Date of Degree

10-2014

Document Type

Dissertation

Degree Name

Ph.D.

Program

Chemistry

Advisor(s)

David R. Mootoo

Subject Categories

Chemistry | Organic Chemistry

Keywords

Carbohydrate, C-glycosides, Crotylation, glycolipid, Inositol, KRN7000

Abstract

C-Glycosides are carbohydrate analogues in which the glycosidic oxygen is replaced with a methylene substituent. Because of their stability under acidic hydrolysis or enzymatic cleavage, they are widely used as mimetics of their parent O-glycosides in medicinal chemistry. This thesis describes the development of new synthetic methods for C-glycosides, which center on the use of readily available, simple C-allyl glycosides as precursors. C- glycosides of three structurally distinct and pharmacologically interesting carbohydrates, the immunostimulatory glycolipid C-KRN700, the insulin mimetic glycoinositol β-galactosamine-(1→4)-3-O-methyl-D-chiro-inositiol (INS-2), and α-mannose-(1→6)-D-myo-inositiol, a subunit of the cell wall in Mycobacterium tuberculosis, will be used as test cases for these methodologies.

Chapter I and II

α-Galactosylceramide (α-GalCer) also called KRN7000 is a potent stimulant of invariant natural killer T (iNKT) cells. The C-glycoside of KRN7000 shows higher activity than its parent O-glycoside against malaria and melanoma in mice models. The high activity of C-KRN7000 could be due to its hydrolytic stability or the way in which it interacts with receptors in the immunological pathway. New analogues of C-KRN7000 are needed to elucidate this picture. Two robust synthetic methodologies that can provide structurally diverse structures in the polar head region were developed.

Chapter 1 describes the first approach, which entails: (i) the convergent union of relatively simple and readily accessible carbohydrate and lipid precursors to give a homoallylic alcohol, (ii) introduction of the amino group in the target via an iodocyclization reaction on derived homoallylic trichloroacetimidates and carboimidothioates. The cyclization reactions were evaluated for both E and Z alkene substrates. The E and Z trichloroacetimidates showed opposite facial selectivities, with the Z isomer providing the desired result for C-KRN7000. This stereochemical result is as expected for related electrophilic cyclizations. In contrast both E and Z carboimidothioates showed the same facial selectivity, in favor of the desired product. The iodo-carbamate products that were obtained from the reactions of the E and Z carboimidothioates were both processed to C-KRN7000 via established and straightforward deiodination and alcohol protecting group procedures. However, the elaboration of the iodo-oxazine products from the tricholoroacetimidate reactions was problematic.

Chapter II describes the second method, which centers on the Lewis acid mediated crotylation reaction of a C-glycoside crotylstannane on a simple α-alkoxy aldehyde to give diastereomeric homoallylic products. These products can be transformed to different diastereomers of C-KRN7000, and homologated and reverse amide analogues thereof. The diasteroselectivity of the crotylation reaction was examined and found to vary with the Lewis acid or the protecting group on the aldehyde. The key step in the processing of the crotylation products to C-glycosides of C-KRN700 was a Curtius rearrangement on the acyl azide derived from the terminal alkene in the crotylation product. This chemistry was applied to C-KRN7000, its amide epimer, and an analogue of C-KRN7000 with a fluorine atom at the pseudoanomeric position.

Chapter III

As an extension to the crotylation chemistry in Chapter II, we developed a new approach to the synthesis of C-glycoinositols, which pivots on late stage construction of the inositol ring. The strategy uses easily accessed 3,4-dialkoxy-4-enals as aldehyde partners for C-linked crotyltins. A ring closing metathesis (RCM) on the crotylation product gives a C-linked dioxygenated cyclohexene that can be converted to a fully oxygenated C-glycoinositol by a dihydroxylation reaction. Different alkene functionalization reactions on the RCM product leads to inositol with different functional groups. Using different combinations of crotylstannane and aldehydes can further increase analogue diversity. For a given crotylstannane the diastereoselectivity of crotylation reaction was found to vary with choice of Lewis acid and the stereochemistry of the aldehyde partner. This methodology was applied to the C-glycosides of INS-2 and α-mannose-(1→6)-D-myo-inositiol.

The results in Chapters II and II illustrate the attributes of the C-glycoside crotyltin methodology: (i) easy availability of the crotyltin and aldehyde precursors; (ii) the compatibility of the key segment coupling reaction with a variety of different functional groups; (iii) the synthetic versatility of the reaction products, which allows for a high throughput of complex and diverse glycomimetic libraries.

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