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.

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.

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.

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.

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.

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.

Formal synthesis of the bisbenzylisoquinoline alkaloid berbamunine by asymmetric substitution of chiral organolithium compounds.

Asymmetric alkylation of enantiomeric tetrahydroisoquinolyl oxazolines was achieved with 96-97% diastereoselectivity. Removal of the oxazoline chiral auxiliary and further transformations provide a straightforward synthesis of the two synthetic intermediates that were previously synthesized by resolution, and which comprise a formal synthesis of berbamunine by Ullman coupling.

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.

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.

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.

Novel modulator of Na(V)1.1 and Na(V)1.2 Na channels in rat neuronal cells.

A novel modulator of sodium ion currents was synthesized in 6 steps from a protected dihydroxypyrrolidine nitrone, via 1,3-dipolar cycloaddition reaction with acrylamide. Sodium ion currents in B50 cells were evaluated in comparison to saxitoxin and tetrodotoxin, and revealed an IC(50) of 15.7 muM. The new compound shows no evidence of binding to the C-lobe of the saxitoxin-binding protein saxiphilin.

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.

The barrier to enantiomerization and dynamic resolution of N-Boc-2-lithiopiperidine and the effect of TMEDA.

The kinetics of enantiomerization and dynamic thermodynamic resolution (DTR) of N-Boc-2-lithiopiperidine have been measured, revealing significant differences in enthalpy and entropy for these processes and a role for the achiral ligand TMEDA; the racemization and the DTR are catalytic and first order in [TMEDA], and this has implications for asymmetric synthesis with chiral organolithiums.

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.

Structures of pahayokolides A and B, cyclic peptides from a Lyngbya sp.

The isolation and structure elucidation of two cyclic peptides, pahayokolides A (1) and B (2), is described. Structural features determined for these compounds include a pendent N-acetyl-N-methyl leucine, both E- and Z-dehydrobutyrines, a homophenylalanine, and an unusual polyhydroxy amino acid that is most likely of mixed polyketide synthase/nonribosomal peptide synthase origin. These peptides were purified from a new species of cyanobacteria of the genus Lyngbya, which was isolated from a periphyton mat from the Florida Everglades.