Double-asymmetric hydrogenation strategy for the reduction of 1,1-diaryl olefins applied to an improved synthesis of CuIPhEt, a C2-symmetric N-heterocyclic carbenoid.

A library of iridium and rhodium phosphine catalysts have been screened for the double-asymmetric hydrogenation of 2,6-di-(1-phenylethenyl)-4-methylaniline to produce the C2-symmetric aniline precursor of the N-heterocyclic carbenoid CuIPhEt. The best catalyst produced the desired enantiomer in 98.6% selectivity. This rare example of a highly selective hydrogenation of a 1,1-diaryl olefin enables a four-step asymmetric synthesis of the C2-symmetric phenylethyl imidazolium ion (IPhEt) from p-toluidine and phenylacetylene and its conversion to the hydrosilylation catalyst CuIPhEt.

Synthetic applications and inversion dynamics of configurationally stable 2-lithio-2-arylpyrrolidines and -piperidines.

In diethyl ether, N-Boc-2-lithio-2-arylpiperidines have been found to be configurationally stable at -80 °C, whereas N-Boc-2-lithio-2-arylpyrrolidines are configurationally stable at -60 °C. Several tertiary benzylic carbanions derived from enantioenriched 2-aryl heterocycles have been successfully alkylated or acylated with little to no loss of enantiopurity. The scope of the reactions has been explored. The enantiomerization dynamics of N-Boc-2-lithio-2-phenylpyrrolidine and N-Boc-2-lithio-2-phenylpiperidine have been studied in the presence of different solvents and achiral ligands.

Dynamics of catalytic resolution of 2-lithio-N-Boc-piperidine by ligand exchange.

The dynamics of the racemization and catalytic and stoichiometric dynamic resolution of 2-lithio-N-Boc-piperidine (7) have been investigated. The kinetic order in tetramethylethylenediamine (TMEDA) for both racemization and resolution of the title compound and the kinetic orders in two resolving ligands have been determined. The catalytic dynamic resolution is second order in TMEDA and 0.5 and 0.265 order in chiral ligands 8 and 10, respectively. The X-ray crystal structure of ligand 10 shows it to be an octamer. Dynamic NMR studies of the resolution process were carried out. Some of the requirements for a successful catalytic dynamic resolution by ligand exchange have been identified.

CATALYTIC DYNAMIC RESOLUTION APPLIED TO THE SYNTHESIS OF 2,6-DISUBSTITUTED PIPERIDINES: PREPARATION OF (+)-LUPETIDINE AND (-)-EPIDIHYDROPINIDINE.

The diastereoselective synthesis of trans-2,6-disubstituted piperidines has been rendered enantioselective by incorporating a catalytic dynamic resolution into the first alkylation step. The method has been applied to the synthesis of (-)-epidihydropinidine and (+)-trans-lupetidine.

Application of a C2-symmetric copper carbenoid in the enantioselective hydrosilylation of dialkyl and aryl-alkyl ketones.

We report excellent reactivity and enantioselectivity of a C(2)-symmetric copper-bound N-heterocyclic carbene (NHC) in the hydrosilylation of a variety of structurally diverse ketones. This catalyst exhibits extraordinary enantioselctivity in the reduction of such challenging substrates as 2-butanone and 3-hexanone. Even at low catalyst loading (2.0 mol %), the reactions occur in under an hour at room temperature and often do not require purification beyond catalyst and solvent removal. The scope of this transformation was investigated in the reduction of 10 aryl-alkyl and alkyl-alkyl ketones.

Design and synthesis of C2-symmetric N-heterocyclic carbene precursors and metal carbenoids.

Chiral, C(2)-symmetric imidazolium and imidazolinium ions, as well as the corresponding copper- or silver-bound carbenoids, have been prepared. Structural study of these compounds by X-ray crystallography reveals a chiral pocket that surrounds the putative carbene site or the metal-carbene bond, at carbon 2, in three of the four ligands prepared. Preliminary investigation into the application of these complexes has shown one of them to be highly enantioselective in the hydrosilylation of acetophenone.

NHC-catalyzed dehydrogenative self-coupling of diphenylsilane: A facile synthesis of octaphenylcyclotetra(siloxane).

A unique application of the CuIPr N-heterocyclic carbene (NHC) to the dehydrogenative self-coupling of diphenylsilane has been discovered. This transformation is carried out open to air at room temperature, yielding octaphenylcyclotetra(siloxane) quantitatively in one hour. This preparation constitutes a significant improvement over existing methods for the preparation of this compound and demonstrates a novel mode of reactivity for CuIPr. The diphenylsilanone tetramer is the precursor to a number of industrially significant polymers.

