Asymmetric direct

Organic-Base Catalyzed. Asymmetric direct aldol reactions have received considerable attention recently (Eq. 8.98).251 Direct asymmetric catalytic aldol reactions have been successfully performed using aldehydes and unmodified ketones together with chiral cyclic secondary amines as catalysts.252 L-proline and 5,5-dimethylthiazolidinium-4-carboxylate (DMTC) were found to be the most powerful amino acid catalysts for the reaction of both acyclic and cyclic ketones as aldol donors with aromatic and aliphatic aldehydes to afford the corresponding... 

List and coworkers reasoned that BINOL phosphates (specific Brpnsted acid catalysis) could be suitable catalysts for an asymmetric direct Pictet-Spengler reaction [26], Preliminary experiments revealed that unsubstituted tryptamines do not undergo the desired cyclization. Introduction of two geminal ester groups rendered the substrates more reactive which might be explained by electronic reasons and a Thorpe-Ingold effect. Tryptamines 39 reacted with aldehydes 40 in the presence of phosphoric acid (5)-3o (20 moI%, R = bearing 2,4,6-triisopropyI-... 

The first asymmetric direct aldol of 1,2-diketones and ketones, to give 2-hydroxy-1,4-diketones, has been reported.100 L-Proline derivatives give high regio-, diastereo-, and enantio-selectivity in the reaction of l-arylpropane-l,2-diones with simple ketones. 

The first asymmetric direct Michael addition of enolizable aldehydes RCH2CH=0 to vinyl sulfones CH2=C(S02Ph)2 catalysed by /V-Pr -2,2 -bipyrrolidine (146) has been reported. The 1,4-adducts were obtained in good yields and enantioselectivities... 

Scheme 2. Synthesis ofthe key intermediate en route to epothilone A based on a catalytic, asymmetric direct aldol addition of acetophenone (5.7 mmol scale) and an a-branched acyclic aldehyde, (a) 1 (8mol%), KHMDS...

Quaternary Ammonium Salt-Mediated Asymmetric Direct Aldol Reaction of Glycinate Benzophenone Schiff Base with 3-Phenylpropanal Under Phase-Transfer Conditions [6] (p. 145)... 

The applicability of the developed chiral complexing agents was further demonstrated by asymmetrically directing [2 + 2]- and [4 + 4]-photocycloaddition... 

Job A, Janeck CF, Bettray W, Peters R, Enders D (2002) Tetrahedron 58 2253 Josephsohn NS, Kuntz KW, Snapper ML, Hoveyda AH (2001) Mechanism of enantioselective Ti-catalyzed Strecker reaction peptide-based metal complexes as bifunctional catalysts. J Am Chem Soc 123 11594—11599 Juhl K, Gathergood N, Jprgensen KA (2001) Catalytic asymmetric direct Man-nich reactions of carbonyl compounds with alpha-imino esters. Angew Chem Int Ed Engl 40 2995-2997... 

Saito S, Yamamoto H. Design of acid-base catalysis for the asymmetric direct aldol reaction. Acc. Chem. Res. 2004 37 570-579. 

Juhl, K., Gathergood, N., Jorgensen, K. A. Catalytic asymmetric direct Mannich reactions of carbonyl compounds with a-imino esters. Angew. Chem., tnt. Ed. Engt. 2001,40, 2995-2997. 

The aldol reachon is one of the most efficient methods for extending the carbon framework of an organic synthon. Since the discovery of the Lewis acid-catalyzed asymmetric aldol reaction of silyl enol ethers by Mukaiyama, numerous variations of this type of reaction have been reported [80]. Recently, more attention has been focused on the development of new organocatalysts for the asymmetric direct aldol... 

Ligand design elements in precious metal homogeneous catalysts for asymmetric direct hydrogenation and asymmetric transfer hydrogenation... 

Similarly, an iridium catalyst with a specific ferrocenylphosphine ligand (Scheme 2) is used in the production of the chiral amine (5)-metolachlor, a herbicide, by the asymmetric direct hydrogenation of a prochiral imine. ... 

