Salvatore Caccamese

Stereoselective synthesis and optical resolution of chiral calix[4]arenes with mixed ligating functionalities

Exhaustive alkylation of syn-proximal bis[(2-pyridylmethyl)oxy]calix[4]arene 1 with t-butyl bromoacetate or 2-(chloromethyl)quinoline hydrochloride in the presence of Cs2CO3 affords selectively a new type of inherently chiral calix[4]arenes 2a,b in the partial cone conformation. (±) 2b has been resolved into its optical antipodes by an HPLC method.

Simulation of the lanthanide induced shifts : Description of a computer method and its applications to conformational equilibria of simple systems

Abstract A computer method to simulate the observed Lanthanide Induced Shifts (LIS) is described and its applications to the study of the conformational equilibria in solution for simple systems are reported. Starting from structurally rigid systems, it is shown that the LIS simulation process allows mistaken assignment to be corrected by systematic permutation of signals with uncertain assignments. Some examples of structurally flexible systems with an internal rotation angle are studied (2-carbonyl derivatives of furan and thiophene, N-vinylpyrrolidone, cyclopropanecarboxyamides), and the results allow the structures actually present in the conformational equilibrium to be determined. It has been also found that it is possible to estimate the population ratio between s - cis and s - trans conformers in a number of α,β-unsaturated systems.

Facile separation of the enantiomers of diethyl N-(aryl)-1-amino-1-arylmethanephosphonates on a rationally designed chiral stationary phase

Separation of the enantiomers of each member of a series of diethyl N-(aryl)-1-amino-1-arylmethanephosphonates is easily accomplished by HPLC using a WHELK-O column. This totally synthetic chiral stationary phase (CSP 1) is designed to utilize specifiable interactions to differentiate between enantiomers. The structural features of these phosphonates suggested that CSP 1 would be applicable to the separation of the enantiomers of this class of compounds even though there was an element of uncertainty owing to the presence of two π-basic interaction sites, one on either side of the stereogenic center. The structures of the π-basic N-aryl and C-aryl substituents have been varied, the structure of the latter being found to have the greatest effect on retention and enantioselectivity.

Enantiomers of naringenin as pleiotropic, stereoselective inhibitors of cytochrome P450 isoforms†

Interactions between naringenin and the cytochrome P450 (CYP) system have been of interest since the first demonstration that grapefruit juice reduced CYP3A activity. The effects of naringenin on other CYP isoforms have been less investigated. In addition, it is well known that interactions with enzymes are often stereospecific, but due to the lack of readily available pure naringenin enantiomers, the enantioselectivity of its effects has not been characterized. We isolated pure naringenin enantiomers by chiral high-performance liquid chromatography and tested the ability of (R)-,(S)- and rac-naringenin to inhibit several important drug-metabolizing CYP isoforms using recombinant enzymes and pooled human liver microsomes. Naringenin was able to inhibit CYP19, CYP2C9, and CYP2C19 with IC50 values below 5 μM. No appreciable inhibition of CYP2B6 or CYP2D6 was observed at concentrations up to 10 μM. Whereas (S)-naringenin was 2-fold more potent as an inhibitor of CYP19 and CYP2C19 than (R)-naringenin, (R)-naringenin was 2-fold more potent for CYP2C9 and CYP3A. Chiral flavanones like naringenin are difficult to separate into their enantiomeric forms, but enantioselective effects may be observed that ultimately impact clinical effects. Inhibition of specific drug metabolizing enzymes by naringenin observed in vitro may be exploited to understand pharmacokinetic changes seen in vivo.

Non-empirical assignment of the absolute configuration of (−)-naringenin, by coupling the exciton analysis of the circular dichroism spectrum and the ab initio calculation of the optical rotatory power

The non-empirical assignment of the absolute configuration of (-)-naringenin, the aglycone of (-)-naringin, a flavanone glycoside abundant in the albedo of immature grapefruits and showing several interesting biological properties, has been approached by two different methods: (a) the exciton analysis of the circular dichroism (CD) spectrum and (b) the ab initio calculation of the optical rotatory power. Both the methods indicate the configurational correlation (-)/(S), as empirically suggested by Gaffield. A comparison of advantages and limitations of the two methods of analysis is also presented.

Enantiomerization of an inherently chiral resorcarene derivative: determination of the interconversion barrier by computer simulation of the dynamic HPLC experiment

Abstract The inherently chiral tetrabenzoxazine resorcarene derivative 1 shows characteristic plateau-formation during enantioselective HPLC separation on the chiral stationary phase Chiralpak AD. By computer assisted peak form analysis of the elution profiles, obtained from temperature dependent dynamic HPLC (DHPLC) experiments, with ChromWin, the enantiomerization barrier Δ G # (298 K)=92±2 kJ mol −1 and the activation parameters Δ H # =53.0±1.8 kJ mol −1 and Δ S # =−131±14 J (K mol) −1 were determined.

Inherently chiral α-picolyloxy-p-tert-butylcalix[5]arene crown ethers: Synthesis, structure proof, and enantioselective HPLC resolution

Abstract Reaction of α -picolyloxy- p - tert -butylcalix[5]arene with tri- to pentaethylene glycol ditosylates and K 2 CO 3 regioselectively affords racemic (1,2)-bridged crown ether derivatives in the cone conformation. Their structure is firmly established by NMR spectroscopy and by comparison with appropriate (1,3)-bridged crown-6 regioisomers, synthesized by unequivocal sequences. The enantiomeric resolution of racemates has been achieved by direct HPLC separation, using enantioselective stationary phases. The enantiomers of the (1,2)-bridged crown-5 derivative exhibit one of the largest separation factors (α) so far reported for inherently chiral calixarenes.

Conformational preferences and electronic effects in selenophene and tellurophene carbonyl derivatives investigated by lanthanide induced shifts

Computer simulation of the lanthanide induced shifts has been applied to study of the conformational preferences in the 2-formyl and 2-acetyl derivatives of furan, thiophene, selenophene and tellurophene. The results assign a nearly equipopulated mixture of s-cis and s-trans conformers to the furan, and a preponderance of the s-trans form to the thiophene, selenophene and tellurophene derivatives. This difference is interpreted as due to the interaction between the heteroatom and carbonyl oxygen lone pairs. The 2-N,N-dimethylcarboxyamide derivatives of furan, thiophene and selenophene are found to exist mainly in a quasi-planar s-cis form. The barriers to the rotation about the amide bond in these amides have been measured and related to the electronegativity of the heteroatom.

Laurencienyne, a new acetylenic cyclic ether from the marine red alga laurencia obtusa

Abstract The structure and absolute stereochemistry of laurencienyne, a non-isoprenoid cyclic ether isolated from Laurencia obtusa , has been established by X-ray and spectroscopic studies.

Resolution of inherently chiral calix[4]arenes with AABB and CDCD substitution patterns on the upper and lower rims, respectively

Abstract Proximal di- tert -butylcalix[4]arene (5,11-di- tert -butylcalix[4]arene-25,26,27,28-tetrol) 1b , obtained by direct partial removal of tert- butyl groups from p-tert- butylcalix[4]arene, gave high yields of inherently chiral derivatives upon ‘symmetry breaking’ by syn -distal di- O -alkylation or di- O -acylation in the presence of K 2 CO 3 . The chirality of these compounds was proven by the splitting of 1 H NMR signals in the presence of Pirkles reagent and in some cases by HPLC enantiomeric resolution using chiral stationary phases and corroborated by mirror-image CD spectra.