Copyright © 1996, 1997, 2001 by Galen Daryl Knight and VitaleTherapeutics, Inc.


Oxidations of disulfides that occur in aqueous iodine solutions have been observed to be iodide-dependent if assistance of intramolecular nucleophiles is limited to 5-membered transition states. Although iodine can also form more soluble complexes (such as periodide) when iodide is present, iodine's solubility in water is usually limited to millimolar. The published synthetic protocol theoretically removes aqueous iodide that may be formed; calcium iodide absorbs CO2 to generate calcium carbonate and "regenerate" iodine which then is extracted into the chloroform layer.

Carbonate absorbed in this manner also may help to buffer the synthetic reactions, a concern of others in some syntheses of the vitaletheine modulators. Hence, these reactions are important, since they limit iodine's solubility as they increase buffering capacity in the aqueous phase. Clearly, running the reaction under an inert gas such as argon to control autoxidation could produce mixed results since carbon dioxide cannot be absorbed from argon to minimize iodide and enhance buffering. An atmosphere of carbon dioxide on this reaction could provide additional, and perhaps even too much, buffering capacity while helping to limit autoxidation reactions incurred from "vigorous stirring" used by others.

It should also be pointed out that stirring the reaction mixture too "vigorously" obviously will increase autoxidation, and that cavitation in air is generally minimized to limit this obvious source of artifactual "autoxidation" in the synthesis of the exemplary vitaletheine modulators. At the same time, a healthy vortex is maintained throughout the published procedures to ensure that upon iodinolysis of the disulfide, the intermediate partitions quickly into the aqueous phase; iodine is less concentrated in the aqueous phase than in the chloroform interface, where initial reaction of the hydrophobic precursor with iodine presumably occurs. As soon as the reaction subsides and the desired intermediary product partitions into the aqueous phase (as indicated by a stabilization of pH), extraction of color (iodine) continues to completion to remove further oxidation potential. Incubation with iodine for longer times obviously will contribute to higher oxidation states.

Irradiation with UV light is known to cause the formation of disulfides from sulfenyl iodides by initially reducing to thiolates and iodide followed by reaction of the thiolate with other sulfenyl iodides to form disulfides. This chemical reaction has an endpoint for sulfur (reduction to the thiolate) different from alleged oxidative endpoints, such as the sulfonate. The tetramer, vitaletheine V4, may be resistant to intramolecular disulfide formation upon photoreduction due to steric constraints, and formation of zinc sulfides may further diminish this tendency to form intramolecular disulfides through an inhibition of thiol and disulfide exchange. This illustrates the importance of constantly adjusting the pH on the synthetic mixtures with ZnO during the reactions and the extractions and not leaving the product on an extractor overnight. In addition to these considerations, an unusual stability for sulfenyl iodides containing cyteamine-like amide moieties (the carboxybenzoxyl amide of penicillamine) has been described, even in mixtures of water and dichloromethane. Since the exemplary vitaletheine modulators also contain the cysteamine moiety, albeit as the decarboxylated equivalent of the above penicillamine analogue, they are expected to be somewhat more stable in mixtures of water and halomethanes as well.

This paper also points out that diethylamine or dimethylformamide reacts with their sulfenyl iodides to either complex the sulfenyl iodide as a sulfenamide or to destroy the sulfenyl iodide, respectively. Consequently, contamination of the CBZ-ß-alethine starting material with amines may result in intermediates incapable of forming vitaletheine V4 in ultraviolet light. In other words, if the sulfenyl iodide reacts first with contaminating amines it may be unavailable for ultraviolet conversion into vitaletheine V4. Furthermore, if the resulting sulfenamide hydrolyzes to regenerate the amine, this amine can serve as a catalyst for the decomposition of additional sulfenyl iodide.

These concerns are particularly relevant to the synthesis of the vitaletheine modulators, since persistent solvent and solute contamination is a real problem with this series of compounds. Inclusion complexes have been observed with various products and organic solvents, and the DCU by-product of dicyclohexylcarbodiimide (DCC) couplings has a tenacious affinity for the bis-CBZ-ß-alethine product used as starting material for all of the vitaletheine modulators.


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