A catalytic asymmetric strecker-type reaction promoted by Lewis acid-Lewis base bifunctional catalyst

A general asymmetric Strecker-type reaction is reported, catalyzed by the Lewis acid-Lewis base bifunctional catalyst 1. The reaction of trimethylsilyl cyanide (TMSCN) with various fluorenyl imines, including n-aldimines and alpha,beta-unsaturated imines, proceeds with good to excellent enantioselectivities in the presence of a catalytic amount of phenol as additive (20 mol%) (catalytic system 1). The products were successfully converted to the corresponding amino acid derivatives in high yields without loss of enantiomeric purity. Furthermore, hydrogenation or dihydroxylation of the products from alpha,beta-unsaturated imines afforded saturated or functionalized aminonitriles also without loss of enantiomeric purity. The absolute configuration of the products and a control experiment using catalyst 2 supported the proposed dual activation of the imine and TMSCN by the Lewis acid (Al) and the Lewis base moiety (phosphine oxide) of 1. From the mechanistic studies including kinetic and NMR experiments of the catalytic species, the role of PhOH seems to be a proton source to protonate the anionic nitrogen of the intermediate. Specifically, we have found that TMSCN is more reactive than HCN in this catalytic system, probably due to the activation ability of the phosphine oxide moiety of 1 toward TMSCN. This fact prompted us to develop the novel catalytic system 2, consisting of 1 (9 mol%), TMSCN (20 mol%) and HCN (1.2 mol eq). This new system afforded comparable results with obtained by system 1 (1 (9 mol%)-TMSCN (2 mol eq)-PhOH (20 mol%)).     

Solvent-effects tuning the catalytic reactivity of prolinamides in asymmetric aldol reactions

Novel prolinamides were prepared and applied as organocatalysts in the asymmetric aldol reaction. Stable imidazolidinones were formed between prolinamides and aromatic aldehydes in organic solvents. It was found that aqueous conditions can significantly suppress the formation of the unwanted imidazolidinone intermediate and improve the catalytic activity of the prolinamides. As a consequence, high chemical yields (up to 99%) and good diastereoselectivity (up to >20:1 dr) and enantioselectivity (up to 95% ee) were achieved in 2-Me-THF or brine. This strategy could serve as a general solution to enhance the performance of prolinamides as organocatalysts.     

The first example of enamine-Lewis acid cooperative bifunctional catalysis: application to the asymmetric aldol reaction

(-)-Sparteine directed lithiation of N-Boc-pyrrolidine, alkylation with chloromethylboronate pinacol ester and acid-based deprotection provides homoboroproline HX salt in 94% ee, which is then an efficient enamine-type pyrrolidine catalyst in an asymmetric aldol reaction when neutralised and especially when esterified in situ with a tartrate ester, for example, providing 90% ee of the aldol adduct derived from acetone and p-nitrobenzaldehyde.     

Anti-selective direct catalytic asymmetric aldol reaction of thiolactams

An anti-selective direct catalytic asymmetric aldol reaction of thiolactam is described. A soft Lewis acid/hard Br?nsted base cooperative catalyst comprised of mesitylcopper/(R,R)-Ph-BPE exhibited high catalytic performance to produce an anti-aldol product with high stereoselectivity. The highly chemoselective nature of the present catalysis allows for the use of enolizable aldehydes as aldol acceptors. The diverse transformations of the thiolactam moiety highlight the synthetic utility of the present anti-aldol protocol.     

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.     

Catalytic asymmetric intermolecular Stetter reaction of enals with nitroalkenes: enhancement of catalytic efficiency through bifunctional additives

An asymmetric intermolecular Stetter reaction of enals with nitroalkenes catalyzed by chiral N-heterocyclic carbenes has been developed. The reaction rate and efficiency are profoundly impacted by the presence of catechol. The reaction proceeds with high selectivities and affords good yields of the Stetter product. Internal redox products were not observed despite of the protic conditions. The impact of catechol has been found to be general, facilitating far lower catalyst loadings than were previously achievable.     

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.     

Direct catalytic asymmetric aldol reaction of thioamides: a concise asymmetric synthesis of (R)-fluoxetine

A direct catalytic asymmetric aldol reaction of aromatic aldehydes and thioamides is described. A soft Lewis acid/hard Brønsted base cooperative catalyst comprising (R,R)-Ph-BPE/[Cu(CH₃CN)₄]PF₆/Li(OC₆H₄-p-OMe) promoted the title reaction efficiently, triggered by in situ generation of the active thioamide enolate through a soft–soft interaction of Cu(I) and the thioamide. The aldol product was transformed into (R)-fluoxetine, an antidepressant agent.     

Aminophosphonates as organocatalysts in the direct asymmetric aldol reaction: towards syn selectivity in the presence of Lewis bases

Chiral alpha-aminophosphonates have been synthesized and their performance was evaluated as organocatalysts in the direct asymmetric aldol reaction. High enantioselectivities (up to 99% ee) were achieved for a range of substituted cyclohexanones and benzaldehydes. Several organic bases, such as DBU, DBN, and TMG, were used together with the alpha-aminophosphonates in the aldol reactions and were found to favor syn-selectivity.     

Crucial role of the ligand of silyl Lewis acid in the Mukaiyama aldol reaction

The Me3SiX-induced Mukaiyama aldol reaction proceeds through each catalytic cycle under the influence of X-: the silyl group of Me3SiNTf2 does not release from -NTf2 and that of silyl enol ether intermolecularly transfers to the product, while the silyl group of Me3SiOTf remains in the product and that of the silyl enol ether becomes the catalyst for the next catalytic cycle.     

