O 9l

Of-Bu Ph^H

Scheme 1.13 Chiral boron reagents

Et3N

continuously inducing intermolecular chirality transfer. Chirality multiplication effect and high selectivity are key features of enzymatic catalysis in all living systems and biocatalysed reactions, not covered here, are currently used in the industrial preparation of aminoacids, alcohols, amines and epoxides [85, 86].

MeO. AcO

MeO. AcO

OH NHAc

PPh2

PPh2

PPh2

PPh2

(S,S)-CHIRAPHOS

PPh2

(S)-BINAP R = Ph (S)-TolBINAP R = 4-MePh (S)-XylBINAP R = 3,5-(Me)2Ph

(S)-BINAP R = Ph (S)-TolBINAP R = 4-MePh (S)-XylBINAP R = 3,5-(Me)2Ph

Cy2P*

R = Ph, R1= Me (S)-BIPHEMP R = Ph, R1= OMe (S)-MeOBIPHEP

R = Ph, R1= Me (S)-BIPHEMP R = Ph, R1= OMe (S)-MeOBIPHEP

Scheme 1.14 Knowles' process for production of L-DOPA at Monsanto (a) and chiral phosphine ligands for asymmetric hydrogenation (b)

Although many purified enzymes or whole cells from a variety of microorganisms have been identified as useful catalysts for different classes of reactions, their high substrate specificity, the need in some instances of cofactors and/or auxiliary enzymatic systems and the difficulty or impossibility in reversing the natural stereopreference can sometimes represent troublesome tasks.

Since the first report of a man-made catalyst for asymmetric cyclopropanation [87] and the first application of a catalytic asymmetric process at industrial level (Monsanto) in the production of the anti-Parkison drug L-DOPA [88], the organic chemists have been faced with the challenge to discover a variety of efficient catalytic stereoselective reactions that complement the biological ones. A part the obvious advantage that a minimal amount of chiral compound is needed, the catalytic approach has opened a new era in the field of asymmetric synthesis for the possibility to modulate and enhance the selectivity by an appropriate catalyst

Ar2 ci H2 R

Ar2 Cl H2

Ar2 ci H2 R

Ar2 Cl H2

"""R2

Ar = Ph, 4-MePh, 3,5-(Me2)Ph R=H, R1=R2= Ph (S,S)-DPEN R= R1= 4-OMePh, R2= i-Pr (S,S)-DAIPEN

OH X

OH X

99% ee X = Me 93% ee X = Br 96% ee X = OMe 99.4% ee

Scheme 1.15 Asymmetric hydrogénation of ketones with Noyori's [Ru/BINAP/diamine] catalysts design, driven by the knowledge of its chemical properties and the elucidation of reaction mechanism.

Asymmetric catalysis has now became a predominant methodology for the production of chiral compounds from achiral molecules and its continuously growing importance has been acknowledged by the Nobel prize awarded in 2001 to Knowles, Noyori and Sharpless for their fundamental research in this field [89-91]. Hydrogenation of olefins, firstly reported using Rh-diphosphine catalysts bearing stereogenic phosphorous atoms [92], has been improved through the introduction of a variety of ligands with carbon backbone chirality [93] (Scheme 1.14) and then extended to ketone substrates thanks to the development of ruthenium complexes with axially chiral binaphtyl- and biaryldiphosphines, whose coupling with chiral 1,4-diamines as ancillary ligands has allowed to achieve extremely high selectivity even with sterically hindered substrates [94] (Scheme 1.15).

Asymmetric epoxidation of allylic alcohols, initially described as a stoichiometric process and then developed in its catalytic version [95, 96], and alkene cis-dihydroxylation promoted by Cinchona alkaloid derivatives [97] as highly specific catalysts proved to be powerful C-O bond forming reactions with large scope and predictability of the induction sense (Scheme 1.16).

