Organocatalytic asymmetric alpha-bromination of aldehydes and ketones

The first organocatalytic enantioselective alpha-bromination of aldehydes and ketones is presented; a C2-symmetric diphenylpyrrolidine catalyst afforded the alpha-brominated aldehydes in good yields and up to 96% ee, while ketones were alpha-brominated by a C2-symmetric imidazolidine in up to 94% ee; furthermore, the organocatalytic enantioselective alpha-iodination of aldehydes is also demonstrated to proceed with up to 89% ee.     

Platinum(II) complex-catalyzed enantioselective aldol reaction with ketene silyl acetals in DMF at room temperature

[{(R)-binap}Pt(μ-OH)]₂2X is a weak Lewis acid, which can catalyze the enantioselective aldol reaction of aldehydes with ketene silyl acetals in DMF at room temperature. The platinum(II) complex-catalyzed the enantioselective aldol reaction of aldehydes with 1-methoxy-2-methyl-(1-trimethylsilyloxy)propene gave the corresponding aldols in high yields with enantioselectivity up to 92%. With 5 mol % loading of the complexes, the enantioselective aldol reaction of aldehydes with 1-benzyloxy-1-(trimethylsilyloxy)propene smoothly proceeded in DMF containing 10% HMPA as to predominantly give anti-propionates with enantioselectivity up to 89%, irrespective of the silyl nucleophile geometry.     

Catalytic asymmetric aziridination of α,β-unsaturated aldehydes

The development, scope, and application of the highly enantioselective organocatalytic aziridination of α,β-unsaturated aldehydes is presented. The aminocatalytic azirdination of α,β-unsaturated aldehydes enables the asymmetric formation of β-formyl aziridines with up to >19:1 d.r. and 99% ee. The aminocatalytic aziridination of α-monosubstituted enals gives access to terminal α-substituted-α-formyl aziridines in high yields and up to 99% ee. In the case of the organocatalytic aziridination of disubstituted α,β-unsaturated aldehydes, the transformations were highly diastereo- and enantioselective and give nearly enantiomerically pure β-formyl-functionalized aziridine products (99% ee). A highly enantioselective one-pot cascade sequence based on the combination of asymmetric amine and N-heterocyclic carbene catalysis (AHCC) is also disclosed. This one-pot three-component co-catalytic transformation between α,β-unsaturated aldehydes, hydroxylamine derivatives, and alcohols gives the corresponding N-tert-butoxycarbonyl and N-carbobenzyloxy-protected β-amino acid esters with ee values ranging from 92-99%. The mechanisms and stereochemistry of all these catalytic transformations are also discussed.     

Asymmetric Morita-Baylis-Hillman reactions catalyzed by chiral Brønsted acids

Chiral BINOL-derived Br?nsted acids catalyze the enantioselective asymmetric Morita-Baylis-Hillman (MBH) reaction of cyclohexenone with aldehydes. The asymmetric MBH reaction requires 2-20 mol % of the chiral Br?nsted acid 2e or 2f and triethylphosphine as the nucleophilic promoter. The reaction products are obtained in good yields (39-88%) and high enantioselectivities (67-96% ee). The Br?nsted-acid-catalyzed reaction is the first example of a highly enantioselective asymmetric MBH reaction of cyclohexenone with aldehydes.     

Direct organocatalytic asymmetric alpha-chlorination of aldehydes

The direct organocatalytic enantioselective alpha-chlorination of aldehydes has been developed. The reaction proceeds for a series of different aldehydes with NCS as the chlorine source using easily available catalysts such as l-proline amide and (2R,5R)-diphenylpyrrolidine. The alpha-chloro aldehydes are obtained in up to 99% yield and up to 95% ee. The synthetic utility of the enantioselective alpha-chlorination of aldehydes is demonstrated by transformation of the alpha-chloro aldehydes to the corresponding alpha-chloro alcohols (>90% yield) by standard reduction and further transformation to both a terminal epoxide and amino alcohol, both obtained without loss of optical purity. Oxidation of the alpha-chloro aldehydes followed by esterification gave optically active alpha-chloro esters without loss of optical purity. It is demonstrated that these optically active alpha-chloro esters can be converted into nonproteinogenic amino acids in overall high yields, maintaining the enantiomeric excess obtained in the catalytic enantioselective alpha-chlorination step.     

