Allylic Halogenation Route to Latent-Active Trans-Glycosylation of Allyl Glycoside Donors

Abstract

Allylic halogenation of allyl glycosides as a new route to allyl glycoside donors in glycosylations is investigated in this thesis. Allyl functionality is one of the commonly adopted protecting groups to hydroxyl groups in sugar chemistry. In addition, allyl glycosides act as glycosyl donors, through isomerization to the corresponding vinyl glycosides. Facile conversion of allyl moiety to other functionalities, as well as, stabilities under acidic and basic conditions offer rich possibilities of this moiety in sugar chemistry. Chapter 1 provides a succinct overview of glycosylation reactions and mechanisms. An area of intense interest is to transform a latent allyl moiety to an active glycosyl donor. In this effort, allylic halogenation reaction is considered appealing, due to the expected reactivity of the mixed halo-acetal of allyl glycoside towards an electrophile and the subsequent transformation to a glycosylation-active intermediate, suitable as an active glycosyl donor. Early experiments show that allylic bromination of allyl glycosides, using N-bromosuccinimide (NBS)/azo-bis-isobutyronitrile (AIBN) in CCl4 generates mixed halo-allyl glycoside intermediate, the reaction of which with an acceptor in the presence of Ag(I) or triflic acid (TfOH) affords the corresponding trans-glycoside in a good yield. The reaction is verified with a number of glycoside acceptors, including allyl glycoside acceptors. In the case of allyl glycoside acceptors, the resulting trans-glycoside possesses allyl moiety at the reducing end, which, in turn, is subjected allylic activation and subsequent glycosylation. Di-, tri- and tetrasaccharide syntheses are accomplished in good yields by this new route. Chapter 2 describes the development of this new method. Radical halogenations in CCl4 warranted a replacement to the solvent, as well as, further optimizations of the reaction. In these efforts, diethylcarbonate (Et2O)2CO) is identified as a suitable solvent to conduct (i) radical halogenation and (ii) the subsequent glycosylation. The glycosylation is promoted either by TfOH or trimethylsilyl triflate (TMSOTf). A one-pot methodology is developed and method is verified with the synthesis of xyloyranoside, mono-, di- and trisaccharides. Chapter 3 provides the details of these developments. Halo-allyl mixed acetal of allyl glycoside is found to undergo S¬N2 and S¬¬¬¬N2’ reactions with thiolate nucleophiles. The SN2’ reaction leads to 3-thiocresylpropenyl (TCP) glycoside, as a stable vinyl glycoside, which can be stored for longer duration, unlike, vinyl glycosides that are quite unstable due to faster hydrolysis. TCP glycoside is subjected to remote activation using iodonium reagent and activation leads to the formation of glycosylation active intermediate. Glycosylations with aglycosyl and glycosyl acceptors are conducted facile and the corresponding trans-glycosides are obtained in excellent yields. Chapter 4 describes the development of this new, stable TCP-based vinyl glycoside methodology in glycosylations. Overall, the thesis illustrates establishing allyl glycosides as glycosyl donors as allylic halogenations and subsequent glycosylations. The new method merits in the repertoire of contemporary glycosylation techniques of remote activation-based glycosylations.