Jik Chin

A Highly Reactive and Enantioselective Bifunctional Organocatalyst for the Methanolytic Desymmetrization of Cyclic Anhydrides : Prevention of Catalyst Aggregation

At present, there is much interest in organocatalysts, as they tend to be less toxic and more environmentally friendly than traditional metal-based catalysts. Although much progress has been made, the development of chiral organocatalysts that are as reactive and stereoselective as some of the best transition-metal catalysts remains a considerable challenge. To attain reasonable reaction rates and stereoselectivity with organocatalysts, a large catalyst loading is often required. One way to address this difficulty is to design bifunctional or multifunctional organocatalysts with functional groups that work cooperatively to stabilize the transition state and accelerate the rate of the reaction. It has been shown that ureaor thiourea-based bifunctional organocatalysts are effective in facilitating a variety of useful organic reactions, including the methanolytic desymmetrization of cyclic anhydrides. However, we showed recently that ureaand thiourea-based organocatalysts can form hydrogen-bonded aggregates, which results in a strong dependence of reactivity and enantioselectivity on concentration and temperature. X-ray crystal structures of monofunctional and bifunctional (thio)urea derivatives show that they form aggregates through hydrogen bonding between the (thio)urea NH groups and the (thio)urea sulfur or oxygen atom in an intermolecular fashion. A recent NMR spectroscopic study also showed that the thiourea IV exists as a dimer, even in solution. Furthermore, thiourea groups tend to degrade under thermal conditions. Herein we present a thermally robust sulfonamide-based bifunctional organocatalyst I (Scheme 1), which shows unprecedented catalytic activity and excellent enantioselectivity in the methanolytic desymmetrization of meso cyclic anhydrides. A detailed mechanistic and computational approach to the design of I resulted in a catalyst that does not self-aggregate to any appreciable extent. To the best of our knowledge, I is the first quinineand sulfonamide-based bifunctional organocatalyst. The quinuclidine group of I may be able to function as a general-base catalyst to activate the nucleophile, and the sulfonamide group may be able to activate the electrophile simultaneously by hydrogen bonding. To investigate the catalytic activity and enantioselectivity of the cinchona-alkaloid-based sulfonamide catalyst I, we examined the asymmetric methanolysis of cis-1,2-cyclohexanedicarboxylic anhydride (1a) in Et2O with various amounts of I at ambient temperature. The results are summarized in Table 1, together with the results obtained with other cinchona-alkaloid-based catalysts (quinine (II), (DHQ)2AQN (III), and the quinine-based thiourea catalyst IV; Scheme 1). The desymmetrization of 1a with I (10 mol%) proceeded surprisingly fast; the reaction was complete within 1 h to Scheme 1. Structures of cinchona-alkaloid-based organocatalysts.

Artificial dinuclear phosphoesterases.

Many elegant dinuclear transition metal and lanthanide complexes that efficiently hydrolyze phosphate esters including RNA and DNA have been reported recently. In most cases, the dinuclear complexes are much more reactive than the corresponding mononuclear metal complexes. Furthermore, structural and kinetic data indicate that substantial rate acceleration for phosphate diester cleavage is obtained by bridging the dinuclear metal centers with the two phosphoryl oxygens. Interestingly, such bridging structures have recently been implicated in several metalloenzyme catalyzed phosphate hydrolyses.

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. In less than two minutes per sample, ee and concentration values can be read with 2% and 8% error, respectively. The speed and accuracy as well as ability to simultaneously measure ee concentration and identity represent clear advantages over traditional methods and makes this method adaptable to true high-throughput screening.

Highly Stereospecific Generation of Helical Chirality by Imprinting with Amino Acids : A Universal Sensor for Amino Acid Enantiopurity

Generation of helical and axial chirality has been the topic of much interest in biology and chemistry. Controlling axial chirality with stereogenic-center-based chirality has shown to be useful for determining the absolute configurations or enantiopurities of chiral acids, alcohols, and natural or unnatural amino acids, and also for stereoselective synthesis of unnatural amino acids. However, it has been a challenge to control axial chirality from stereogenic-center-based chirality with a high degree of stereospecificity. In biology, amino acid chirality (the l form) is used for the stereospecific generation of helical chirality (for example, the right-handed a helix of proteins). The energy difference between the rightand left-handed a-helical peptides is small per amino acid residue, and more than twenty l amino acids are required to favor the right-handed a helix. Finding the minimal structural requirement of a receptor for generating helical chirality from amino acid chirality may provide interesting insights into stereospecific folding and stereoselective recognition of molecules. Herein we report how helical chirality can be imprinted onto 2,2’-dihydroxybenzophenone (1) in a highly stereospecific manner with a single amino acid (Scheme 1). A signaling group can also be attached to the receptor 2 for general sensing of amino acid enantiopurity. Compound 1 is readily available commercially. It has axial or helical chirality and exists as an equal mixture of rapidly interconverting P and M forms (P-1 and M-1 in Scheme 1a). Receptor 1 resembles [4]helicene in that they are both helical with four consecutive six-membered rings (including hydrogen bonds in 1). Amines react with 1 to form imines within minutes at ambient temperatures (Scheme 1b). Under the same conditions, it takes weeks to form imines with benzophenone. Thus the two hydroxy groups in 1 greatly activate the carbonyl group towards nucleophilic attack through double H bonding. If the tetramethylammonium salt of alanine (0.1m) is added to a solution of 1 (0.1m) in a protic solvent, such as CD3OD (Scheme 1c), two sets of signals are detected in the H NMR spectrum (Figure 1a). The two compounds in Scheme 1c are diastereomeric and are expected to give distinct NMR signals. However, if an aprotic solvent, such as CD3CN is used (Scheme 1b), a remarkably clean H NMR spectrum results with just one set of signals (Figure 1b). Computation can be used to help explain the high stereospecificity for imine formation in an aprotic solvent such as CD3CN. Density functional theory computation (DFT; B3LYP at the 6-31G* level) shows that the global minimum-energy structure of the imine 1-A-G formed between anionic l-alanine and 1 has two internal H bonds (Figure 2a). One internal H bond in 1-A-G is a resonanceScheme 1. Generating helical chirality in 2,2’-dihydroxybenzophenone 1 with a single amino acid. A= l-alanine, G=global minimum, L= local minimum. See text for details.

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. Density functional theory computation shows that resonance-assisted hydrogen-bond is the main driving force behind all the rearrangement reactions. Chiral high performance liquid chromatography and circular dichroism spectroscopy show that the highly stereospecific rearrangement reactions take place with apparent inversion of stereochemistry.

A RATIONAL APPROACH TO SELECTIVE RECOGNITION OF NH4+ OVER K+

An ion-selective electrode (ISE) based on receptor 1 is highly selective for binding NH(4)(+) over K(+) (lg K(NH(4)(+)/K(+))=-2.6); the three imine nitrogen atoms in 1 are ideally positioned for hydrogen bonding with the tetrahedral NH(4)(+) ion. This selectivity is considerably greater than that found for commercial ISEs based on nonactin (lg K(NH(4)(+)/K(+))=-1.0).

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.

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.

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. A crystal structure of the ternary complex together with DFT computation provided detailed insight into the origin of the stereoselective recognition of amino acids.