New entries in Lewis acid-Lewis base bifunctional asymmetric catalyst: catalytic enantioselective Reissert reaction of pyridine derivatives

The first catalytic enantioselective Reissert reaction of pyridine derivatives that affords products with excellent regio- and enantioselectivity is described. The key for success is the development of new Lewis acid-Lewis base bifunctional asymmetric catalysts containing an aluminum as a Lewis acid and sulfoxides or phosphine sulfides as a Lewis base. These reactions are useful for the synthesis of a variety of chiral piperidine subunits, and catalytic enantioselective formal synthesis of CP-293,019, a selective D4 receptor antagonist, was achieved. Preliminary mechanistic studies indicated that both sulfoxides and phosphine sulfides can activate TMSCN as a Lewis base. In addition, the sulfoxides with appropriate stereochemistry might stabilize a highly enantioselective bimetallic complex (a presumed active catalyst) through internal coordination to aluminum.     

A Lewis acid-Lewis base bifunctional catalyst from a new mixed ligand

Covalent attachment of quinine to a salen framework through a racemic linker gave a new mixed ligand in a 1:1 diastereomeric mixture, from which an active Lewis acid-Lewis base (LA*-LB*) bifunctional catalyst derived from Co(II) was discovered by the screening of metal complexes. The remarkable intramolecular bifunctional catalytic activity (1 mol % catalyst loading) of the new catalyst was demonstrated using a proof-of-principle reaction. [reaction: see text].     

A mild and efficient cyanosilylation of ketones catalyzed by a Lewis acid-Lewis base bifunctional catalyst

A new family of bifunctional catalysts (N-oxides-Ti(OⁱPr)₄ (2:1)) containing a Lewis acid and a Lewis base was developed and applied to the catalytic cyanosilylation of ketones. Utilizing rac((1R,2S) and (1S,2R))-1-(2′-pyridylmethyl)-2-diphenylhydroxymethylpyrrolidine N-oxide-titanium (2:1) complex and N-benzyl-diethanolamine N-oxide-titanium (2:1) complex as catalysts, the cyanosilylation products were obtained in 42-97% yield. Based on experimental phenomena and kinetic studies, a catalytic cycle was proposed to explain the remarkable activities of these catalysts. Investigations indicated that rac((1R,2S) and (1S,2R))-1-(2′-pyridylmethyl)-2-diphenylhydroxymethylpyrrolidine N-oxide-titanium (2:1) complex and N-benzyl-diethanolamine N-oxide-titanium (2:1) complex should promote the reaction via a dual activation of the ketone by the titanium and TMSCN by the N-oxide.     

Lewis acid-Lewis base catalyzed enantioselective hetero-Diels-Alder reaction for direct access to delta-lactones

A complex formed in situ from Er(OTf)3 and a simple commercially available norephedrine ligand promotes an unprecedented [4 + 2] cycloaddition of alpha,beta-unsaturated acid chlorides with a broad range of aromatic and heteroaromatic aldehydes by a cooperative bifunctional Lewis acid-Lewis base catalytic mode of action providing valuable delta-lactone building blocks with excellent enantioselectivity.     

Chiral ammonium betaines: a bifunctional organic base catalyst for asymmetric Mannich-type reaction of alpha-nitrocarboxylates

A chiral ammonium betaine, an intramolecular ion-pairing quaternary ammonium aryloxide 3, has been designed and its vast potential as an enantioselective organic base catalyst has been successfully demonstrated in the highly enantioselective direct Mannich-type reaction of alpha-substituted alpha-nitrocarboxylates 2 with various N-Boc imines 1. The present study provides a conceptually new approach toward the design of bifunctional, chiral quaternary ammonium salts and their utilizations as a homogeneous organic molecular catalyst.     

Enantioselective aldol reaction of silyl ketene acetals promoted by a Lewis base-activated Lewis acid catalyst

The enantioselective aldol reaction of a silyl ketene acetal was promoted by chiral phosphine oxide-activated tetrachlorosilane to afford the corresponding adduct in high yield with moderate enantioselectivity.     

