiral diphosphine rhodium cyclooctadiene complexes based on HO-DIOPs is presented. The investigations have been carried out in order to show the influence of a remote hydroxy group on the rate of the reaction. Since in methanol under standard conditions the reactivities of all catalysts elaborated were too high, the hydrogenation experiments have been performed under reduced hydrogen pressure affording the desired reduction in rate. To avoid the induction period caused by the hydrogenation of the cyclooctadiene all precatalysts were prehydrogenated before the prochiral substrates were added. For comparison analogous Rh-DIOP complexes with the same structural framework, but without the hydroxy group in the backbone have been proven. For all hydroxy catalysts investigated a lower reactivity has been observed compared to the parent complexes, although a direct interaction between HO-group and reaction center can be presumably excluded. This assumption is supported by the X-ray structural analysis of one of the complexes which shows the remote position of the HO-group related to the metal center.

Asymmetric Synthesis of (R)-Nilvadipine and (S)-NB 818 via Regioselective Bromination of Chiral 1,4-Dihydropyridines as a Key Step and Enzymatic Resolution of Racemic 2-Hydroxymethyl-1,4-dihydropyridine Derivatives.

Optically active 2-hydroxymethyl-1, 4-dihydropyridines were obtained by lipase-catalyzed hydrolysis or transesterification of racemic materials. Chiral NB 818 and nilvadipine have been synthesized from chiral 2-hydroxymethyl-1, 4-dihydropyridine. On the other hand, chiral 1, 4-dihydropyridines obtained from prochiral substrates have been converted into (S)-NB 818 and (R)-nilvadipine via regioselective bromination of methyl groups under mild conditions.

Asymmetric hydrogenation by ruthenium cluster hydrides containing atropoisomeric diphosphine ligands

Ruthenium clusters containing atropoisomeric diphosphines, namely [Ru 4(μ-H) 4(CO) 10{( S)-(−)-BINAP}], where BINAP is 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and [Ru 4(μ-H) 4(CO) 10{( S)-(−)-MOBIPH}], where MOBIPH is 2,2′-bis(diphenylphosphino)-6,6′-dimethoxy-1,1′-diphenyl, have been used as catalysts in the asymmetric hydrogenation of some prochiral substrates containing CC or CO double bonds. With the BINAP derivative optical purities up to 30% were achieved.

A Re-Examination of Pressure Effects on Enantioselectivity in Asymmetric Catalytic Hydrogenation

Marked shifts in enantioselectivity in the asymmetric hydrogenation of several prochiral substrates were observed as a function of the availability of hydrogen to the catalyst in both heterogeneous and homogeneous catalytic reactions. The key kinetic parameter affecting enantioselectivity was found to be concentration of molecular hydrogen in the liquid phase, [H2], rather than hydrogen pressure in the gas phase, and it was observed that under typical reaction conditions, [H2] could differ widely from its equilibrium saturation value. It was demonstrated that the reported pressure dependence on enantioselectivity may in fact be reproduced at constant pressure for several systems by varying the rate of gas−liquid mass transfer. The general significance of the conclusions suggest that considerations of hydrogen diffusion limitations might be important in other asymmetric hydrogenation studies reported in the literature. For systems where enantioselectivity depends positively on hydrogen pressure, the intrinsic ability of a catalyst to effect asymmetric hydrogenation may be masked in a reaction carried out under conditions where gas−liquid diffusion is the rate-limiting step.

β‐Alkoxy‐ and β‐Hydroxyalkylphosphanes as Ligands in the Stereoselective Hydrogenation — A Comparison

Optically pure 1,4-bis(diphenylphosphanyl)-2-hydroxy-butane (2) and its methyl ether 1 can be conveniently prepared by starting from chiral pool substances such as malic or L-ascorbic acid. Different pathways to these compounds were elucidated. In one case an interesting migration of an acetalic OH-protective group was observed. The reaction of the bisphosphanes with Rh1 or PdII gave uniform metal complexes. On the basis of X-ray structural analysis, NMR and IR data it was concluded that in the investigated precatalysts of the type [Rh(COD)(bisphosphane)]BF4 a coordination of the alkoxy or hydroxy oxygen to the metal does not take place. Nevertheless, significant differences in enantioselectivity and activity could be observed when several prochiral substrates were hydrogenated.