A catalytic reaction evolves through a cyclic sequence of coordination of the reactants to the catalyst in a well-organized transition state followed by the formation of the reaction product, that is then released regenerating at the same time

DHQD/PHAL (1%) OsO4 (1%),K3Fe(CN)6 f-BuOH/H2O 1:1, 0 °C

DHQ/PHAL (1%) OSO4 (1%),K3Fe(CN)6 f-BuOH/H2O 1:1, 0 °C

Scheme 1.16 Sharpless' asymmetric epoxidation of allylic alcohols (a) and dihydroxylation of olefins (b)

the catalyst. In this context, transition metal complexes with chiral ligands act as effective enantioselective catalysts for their ability in coordinating the prochiral centre of a given substrate in the metal close proximity and for the intrinsic electronic properties of transition metals that change their oxidation state during the cycle giving rise to different oxidative or reductive reactions (addition, elimination, insertion) in their coordination sphere. The chiral ligands play a key role in the discrimination of the possible diastereoisomeric reaction states leading to the opposite enantiomers and the stabilization of one of them over the others, in many cases through additional secondary interactions between ligands and substrates, determines the enantioselectivity of the process.

As an example, in the hydrogenation of N-acyl-dehydroaminoacids catalysed by Rh(I)-chiral phosphines complexes the substrate is fastly coordinated to Rh(I), through the interaction of both the olefinic bond and amide carbonyl oxygen with the metal centre, to give the chelate complex I. In the rate-limiting step I undergoes the irreversible oxidative addition of H2 to afford a five-membered Rh(III)-inter-mediate II and following a migratory insertion step, hydrogen is then transferred to the olefinic bond of enamide. A reductive elimination final step accounts for the simultaneous release of the aminoacid reaction product and regeneration of the initial Rh-ligand [98-100] (Scheme 1.17).

The origin of efficient transfer of chirality resides in the use of C2-symmetrical ligands to reduce the possible diastereoisomeric transition states and in the asymmetric array of diphosphine substituents in the ligands bound to the metal in cyclic chelates, whose absolute k or ¿ configuration determines the sense of asymmetric inductions in agreement with a quadrant diagram model [101] (Scheme 1.18).

The elucidation of a reaction mechanism, usually supported by kinetic isotope effects studies [102], NMR structural characterization of intermediates [103] and computer-aided calculations [104, 105] is often complicated by the presence of different metal complexes as active catalysts, as in the Ti-binaphtol promoted glyoxylate-ene reaction [106], or by the occurrence of different catalytic pathways becoming operative in function of the reagents' features, as in Pd-catalysed allylic alkylations [107].

The performance of a catalyst is mainly expressed by its enantioselectivity, i.e. the enantiomeric excess of the obtained products, but other parameters need to be also taken into the account in determining the effectiveness and the scale-up feasibility of an asymmetric catalytic reaction. Functional group tolerance and chemoselectivity are especially important when a complex substrate must be transformed selectively whereas the catalyst productivity, given as turnover number (TON = mol product/mol catalyst) or substrate/catalyst ratio (s/c), and catalyst activity, given as turnover frequency (TOF = mol product/mol catalyst/ reaction time, h-1), have an obvious incidence on the overall costs of an enantioselective process. Hydrogenation of olefins and ketones are by far the predominant asymmetric chemical transformations that have been successfully developed at industrial level [108, 109] followed by epoxidation and hydroxylation reactions whereas addition to C=C or C=O and C=N bonds and carbon-carbon bond forming reactions are currently limited to bench-scale development, despite of their high synthetic potential and the large number of new catalysts reported in last years [110, 111].

Among the production processes shown in Scheme 1.19 the Solvias hydrogenation of imine 21 to give an intermediate for (S)-metolachlor herbicide makes use of Ir-complex 23 as catalyst, whose excellent performances (TON 2.000.000; TOF 400000 h-1) were achieved through a careful structural tuning of the planar chiral ferrocenylphosphine ligand [112]. The Astra-Zeneca production of anti-ulcer drug esomeprazole relies on the Ti/diethyltartate catalysed stereoselective oxidation at the sulphur atom of 26 [113] while asymmetric allyl isomerisation,

Scheme 1.17 Catalytic cycle in the Rh-promoted hydrogénation of enamides

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