Enantioselective addition of phenylacetylene to aldehydes catalyzed by a d-glucosamine-derived sulfonamide-titanium complex

We present the synthesis of β-hydroxy sulfonamides derived from d-glucosamine and their application as ligands in titanium tetraisopropoxide promoted enantioselective addition of phenylacetylene to benzaldehyde and selected aromatic and aliphatic aldehydes. The N-3,5-bis(trifluoromethyl)benzenesulfonamido-d-glucosamine derivative was chosen as the most efficient ligand for this addition. The reaction is highly enantioselective for several aromatic aldehydes and enantiomeric excesses up to 92% were obtained.     

The first direct and enantioselective cross-aldol reaction of aldehydes

The first enantioselective catalytic direct cross-aldol reaction that employs nonequivalent aldehydes has been accomplished using proline as the reaction catalyst. Structural variation in both the aldol donor (R1 = Me, n-Bu, Bn, 91 to >99%) and aldol acceptor (R2 = I-Pr, I-Bu, c-C6H11, Et, Ph, 97-99% ee) are possible while maintaining high reaction efficiency (75-88% yield). Significantly, this new aldol variant allows facile enantioselective access to a broad range of beta-hydroxy aldehydes which are valuable intermediates in polyketide syntheses.     

Organocatalytic asymmetric epoxidation reactions in water-alcohol solutions

The diastereo- and enantioselective organocatalytic epoxidation of alpha,beta-unsaturated aldehydes in aqueous solutions is presented. By the screening of the reaction conditions for the epoxidation of cinnamic aldehyde applying hydrogen peroxide as the oxidant and 2-[bis-(3,5-bis-trifluoromethyl-phenyl)-trimethylsilanyloxy-methyl]-pyrrolidine as the catalyst, a highly stereoselective reaction has been developed. The scope of the diastereo- and enantioselective organocatalytic epoxidation in aqueous solutions is documented by the asymmetric epoxidation of alpha,beta-unsaturated aldehydes with enantioselectivities up to 96% ee.     

Asymmetric catalysis of Nozaki-Hiyama allylation and methallylation with a new tridentate bis(oxazolinyl)carbazole ligand

This work describes the development of a new tridentate ligand effective for the asymmetric catalysis of Nozaki-Hiyama allylation and methallylation. Various aldehydes were allylated or methallylated with good enantioselectivity (86-96%), and a key intermediate of calcitriol lactone synthesis was also obtained with excellent diastereoselectivity (97% de, 91%). The enantioselective reaction catalyzed by this Cr-ligand complex is applicable to a broad range of aldehydes and has great potential for natural product synthesis. Another remarkable feature of this ligand is the stability of the Cr-ligand complex which was recovered after the enantioselective reaction and recycled twice without diminishing the enantioselectivity and yield.     

Highly enantioselective direct aldol reaction catalyzed by cinchona derived primary amines

Highly enantioselective aldol reactions of aldehydes with cyclic ketones catalyzed by a primary amine derived from cinchonine are reported. Aromatic aldehydes reacted with various cyclic ketones cleanly to afford the anti-aldol adducts in up to 99% yield, with good diastereoselectivities (up to 9 : 1) and excellent enantioselectivities (up to 99% ee).     

Polystyrene-supported amino alcohol ligands for the heterogeneous asymmetric addition of phenyl zinc reagents to aldehydes

A family of polystyrene-supported amino alcohols, characterized by a high catalytic activity in alkyl transfer from zinc to formyl groups has been successfully tested in the enantioselective addition of phenyl zinc reagents to aldehydes to afford chiral diarylmethanols. Enantioselectivities higher than 90% (mean ee 90.5%; eight examples) are recorded with aromatic aldehydes in what represents the first successful use of heterogeneous, polymeric reagents for enantiocontrol in the phenylation of aldehydes.     

An improved asymmetric reformatsky reaction mediated by (-)-N,N-dimethylaminoisoborneol

[reaction: see text] (-)-N,N-Dimethylaminoisoborneol ((-)-DAIB) was found to be an excellent ligand for the enantioselective addition of Reformatsky reagents to aromatic and aliphatic aldehydes. Enantioselectivities up to 93% ee were obtained with sulfur-containing aldehydes.     

Tetrazolic acid functionalized dihydroindol: rational design of a highly selective cyclopropanation organocatalyst

Herein we wish to report our development of an improved catalyst (S)-(-)-indoline-2-yl-1H-tetrazole (1) for the enantioselective organocatalyzed cyclopropanation of alpha,beta-unsaturated aldehydes with sulfur ylides. The new organocatalyst readily facilitates the enantioselective organocatalytic cyclopropanation, providing cyclized product in excellent diastereoselectivities ranging from 96% to 98% along with enantioselectivities exceeding 99% enantiomeric excess for all reacted alpha,beta-unsaturated aldehydes. The new catalyst provides the best results so far reported for intermolecular enantioselective organocatalyzed cyclopropanation.     