Kinetische Untersuchungen zur Ligandenhydrierung in Katalysatorvorstufen für die asymmetrische Reduktion prochiraler Olefine

Kinetic Investigations of the Hydrogenation of Ligands in Catalyst Precursors for Asymmetric Reduction of Prochiral OlefinesHerrn Professor Kurt Madeja zum 70. Geburtstag gewidmet. The comparison of chiral rhodium(I) complex catalysts of the type [Rh(L)PP*]A (L = cyclic diolefin; PP* = chiral bis(phosphane) and A = anion like BF) regarding their hydrogenating activity against prochiral substrates is hampered by the induction period in the hydrogen consumption which can be attributed to the formation of the catalytically active species from the diolefin precatalyst. The competing hydrogenation of diolefin [e.g. cis,cis‐cycloocta‐1,5‐diene (COD), norborna‐2,5‐diene (NBD)] and prochiral substrate may cause a maximum of the hydrogenation rate, which is characteristic for different catalyst/substrate/solvent systems. Michaelis‐Menten rate constants for the hydrogenation of COD and NBD were determined for different chiral catalysts by stoichiometric and catalytic hydrogenations. The rate constants differ for one selected diolefin up to a factor of 40. The hydrogenation of NBD is generally 5–8 times faster than the COD hydrogenation. In the special case of precatalysts based on he‐xopyranoside bis(phosphinites) the rate constants for the NBD hydrogenation in comparison with those for COD are higher up to a factor of 48. In some cases the hydrogenation of the mono‐ene is faster than that of the diolefin (e.g. COD, NBD). The high hydrogenation rate reported in the literature for some precatalysts in the asymmetric hydrogenation of prochiral olefins is caused in part by the relatively fast diolefin hydrogenation which facilitates the complete formation of the catalyst. The influence of substrate, solvent, and some experimental conditions on the induction period will be discussed.

Biocatalytic preparation of chiral alcohols by enantioselective reduction with immobilized cells of carrot

The ability of immobilized cells of Daucus carota to reduce enantioselectively organic foreign substrates has been examined. The immobilized plant cells reduced, with excellent enantioselectivity, prochiral ketone substrates such as keto esters, aromatic ketones and heterocyclic aromatic ketones, leading to the corresponding chiral secondary alcohols with an enantiomeric purity of 52–99% ee in a chemical yield of 30–63%.

Lipase-catalyzed asymmetric hydrolysis and regioselective bromination of 1,4-dihydropyridine. Synthesis of ( R)-(=)-nilvadipine

Homochiral ( R)-nilvadipine was synthesized from a prochiral substrate using lipase-catalyzed asymmetric hydrolysis and subsequent regioselective bromination as key steps.

Enantioselective hydrogenation reactions with a full set of preformed and prepared in situ chiral diphosphine-ruthenium (II) catalysts.

The new class of 2-methylallyl ruthenium chiral diphosphines 1 are efficient in asymmetric hydrogenation of α,β unsaturated acids and allylic alcohols. The related chiral halogen-containing ruthenium catalysts 2 are prepared from 1 or in situ from (COD)Ru(η) 3-(CH 2) 2CHCH 3) 2 by ligand exchange with the chelating diphosphine followed by protonation (HX) in acetone. This procedure allows rapid screening of chiral phosphines, such as Diop, Chiraphos, Cbd, Bppm, Binap, β-glucophos, Biphemp, MeO-Biphep, Me-Duphos, in ruthenium mediated hydrogenations of prochiral substrates. A high efficiency is displayed by Ru-catalysts having atropisomeric ligands (e.e. up to 99%), and a C 2 symmetric bis(phospholane) has also emerged as a valuable ligand (Me-Duphos, e.e. up to 87% not optimized). Asymmetric hydrogenation of β-keto esters can be conducted under quite mild conditions (4 atm. of H 2, 50°C, e.e. up to 99%), β-keto esters having a disubstituted double bond are also hydrogenated chemoselectively to unsaturated chiral alcohols under controlled conditions with excellent optical purities.