Dramatic ligand effect in catalytic asymmetric reductive aldol reaction of allenic esters to ketones

A general catalytic asymmetric reductive aldol reaction of allenic esters to ketones is described. Two distinct constitutional isomers were selectively produced depending on the reaction conditions. A combination of CuOAc/(R)-DTBM-SEGPHOS/PCy3 as the catalyst predominantly produced gamma-cis-products in high yield with excellent enantioselectivity (up to 99% ee). The reaction was applicable to both aromatic and aliphatic ketones, including unsaturated ketones. On the other hand, CuF-Taniaphos complexes produced alpha-aldol products with high diastereo- and enantioselectivity (up to 84% ee). The new Taniaphos derivative L3, containing di(3,5-xylyl)phosphine and morpholine units, produced optimum results in the alpha-selective reaction. The products are versatile chiral building blocks in organic synthesis. Furthermore, the basic reaction pattern (i.e., conjugate addition-aldol reaction) was extended to a catalytic enantioselective alkylative aldol reaction to ketones using dialkylzinc reagents as the initiator.     

Sterically and electronically tunable and bifunctional organocatalysts: design and application in asymmetric aldol reaction of cyclic ketones with aldehydes

Sterically and electronically tunable and bifunctional organocatalysts have been developed and evaluated in the direct aldol reaction of heterocyclic ketones. Catalysts with different substituents showed variable catalytic efficiency for analogous substrates, indicating the importance of fine-tuning the strength of the hydrogen bonding in the two NH groups. The reactions all proceeded in good to high yield and with excellent enantioselectivities ranging from 90% to >99% ee. In most cases, high diastereoselectivities ranging from 96/4 to 99/1 were obtained for the anti aldol adduct.     

Concise enantioselective synthesis of duloxetine via direct catalytic asymmetric aldol reaction of thioamide

Direct catalytic asymmetric aldol reaction of thioamide offers a new entry to the concise enantioselective synthesis of duloxetine. The direct aldol protocol was scalable (>20 g) to afford the aldol product in 92% ee after LiAlH(4) reduction, and 84% of the chiral ligand was recovered after recrystallization. The following four steps of transformation delivered duloxetine.     

Formal total synthesis of (+)-wortmannin using catalytic asymmetric intramolecular aldol condensation reaction

A catalytic process for the synthesis of optically active C4-substituted tetrahydroindandiones using an asymmetric intramolecular aldol condensation reaction was developed. When 30 mol% of phenylalanine and 50 mol% of pyridinium p-toluenesulfonate were used under highly concentrated conditions, a variety of C4-substituted tetrahydroindandiones and octahydronaphthalenediones were obtained in high yield (up to 89% yield) and high enantiomeric excess (up to 94% ee). One of the products was successfully transformed into the key intermediate for the synthesis of the phosphatidylinositol 3-kinase inhibitor wortmannin, achieving formal total synthesis of (+)-wortmannin.     

Current progress in the asymmetric aldol addition reaction

Control of stereochemistry during aldol addition reactions has attracted considerable interest over the years as the aldol reaction is one of the most fundamental tools for the construction of new carbon-carbon bonds. Several strategies have been implemented whereby eventually any single possible stereoisomeric aldol product can be accessed by choosing the appropriate procedure. With earlier methods, stoichiometric quantities of chiral reagents were required for efficient asymmetric induction, with the auxiliary most often attached covalently to the substrate carbonyl. Lewis acid catalyzed addition reactions of silyl enolates to aldehydes (Mukaiyama reaction) later opened the way for catalytic asymmetric induction. In the last few years, both chiral metal complexes and small chiral organic molecules have been found to catalyse the direct aldol addition of unmodified ketones to aldehydes with relatively high chemical and stereochemical efficiency. These techniques along with the more recent developments in the area are discussed in this tutorial review.     

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.     

Boron-mediated aldol reaction of carboxylic esters: complementary anti- and syn-selective asymmetric aldol reactions

The boron-mediated aldol reaction of carboxylic esters is described in detail. Contrary to the general belief that carboxylic esters are inert under the condition of the boron enolate formation, propionate esters are enolized with certain combinations of a boron triflate and an amine. More importantly, the stereochemical course of the aldol reaction can be controlled by the judicious selection of the enolization reagents. Treatment of propionate esters with c-Hex2BOTf and triethylamine produces anti-aldol products, and that with Bu2BOTf and diisopropylethylamine gives syn-aldol products selectively after reaction with aldehydes. Complementary anti- and syn-selective asymmetric aldol reactions with structurally related, readily available chiral norephedrine-derived propionate esters are developed.     

Direct catalytic asymmetric aldol reactions of pyruvates: scope and mechanism

The direct aldol reaction of 2-ketoesters catalyzed by chiral bisoxazoline copper(II) complexes has been investigated. First the direct homo-aldol reaction of ethyl pyruvate is reported which proceeds to give diethyl 2-hydroxy-2-methyl-4-oxoglutarate. This was isolated as the more stable optically active isotetronic acid in good yield and enantiomeric excess in the absence of bases such as amines. Detailed investigations of the use of different chiral Lewis acids as the catalyst, amines, ratios of chiral bisoxazoline copper(II) salts:amine, and solvents gave up to 96% ee of the isotetronic acid. Then the reaction was extended to a cross-aldol reaction of various 2-ketoesters with activated carbonyl compounds to give the cross-aldol adduct with excellent enantiomeric excess. Furthermore, the synthesis of the isotetronic acids was investigated from these cross-aldol adducts giving important information about the formation of the stereogenic centers during the aldol reaction. Based on the absolute configuration of the homo-aldol adduct the mechanism for the aldol reaction is discussed.