The first catalytic highly enantioselective alkylation of ketimines--a novel approach to optically active quaternary alpha-amino acids

A series of novel ketimines with intrinsic protecting group anchoring was synthesized and allowed to react with various silylketene acetals in the presence of 5-10 mol % of a chiral Zn(OTf)(2)-(R,R)-Ph-pybox-aqua complex. The corresponding optically active quaternary alpha-amino acid derivatives were obtained in high yields and with enantioselectivities ranging from 34 % up to 95 % ee. The catalyst was studied by (1)H NMR spectroscopy and X-ray crystallography, and a dynamic equilibrium of two species was identified in solution. These are a homo-chiral 1:2 metal-ligand complex and a 1:1 metal-ligand complex, of which the latter is expected to be the actual catalyst of the diastereo- and enantioselective reaction. A strong positive nonlinear effect was observed due to the formation of a catalytically inactive 1:2 metal-ligand hetero-chiral complex. On the basis of DFT calculations and the absolute stereochemistry of the products, simultaneous coordination of the imino electrophile and a single molecule of H(2)O to the chiral Lewis acid complex is proposed. Coordination of the imine-nitrogen atom in the axial position of an octahedral complex can account for the facial selectivity as well as the diastereoselectivity observed.     

Catalytic enantioselective stereoablative reactions: an unexploited approach to enantioselective catalysis

Approaches to the preparation of enantioenriched materials via catalytic methods that destroy stereogenic elements of a molecule are discussed. Although these processes often decrease overall molecular complexity, there are several notable advantages including material recycling, enantiodivergence and convergence, and increased substrate scope. Examples are accompanied by discussion of the critical design elements required for the success of these methods.     

Catalytic asymmetric synthesis of alpha-amino phosphonates using enantioselective carbon-carbon bond-forming reactions

We have developed highly enantioselelctive reactions of silicon enolates with N-acyl-alpha-iminophosphonates leading to optically active alpha-amino phophonates. A copper (II)-diamine complex was shown to be effective in this reaction, and high levels of yield and selectivity were achieved. It is noteworthy that this reaction opens a way to various biologically important, optically active alpha-amino phosphonate derivatives.     

Catalytic enantioselective 1,3-dipolar cycloaddition reactions of cyclic nitrones: a simple approach for the formation of optically active isoquinoline derivatives

The first highly diastereo- and enantioselective catalytic 1, 3-dipolar cycloaddition reaction of cyclic nitrones activated by chiral Lewis acids with electron-rich alkenes has been developed. The nitrones, mainly 3,4-dihydroisoquinoline N-oxides, are activated by chiral 3,3'-aryl BINOL-AlMe complexes and undergo a regio-, diastereo-, and enantioselective 1,3-dipolar cycloaddition reaction with especially alkyl vinyl ethers, giving the exo diastereomer of the cycloaddition products in high yield, >90% de and up to 85% ee. The reaction has been investigated under various conditions, and it is demonstrated that the reaction is an attractive synthetic procedure for the introduction of a chiral center in the 1-position of the isoquinoline skeleton. The mechanism of the reaction is discussed on the basis of the assignment of the absolute configuration of the cycloaddition product and theoretical calculations.     

An easy approach to optically active alpha-amino phosphonic acid derivatives by chiral Zn(II)-catalyzed enantioselective amination of phosphonates

A catalytic direct enantioselective electrophilic amination of beta-keto phosphonates has been developed applying chiral bisoxazoline-zinc(II) complexes as the catalyst. The reaction proceeds well for both acyclic and cyclic substrates in high yields and with up to 98% ee using azodicarboxylates as the nitrogen source. The scope of the reaction is, for example, the further transformation to optically active beta-hydroxy-alpha-amino phosphonates with very high stereoselection.     

Catalytic enantioselective organozinc addition toward optically active tertiary alcohol synthesis

A highly enantioselective organozinc (R₂Zn) addition to a series of aldehydes and ketones was developed based on conjugate Lewis acid–Lewis base catalysis. Optically active secondary and tertiary alcohols were obtained in high yields with high enantioselectivities without Ti(IV) compounds. Bifunctional chiral 3,3′‐diphosphoryl‐BINOL ligands were designed and prepared through a phospho‐Fries rearrangement as a key step. On the other hand, bifunctional chiral phosphoramide ligands were designed and prepared from L ‐valine. Mechanistic studies were performed by X‐ray analyses of Zn(II) cluster and chiral ligands, a ³¹P NMR experiment on Zn(II) complexes, and stoichiometric reactions with some chiral or achiral Zn(II) complexes to propose a transition state assembly that includes monomeric active intermediates. © 2008 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 8: 143–155; 2008: Published online in Wiley InterScience ( www.interscience.wiley.com ) DOI 10.1002/tcr.20146     

Synthesis of cyclopropene alpha-amino acids via enantioselective desymmetrization

[reaction: see text] The preparation of cyclopropene alpha-amino acids via the enantioselective desymmetrization of cyclopropene bis-carboxylic acid derivatives is described. The amino acids are stable to harsh reaction conditions, and a derivative has been incorporated into a tripeptide using conventional methods for peptide synthesis.     

