Biologically Active Compounds
Iminosugars and related compounds
Former work: Nitrosugar-based approaches
Our research group, which posses a large experience in the chemistry of sugars, has made relevant contributions to the chemistry of nitro sugars, a class of compounds of great synthetic interest, as they combine the possibility of creating chemical diversity offered by sugars with the potential of nitro-compounds to generate carbon-carbon bonds, prior to the transformation of the nitro group into a wide range of functional groups.
Specifically, we have developed the transformation of nitro sugars into iminosugars, a type of sugar mimetics resulting from the replacement of endocyclic oxygen by nitrogen. These compounds are of great biological potential, due to their ability to inhibit glycosidases. Because glycosidase inhibitors have the potential to produce antiviral, antidiabetic, and anticancer effects as well as immune-modulatory properties, they have attracted much attention.
Our first synthetic approach (Scheme 1), which combines new chemistry in the field of nitrosugars with the classical strategy of iminosugar preparation based on the reductive amination protocol, has allowed the preparation of a library of known and novel iminosugars and related compounds (for access, press on the scheme).
A modification of this strategy, involving the formation of the nitrogen ring by intramolecular amine alkylation (Scheme 2), allowed access to more iminosugars (click on the scheme).
Ongoing work: Sugar mono- and di- tosylate or triflate approaches
These nitrosugar-based approaches, which involves the sequential construction of the two C-N bonds, require long sequences of steps. We are now working on two shorter, more efficient approaches that allow the nitrogen ring to be generated by simultaneous construction of the C-N bonds.
The first approach involves a double nucleophilic displacement of a sugar ditriflate by ammonia or amines (Scheme 3).
This approach is clearly more convenient than the previous alternative approach based on opening the oxygen ring of the starting sugar prior to nitrogen ring formation. Our approach allows stereocontrolled access to iminosugars and sugar iminoacids. But it suffers from a limitation, since it is applicable only to sugars that have the stereochemistry required for the double nucleophilic displacement leading to the nitrogen ring.
Preliminary results allowed the development of divergent access to five- and six-membered iminosugars and sugar imino acids, which can be visualized by clicking on the scheme. Ongoing work includes the development of a new approach for the synthesis of loline alkaloids.
A second ongoing approach for divergent syntheses of iminosugars and sugar imino acids is depicted in Scheme 4. It involves the reaction of a sugar O-tosylate with amines, a process that directly provides an iminium salt, as a result of the simultaneous formation of the two C-N bonds of the nitrogen ring. This iminium salts are able to react with nucleophiles and thence to provide access to a large variety of iminosugar derivatives, including second generation iminosugars.
Preliminary results consisted of the transformation of D-ribose into the D-ribose derivative 4.1 and this into the iminosugars 4.4 and 4.6 and the polyhydroxylated pipecolic acid 4.5, via iminium salt 4.2 and 2-cyanopiperidine 4.3 (Scheme 5).
