Asymmetric synthesis of alpha-amino 1,3-dithioketals from sulfinimines (N-sulfinyl imines). Synthesis of (2S,3R)-(-)-3-hydroxy-3-methylproline

[reaction: see text] N-Sulfinyl alpha-amino 1,3-dithioketals are prepared in high de and good yield by treating sulfinimines with lithio-1,3-dithianes. Selective removal of the N-sulfinyl or the thioketal groups affords stable alpha-amino 1,3-dithioketals and N-sulfinyl alpha-amino ketones, respectively. This new sulfinimine-derived chiral building block is employed in the asymmetric synthesis of polyoxypeptin amino acid (2S,3R)-(-)-3-hydroxy-3-methylproline.     

Enantioselective synthesis of alpha-amino nitriles from N-benzhydryl imines and HCN with a chiral bicyclic guanidine as catalyst

[formula: see text] A novel catalytic enantioselective Strecker synthesis of chiral alpha-amino nitriles and alpha-amino acids is described and analyzed with regard to the possible mechanistic basis for stereoselectivity. Key features of the enantioselective process include (1) the use of the chiral bicyclic guanidine 1 as catalyst and (2) the use of the N-benzhydryl substituent on the imine substrate.     

N-methyl-N-nosyl-beta(3)-amino acids

N-Methyl-beta(3)-amino acids are important building blocks in the synthesis of biologically active molecules. A very simple and efficient approach to transform natural alpha-amino acids into their corresponding N-methyl-beta(3)-amino acids is here presented. In the method, the key intermediates N-methyl-N-nosyl-alpha-aminoacyldiazomethanes are prepared in only one step, by a simple treatment of the corresponding N-nosyl-alpha-aminoacyl chlorides with diazomethane. The synthetic route takes advantage from the use of the nosyl group. This N-masking moiety activates the NH function, and the N-methylation can directly occur during the acylation step of diazomethane, rendering useless a second step that instead is shown to be necessary in all the classical procedures already reported for the preparation of N-methyl-beta(3)-amino acids. The Wolff rearrangement of N-methyl-N-nosyl-alpha-aminoacyldiazomethanes provides the corresponding N-methyl-N-nosyl-beta(3)-amino acids with total retention of the chiral configuration of the starting alpha-amino acids. No epimerization of the chiral carbon atom is observed also when N-methyl-N-nosyl-beta(3)-amino acids are transformed into chlorides and coupled with alpha-amino acid methyl esters to achieve model scaffolds for biologically important modified peptides.     

Stereocontrolled synthesis of psi[CH(CF3)NH]gly-peptides

[reaction: see text] A novel class of peptidomimetics having a stereogenic [CH(CF(3))NH] replacement for a [CONH] peptide bond has been synthesized. The new compounds have been obtained in a stereocontrolled fashion using a kinetically controlled aza-Michael addition of chiral alpha-amino acid esters to trans-3,3,3-trifluoro-1-nitropropene. The stereoselectivity is strongly influenced by the solvent, the base, its stoichiometry, and the R side-chain. Diastereomeric ratios higher than 11:1 were achieved using H-Val-OtBu.HCl in toluene with 1.1 equiv of DIPEA.     

(S,S)-(+)-pseudoephedrine alpha-iminoglyoxylamide as a chiral glycine cation equivalent: a modular and flexible approach to enantioenriched alpha-amino ketones

We have studied the ability of an alpha-imino glyoxylamide derived from (S, S)-(+)-pseudoephedrine as a valuable chiral electrophile for the preparation of alpha-amino carbonyl compounds. In this context, the addition of Grignard reagents to the azomethine moiety of this chiral electrophile afforded the expected alpha-amino amide adducts in good yields and diastereoselectivities. Moreover, these adducts have been transformed into enantioenriched alpha-amino ketones by exploiting the ability of pseudoephedrine amides to undergo selective monoaddition to the carbamoyl group with organolithium reagents.     

Asymmetric synthesis of functionalized aza-cyclic amino acids with quaternary stereocenters by a phase-transfer-catalyzed alkylation strategy

[Reaction: see text] Practical asymmetric synthesis of functionalized aza-cyclic alpha-amino acid derivatives possessing quaternary stereocenters has been achieved by the phase-transfer-catalyzed alkylation of 2 or 3 using chiral quaternary ammonium bromide 1 as catalyst. Subsequent reduction and alkylation of the 3-keto carbonyl moiety of 4 proceeded with complete diastereochemical control to afford the corresponding beta-hydroxy aza-cyclic alpha-amino acid derivatives having stereochemically defined consecutive quaternary carbon centers.     