Highly enantioselective catalytic dynamic resolution of N-Boc-2-lithiopiperidine: synthesis of (R)-(+)-N-Boc-pipecolic acid, (S)-(-)-coniine, (S)-(+)-pelletierine, (+)-beta-conhydrine, and (S)-(-)-ropivacaine and formal synthesis of (-)-lasubine II and (+)-cermizine C.

The catalytic dynamic resolution (CDR) of rac-2-lithio-N-Boc-piperidine using chiral ligand 8 or its diastereomer 9 in the presence of TMEDA has led to the highly enantioselective syntheses of both enantiomers of 2-substituted piperidines using a wide range of electrophiles. The CDR has been applied to the synthesis of (R)- and (S)-pipecolic acid derivatives, (+)-beta-conhydrine, (S)-(+)-pelletierine, and (S)-(-)-ropivacaine and the formal synthesis of (-)-lasubine II and (+)-cermizine C.

Signal amplification in a microchannel from redox cycling with varied electroactive configurations of an individually addressable microband electrode array.

Amperometric detection at microelectrodes in lab-on-a-chip (LOAC) devices lose advantages in signal-to-background ratio, reduced ohmic iR drop, and steady-state signal when volumes are so small that diffusion fields reach the walls before flux becomes fully radial. Redox cycling of electroactive species between multiple, closely spaced microelectrodes offsets that limitation and provides amplification capabilities. A device that integrates a microchannel with an individually addressable microband electrode array has been used to study effects of signal amplification due to redox cycling in a confined, static solution with different configurations and numbers of active generators and collectors. The microfabricated device consists of a 22 microm high, 600 microm wide microchannel containing an array of 50 microm wide, 600 microm long gold microbands, separated by 25 microm gaps, interspersed with an 800 microm wide counter electrode and 400 microm wide passive conductor, with a distant but on-chip 400 microm wide pseudoreference electrode. Investigations involve solutions of potassium chloride electrolyte containing potassium ferrocyanide. Amplification factors were as high as 7.60, even with these microelectrodes of fairly large dimensions (which are generally less expensive, easier, and more reproducible to fabricate), because of the significant role that passive and active (instrumentally induced) redox cycling plays in confined volumes of enclosed microchannels. The studies are useful in optimizing designs for LOAC devices.

Enantiomerization dynamics and a catalytic dynamic resolution of N-trimethylallyl-2-lithiopyrrolidine.

The barriers to enantiomerization of N-trimethylallyl-2-lithiopyrrolidine have been measured in the presence of sparteine,1, N,N'-diisopropylbispidine, 2, and diaminoalkoxide 3. We have additionally demonstrated a rare example of a catalytic dynamic resolution using either of two ligands, achieving enantiomer ratios of up to 93:7.

The barrier to enantiomerization of N-Boc-2-lithiopyrrolidine: the effect of chiral and achiral diamines.

(-)-Sparteine and TMEDA dramatically lower both enthalpy and entropy of activation for the barrier to enantiomerization of N-Boc-2-lithiopyrrolidine in diethyl ether, whereas N,N'-diisopropylbispidine has little effect; the entropy of activation for enantiomerization is zero in the presence of TMEDA and slightly negative in the presence of sparteine; these data suggest a subtle change in mechanism of enantiomerization in the presence of TMEDA and sparteine.

Dynamics of saxitoxin binding to saxiphilin c-lobe reveals conformational change.

Thermodynamic parameters (DeltaG, DeltaH, DeltaS, DeltaC(p)) have been determined to evaluate the dynamics of binding of saxitoxin to the c-lobe of saxiphilin. We have developed an improved method to rapidly express and purify recombinant saxiphilin c-lobe, and fully characterized it by mass spectrometry for the first time. Surface plasmon resonance (SPR) was used to characterize the interaction between saxitoxin and immobilized c-lobe. At 298 K, c-lobe binds saxitoxin with K(D)=1.2 nM, DeltaH degrees =-11.7+/-0.8 kcal/mol, and DeltaS degrees =1.17+/-0.07 cal/molK. Analysis of DeltaC(p) of toxin association at several temperatures suggests that hydrophobic forces contribute to the binding event. Additionally, changes in 8-anilino-1-naphthalene sulfonic acid (ANS) fluorescence upon binding to c-lobe in the presence and absence of saxitoxin support a conformational change in c-lobe upon saxitoxin binding.

Stereoselective [2,3]-sigmatropic rearrangements of unstabilized nitrogen ylides.

