Hydrogen Bond Assisted l to d Conversion of α-Amino Acids.

l to d conversion of unactivated α-amino acids was achieved by solubility-induced diastereomer transformation (SIDT). Ternary complexes of an α-amino acid with 3,5-dichlorosalicylaldehyde and a chiral guanidine (derived from corresponding chiral vicinal diamine) were obtained in good yield as diastereomerically pure imino acid salt complexes and were hydrolysed to obtain enantiopure α-amino acids. A combination of DFT computation, NMR spectroscopy, and crystal structure provide detailed insight into how two types of strong hydrogen bonds assist in rapid epimerization of the complexes that is essential for SIDT.

Synthesis of Enantiopure Mixed Alkyl-Aryl Vicinal Diamines by the Diaza-Cope Rearrangement: A Synthesis of (+)-CP-99,994.

The stereoselective synthesis of mixed alkyl-aryl vicinal diamines was demonstrated by the use of 1,2-bis(2-hydroxyphenyl)-1,2-diaminoethene (hpen). A sequential addition of aryl and alkyl aldehyde to hpen gave a fused imidazolidine-dihydro-1,3-oxazine ring stereoselectively, which undergoes the diaza-Cope rearrangement to provide mixed vicinal diimines at elevated temperature in good yields and excellent stereoselectivity. We also showed that (+)-CP-99,994 can be readily prepared by the diaza-Cope rearrangement in overall 42% yield.

Catalytic Stereoinversion of L-Alanine to Deuterated D-Alanine.

A combination of an achiral pyridoxal analogue and a chiral base has been developed for catalytic deuteration of L-alanine with inversion of stereochemistry to give deuterated D-alanine under mild conditions (neutral pD and 25 °C) without the use of any protecting groups. This system can also be used for catalytic deuteration of D-alanine with retention of stereochemistry to give deuterated D-alanine. Thus a racemic mixture of alanine can be catalytically deuterated to give an enantiomeric excess of deuterated D-alanine.

Highly stereoselective recognition and deracemization of amino acids by supramolecular self-assembly.

The highly stereoselective supramolecular self-assembly of α-amino acids with a chiral aldehyde derived from binol and a chiral guanidine derived from diphenylethylenediamine (dpen) to form the imino acid salt is reported. This system can be used to cleanly convert D-amino acids into L-amino acids or vice versa at ambient temperature. It can also be used to synthesize α-deuterated D- or L-amino acids.

Stereospecific synthesis of a twinned alanine ester.

Reaction between 1,2-bis(2-hydroxyphenyl)-ethylenediamine (hpen) and methyl pyruvate gives the diaza-Cope rearrangement product with good yield and excellent stereospecificity. The product containing two chiral quaternary carbon centers is characterized by high performance liquid chromatography and X-ray crystallography. DFT computation provides insight into why the diaza-Cope rearrangement takes place readily with methyl pyruvate but not with other ketones like acetone and substituted acetophenones.

2,2'-[(1S,2S)-1,2-Bis(2-hy-droxy-phen-yl)ethane-1,2-di-yl]bis(isoindoline-1,3-dione) ethanol monosolvate hemihydrate.

In the title compound, C30H20N2O6·C2H6O·0.5H2O, the solvent water mol-ecule lies on a twofold rotation axis. The dihedral angle between the essentially planar isoindole ring systems [maximum deviations = 0.

Short synthesis of enantiopure trans-3-arylpiperazine-2-carboxylic acid derivatives via diaza-Cope rearrangement.

An efficient synthetic method was developed for the construction of enantiomerically pure trans-3-arylpiperazine-2-carboxylic acid derivatives using diaza-Cope rearrangement (DCR) as a key step starting from (R,R)/(S,S)-1,2-bis(2-hydroxyphenyl)-1,2-diaminoethane (HPEN). A complete transfer of stereochemical integrity was observed for the transformation. Piperazine ring formation from the chiral 1,2-ethylenediamine derivatives using diphenylvinylsulfonium triflate followed by oxidation using ruthenium(III) chloride monohydrate in the presence of sodium periodate provided the desired enantiopure trans-3-arylpiperazine-2-carboxylic acid derivatives.

Understanding the interplay of weak forces in [3,3]-sigmatropic rearrangement for stereospecific synthesis of diamines.

Chiral diamines are important building blocks for constructing stereoselective catalysts, including transition metal based catalysts and organocatalysts that facilitate oxidation, reduction, hydrolysis, and C-C bond forming reactions. These molecules are also critical components in the synthesis of drugs, including antiviral agents such as Tamiflu and Relenza and anticancer agents such as oxaliplatin and nutlin-3. The diaza-Cope rearrangement reaction provides one of the most versatile methods for rapidly generating a wide variety of chiral diamines stereospecifically and under mild conditions.

Stereospecific synthesis of alpha-substituted syn-alpha,beta-diamino acids by the diaza-Cope rearrangement.

Diaza-Cope rearrangement is used to make a variety of alpha-substituted syn-alpha,beta-diamino acids. The rearrangement takes place with complete transfer of stereochemical integrity (>97% de and >98% ee) giving only one of four possible stereoisomers as determined by X-ray crystallography, (1)H NMR, and chiral HPLC. The observed stereospecificity can be explained in terms of DFT computation.

