During the development of aspartame, why was the methyl ester chosen?

Question

One frequent argument against the safety of the synthetic sweetener aspartame is that it can be hydrolyzed, with one of the hydrolysis products being methanol, which is known to be toxic. Of course, usually not much aspartame is added in food anyway to yield a sufficient amount of methanol or its oxidation product formaldehyde, but this does beg the question: why wasn't, say, the ethyl ester chosen to be developed as an artificial sweetener? Is there a structure-activity relationship between the alcohol used to esterify the dipeptide and the sweetness of the product?

Answer 1

I believe if I remember the lore correctly that this was a laboratory accident:

Aspartame was discovered in 1965 by James M. Schlatter, a chemist working for G.D. Searle & Company. Schlatter had synthesized aspartame as an intermediate step in generating a tetrapeptide of the hormone gastrin, for use in assessing an anti-ulcer drug candidate.^[69] He discovered its sweet taste when he licked his finger, which had become contaminated with aspartame, to lift up a piece of paper.^[

^{I doubt metabolism into alcohol was a primary consideration in this development.}

^{It is interesting that many of the folks involved in its development dont in general use it.}