Chiral copper-Schiff base catalyst for asymmetric henry reaction

Five copper-Schiff base complexes were synthesized conveniently from copper(II) acetate monohydrate, salicylaldehydes, and amino alcohols. The complexes were shown to be effective as catalysts in the asymmetric Henry reaction affording nitro alkanols in up to 98% yield with moderate and good enantiomeric excess (up to ee 38.6%). Published in Russian in Zhurnal Organicheskoi Khimii, 2007, Vol. 43, No. 12, pp. 1754–1755. The text was submitted by the authors in English.     

Unusual concerted Lewis acid-Lewis base mechanism for hydrogen activation by a phosphine-borane compound

Density functional theory calculations have been carried out to investigate the possible reaction mechanisms for the reversible dihydrogen activation catalyzed by a phosphine-borane compound, (C6H2Me3)2P(C6F4)B(C6F5)2 (Welch, G. C.; Juan, R. R. S; Masuda, J. D.; Stephan, D. W. Science. 2006, 314, 1124-1126). The present calculations show that an unusual concerted Lewis acid-Lewis base mechanism is more favorable than the proton transfer or hydride transfer mechanisms suggested previously. In the concerted Lewis acid-Lewis base mechanism, the H-H heterolytic cleavage is achieved through the simultaneous electron transfer from the lone-pair orbital of the Lewis base P center to the sigma* orbital of H2 and from the sigma orbital of H2 to the empty orbital of the Lewis acid B center. The solvent is found to dramatically change the potential energy surface. The proposed mechanism can account well for the bimolecular H-D exchange process observed in deuteration experiments and the experimental fact that the H2 activation is reversible at mild conditions.     

Mechanism and optimisation of the homoboroproline bifunctional catalytic asymmetric aldol reaction: Lewis acid tuning through in situ esterification

The use of homoboroproline as a bifunctional catalyst in the asymmetric aldol reaction has been investigated mechanistically, particularly with respect to tuning the Lewis acidity of boron by in situ esterification with mildly sigma-electron withdrawing diols such as hydrobenzoin and tartrate esters. The stability of simple cyclohexyl and cyclopentyl boronate diol esters shows that the 5-ring boronate esters are more stable, which sheds light on the mode of action of esterified homoboroproline catalyst in the enamine-mediated aldol reaction, which is also studied by NMR. The result is reaction optimisation to provide an efficient aldol reaction and a proposed mechanistic proposal.     

Sequential catalytic role of bifunctional bicyclic guanidine in asymmetric phospha-Michael reaction

The catalytic mechanism and origin of enantioselectivity of bicyclic guanidine-catalyzed phospha-Michael reaction between diphenyl phosphine oxide and β-nitrostyrene were investigated by DFT calculations at M06-2X/cc-pVTZ//M06-2X/cc-pVDZ level in conjunction with the implicit SMD solvation method. The catalyst is found to be involved in all 3 steps of the proposed catalytic cycle, namely (1) tautomerization of phosphine oxide, (2) C-P bond formation and (3) concerted hydrogen transfer. The bifunctional role of the guanidine catalyst is clearly demonstrated in all 3 key steps. Due to the geometry of the bicyclic guanidine catalyst, the preferred orientation of the reactants in the transition state of enantioselective C-P bond forming step favours the R enantiomer, in excellent accord with the observed enantioselectivity. Analysis of various transition states suggests that the asymmetric C-P bond formation is controlled by the hydrogen bonding interaction and steric effect between the catalyst and substrate. Various weaker C-H···X (X = N, O and π) interactions also play a role in stabilizing the key transition states.     

Chiral phosphine oxide BINAPO as a Lewis base catalyst for asymmetric allylation and aldol reaction of trichlorosilyl compounds

Chiral phosphine oxide BINAPO, which was readily prepared from chiral phosphine BINAP, exhibited good catalytic activities in the reaction of trichlorosilyl compounds via hypervalent silicate intermediates. The allylation of aldehydes with allyltrichlorosilanes in the presence of a catalytic amount of BINAPO gave the allylated adducts in good enantioselectivities (up to 79% ee) wherein a combination of diisopropylethylamine and tetrabutylammonium iodide as additives was crucial to accelerate the catalytic cycle. ³¹P NMR analysis of the phosphine oxide suggested that the amine promoted the dissociation of phosphine oxide from silicon atom. BINAPO also promoted the enantioselective aldol reaction of aldehydes with trichlorosilyl enol ethers in the presence of diisopropylethylamine as an additive to afford the corresponding aldol adducts in high diastereo- and enantioselectivities (up to syn/anti=1/25, 96% ee (anti)).     