Hydroxyacetone 96 is a reagent in an even more remarkable reaction the asymmetric direct three-component Mannich reaction. It is combined with an aromatic amine 98 and the inevitable isobutyraldehyde 89 with proline catalysis to give a very high yield of a compound 99 that might have been made by an asymmetric amino-hydroxylation. The proline enamine of hydroxyacetone, must react with the imine salt formed from the amine and isobutyraldehyde. This is a formidable organisation in the asymmetric step. 

Novel organic molecules derived from L-proline and amines or amino alcohols, were found to catalyse the asymmetric direct aldol reaction with high efficiency. Notably those containing L-proline amide moiety and terminal hydroxyl group could catalyse direct asymmetric aldol reactions of aldehydes in neat acetone with excellent results[1]. Catalyst (1), prepared from L-proline and (IS, 2Y)-diphcnyl-2-aminoethanol, exhibits high enantioselectivities of up to 93% ee for aromatic aldehydes and up to >99% ee for aliphatic aldehydes. 

Addition to ArCHO. Synthesis of chiral secondary benzyUc alcohols by addition of organometaUic reagents (including Me2Zn and ArsBi) can be asymmetrically directed by... 

The directed metalation reaction—lithiation with n-butyl-lithium of a position ortho to a substituent on an aromatic ring—is described. Aromatic systems in which the reaction has been studied are benzene, thiophene, naphthalene, and ferrocene. A systematic listing of the bond types that can be formed at the site of metalation is provided. Also of interest is the assessment of the relative directing abilities of directing substituents and comments and observations on the mechanism of the reaction. Utility of the reaction is indicated by the results from asymmetric-directed lithiation and the synthesis of heterocycles. 

The only compounds meeting all these criteria were ferrocene compounds prepared by Ugi via the asymmetric directed metalation method, shown in Reaction 35. 

Goldberg and Bailey (44) have used the asymmetric-directed metalation procedure as a route to compounds demonstrating (for the first time) pseudoasymmetry in ferrocenes. A pseudoasymmetric 1,2-disubsti-tuted ferrocene was prepared by procedures such as those illustrated in Figure 1. 

Our conclusion is that the asymmetric lithiation procedure and the asymmetric directed metalation reaction are of great potential value for synthesizing a variety of chiral compounds as well as being elegant and profound exercises in stereochemistry. 

Design of Acid-Base Catalysis for the Asymmetric Direct Aldol Reaction ... 

Progress in the study on the reaction mechanisms of proline-catalyzed asymmetric direct aldol reactions 06CJO1463. 

J. Huang, X. Zhang, D. W. Armstrong, Highly efficient asymmetric direct stoichiometric Aldol-reactions on/in water, Angew. Chem. Int. Ed., 2007, 46, 9073-9077. 

The first asymmetric direct a-iodination of aldehydes has also been described to provide products in moderate to good enan-tioselectivities using an organocatalyst. 3-Methyl-1-butanal was reacted with NIS in the presence of a chiral pyrrolidine catalyst to provide the halogenated product in 78% yield with 89% ee (eq 27). 

Reproduced from Tanaka K, Asakura A Muraoka T. Kalicki P. Urtanczyk-Upkawaka Z Asymmetric direct aldol reactions catalyzed by chiral amine mscrocycle-metaKll) complexes under soh/ent-lfee conditions. N J Chem 2013 37 2851-5. With permission from the Royal Society of Chemistry. 

Fteproduced from GuiSena G, del Carmen Hita M. Nijera C, Vidzquez SF Solvent-free asymmetric direct aldol reactions organocatalysed by recoverable (SJ-binam-L-prolinamide. Tetrahedron Asymm 2007 18 2300-4. Copyright (2007). with permission from Elsevier. 

A highly efficient solvent-free asymmetric direct aldol reaction organocatalyzed by recoverable (S)-Binam-L-Prollnamldes. ESI-MS evidence of the enamine-iminium formation. J Org Chem 2008 73 5933-43. Copyright (2008), American Chemical Society. 

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