Induced folding by chiral nonplanar aromatics.

We report a structural motif based on a C(3)-symmetric bowl-shaped core, on which three substituted amino acids on the periphery adopt either a folded or a spread-out conformation. This class of chiral folded structures is achieved by controlling the reactivity of the stereogenic protons on the nonplanar aromatic rings of trioxatricornan to afford predominantly C(3)-symmetric isomers. Bromination of trioxatricornan afforded a C(1)-symmetric and a C(3)-symmetric trisubstituted isomer, with the former being the major product as a statistical consequence during the reaction cascade. To obtain the C(3) symmetric isomer as the major product, C-H activation by means of ortho-lithiation with the bulky tert-butyl lithium and tetramethylethylenediamine was followed by a nucleophilic substitution that successfully reversed the statistically controlled regioselectivity. Further derivatization of the trioxatricornan with amino acids or menthol afforded diastereomers that were resolved by preparative chromatography. The absolute configurations of the diastereomers were determined by vibrational circular dichroism (VCD) in combination with density functional theory (DFT) and electronic circular dichroism (ECD). The folding structure of cysteine-derivatized trioxatricornan diastereomers was determined by two-dimensional NMR spectroscopy and molecular dynamics calculation, which revealed that one diastereomer has the amino acids folded toward the cavity of trioxatricornan and the other has a "spread-out" structure.

Observation and calculation of vibrational circular birefringence: a new form of vibrational optical activity.

We report the first mid-infrared observation of vibrational circular birefringence (VCB) arising from individual chiral molecules. VCB can also be called vibrational optical rotatory dispersion (VORD) and is the Kramers-Kronig transform of vibrational circular dichroism (VCD). The method of measurement involves a simple change in the optical set-up and electronic processing of a VCD spectrometer such that the VCB spectrum appears at twice the polarization modulation frequency as a pseudo vibrational linear dichroism (VLD) spectrum. VCB spectra are also calculated with density function theory (DFT) for the first time using a commercially available program for rotational strengths where the calculated intensities are convolved with the real, dispersive part of a normalized complex Lorentzian lineshape rather than the imaginary, absorptive part, normally used for IR and VCD intensity calculations. Comparison of the measured and calculated VCB, VCD, and IR spectra of (+)-R-limonene and (-)-S-alpha-pinene show close agreement and confirm the validity of the new VCB measurements.

A comparison of the Low Mode and Monte Carlo conformational search methods.

The Low Mode (LM) and Monte Carlo (MC) conformational search methods were compared on three diverse molecular systems; (4R, 5S, 6S, 7R)-hexahydro-5,6-dihydroxy-1,3,4,7-tetrakis(phenylmethyl)-2H-1,3-diazapin-2-one (1), 2-methoxy-2-phenyl-2-triflouromethyl-N-alpha-methyl benzyl propanamide (2) and a trimeric 39-membered polyazamacrolide (3). We find that either method, or a combination of the methods, is equally efficient at searching the conformational space of the smaller molecular systems while a 50:50 hybrid of Low Mode and Monte Carlo is most efficient at searching the space of the larger molecular system.

Vibrational circular-dichroism spectroscopy of homologous cyclic peptides designed to fold into ß helices of opposite chirality.

Cyclic ß-helical peptides have been developed as model structured biomolecules for examining peptide adsorption and conformation on surfaces. As a key prerequisite to circular-dichroism (CD) analysis of these model peptides on surfaces, their conformations and the corresponding vibrational spectra in the 1400-1800 cm⁻¹ range were analyzed by vibrational circular-dichroism (VCD) spectroscopy in solution. The two model peptides ("ß Leu and ß Val") were examined in chloroform, where they each fold into a homogeneous well-defined antiparallel double-stranded ß-helical species, as determined previously by NMR and electronic CD spectroscopy. Because the ß-helical conformations of ß Leu and ß Val are well characterized, the VCD spectra of these peptides can be unambiguously correlated with their structures. In addition, these two ß-helical peptides differ from one another in two key respects that make them uniquely advantageous for CD analysis--first, while their backbone conformations are topologically similar, ß Leu and ß Val form helices of opposite chiralities; second, the two peptides differ in their sequences, i.e., composition of the side chains attached to the backbone. The observed VCD spectra for ß Leu and ß Val are roughly mirror images of each other, indicating that the VCD features are dominated by the chirality and conformation of the peptide backbone rather than by the peptide sequence. Accordingly, spectra similarly characteristic of peptide secondary structure can be expected for peptides designed to be structural analogs of ß Leu and ß Val while incorporating a variety of side chains for studies of surface adsorption from organic and aqueous solvents.

Direct observation and pH control of reversed supramolecular chirality in insulin fibrils by vibrational circular dichroism.

The controlled reversal of supramolecular helical chirality in protein fibrils is reported for the first time. Normal or reversed insulin fibrils were grown by precise adjustment of pH. AFM images show two polymorphs corresponding to opposite senses of helical twist of the supramolecular structure with the same cross-ß-sheet core.

Subtle chirality in oxo- and sulfidorhenium(v) complexes.

Enantioenriched square-pyramidal oxo- and sulfidorhenium(v) complexes have been prepared and their stereochemistry studied by vibrational circular dichroism (VCD) spectroscopy.

Synthesis and vibrational circular dichroism of enantiopure chiral oxorhenium(V) complexes containing the hydrotris(1-pyrazolyl)borate ligand.

The infrared and vibrational circular dichroism (VCD) spectra of six chiral oxorhenium(V) complexes, bearing a hydrotris(1-pyrazolyl)borate (Tp) ligand, have been investigated. These complexes are promising candidates for observation of parity violation (symmetry breaking due to the weak nuclear force). New chiral oxorhenium complexes have been synthesized, namely, [TpReO(eta2-O(CH3)CH2CH2O-O,O)] (4a and 4b) diastereomers and [TpReO(eta2-N(CH3)CH2CH2O-N,O)] (5) and [TpReO(eta2-N(tBu)CH2CH2O-N,O)] (6) enantiomers. All compounds could be obtained in enantiomerically pure form by using either column chromatography or HPLC over chiral columns. VCD spectroscopy of these compounds and of [TpReO(eta2-N(CH3)CH(CH3)CH(Ph)O-N,O)] (2) and [TpReO(eta2-N(CH2)3CHCO2-N,O)] (3) (with chiral bidentate ligands derived, respectively, from ephedrine and proline) were studied. This allowed the absolute configuration determination of all compounds together with their conformational analysis, by comparing calculated and experimental spectra. This is the first VCD study of rhenium complexes which further demonstrates the applicability of VCD spectroscopy in determining the chirality of inorganic complexes.