Effect of the residual silanol group protection on the liquid chromatographic resolution of racemic primary amino compounds on a chiral stationary phase based on optically active (3,3'-diphenyl-1,1'-binaphthyl)-20-crown-6

A liquid chromatographic chiral stationary phase (CSP) based on (3,3'-diphenyl-1,1'-binaphthyl)-20-crown-6, which has been utilized in the resolution of alpha-amino acids, amines and amino alcohols, was treated with excess of n-octyltriethoxysilane to prepare a new improved CSP. The residual silanol groups of the original CSP were protected by n-octyl groups in the new CSP. The chiral recognition ability of the new CSP was superior to that of the original CSP in the resolution of alpha-amino acids, amines and amino alcohols. Retention factors (k1) for the resolution of alpha-amino acids were lower on the new CSP than on the original CSP while those for the resolution of amines and amino alcohols were higher on the new CSP than on the original CSP. The improved chiral recognition ability of the new CSP and the retention behaviors of the two enantiomers on the new CSP have been rationalized to stem from the removal of the non-enantioselective interactions between the analytes and the residual silanol groups of the original CSP and the improved lipophilicity of the CSP.     

Copper(II) diamino acid complexes: quantum chemical computations regarding diastereomeric effects on the energy of complexation

[reaction: see text] Quantum chemical calculations were used to rationalize the observed enantiodifferentiation in the complexation of alpha-amino acids to chiral Cu(II) complexes. Apart from Cu(II)[bond]pi interactions and steric repulsions between the anchoring cholesteryl-Glu moiety and an aromatic amino acid R group, hydrogen bonding also plays a role. In fact, in the case of tryptophan, C[double bond]O...H[bond]N hydrogen bonding between the glutamate moiety and the tryptophan N[bond]H group compensates for the loss of intramolecular hydrogen-bonding and diminished Cu(II)[bond]pi interactions.     

Stereoselective synthesis of pyridinones: application to the synthesis of (-)-barrenazines

[reaction: see text] The stereoselective synthesis of pyridinones was accomplished by the nucleophilic addition of Grignard reagents to a chiral pyridinium salt derived from 4-methoxypyridine. This methodology was applied to an expedient synthesis of (-)-barrenazine A and B. After N-functionalization and 1,4-reduction of the pyridinone system, the corresponding alpha-amino piperidinones readily undergo dimerization to give the hexahydrodipyridinopyrazine skeleton of the barrenazine alkaloids.     

Enantioselective benzoylation of alpha-amino esters using (S)-1-benzoyl-2- (alpha-acetoxyethyl)benzimidazole, a chiral benzimidazolide

A new chiral benzimidazolide is developed as a nonenzymatic acylating agent for enantioselective benzoylation of racemic alpha-amino esters. The process is highly efficient, which exhibits uniformly high enantioselectivity for alpha-amino esters with or without aryl substituents under mild reaction conditions. The chiral benzimidazolide is inexpensive and is easily accessible.     

Barbier-type diastereoselective allylation of alpha-amino aldehydes with an enantiopure 2-sulfinylallyl building block.

An optimized procedure for the diastereoselective allylation under aqueous Barbier conditions of a series of alpha-amino aldehydes with our new chiral building block (S(s))-3-chloro-2-(p-tolylsulfinyl)-1-propene [(S(s))-1a] to afford enantiomerically pure sulfinylamino alcohols in good yields and diastereoselectivites is reported. High levels of diastereoinduction can be achieved from alpha-amino aldehydes configurationally related to natural alpha-amino acids.     

An extended planar C5 conformation and a 310-helical structure of peptide foldamer composed of diverse alpha-ethylated alpha,alpha-disubstituted alpha-amino acids

Optically active peptide foldamers Tfa-[(S)-(alphaEt)Leu]-[(S)-(alphaEt)Nva]-Deg-[(S)-(alphaEt)Nle]-OEt (10) and Tfa-[(S)-(alphaEt)Val]-[(S)-(alphaEt)Leu]-[(S)-(alphaEt)Nva]-Deg-[(S)-(alphaEt)Nle]-OEt (11) composed of diverse alpha-ethylated alpha,alpha-disubstituted alpha-amino acids were synthesized. The dominant conformation of these peptides in solution was an unusual, fully extended planar conformation, and that in the crystal state was both right-handed (P) and left-handed (M) 3(10)-helical structures in 10 and a P 3(10)-helical structure in 11, respectively. The preferred planar C(5) conformation of the peptides prepared from chiral alpha-ethylated alpha,alpha-disubstituted alpha-amino acids was drastically different from the 3(10)-helical structure of the peptides prepared from chiral alpha-methylated alpha,alpha-disubstituted alpha-amino acids.     

