Copyright © 1996, 2000, 2001 by Galen Daryl Knight and VitaleTherapeutics, Inc.

Other's Proton NMR of Vitaletheine Modulators

Subtle adjustments to the shifts of these spectra may have occurred as the reference signals were aligned for TMS (0), DMSO (2.5), and water (4.75); assignment priorities are given to TMS, then DMSO, and then water. When none of these reference signals are present, the alignment is kept as close as possible to the originally-obtained spectra. Note that only traces of water are observed in the DMSO spectra of vitaletheine V4 and its benzyl derivative indicating a greater potential in these preparations for dehydration than in the authentic preparations.

When dissolved in DMSO, the spectra of the benzyl derivative is similar to that of bis-CBZ-ß-alethine in every way except for the methylene peak presumed to be adjacent to sulfur.

The benzyl derivative produces a different spectra in water than it does in DMSO which may be consistent with different solvating mechanisms in protic and aprotic solvents, respectively.

The proton spectra of vitaletheine V4 is unique compared with other spectra in this family of compounds. Although, the couplings and relative intensities of the protons on the nitrogen (far-downfield triplets) and on the methylenes adjacent to the nitrogen (quartets around 3 ppm) are very similar to those for the CBZ starting material and the benzyl derivative, there is no evidence for the benzyl moiety at about 5 and 7.4 ppm. This indicates that the carboxyl moiety is still attached to the terminal amine, and makes a strong case for the carbamate tautomer in DMSO solution; the carbonimidate tautomer may be more abundant in aqueous solution, but its dominating presence in DMSO would have resulted in the observation of triplets instead of quartets for the methylenes coupled to the nitrogen moieties. Vitaletheine V4 is easily decarboxylated and there is some evidence that DMSO facilitates this reaction, possibly by helping to remove zinc ions from the more stable complex.

As expected from theoretical calculations of chemical shifts, the decarboxylation of vitaletheine V4 has an almost imperceptible effect upon the shifts of its methylenes. Similarly, phosgenations to vitalethine and reductions of ß-alethine to ß-aletheine in the presence of zinc ions do not cause dramatic changes in proton NMR spectra. Unfortunately, these reasonably small changes in NMR spectra upon reduction and carboxylation (phosgenation) lead many to suspect that their attempts to phosgenate ß-alethine to vitalethine have failed, and in some instances this is clearly the case due to departures from the established protocols.

These examples help to illustrate the limits of using NMR for making structural assignments for these compounds since phosgenation and decarboxylation cause shifts in proton and carbon spectra that are so subtle that they can be missed altogether. Because of this, other forms of analyses always should be performed on each preparation containing carbamates or carbonimidates.

In stark contrast to these results, reduction of the benzyl derivative under certain mild conditions causes some striking changes consistent with a rearrangement to a vitaletheine V4-like compound.


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