This feature article reviews dimeric metalloporphyrin hosts employed as chirality probes in chiral recognition processes involving synthetic compounds and natural products. Upon formation of a chiral host-guest supramolecular complex between an achiral bis-metalloporphyrin derivative and a chiral non-racemic guest, a CD response occurs in the porphyrin spectral region, which is diagnostic of the guest's absolute configuration. Several bis-porphyrin hosts used in the stereochemical investigation of organic compounds are described and the scope of their application as chirality probes critically assessed. The review encompasses the description of structural features of the host-guest complexes, the nature of the chirality transfer mechanism and the practical application in solving stereochemical problems. In particular, with reference to the method based on bis-porphyrin tweezers, we describe recent advances based on the use of molecular modeling, which have broadened the applicability of the tweezer methodology and allowed extraction of deeper structural information contained in the experimental CD data.

The absolute configuration (AC) of the bioactive metabolites phyllostin (1) and scytolide (2), two hexahydro-1,4-benzodioxines produced by Phyllosticta cirsii, and oxysporone (3), a dihydrofuropyranone recently isolated from a strain of Diplodia africana, has been assigned by computational analysis of their optical rotatory dispersion (ORD), electronic circular dichroism (ECD), and vibrational circular dichroism (VCD) spectra. Computational prediction of ORD, ECD, and VCD allowed us to assign (3S,4aR,8S,8aR) AC to naturally occurring (-)-1, while (4aR,8S,8aR) AC was assigned to (-)-2 employing only ECD and VCD, because in this case ORD analysis turned out to be unsuitable for AC assignment. Theoretical prediction of both ORD and ECD spectra of 3 led to assignment of (4S,5R,6R) AC to (+)-3. In this case a satisfactory agreement between experimental and calculated VCD spectra was obtained only after taking into account solvent effects. This study shows that in the case of flexible and complex natural products only a concerted application of more than a single chiroptical technique permits unambiguous assignment of absolute configuration.

We examined the structural requirements for cell surface expression, signaling, and human immunodeficiency virus co-receptor activity for the chemokine receptor, CCR5. Serial C-terminal truncation of CCR5 resulted in progressive loss of cell surface expression; mutants truncated at the 317th position and shorter were not detected at the cell surface. Alanine substitution of basic residues in the membrane-proximal domain (residues 314 -322) in the context of a full-length C-tail resulted in severe reduction in surface expression. Cterminal truncation that excised the three cysteines in this domain reduced surface expression, but further truncation of upstream basic residue(s) abolished surface expression. Substituting the carboxyl-terminal domain of CXCR4 for that of CCR5 failed to rectify the trafficking defect of the tailless CCR5. In contrast, tailless CXCR4 or a CXCR4 chimera that exchanged the native cytoplasmic domain for that of wild type CCR5 was expressed at the cell surface. Deletion mutants that expressed at the cell surface responded to chemokine stimulation and mediated human immunodeficiency virus entry. Substitution of all serine and threonine residues in the C-terminal tail of CCR5 abolished chemokine-mediated receptor phosphorylation but preserved downstream signaling (Ca 2؉ flux), while substitutions of tyrosine residues in the C-tail affected neither phenotype. CCR5 mutants that failed to traffic to the plasma membrane did not exhibit obvious changes in metabolic turnover and were retained in the Golgi or pre-Golgi compartments(s). Thus, the basic domain (-KHIAKRF-) and the cysteine cluster (-CKCC-) in the C-terminal tail of CCR5 function cooperatively for optimal surface expression.

The intrinsic rotation, limiting value of specific rotation at zero concentration, of (R)-(-)-epichlorohydrin was measured in four different solvents, CH(3)OH, CH(2)Cl(2), CHCl(3) and CCl(4). It was found that the sign of rotation in CH(3)OH, and CH(2)Cl(2) solvents is opposite to that in CCl(4). The intrinsic rotation in CHCl(3) is close to zero. This observed pattern was explained using density functional calculations of specific rotation using very large basis sets. It was found that the g-I and g-II conformations of epichlorohydrin have nearly the same magnitude of specific rotation but with opposite sign. When these two conformations have equal populations, as in CHCl(3) solvent, the net rotation is close to zero. When g-II conformation dominates, as in CCl(4) solvent, the observed sign of rotation will be opposite to that when g-I conformation dominates, as in CH(2)Cl(2) and CH(3)OH solvents. A combination of intrinsic rotation measurement with density functional prediction of specific rotation is demonstrated to be a practical method for determining the structures of molecules.