Natural products by enantioselective catalysis with transition metal compounds

Abstract

The Effects of Surfactants on Lipase-Catalysed Hydrolysis of Esters: Activities and Stereoselectivity

The effect of surfactants on the hydrolysis of prochiral and chiral substrates by crude and purified porcine pancreatic lipase (PPL, EC 3.1.1.3)) has been studied. Rather than accelerating the reactions, surfactants slowed down (“inhibited”) the reactions relative to the rate in the absence of surfactant. Surfactants varied in the extent to which the reaction was inhibited. With the crude enzyme there was a correlation between degree of inhibition and the optical purity of the product of hydrolysis of an achiral diester substrate 1. There was no special effect associated with use of surfactants in the concentration range corresponding to critical micelle formation, nor was there any increase in rate of reaction when stable emulsions were formed by using mixtures of surfactants to generate an appropriate hydrophile-lipophile (HLB) balance. A study of the effect of sodium dodecyl sulphate (SDS) on the hydrolysis of the diester 1 by crude PPL showed that the rate of the reaction steadily decreased with incre...

The temperature dependence of steady‐state kinetics: What can be learned about pig liver esterase stereospecificity?

The steady-state kinetic parameters for pig liver carboxylesterase (PLE)-catalyzed hydrolysis of the prochiral substrate dimethyl phenylmalonate (DMPM) (product enantioselectivity) and the separate enantiomers of three chiral 2-phenylpropionic acid esters (substrate enantioselectivity) were measured at seven temperatures between 288 K and 312 K. Arrhenius plots of turnover numbers against the reciprocal of experimental temperatures yielded enthalpies and entropies of activation at enzyme saturation. (+)-(S)-methyl-2-phenylpropionate, (+)-(S)-4-nitrophenyl 2-phenylpropionate, and both enantiomers of phenyl 2-phenylpropionate showed very similar activation enthalpies and entropies (approximately 50 kJ mol-1 and -50 J mol-1 K-1, respectively), but differences were observed for (-)-(R)-methyl 2-phenylpropionate and (-)-(R)-4-nitrophenyl 2-phenylpropionate. Whereas the entropies of activation of all 2-phenylpropionates were negative, positive entropies of activation were measured in the formation of monomethyl phenylmalonate enantiomers from DMPM. Enthalpy-entropy compensation analysis of the data indicates a common mechanism of PLE substrate and product enantiospecificity in the reactions studied here.

Asymmetric metabolic N-oxidation of N-ethyl-N-methylaniline by purified flavin-containing monooxygenase.

The prochiral tertiary amine N-ethyl-N-methylaniline (EMA) is known to be metabolically N-oxygenated in vitro with microsomal preparations. This biotransformation is thought to be mediated predominantly by the flavin-containing monooxygenase (FMO) enzyme system. Microsomal N-oxygenation of EMA is known to be stereoselective and varies between species. In order to further characterise this metabolic transformation, we have examined the in vitro metabolism of EMA using purified porcine hepatic FMO. Following incubation of EMA with purified FMO, EMA N-oxide, the only metabolic detected, was found to be produced stereoselectively [ratio (-)-(S):(+)-(R), ca. 4:1]. The enantiomeric ratio of the N-oxide product did not change markedly with respect to time, enzyme or substrate concentration. Determination of the kinetics of formation of the N-oxide indicated a single affinity for the prochiral substrate with differential rates of formation of the enantiomers. The extent of EMA N-oxide formation was shown to be affected by activators and inhibitors of FMO and pH, but its stereoselectively was unaltered.

