Stevioside and Steviol as Starting Materials in Organic Synthesis

Steviol glycosides, a collection of natural sweeteners extracted from the leaves of the Paraguayan shrub Stevia rebaudiana, have been drawing an increased amount of attention in the last decades. Very recently, the steviol glycosides were approved as a novel food additive in the European Union, which resulted in a growing interest by the general public. The structure of the steviol glycosides consists out of a diterpene ent-kaurene core, steviol, linked to one or more glucose units. Various benign medicinal properties have been assigned to the structure of stevioside, including antihypertensive and antihyperglycemic effects. These effects have encouraged many organic chemists to investigate the synthesis of possible analogues of the structure of both stevioside and its aglycon steviol. In previous work we discussed the known modifications of the structure of the ent-beyerane isosteviol, which is obtained via a Wagner-Meerwein rearrangement of steviol. In this review, we offer an organized overview of the available modifications of both stevioside and steviol. These modifications cover various fields in research, including medicinal chemistry, combinatorial chemistry or the synthesis of sweeteners with improved taste. For stevioside, the enzymatic transglycosylations are discussed, followed by all reported chemical transformations, which are not widespread in the literature. The possible microbiological transformations of stevioside and steviol are also discussed. These transformations have been carried out with various microorganisms or enzymes, resulting mainly in gibberellin-like structures or hydroxylated steviol analogues. An overview of all possible hydroxylations and their corresponding yields is provided. Compared to stevioside, the chemical modifications of steviol are more numerous. An overview, where each analogue is grouped according to the reactive site of steviol used, is provided. If possible, a comparison between the resulting yields of similar reactions is made. Keywords: Derivatisation, Diterpene, Hydroxylation, Microbiological, Rearrangements, Ringtransformation, Steviol, Stevioside, Supramolecular, Steviol glycosides