Search

Summary Treatment of 5-(tert-butyldimethylsilyl)-2,3-O-isopropylidene-D-ribose with lithium acetylides gave mixtures of syn- and anti-alkynols 2a– 2c which were separated following protection as methoxymethyl ethers. These were converted to the corresponding iodides which underwent 6-exo-dig radical cyclisation to afford chiral cyclohexanes and carbasugars. Oxidation of the primary alcohols 6a– b gave the corresponding aldehydes which on treatment with Grignard reagents afforded a mixture of alcohols. The corresponding iodides underwent similar 6-exo-dig cyclisation to give fully functionalised cyclohexanes.

Synthesis of polyhydroxylated oxabicyclo[4,4,0]decanes, which constitute a new family of annulated carbasugars, has been accomplished in a stereoselective manner by employing readily available 1,2-anhydro-3,4,6-tri-O-benzyl-alpha-d-glycopyranoses.

The synthesis and reactions of vinyl sulfone-modified pyranosides, furanosides, acyclic sugars, nucleosides and carbasugars are reviewed. Figure options Download full-size image Download as PowerPoint slide

Mother Nature utilizes simple precursors to build up complex organic molecules efficiently. One important example is the C3 building block dihydroxyacetone phosphate, which is used in various enzyme-catalyzed reactions. Following this biosynthetic strategy the DHAP equivalent ‘dioxanone’ can be used in organocatalytic reactions to synthesize sugars, aminosugars, carbasugars, polyoxamic acids and sphingosines. In this respect, organocatalytic domino reactions can also be seen as biomimetic as they are reminiscent of tandem reactions that may occur during biosyntheses of complex natural products. In nature, the coenzyme thiamin (vitamin B1), a natural thiazolium salt, is used in biochemical nucleophilic acylations (‘Umpolung’). The catalytic active species is a nucleophilic carbene. Mimicking this approach, organocatalytic carbene catalysis has emerged to an exceptionally fruitful research area, which is used in asymmetric C–C bond formations.

By virtue of carefully chosen protecting groups, d-glucosamine trimethylene dithioacetal derivatives were successfully oxidized to the corresponding 6-aldehydes. This methodology reverses the donor and acceptor position on a normal open chain sugar and changes the relative position of the N-substituent. From the 6-aldehydes, heptose epoxide derivatives were prepared by a Corey-Chaykovsky reaction, and cyclized by the Corey-Seebach method. Depending on the designed protecting groups, the orthogonally protected six- and seven-membered ring amino carbasugars can be produced selectively and efficiently. (-)-Calystegine B(3) was synthesized from one of those products with high yield. This is the first anionic cyclization pathway to calystegine type structures.

Three factors that can direct 6-endo radical cyclization over 5-exo ring closure: substitution at C-5, vinyl radical cyclization and ring strain, have been considered in the context of the preparation of carbapyranoses from carbohydrate derivatives. As a result, alkyl radicals in substrates containing a strain inducing 2,3-O-isopropylidene ring, and vinyl radical in non-strained compounds undergo a completely regioselective 6-endo-trig ring closure leading to carbasugar derivatives.

In this thesis, carbohydrate mimicry is investigated through the syntheses of carbohydrate analogues and evaluation of their inhibitory effects on carbohydrate-processing enzymes. Galactofuranosides are interesting structures because they are common motifs in pathogenic microorganisms but not found in mammals. M.tuberculosis, responsible for the disease tuberculosis, has a cell wall containing a repeating unit of alternating (1→5)- and (1→6)-linked β-D-galactofuranosyl residues. Synthetic inhibitors of the enzymes involved in the biosynthesis of the cell wall could find great therapeutic use. The first part of this thesis describes the first synthesis of the hydrolytically stable carbasugar analogue of galactofuranose, 4a-carba-β-D-Galf, and the synthetic work of synthesising β-linked pseudodisaccharides containing carba-Galf, which were tested for glycosyltransferease inhibitory activity. The pseudodisaccharide carba-Galf-(β1→5)-carba-Galf was found to be a moderate inhibitor of the glycosyltransferase GlfT2 of M.tuberculosis. The thesis also describes how a general method towards biologically relevant α-linked carba-Galf ethers was developed. The final part of this thesis is focussed on the formation of nitrogen-linked monosaccharides without the participation of the anomeric centre. Such a mode of coupling is called tail-to-tail neodisaccharide formation. The couplings of carbohydrate derivatives via the Mitsunobu reaction are successfully reported herein. The method describes the key introduction of an allylic alcohol in the electrophile and the subsequent functionalisation of the alkene to obtain the neodisaccharide. Two synthesised neodisaccharides presented in this thesis have been sent to be tested for glycosidase inhibitory activity.