The steric course of the [2,3]-rearrangement of several unstabilized nitrogen ylides has been investigated. The reactions proceed cleanly through an anti transition state, affording modest to good yields of a single diastereomer of the product. In two examples containing an N-cinnamyl group, a competing [1,2]-rearrangement affords a minor product.

Spectroscopic detection of Saxitoxin: an alternative to mouse bioassay.

Herein, we report the surface modification of quartz with a coumaryl-aza-crown-6 derivative to detect Saxitoxin using fluorescence enhancement through Photoinduced Electron Transfer and the sensitivity with this system approaches the limit of the mouse bioassay which is the current benchmark for Saxitoxin detection.

Heptapeptide mimic of ohmefentanyl binding in the discontinuous mu-opiod receptor.

[reaction: see text] Ohmefentanyl binds to the rat mu-opiod receptor via two dipeptide sequences (Trp-His and Asp-Tyr) that are separated by 170 residues. A turn-inducing tripeptide, Pro-Aib-Aib, holds the dipeptides in a conformation that binds the narcotic (K(b) = 7.1 x 10(4) M(-)(1)) in THF. Binding is specific for ohmefentanyl over morphine and is accompanied by a conformational change in the heptapeptide host. Control experiments with a Gly-Gly-Gly tripeptide linking the dipeptides show no evidence of binding.

Stannyl cyclopropanes by diastereoselective cyclopropanations with (tributylstannyl)-diazoacetate esters catalyzed by Cu(I) N-heterocyclic carbene.

Catalyzed cyclopropanations of alkenes with Bu3SnC(=N2)CO2R (R = Et, t-Bu) have been achieved in good yield with excellent diastereoselectivity to make stannyl cyclopropanes having two or three stereocenters, one of which is quaternary.

Selective detection of saxitoxin over tetrodotoxin using acridinylmethyl crown ether chemosensor.

At pH 7.1, saxitoxin decomposes to produce a trace impurity that can interfere with fluorescence sensing when using irradiation wavelengths near 325 nm. The fluorophore acridine is found to be a suitable component of arylmethyl crown ether chemosensors for the fluorescent detection of saxitoxin. These sensors are selective for the detection of saxitoxin over tetrodotoxin.

A theoretical investigation into the inversion barrier of dipole-stabilized alpha-aminoorganolithiums.

[reaction: see text] Results from density functional theory calculations (B3LYP/6-31+G) suggest that inversion of the monomer of 2-lithio-N-formylpyrrolidine (2) in coordinating ethereal solvent occurs with an activation barrier of 15.7 kcal/mol, while the inversion of the monomer in a noncoordinating hydrocarbon solvent is considerably slower. However, aggregation into a trimer in hydrocarbon solvent restores the low inversion barrier. This study suggests that solvation and aggregation may influence the mechanism and rate of racemization of dipole-stabilized alpha-aminoorganolithiums.

1-Magnesiotetrahydroisoquinolyloxazolines as Chiral Nucleophiles in Stereoselective Additions to Aldehydes: Auxiliary Optimization, Asymmetric Synthesis of (+)-Corlumine, (+)-Bicuculline, (+)-Egenine, and (+)-Corytensine, and Preliminary (13)C NMR Studies of 1-Lithio- and 1-Magnesiotetrahydroisoquinolyloxazolines.

Transmetalation of 1-lithiotetrahydroisoquinolyloxazolines with magnesium halides affords Grignard reagents that add to aldehydes with up to 80% selectivity for one of the four possible diastereomeric products. An oxazoline chiral auxiliary derived from camphor provides an optimal blend of diastereoselectivity and isomer separability. Synthetic applications of the optimal auxiliary, patterned after a literature approach in the racemic series, comprise an improved (formal) synthesis of bicuculline, egenine, and corytensine, as well as an efficient synthesis of corlumine. Preliminary NMR studies show that both 1-lithio- and 1-magnesiotetrahydroisoquinolyloxazolines are dynamic mixtures in THF solution at low temperatures. The barrier to pyramidal inversion of the secondary Grignard reagent is in the 9.8-10.1 kcal/mol range, while an upper limit of about 8.2 kcal/mol can be assigned to the barrier to the organolithium inversion.

Application of catalytic dynamic resolution of N-Boc-2-lithiopiperidine to the asymmetric synthesis of 2-aryl and 2-vinyl piperidines.

The highly enantioselective synthesis of 2-aryl- and 2-vinyl-piperidines has been accomplished through a catalytic dynamic resolution (CDR) of N-Boc-2-lithiopiperidine. The method has been applied to the synthesis of both enantiomers of the tobacco alkaloid anabasine.