Commments and Responses

The individual most responsible for making most of these allegations has reported previously that a strong stench comes from some of his reaction mixtures. These problems were not observed when the published procedures were followed, perhaps since all contact with phosgene-containing mixtures was avoided by the inventors. Phosgene is a deadly poisonous gas, and no one in their right mind would even want to try to confirm this allegation by sniffing the reaction mixture. Although it definitely is not recommended that this method of observation be routinely employed, such a stench might indicate contamination of other's preparations with exogenously added halides or amines and/or poor control of pH at critical points throughout the synthetic processes. Strong odors probably indicate the well-known reaction of HBr with dimethyl-sulfoxide to produce the volatile gases, bromine and dimethyl-sulfide, the latter of which has a stench that may signify other possible redox problems, including overt (artifactual?) oxidation of sulfur to higher oxidation states by the generally more reactive bromine and iodine monobromide. Hydrogen halides can be artifactually introduced by i) using the hydrogen halide salts of cystamine (instead of the sublimed free base as outlined in the exemplary synthesis of bis-CBZ-ß-alethine) by using impure reagents in equilibrating the ion-exchange columns, and/or iii) through an incomplete chromatographic removal of HBr in the synthesis of vitalethine from ß-alethine. In addition, acetic acid, halides, and added amines such as triethylamine may alter the products of the reaction mixtures and decrease the efficiency of bromide removal in the DEAE ion exchange chromatographic step. Free amines, such as ammonium ions and presumably ß-alethine, have been observed to lower the temperature necessary for thermal decomposition of other salts of free carbamic acids in aqueous solution, indicating that the synthesis of stable vitalethine may be an all or none proposition. The several fold excess of phosgene in the exemplary reaction mixture is designed to completely carboxylate ß-alethine, and judging from the very real differences in the biological activities of the resulting authentic vitalethine and ß-alethine, the conversion is complete if the exemplary procedures are followed closely. The chemical company making these allegations seems to be unusually resistant to following the exemplary procedures.

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