Regioselective Alkylation Of The Hydroxyl Groups Of Carbohydrates Catalyzed By Ferric Chloride

The polyhydroxy structure of carbohydrates makes it difficult to control the site selectivity during the glycosylation reaction.Therefore,selective protection of hydroxyl groups is essential in oligosaccharide synthesis.There are many types of selective protective groups.Among them,alkyl is one of the important protective groups because the alkyl group is relatively stable and easyly removed under mild conditions.Many methods for selective alkylation have been developed so far.The selective alkylation method based on organotin reagents have been widely used because of its applicability,but it has been restricted due to its potential toxicity.Organic boron-catalyzed selective alkylation was once the best green method to replace organotin method.In 2016,an organic iron-catalyzed alkylation method was developed by our group and became a method that can compete with the organic boron method.The organic iron catalysts are[Fe(dibm)₃](dibm:diisobutyrylmethane)and[Fe(dipm)₃](dipm:dipivaloylmethane).However,neither[Fe(dipm)₃]nor[Fe(dipm)₃]has a commercial source,and it needs to be prepared by ourselves,which may limit the application of this method.In this paper,a highly selective alkylation method directly catalyzed by a catalytic amount of ferric chloride with the assistance of an acylacetone ligand(Hdipm)was developed.The ratio of FeC l₃ to Hdipm only needs to be 1:2,not 1:3.This method showed good selectivity and high yield for glycosides containing cis-diol configuration,1,2-diol and 1,3-diol,and the yield is up to 96%.Mechanism studies showed that[Fe(dipm)₃]was formed by the coordination of FeCl₃ with two equivalents of acylacetone ligands(Hdipm)in the presence of a base,followed by the formation of a five or six-membered ring intermediate between Fe(dipm)₃and two hydroxyl groups of the substrates while releasing one molecule of Hdipm.Finally,the reaction between the cyclic intermediate and the alkylating agent leads to selective alkylation of the substrate.This mechanism was demonstrated for the first time by capturing all key intermediates in mass spectrometry.The released molecule of Hdipm may react with an excess of FeC l₃ to form[Fe(dipm)₃]again,until FeC l₃ is completely consumed in this cycle.This explains why the ratio of FeC l₃ to Hdipm only needs to be 1:2,and the comparative experiments and NMR tests verified this supposition.Compared with the previous methods,Either FeC l₃ or Hdipm is very inexpensive and nontoxic reagent in the lab,thereby making the process much greener.These advantages increase possibilities for industrial applications.