Synthesis of 1,2-dithiolane analogues of leucine for potential use in peptide chemistry

[reaction: see text]1,2-Dithiolanes present several points of interest for both peptide and medicinal chemistry, yet no chiral alpha-amino acids containing this five-membered heterocyclic system are available. We report here the first synthesis of N- and C-protected derivative of (S)-2-amino-3-(1,2-dithiolan-4-yl)propionic acid (Adp) and its 1,3-dithiolic form.     

Versatile synthons for optically pure alpha-amino aldehydes and alpha-amino acids: (+)- and (-)-4,5-dialkoxy-2-oxazolidinones

Both enantiomers of trans-5-benzyloxy-4-methoxy- (BMOx) and trans-4,5-dimethoxy-2-oxazolidinones (DMOx), which are readily accessible from simple 2-oxazolone heterocycles, represent good candidates for a new class of chiral synthons for use in the preparation of optically pure alpha-amino aldehydes and alpha-amino acids, respectively.     

Stereocontrolled formation of amino acids and N-heterocycles bearing a quaternary chiral carbon

[STRUCTURE: SEE TEXT] Stereocontrolled formation of tertiary or quaternary chiral carbons bearing nitrogen was achieved using the [3,3]-sigmatropic rearrangement of cyanate to isocyanate as a key element. A short and highly selective sequence of reactions, starting from p-menthane-3-carboxaldehyde, was developed leading to alpha,alpha-dialkylated alpha-amino acids or N-heterocycles, depending on the method of cleavage of the auxiliary.     

Chiral tricyclic iminolactone derived from (1R)-(+)-camphor as a glycine equivalent for the asymmetric synthesis of alpha-amino acids

The development of a highly efficient and stereoselective methodology for the preparation of alpha-amino acids is described. The chiral template, tricyclic iminolactone 7, was synthesized from (1R)-(+)-camphor in five steps in 50% overall yield. Alkylation of iminolactone 7 afforded the alpha-monosubstituted products in good yields (74-96%) and excellent diastereoselectivities (>98%). Hydrolysis of the alkylated iminolactones furnished the desired alpha-amino acids in good yields and enantioselectivities with nearly quantitative recovery of the chiral auxiliary 4.     

A novel highly stereoselective synthesis of 2,3-disubstituted 3H-quinazoline-4-one derivatives

[structure: see text]. An efficient three-step synthesis of chiral 3H-quinazoline-4-one derivatives from commercial materials is disclosed. The Mumm reaction of imidoyl chloride with alpha-amino acids followed by reductive cyclization affords enantiomerically pure (ee >93%) quinazoline-4-ones in good overall yield. A comparison with existing approaches indicates that this method is superior for hindered substrates.     

Preparation and evaluation of a novel chiral stationary phase based on covalently bonded chitosan for ligand-exchange chromatography

A novel chiral stationary phase based on chitosan covalently bonded onto silica gels has been prepared and used for the separation of various alpha-amino acid enantiomers as well as alpha-hydroxycarboxylic acid enantiomers by chiral ligand-exchange chromatography with copper(II) as a complexing ion. The methanol content and copper(II) ion concentration in the eluent affected retentivity and enantioselectivity. Furthermore, a plausible chiral recognition mechanism for resolution of alpha-amino acids was proposed.     

Preparation and application of a new ligand exchange chiral stationary phase for the liquid chromatographic resolution of alpha-amino acid enantiomers

A new liquid chromatographic ligand exchange CSP has been prepared by covalently bonding (S)-N,N-carboxymethyl undecyl leucinol monosodium salt onto silica gel and employed in resolving various alpha-amino acids. The new CSP was quite good in resolving various a-amino acids and the resolution results were dependent on the type and content of organic modifier in the mobile phase. From these results, a chiral recognition model using a lipophilic interaction between the tethering alkyl group of the CSP and the substituent at the chiral center of alpha-amino acids was proposed. The liquid chromatographic resolution of alpha-amino acids on the new CSP was also found to be dependent on the Cu(II) concentration in the mobile phase and the column temperature.     

Development of a recyclable fluorous chiral phase-transfer catalyst: application to the catalytic asymmetric synthesis of alpha-amino acids

[structure: see text] A recyclable fluorous chiral phase-transfer catalyst was synthesized and successfully applied for the catalytic asymmetric synthesis of both natural and unnatural alpha-amino acids. The reaction involves alkylation of a glycine derivative followed by extractive recovery of the chiral phase-transfer catalyst using fluorous solvent.