Robert Rothchild

19F NMR studies of the Diels-Alder adduct of N-pentafluorophenylmaleimide with phencyclone. Hindered rotation about a N-6F5 bond

Abstract N-pentafluorophenyl maleimide acts as an efficient Diels-Alder dienophile to form an adduct with phencyclone. The adduct was found to exhibit five distinct 19F NMR signals (282 MHz, ambient temperature, CDCl6) consisting of two gross doublets and three gross triplets. We interpret this as consistent with a severely hindered rotation about the N-C6F5 bond in the adduct, leading to a slow exchange limit (SEL) spectrum. The C6F5 group is thought to lie, on average, on the effective mirror plane of the adduct, perpendicular to the pyrrolidinedione ring system, to reduce steric interactions of the ortho fluorines with the imide N(CO)2 carbonyls. 19F-19F COSY45 NMR allowed assignment of vicinal fluorines in the C6F5. Comparative data is presented for the precursors, N-pentafluorophenyl maleamic acid and N-pentafluorophenyl maleimide. Variable temperature 19F NMR results for the maleamic acid are presented.

AB INITIO STUDIES OF HINDERED ROTATION OF SOME AROMATIC RINGS IN N-2,6-DIFLUOROPHENYL IMIDES AND UNSUBSTITUTED BRIDGEHEAD PHENYLS

Ab initio calculations are applied to the study of steric hindrance upon rotation of aromatic rings in N-2,6-difluorophenyl-maleimide, 2, and in 3, which represents a simplified model of a Diels-Alder adduct of phencyclone and 2. The systems adopt geometries minimizing the hindrance in a number of ways, including pyramidalization of the nitrogen in the N-aryl imide and deviation from planarity of the aryl rings. Note: All designated Structures for Compounds 1 through 3 are shown in Figure 1. Figure 1. Structures and atom numbering for compound 2, N-2,6–difluorophenyl-maleimide, and for compound 3, a simplifield model for the Diels-Alder adduct of 2 with phencyclone, 1.

1H NMR studies of drugs with achiral and chiral lanthanide shift reagents: applications to the anticonvulsant pheneturide.

The anticonvulsant pheneturide, PNT, has been studied by 300 MHz 1H NMR in CDCl3 at ambient temperatures with the achiral lanthanide shift reagent (LSR) Eu(FOD)3, and with the chiral LSR, Eu(HFC)3. Both LSRs produced spectral simplification of the aryl proton signal region, and substantial lanthanide-induced shifts (LIS). With added Eu(HFC)3, enantiomeric shift differences (DeltaDeltadelta) were induced for most nuclei of PNT, indicating substantial potential for direct determination of enantiomeric excess. Valley heights between corresponding signals in the PNT enantiomers as low as 3.6% were achieved for the meta resonance. Least squares line-fitting was applied to the variation of chemical shift vs. [LSR]/[PNT] molar ratios for both LSRs. Tentative assignments were made for the NH absorptions based on two-dimensional NMR (COSY45), as well as their relative magnitudes of LIS, DeltaDeltadelta, and lanthanide-induced line broadening. The PNT conformation reported in the crystal is believed to be retained in solution with added LSR. The relative senses of magnetic nonequivalence were found to be the same among the three sets of aryl protons, and among the three kinds of protons in the ethyl moiety, with high levels of added chiral LSR, using 2D NMR.

NMR Studies of Drugs. Applications of a Chiral Lanthanide Shift Reagent to Methoxamine in Chloroform-d or Acetonitrile-d 3.

Abstract The 1H NMR spectra of racemic (erythro) methoxamine free base, 1, 1-(1-aminoethyl)-2,5-dimethoxybenzenemethanol, have been studied at or near ambient temperatures in CDCl3 or CD3CN with the added chiral lanthanide shift reagent (LSR), tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorato] europium (III), 2. Spectrometers operating at 60, 200 and 300 MHz were employed; some COSY spectra were acquired to support assignments. Enantiomeric shift differences (Δ Δ Δ) were observed for several nuclei of 1 with added 2 in either CDCl3 or CD3CN and an “anomalous” (upfield) shift was seen for the NCH signal. A high degree of signal broadening was seen for runs with either solvent, and surprising similarity was found for the slopes in plots of chemical shift versus [2]/[1] molar ratios for the different nuclei of 1 whether the hydrogen bond donor solvent (CDCl3) or the hydrogen bond acceptor solvent (CD3CN) was used. Together with the anomalous shift noted above, these results are interpreted as consist...

NMR Studies of Drugs. Applications of Achiral and Chiral Lanthanide Shift Reagents to Acifran Methyl Ester. LSR Binding to a Multifunctional Substrate.

Abstract The antihyperlipoproteinemic agent, acifran, has been studied as its racemic methyl ester, 1, by 60 MHz 1H NMR in CDC13 solution at 28±1° with the added achiral lanthanide shift reagent (LSR), tris(6, 6, 7, 7, 8, 8, 8-heptaf luoro-2, 2-dimethyl-3, 5-octanedionato-europium(III), Eu (FOD)3, 2, for spectral simplification, and with the chiral LSRs, tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorato]europium(III), Eu(HFC)3, 3, and tris[3-(trifluoromethylhydroxymethylene)-(+)-camphorato]europium(III), Eu (FACAM)3, 4, for potential determinations of enantiomeric excess. Relative lanthanide-induced shift (LIS) magnitudes with the three LSRs were interpreted as consistent with major lanthanide binding at the 4-oxo carbonyl, but contrasting behavior in observed enantiomeric shift differences (ΔΔδ) with 3 versus 4 may suggest different bound complex geometries for 3 or 4 with 1.

Ab Initio Calculations on (-)-Calicheamicinone and Some of its Reactions Involved in its Activation and Interaction with DNA

Abstract Ab initio calculations were performed on (-)-calicheamicinone, and on the product (Z or E) of the Michael addition via a reaction with methanethiol. It is found that the sulfur moiety position versus the rest of the molecule is quite flexible. The Michael adduct featuring the carbamate group E to the sulfur moiety is more stable than the Z isomer. The Bergman reaction of the diradical formation is strongly exothermic.

Semi-empirical, ab initio and molecular modeling studies on the DNA binding of a calicheamicinone-polyamide conjugate.

Abstract AMI semi-empirical and ab initio calculations were performed on certain synthetic polyamide conjugates of the aglycone of the minor groove binding antibiotic calicheamicin. Geometry optimized conformations and heats of formation were obtained. The binding of the optimized conformations of the drug to both alternating and non-alternating (AT)n and to (G)n•(C)n sequences were studied and the energies of binding were compared to each other. The results can be utilized in the design of novel enediyne-based drugs.