Microbial Alkene Epoxidation—Merits and Limitations

The direct epoxidation of olefins using monooxygenases offers the realistic prospect of stoichiometric conversion of a pro-chiral substrate into an enantiomerically pure product. A number of microbial systems are available in which the mechanism of oxygen activation, and consequently the oxygen reactivity, differs. This paper discusses some of the merits and potential problems associated with these different systems.

Introduction of a New Class of Ligands for the Metal‐Catalyzed Enantioselective Synthesis

AbstractProtected thiosugars were prepared as ligands for the metal‐catalyzed enantioselective synthesis. The protecting groups in these ligands were varied to test a proposed new concept for the metal‐catalyzed enantioselective synthesis. This new concept centres on the use of a stair‐like ligand with a large substituent on one side and a small substitutent on the other rather than the commonly employed ligands which have C2 symmetry (see Fig.3). In such a ligand, both substituents should have a major influence on the coordination of a prochiral substrate. To test this proposal, 3‐thio‐α‐D‐glucofuranose derivatives with the following substituents were synthesized: 1,2‐O‐isopropylidene‐5,6‐O‐methylidene (see 24), 1,2:5,6‐di‐O‐isopropylidene (see 2), 5,6‐O‐cyclohexylidene‐1,2‐O‐isopropylidene (see 23), 1,2‐O‐cyclohexylidene‐5,6‐O‐isopropylidene (see 14), 1,2:5,6‐di‐O‐cyclohexylidene (see 13), 5,6‐O‐(adamantan‐2‐ylidene)‐1,2‐O‐isopropylidene (see 21), and 1,2:5,6‐di‐O‐(adamantan‐2‐ylidene) (see 25, Table 2). As a representative of the allofuranoses, 1,2:5,6‐di‐O‐isopropylidene‐3‐thio‐α‐D‐allofuranose (6) was chosen. The following derivatives of 1,2‐O‐isopropylidene‐α‐D‐xylofuranose were also synthesized: 1,2‐O‐isopropylidene‐5‐deoxy‐3‐thio‐α‐D‐xylofuranose (29), 1,2‐O‐isopropylidene‐3‐thio‐α‐D‐xylofuranose (28) and 5‐O‐[(tert‐butyl)‐diphenylsilyl]‐1,2‐O‐isopropylidene‐3‐thio‐α‐D‐xylofuranose (15, see Table 2). The proposed concept was tested using the copper‐catalyzed 1,4‐addition of BuMgCl to cyclohex‐2‐en‐1‐one. The enantioselectivity was very dependent on the ligand used and was up to 58%.

Asymmetric synthesis by reduction or by oxidation of prochiral substrates absorbed into chiral polymer supports

Prochiral ketones absorbed into chiral polymer supports were reduced with aqueous potassium borohydride. 2-Substituted naphthoquinones absorbed into chiral polymer supports were epoxidized using aqueous alkaline hydrogen peroxide. In both systems asymmetric synthesis was achieved. Best results were obtained with microcrystalline cellulose triacetate as the polymer support: 8.6% ee in a reduction, 4.5% ee in an epoxidation. Use of tetra- n-butylammonium bromide as a phase transfer catalyst tended to improve chemical yields and ees. The potential of this type of approach in asymmetric synthesis is discussed.

A D-antifreeze polypeptide displays the same activity as its natural L-enantiomer.

The D- and L-forms of an alpha-helical antifreeze polypeptide (AFP) have been chemically synthesized. Circular dichroism spectra of the molecules show equal and opposite ellipticites. The D- and the L-enantiomers alone, and a 50:50 mixture of the two, all show identical antifreeze activity, but the enantiomeric forms are predicted to bind to the ice surface with different orientations. It is suggested that symmetry properties of certain ice surfaces permit the asymmetric binding of AFPs, and thus that AFPs are analogous to enzymes that act upon prochiral substrates.