The First Catalytic Enantioselective Nozaki-Hiyama Reaction

The Nozaki-Hiyama reaction can be performed in an enantioselective catalytic way! The catalytic system utilizes 10 mol % of an inexpensive chiral [Cr(salen)] complex. The [Cr(salen)]/Mn/Me(3)SiCl system effectively promotes the enantioselective addition of allyl chloride to aliphatic and aromatic aldehydes at room temperature (65-89 % ee, 40-60 % yield).     

Enantioselective organocatalytic alpha-fluorination of aldehydes

The first direct enantioselective catalytic alpha-fluorination of aldehydes has been accomplished. The use of enamine catalysis has provided a new organocatalytic strategy for the enantioselective fluorination of aldehydes to generate alpha-fluoro aldehydes, an important chiral synthon for medicinal agent synthesis. The use of imidazolidinone 1 as the asymmetric catalyst has been found to mediate the fluorination of a large variety of aldehyde substrates with N-fluorobenzenesulfonimide serving as the electrophilic source of fluorine. A diverse spectrum of aldehyde substrates can also be accommodated in this new organocatalytic transformation. While catalyst quantities of 20 mol % were generally employed in this study, successful halogenation can be accomplished using catalyst loadings as low as 2.5 mol %.     

Direct and enantioselective organocatalytic alpha-chlorination of aldehydes

The first direct enantioselective catalytic alpha-chlorination of aldehydes has been accomplished. The use of enamine catalysis has provided a new organocatalytic strategy for the enantioselective chlorination of aldehydes to generate alpha-chloro aldehydes, an important chiral synthon for chemical and medicinal agent synthesis. The use of imidazolidinone 3 as the asymmetric catalyst has been found to mediate the halogenation of a large variety of aldehyde substrates with the perchlorinated quinone 1 serving as the electrophilic chlorinating reagent. A diverse spectrum of aldehyde substrates can also be accommodated in this new organocatalytic transformation. The capacity of catalyst 3 to override the inherent bias of resident stereogenicity in the chlorination of enantiopure beta-chiral aldehydes is also described. Catalyst quantities of 5 mol % were generally employed in this study.     

Synthesis of enantiopure axially chiral C3-symmetric tripodal ligands and their application as catalysts in the asymmetric addition of dialkylzinc to aldehydes

The enantioselective synthesis of a novel-type C(3)-symmetric tripodal ligand that is composed of a central mesitylene-derived core and three functionalized, axially chiral biaryl subunits is described. The triol (M,M,M)-3 is a suitable catalyst for the enantioselective addition of dialkylzinc to various aromatic aldehydes with asymmetric inductions of up to 98% ee.     

Effect of microwave heating in the asymmetric addition of dimethylzinc to aldehydes

Microwave-heated enantioselective additions of dimethylzinc to various aldehydes are reported. Dramatically reduced reaction times and lower catalyst loadings (5%), compared with conventionally used conditions, can be achieved, with excellent yields and just small loss of enantioselectivity (up to 83% enantioselectivity is achieved). In the reaction with aliphatic aldehydes the same enantioselectivity has been achieved for microwave-heated and conventional room temperature conditions.     

Enantioselective organocatalytic Mukaiyama-Michael addition of silyl enol ethers to alpha,beta-unsaturated aldehydes

[reaction: see text] A highly enantioselective, organocatalytic Mukaiyama-Michael addition reaction of silyl ethers and alpha,beta-unsaturated aldehydes has been developed. The process, catalyzed by MacMillan's chiral imidazolidinone, affords delta-keto aldehydes in high yields (56-87%) and high enantioselectivities (85-97% ee). Moreover, the reaction is applicable to a wide range of silyl ethers and alpha,beta-unsaturated aldehydes and, as such, provides access to a range of important synthetic building blocks.     

The design of chiral dendritic catalysts and ligands bearing chiral sites at the periphery for the highly enantioselective addition of dialkylzincs to aldehydes and N-diphenylphosphinylimines

Chiral dendrimers bearing β-amino alcohols on their hyperbranched chain-ends serve as highly enantioselective catalysts and ligands in the enantioselective addition of dialkylzincs to aldehydes with up to 93% ee, and in the enantioselective addition of dialkylzincs to N-diphenylphosphinylimines with up to 94% ee, respectively. To cite this article: K. Soai and I. Sato, C. R. Geoscience 6 (2003).