Synthesis of Complex Natural Products and Analogues: Novel Applications of the Amadori and Heyns Rearrangements

The Amadori rearrangement is a reaction of free aldoses with suitable amines frequently performed in the presence of an acidic catalyst. In the course of this transformation, the aldose is converted into the corresponding 1 - aminodeoxy ketose. For example, reaction Of D-glucose with dibenzylamine yields 1-dibenzylamino-1-deoxy-D- fructose. Traditionally, yields are poor and applications limited despite the fact that the Amadori rearrangement is the first step of the Maillard cascade, the non-enzymatc browning of food. The Heyns rearrangement is related to the Amadori rearrangement, as in this particular reaction ketoses are transformed into the corresponding 2-aminodeoxy aldoses. For example, D-glucosamine is obtained as the main product from the Heyns rearrangement of D-fructose. As with the Amadori rearrangement, the reaction has hardly ever been employed for truely preparative purposes. Preliminary research has now revealed that the Amadori and Heyns rearrangements have been highly underrated in terms of synthetic applicability. The proposal under consideration is dealing with several novel applications of these interesting reactions in the synthesis of complex natural products analogues as well as other unusual structural types of compounds. The chemistry involved is outlined in seven sections with distinct synthetic targets and aims.

This project could demonstrate that the Amadori and Heyns rearrangements are very useful tools for the synthesis of a range of biologically important substance classes and a wide range of useful compounds could be synthesised employing these reactions. The Amadori and Heyns rearrangements are two longs known reactions in the carbohydrate field. As early as 1860, Emil Fischer could observe and describe both reactions during his study of the structures of sugars. Both reactions play important roles in living organisms, for example they are the initial steps during the Maillard reaction cascade, the non-enzymatic browning of food. Despite their biological importance, both reactions remained underestimated for synthetic purposes in organic chemistry. The aim of this project was the evaluation of the Amadori and Heyns rearrangements for novel applications in natural products and carbohydrate synthesis. The Amadori rearrangement could be shown to be very useful for the synthesis of glycosidase inhibitors, so-called iminosugars. Such structures inhibit enzymes, named glycosidases, which are responsible in living organisms for processing glycan structures and are employed for the treatment of diabetes, some of them are in clinical trials for anti-cancer pharmaceuticals. We were able to synthesise a library of such compounds which were exploited to investigate structure-activity relationships of glycosidases. The biological interaction of such compounds can now be predicted based on their structural features. The Heyns rearrangement could be applied for the synthesis of important carbohydrate building blocks which will be employed for building up complex structures. Important examples are galactosamine and lactosamine derivatives which could be synthesised via this reaction. Galactosamine is present in blood group determinants and antigen structures. Lactosamine is a sub-structure of complex glycans which are responsible for inflammation and cell-cell-recognition processes in living systems. The method developed for the synthesis of such structures is very cheap and easy to perform and clearly suitable for scale-up and industrial fabrication of these important molecules.