Electronic effect on the kinetics of the diaza-cope rearrangement.

Hammett plot reveals that there is a significant electronic effect on the rate of resonance assisted hydrogen bond (RAHB) directed diaza-Cope rearrangement reaction with a rho value of 1.6. DFT computation shows that the rearrangement reaction becomes thermodynamically more favorable for the substrates with electron withdrawing substituents.

Stereospecific synthesis of alkyl-substituted vicinal diamines from the mother diamine: overcoming the "intrinsic barrier" to the diaza-Cope rearrangement reaction.

Addition of isobutyraldehyde to 1,2-bis(2-hydroxyphenyl)-1,2-diaminoethane (mother diamine) cleanly gives a stable, fused imidazolidine-dihydro-1,3-oxazine ring complex. However, vigorous heating of the fused ring complex gives the diaza-Cope rearrangement product with excellent yield and stereoselectivity. A variety of alkyl aldehydes have been used to make corresponding alkyl diamines with excellent yield and stereospecificity.

Rapid enantiomeric excess and concentration determination using simple racemic metal complexes.

Racemic-metal complexes were used to determine identity, enantiomeric excess, and concentration of chiral diamines using metal-to-ligand charge transfer bands in circular dichroism spectroscopy. It takes under just 2 min per sample to determine [G]t and %R with tolerable errors (19% and 4%, respectively). The simplicity of the achiral receptors employed confers to this technique great potential for high-throughput screening.

Stereoconversion of amino acids and peptides in uryl-pendant binol schiff bases.

(S)-2-Hydroxy-2'-(3-phenyluryl-benzyl)-1,1'-binaphthyl-3-carboxaldehyde (1) forms Schiff bases with a wide range of nonderivatized amino acids, including unnatural ones. Multiple hydrogen bonds, including resonance-assisted ones, fix the whole orientation of the imine and provoke structural rigidity around the imine C==N bond. Due to the structural difference and the increase in acidity of the alpha proton of the amino acid, the imine formed with an L-amino acid (1-l-aa) is converted into the imine of the D-amino acid (1-D-aa), with a D/L ratio of more than 10 for most amino acids at equilibrium.

Tight binding and fluorescent sensing of oxalate in water.

A dinuclear copper complex that binds tightly and selectively to oxalate over other dicarboxylates like malonate, succinate, and glutarate has been developed. This receptor can be used for fluorescent detection of oxalate in water at physicological pH by chemosensing ensemble approach. Crystal structure of oxalate bound to the receptor together with molecular mechanics and DFT computations provide insights into the tight and selective binding of the anion by the receptor.

Stereospecific synthesis of C2 symmetric diamines from the mother diamine by resonance-assisted hydrogen-bond directed diaza-Cope rearrangement.

Sixteen diphenylethylenediamine analogues including those with electron donating, electron withdrawing, and sterically bulky substituents have been prepared in good overall yields (70-90%) and in enantiomerically pure form (>99% ee) by diaza-Cope rearrangement reaction. A single chiral mother diamine, ((R,R)-1,2-bis-(2-hydroxyphenyl)-1,2-diaminoethane), is reacted with appropriate aldehydes to form the initial diimines that rearrange to give all the product diimines in the (S,S) form. The daughter diamines are obtained by hydrolysis of the product diimines.

Reactive extraction of enantiomers of 1,2-amino alcohols via stereoselective thermodynamic and kinetic processes.

(R)-amino alcohol with an enantiomeric excess of >95% was resolved by reactive extraction processes from 2 equiv of racemic alcohol using a chiral receptor 2 as an enantioselective extractant. One resolution cycle is composed of three extractions: a stereoselective reversible imine formation, a stereoselective irreversible imine hydrolysis, and the recovery of 2 and enantiomeric amino alcohols.

High-throughput screening of identity, enantiomeric excess, and concentration using MLCT transitions in CD spectroscopy.

This manuscript describes a protocol for the fast determination of identity, enantiomeric excess (ee) and concentration of chiral 1,2-diamines, the combination of which has not previously been achieved, using the changes in the circular dichroism (CD) spectra of the charge-transfer bands of the Cu(I)-Binap complex. The spectra were analyzed with a variety of pattern recognition (PR) protocols. PR techniques were used to analyze unknown samples in a robotically controlled 96-well plate interfaced CD instrument.

Diastereoselective diaza-Cope rearrangement reaction.

Steric effect is used to obtain a highly diastereoselective rearrangement reaction.

Bifunctional organocatalyst for methanolytic desymmetrization of cyclic anhydrides: increasing enantioselectivity by catalyst dilution.

Highly enantioselective methanolysis of meso-cyclic anhydride was achieved with bifunctional organocatalyst containing a quinine-thiourea moiety; unusual concentration, temperature and solvent effects on the enantioselectivity can be explained in terms of a mechanism involving monomer-dimer equilibration of the catalyst.

High-affinity pyrophosphate receptor by a synergistic effect between metal coordination and hydrogen bonding in water.

We have developed the tightest binding PPi receptor reported to date by a combination of metal coordination and hydrogen bonding interaction in water.

Imprinting and locking chiral memory for stereoselective catalysis.

A salen ligand based Co(III) complex +/- with imprintable chiral memory was locked-in and used for stereoselective catalysis.