Enantioselective Morita-Baylis-Hillman (MBH) reaction promoted by a heterobimetallic complex with a Lewis base

A new double-activation catalysis is presented for the Morita-Baylis-Hillman (MBH) reaction of an α,β-unsaturated ketone and an aldehyde by the combined use of a heterobimetallic asymmetric complex and tributylphosphine ((n-Bu)₃P) to afford the α-methylene-β-hydroxy ketone with up to 99% ee.     

Catalytic asymmetric Nazarov reactions promoted by chiral Lewis acid complexes

Divinyl ketones bearing alpha-ester or alpha-amide groups undergo Nazarov cyclizations to give cylopentenones using copper-bisoxazoline Lewis acid complexes with moderate to good ees. [reaction: see text]     

A novel asymmetric hydroarsination reaction promoted by a chiral organopalladium complex

The dissymmetrical chiral bidentate (R)-(+)-1-(diphenylphosphino)-2-(diphenylarsino)propane was prepared stereoselectively via the novel asymmetric hydroarsination reaction between diphenylarsine and diphenyl-1-propenyl-(E)-phosphine using di-mu-chlorobis{(S)-1-[1-(dimethylamino)ethyl]-2-naphthalenyl-C,N}dipalladium(II) as the chiral reaction promoter.     

A catalytic asymmetric vinylogous Mukaiyama aldol reaction

A vinylogous Mukaiyama aldol reaction, conducted using 10 mol % of a BITIP catalyst and B(OMe)3 as an additive, effects an enantioselective four-carbon chain extension to give versatile E-alpha,beta-unsaturated thiol esters.     

Intermolecular asymmetric reductive aldol reaction of ketones as acceptors promoted by chiral Rh(Phebox) catalyst

[reaction: see text] The conjugate reduction of cinnamates with hydrosilane and chiral Rh(Phebox-ip) catalyst in the presence of excess acetone is shown to provide the corresponding intermolecular reductive aldol product in extremely high enantioselectivity (up to 98%). Several cinnamates and crotonate substrates and several ketone acceptors were also examined.     

A catalytic asymmetric reaction involving enolizable anhydrides

In the presence of a highly efficient novel bifunctional organocatalyst at low loadings under mild conditions, enolizable homophthalic anhydrides can be added to a range of aromatic and aliphatic aldehydes to give dihydroisocoumarins, with excellent yields and diastereo- and enantiocontrol (up to 99% ee).     

Application of the Lewis acid-Lewis base bifunctional asymmetric catalysts to pharmaceutical syntheses: stereoselective chiral building block syntheses of human immunodeficiency virus (HIV) protease inhibitor and beta3-adenergic receptor agonist

Chiral building block syntheses of promising drugs were achieved using two types of catalytic stereoselective cyanosilylations of aldehydes promoted by Lewis acid-Lewis base bifunctional catalysts 1 and 2 as the key steps (diastereoselective cyanosilylation of amino aldehyde and enantioselective cyanosilylation). In the first part of this article, syntheses of chiral building blocks (6) of Atazanavir (3: human immunodeficiency virus (HIV) protease inhibitor) using the bifunctional catalyst 2 are discussed. The reaction of Boc-protected phenylalaninal 21 in the presence of 1 mol% catalyst 2 selectively afforded the anti isomer 22 as the major product (diastereomeric ratio=97 : 3), which was successively converted to the corresponding epoxide 6 in six steps. In the second part, we describe a chiral building block synthesis of beta(3)-adrenergic receptor agonists. The enantioselective cyanosilylation of 3-chlorobenzaldehyde (38) with 9 mol% catalyst 1 gave the chiral cyanohydrin 39, which was converted to beta-hydroxyethylamine 40 by reduction. Moreover, the chiral ligand of catalyst 1 could be recovered without column chromatography and reused without decreasing its activity.