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In this article we demonstrate how asymmetric total synthesis of (S)-rivastigmine has been achieved using direct asymmetric reductive amination as the key transformation in four steps. The route started with readily available and cheap m-hydroxyacetophenone, through esterification, asymmetric reductive amination, N-diphenylmethyl deprotection and reductive amination, to provide the final (S)-rivastigmine in 82% overall yield and 96% enantioselectivity. In the asymmetric reductive amination, catalysed by the iridium&ndash, phosphoramidite ligand complex and helped by some additives, the readily prepared 3-acetylphenyl ethyl(methyl)carbamate directly reductively coupled with diphenylmethanamine to yield the chiral amine product in 96% ee and 93% yield.

Copper-catalyzed intramolecular conjugate addition–cyclization in the presence of chiral phosphoramidite ligands was described. Cyclic products with multiple chiral centers were obtained with up to 93:7 diastereomeric ratio and 94% ee.

The rhodium-phosphoramidite-catalyzed asymmetric conjugate addition of arylboronic acids to enones proceeds at room temperature using [Rh(OH)(cod)](2) or [RhCl(cod)](2)/KOH as stable and readily available catalyst precursors. (c) 2005 Published by Elsevier Ltd.

Mixtures of chiral and achiral monodentate phosphoramidite ligands lead to improved enantioselectivity in the rhodium-catalyzed boronic acid addition. (c) 2005 Published by Elsevier Ltd.

New phosphoramidites were applied as chiral ligands in the Cu-catalyzed allylic alkylation with dialkylzinc reagents. A variety of substrates, reagents and chiral ligands were screened, resulting in improved catalytic methodology for allylic bromides in which enantioselectivities up to 88% were reached.

The stereoselective synthesis of 1,2-diamines has remained a formidable challenge. A recent palladium-catalyzed asymmetric diamination of conjugated double bonds using di-tert-butyldiaziridinone appears promising. The axially chiral binol phosphoramidite ligands are successful in offering high enantioselectivity. The density functional theory investigations revealed that the energies of the stereo-controlling transition states for the C-N bond formation depend on a number of weak non-covalent interactions such as C-H center dot center dot center dot pi, C-H center dot center dot center dot O and anagostic interactions. We envisaged that the modulation in these interactions in the transition states, through subtle changes in chiral phosphoramidite substituents, could be exploited toward steering the stereoselectivity. The effect of systematic modifications on both 3,3' positions of the binol as well as on the amido nitrogen on the stereochemical outcome is predicted. It is identified that high enantioselectivity requires a balance between the nature of the substituents on binol and amido groups. The reduced size of the amido substituents demands increased bulk on the binol whereas lowering the size on the binol demands increased bulk on the amido for higher stereoselectivity. The substituent at the alpha-position of the amido group is found to be vital and appears to be a hot spot for modifications. These insights derived from studies on the stereocontrolling transition states could help improve the catalytic efficacies in palladium-catalyzed asymmetric diamination reactions.

An efficient method is reported for the highly enantioselective copper-catalyzed conjugate addition of dialkylzinc reagents to alpha,beta-unsaturated sulfones using a monodentate phosphoramidite ligand.

A catalyst system able to perform highly enantioselective Cu-catalysed allylic alkylations with Grignard reagents is described.

Trimethyl- and triethylaluminum undergo enantioselective conjugate addition to 3- and 2-substituted cyclohexenones in the presence of catalytic amounts of a Cu salt and a phosphoramidite ligand L* (see scheme). Thus, chiral quaternary centers can be built with up to 96.6 % ee. Functionalized enones lead to bicyclic structures by a subsequent aldol reaction.

Different tropos deoxycholic acid derived biphenylphosphites were used as Rh(I) chiral ligands, at P/Rh 1:1 and 2:1 molar ratios, to obtain mono- or disubstituted Rh(I) complexes, which act as cata...

Enantioselective copper-catalyzed allylic alkylations were performed on allylic bromides with a protected hydroxyl or amine functional group using several Grignard reagents and Taniaphos L1 as a ligand. The terminal olefin moiety in the products was transformed into various functional groups without racemization, providing facile access to a variety of versatile bifunctional chiral building blocks.

The enantioselective, copper/phosphoramidite-catalyzed 1,4-addition of dialkylzinc reagents to acyclic dienones is described. The products of this reaction, obtained with enantioselectivities of up to 95%, can be further functionalized by a second conjugate addition, or employed in an enolate trapping, ring-closing metathesis protocol.

A series of protected beta(2)-dehydroamino acids has been prepared in three steps from commercially available starting materials in good yields. These were used as substrates in rhodium-catalyzed asymmetric hydrogenation applying a mixed ligand system of monodentate phosphoramidites and phosphines. Optimization of the catalyst structure was achieved by high throughput experimentation. High enantioselectivities were obtained ( up to 91%) with full conversion for a number of beta-amino acids.

The complex derived from Taniaphos ligand 4 and CuBr*Me2S catalyzes the asymmetric addition of Grignard reagents to 3-bromopropenyl esters 1 to provide allylic esters 2 in high yields and high chemio-, regio-, and enantioselectivities. The work demonstrates that allylic asymmetric alkylation (AAA) can be done on substrates bearing a heteroatom at the gamma-position. The method is a practical route to chiral, nonracemic allylic alcohols. The use of functionalized substrates 1 or Grignard reagents leads to more complex products 2, which can be further manipulated as demonstrated in conversion to (S)-5-ethyl-2(5H)-furanone 6 and (S)-benzoic acid-cyclopent-2-enyl ester 7.