A highly enantioselective amino acid-catalyzed route to functionalized alpha-amino acids

The development of syntheses providing enantiomerically pure alpha-amino acids has intrigued generations of chemists and been the subject of intense research. This report describes a general approach to functionalized alpha-amino acids based on catalytic asymmetric synthesis. Proline catalyzed Mannich-type reactions of N-PMP-protected alpha-imino ethyl glyoxylate with a variety of unmodified ketones to provide functionalized alpha-amino acids in high yields with excellent regio-, diastereo-, and enantioselectivities. Study of seven examples yielded six with product ee values of > or = 99%. In reactions involving ketone donors where diastereoisomeric products could be formed, two adjacent stereogenic centers were created simultaneously upon carbon-carbon bond formation with complete syn-stereocontrol. Significantly, this methodology utilizes readily available and rather inexpensive starting materials, does not require any preactivation of substrates or metal ion assistance, and can be carried out on a gram scale under operationally simple reaction conditions. The keto-functionality present in the products provides a particularly attractive site for versatile modifications. This study compliments and extends our bioorganic approach to asymmetric synthesis to a versatile synthon class. Given that we have shown that a variety of optically active amino acids can be synthesized with proline catalysis, where an L-amino acid begets other L-amino acids, our results may stimulate thoughts concerning prebiotic syntheses of optically active amino acids based on this route.     

Catalytic asymmetric addition of beta-keto phosphonates to an activated imine--formation of optically active functionalized phosphonate alpha-amino acid derivatives

The direct stereoselective addition of an activated imine to beta-keto phosphonates in the presence of chiral Lewis acid complexes is developed. The evaluation of different activated imines shows that an N-tosyl-alpha-imino ester adds in a diastereo- and enantioselective fashion to beta-keto phosphonates activated by especially chiral copper(II)-bisoxazoline complexes. An evaluation of Lewis acids, chiral ligands and reaction conditions, such as solvent, bases and other additives, shows that high yields, moderate diastereoselectivity and good enantioselectivity are obtained. The scope of the reaction is demonstrated for the reaction of beta-keto phosphonates and finally, the mechanism for the catalytic stereoselective step is presented.     

An Ireland-Claisen approach to beta-alkoxy alpha-amino acids

A diastereoselective Ireland-Claisen approach to beta-alkoxy alpha-amino acid esters is reported. Amino acid esters of enol ethereal allylic alcohols undergo facile syn-selective [3,3]-sigmatropic rearrangement via silyl ketene acetals. Substrate synthesis, rearrangement development, stereoselectivity, and product elaboration are discussed.     

Catalytic asymmetric direct alpha-amination reactions of 2-keto esters: a simple synthetic approach to optically active syn-beta-amino-alpha-hydroxy esters

The catalytic enantioselective direct alpha-amination reaction of 2-keto esters with easily available azo dicarboxylates as the nitrogen source and chiral bisoxazoline-copper(II) complexes as the catalyst is presented. The reactions proceed with excellent enantioselectivities and high yields. The scope of the reaction is demonstrated by the direct amination of a series of 2-keto esters having different substituent patterns. The reaction provides an easy catalytic route to optically active syn-beta-amino-alpha-hydroxy esters, as demonstrated for the synthesis of masked syn-beta-amino-alpha-hydroxy esters (as oxazolidinones) and N-Boc-syn-beta-amino-alpha-hydroxy esters. On the basis of the absolute configuration of the products a tentative model for the transition state is suggested.     

Catalytic enantioselective transamination of alpha-keto esters: an organic approach to enzymatic reactions

The half-transamination reaction of alpha-keto esters with pyridoxamine or 4-picolylamine was found to be catalysed by different metal catalysts in organic solvents giving moderate yields and enantioselectivities of up to 37% ee for methyl-3-indole pyruvate.     

Catalytic enantioselective O-H insertion reactions

The first effective method for catalytic enantioselective insertions into O-H bonds has been developed. Specifically, a copper/bisazaferrocene catalyst couples alcohols such as 2-trimethylsilylethanol with alpha-aryl-alpha-diazo esters in high yield and good ee.     

Catalytic, highly enantioselective Friedel-Crafts reactions of aromatic and heteroaromatic compounds to trifluoropyruvate. A simple approach for the formation of optically active aromatic and heteroaromatic hydroxy trifluoromethyl esters.

A new catalytic enantioselective synthetic method for the formation of optically active aromatic and heteroaromatic hydroxy-trifluoromethyl ethyl esters is presented. This catalytic enantioselective Friedel-Crafts reaction of trifluoromethyl pyruvate with aromatic and heteroaromatic compounds is catalyzed by a chiral bisoxazoline copper(II) complex and proceeds in good yield and with high enantiomeric excess. For a series of substituted indoles, the corresponding 3-substituted hydroxy-trifluoromethyl ethyl esters are formed in up to 93% yield and 94% ee. Pyrrole and 2-substituted pyrroles also react with trifluoromethyl pyruvate in a highly enantioselective aromatic electrophilic reaction and up to 93% ee and good yields are obtained. Furanes and thiophenes give the corresponding 2-hydroxy-trifluoromethyl ethyl esters in high enantiomeric excess; however, the yields of the products are only moderate. Various types of aromatic compounds react in this catalytic reaction with trifluoromethyl pyruvate to give the aromatic electrophilic addition product in good yield. To obtain high enantiomeric excess (> 80% ee) it is necessary that aromatic amines are protected with sterically demanding protecting groups such as benzyl or allyl. This prevents coordination of the amine nitrogen atom to the catalyst, as aromatic amines having a N,N-dimethyl group probably coordinate to the catalyst, leading to a significant reduction of the enantioselective properties of the catalyst. On the basis of the experimental results and the absolute configuration of the formed chiral center, the mechanism for the catalytic enantioselective Friedel-Crafts reaction is discussed.