Project code: PN-II-RU-TE-2011-3-0298      Contract no.: 8/5.10.2011
AZASUGARS Synthesis of biologically active iminosugars using unconventional methods - microwave and ultrasonic irradiation
Contracting authority: UEFISCDI

Iminosugars are the most attractive class of carbohydrate mimetics. They show powerful inhibition and modulation of carbohydrate processing enzymes, alterations which are implicated in a wide variety of diseases. Iminosugars, initially known as potent glycosidase inhibitors, have also been found to be inhibitors of glycosyl transferases, glycogen phosphorylase, nucleoside processing enzymes, metalloproteinases, etc. widening the area of their medical applications.

To date over 100 compounds have been isolated from natural sources, most of them from plants and only a limited number from bacteria or fungi.

Structurally, iminosugars can be classified according to the size of the ring (pyrollidine, piperidine, azepane or bicyclic), the type of substituent (typically hydroxyls, but also carboxylic acids and amides are found in nature) and the stereochemistry of their chiral centers.

The principal approach to synthesis adopts carbohydrate or other chirons as starting materials, introducing the endocyclic nitrogen through synthetic manipulations. Such routes are hampered by long synthetic sequences that have lessened their commercial potential. The field is also now beginning to attract further interest for de novo and enzymatic synthesis, which may offer advantages in certain cases.

The polar nature of the molecules coupled with their typical lack of UV chromophores has also required specialized analytical methods to be developed.

Alfred L. Loomis was the first to introduce ultrasound to chemistry in 1927. He realized that intense sound waves brought in chemical reactions would alter normal chemical response. When reliable generators became available in the 1980s, there was a renewed interest in ultrasonics.

The effects of ultrasound on chemical transformations are not the result of any direct coupling of the sound field with the chemical species involved on a molecular level. The ultrasonic wave length -frequency is far-off from the vibration frequency of the bonds between atoms in a molecule: ultrasonic frequency is in the range of kHz or MHz compared with GHz for bonds between atoms in molecules. The reason why ultrasounds are able to produce chemical effects is through the phenomenon of cavitation: generation, growing and violent collapse of cavitation bubbles with enormous energy locally delivered. Cavitation in a liquid occurs due to the stresses induced in the liquid by the passing of a sound wave.

The energy liberated in the breakdown (collapse) of a bubble is adequate for excitation, ionization and dissociation of molecules. Under ultrasonic irradiation chemical reactions that take place under conventional conditions are accelerated, or even yield totally different products. The reason for this can be due to either physical or chemical effects of cavitation.

The physical effects can enhance the reactivity of a catalyst by enlarging the surface area, or accelerate a reaction by proper mixing of reagents. Furthermore, the collapse causes a couple of strong physical effects outside the bubble: shear forces, jets and shock waves.

Chemical effects of ultrasound affect the reaction rates because of the formation of highly reactive radical species during cavitation.

Ultrasound activation, when applied to carbohydrates, is known to favor formation of carbon-heteroatom bonds, acetalization reactions, glycosylation reactions, formation of carbon-carbon bonds by reaction of aldehydic functions of carbohydrates with organometallic nucleophiles and improved selectivity in the removal of protecting groups.

Microwaves have wavelength in the range of 1 mm to 1 m, corresponding to frequencies between 30 and 3 GHz. Telecommunications and microwave radar equipments occupy many of the band frequencies in this region. Hence, the microwave frequencies for industrial and scientific purposes are imposed by international convention being the 2.45 GHz (wavelength of 12.2 cm) the most routinely used.

The use of microwave heating in the laboratory can be traced back to the 1950’s.

Typically, some reactions that do not occur by classical heating, or that lead to very low yields can be performed in good yields under microwave irradiation. Some authors suggest the existence of a specific effect derived from the microwave field, recognized as “microwave effect”, and not from the rapid heating.

The benefits of microwave over conventional heating are acceleration of reaction rate, milder reaction conditions, higher chemical yield, lower energy usage, different selectivities.

Microwave activation under controlled conditions has been shown to be an invaluable technology for medicinal chemistry and drug discovery applications since it often reduces dramatically the reaction time (from days to minutes). This can also have a positive effect on the yield and selectivity especially in the conversion of carbohydrates in which long reaction times of the classical methods lead to degradations of the starting material.