Posted by Precise heterofunctionalisation of cyclodextrins is a well-known bottleneck in the chemistry of cyclodextrins. In fact, although many applications of cyclodextrins rely on their multifunctionalization, random functionalization is commonly used nowadays, instead of a regioselective method that is still considered a challenging task. It is true that due to the presence of multiple equivalent OH groups, the random reaction of just the 7 primary hydroxyls of b-cyclodextrin, with 7 different reagents of equal reactivity statistically leads to a mixture of 117655 different molecules, ranging from 7 molecules bearing the same substituent 7 times to 720 molecules with 7 different substituents.
Matthieu Sollogoub and his team [1] have achieved the exploit of synthesizing a b-cyclodextrin carrying 7 different chemical functions, one on each sugar unit, an achievement that could be compared to the Grail of this chemistry. To do so, they relied on a strategy they have been developing for quite a few years based on diisobutylaluminum hydride (DIBAL-H)-induced regioselective debenzylations.
They found that thioesters could be used as orienting groups with DIBAL-H and that thioethers were inert in the reaction conditions. Very interestingly due to the odd number of sugars the debenzylation reaction is regioselective and occurs on the third sugar, from the one bearing the SAc group, in the counterclockwise direction, hence SAc b-cyclodextrin is converted into a thiol-alcohol selectively. This simple fact made Sollogoub and his group realize that they could reach the Holy Grail: heptadifferentiated b-cyclodextrin, through a very simple algorithm: begin with a thioacetate-cyclodextrin, DIBAL-H reaction, protect thiol, convert OH into thioacetate, repeat process until hepta-differentiation is reached. Indeed, as illustrated on the scheme, 5 successive rounds of this algorithm led to the formation of a b-cyclodextrin with 4 different thioethers, a thiol, a benzyl ether and a hydroxyl group.
Heptadifferentiated cyclodextrin might not bring new applications of cyclodextrins right now, but the synthetic strategies and practical solutions that are presented in this work offer a wide range of possibilities to the community. In this work alone, 18 different tetra-differentiated b-cyclodextrins, 3 pentadifferentiated cyclodextrins and 3 hexadifferentiated cyclodextrins were synthesized. We can now also think of the many combinations that are offered by all the reactions developed in the Sollogoub group: tandem reactions azide reduction/debenzylation. and thioester reduction/debenzylation, a bridging strategyand one can envisage many many different useful patterns of functionalization of cyclodextrins.
J. Liu, B. Wang, C. Przybylski, O. Bistri-Aslanoff, M. Ménand, Y. Zhang, M. Sollogoub (2021) Programmed Synthesis of Hepta-Differentiated β-Cyclodextrin: 1 out of 117655 Arrangements. Angewandte Chemie 60, 12090-12096. https://doi.org/10.1002/anie.202102182
Selected references of other regioselective functionalizations by the Sollogoub group:
-Chemical clockwise tridifferentiation of α– and β-cyclodextrins : Bascule-bridge or deoxy-sugars strategies, O. Bistri, P. Sinaÿ, J. Jiménez Barbero, M. Sollogoub, Chem. Eur. J. 2007, 13, 9757
-Regiospecific Tandem Azide-Reduction/Deprotection To Afford Versatile Amino Alcohol-Functionalized a- and b-Cyclodextrins, S. Guieu, M. Sollogoub, Angew. Chem. Int. Ed. 2008, 47, 7060
-An “Against-the-Rules” Double Bank Shot with Diisobutylaluminium Hydride allows Triple Functionalisation of a-Cyclodextrin,E. Zaborova, M. Guitet, G. Prencipe, Y. Blériot, M. Ménand, M. Sollogoub, Angew. Chem. Int. Ed. 2013, 52, 639
-Site-selective hexa-hetero-functionalization of a-cyclodextrin an archetypical C6-symmetric concave cycle, B. Wang, E. Zaborova, S. Guieu, M. Petrillo, M. Guitet, Y. Blériot, M. Ménand, Y. Zhang, M. Sollogoub Nature Comms. 2014, 5, 5354