A new approach to carbasugars in enantiomerically pure form is reported. The key step involves ring-closing metathesis of dienols 6 derived from a (R)-(+)-glyceraldehyde derivative 4 to form the substituted cyclopentenol 9 and cyclohexenol 34a. Stereocontrolled addition of hydroxyl groups followed by conversion of the ketal unit to hydroxymethyl group in these intermediates led to carbapentoses and -hexoses. Stereoselectivity during introduction of hydroxyl groups arises through the steric hindrance posed by the allylic substituents. A remarkable feature of the present approach is the accessibility of both d- and l-series of carbapentoses as illustrated by the synthesis of beta-D- and beta-L-carbaribofuranoses 17 and 20, respectively. Carba-alpha-D-ribofuranose 25, the biosynthetic intermediate to the antibiotic aristeromycin, has also been synthesized from the same cyclopentenol 9. Functional group manipulation in the cyclopentenol 9a also enabled access to carbaarabinofuranose 32. The present synthetic strategy can be extended for the synthesis of carbahexopyranose, as illustrated by the synthesis of carba-alpha-L-gulopyranose 40b.

A set of alpha,beta-unsaturated cyclic acetals were reacted with t-butyllithium in THF. A conjugate elimination took place, triggering a ketal ring cleavage when two eq. of TMEDA were added to the medium. The lithium alcoholate thus obtained could be trapped in situ by 2,2,2-trifluoroethyl acrylate. The resulting acryloyl (1Z,3E)-dienyl ether was then submitted to an intramolecular Diels-Alder cycloaddition under high pressure (12 kbar, 50 degrees C). Depending on the structure of the linkage between the diene and the acrylate, the expected ("fused") lactones were obtained with total endo- or exo-selectivities and high to complete diastereoselectivities. A remarkable inversion of selectivity, from endo to exo, with respect to the stereochemical elements of the tether could be observed in these cases. A five step diastereoselective transformation of two of the resulting nine-membered ring lactones into modified carbasugars was finally achieved in 23% overall yield.

Carbasugars, carbocyclic structures where a carbon atom – usually a methylene – replaces oxygen in the heterocyclic motif of the carbohydrates, represent an important class of natural and synthetic compounds that exhibit far-reaching biological effects. In this article the carbasugars have been divided into three main categories, those embodying a cyclopentane motif (furanoid carbasugars), those incorporating a cyclohexane motif (pyranoid carbasugars), and those bearing rather rare cyclopropane, cyclobutane, cycloheptane, and cyclooctane cores (contracted and expanded carbasugars). In the three major sections of this article, the most representative syntheses of the carbasugars and their closest analogues are analyzed, and the key carbocycle forming manoeuvres are focused on in particular detail. Reference to the observed biological activity is also included, where sufficient data is available. Only recent literature from the 90s onwards was considered, although the most pioneer works on this matter have also been remembered. Lack of space did not permit us to cover this field completely; however, in order to offer the reader a wider coverage of this subject matter, two tables listing important review articles and papers dealing with carbasugars, not discussed in the text, have been included in the final section of this account.

The synthesis of carbasugars and various aminocyclitols, related to voglibose and acarbose used in the treatment of non-insulino-dependant diabetes, is described from C 2 -symmetrical bis-epoxides derived from d -mannitol. The methodology involves two key steps: a domino alkylation–cyclization with 2-lithio-1,3-dithiane derivatives, and reduction or reductive amination with a primary amine. These compounds have been evaluated as inhibitors of several glycosidases, and this study indicates notably that the l - ido or d - manno 1-aminocycloheptane-3,4,5,6-tetrol are inhibitors of α- d -glucosidase with K i in the micromolar range.

Polyhydroxylated aminocyclopentanes are an interesting class of glycosidase inhibitors. The reactions between chelated α-allylglycine esters and crotonaldehyde gave the corresponding aldol products in good yields and selectivities. Those compounds could be converted into enantiopure polyhydroxylated aminocyclopentanes by ring-closing metathesis, enzymatic separation and dihydroxylation. In the final deprotection step, three different protection groups were removed simultaneously in excellent yield, either by reduction or by basic hydrolysis. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

Carbasugars, carbocyclic structures where a carbon atom – usually a methylene – replaces oxygen in the heterocyclic motif of the carbohydrates, represent an important class of natural and synthetic compounds that exhibit far-reaching biological effects. In this article the carbasugars have been divided into three main categories, those embodying a cyclopentane motif (furanoid carbasugars), those incorporating a cyclohexane motif (pyranoid carbasugars), and those bearing rather rare cyclopropane, cyclobutane, cycloheptane, and cyclooctane cores (contracted and expanded carbasugars). In the three major sections of this article, the most representative syntheses of the carbasugars and their closest analogues are analyzed, and the key carbocycle forming manoeuvres are focused on in particular detail. Reference to the observed biological activity is also included, where sufficient data is available. Only recent literature from the 90s onwards was considered, although the most pioneer works on this matter have also been remembered. Lack of space did not permit us to cover this field completely; however, in order to offer the reader a wider coverage of this subject matter, two tables listing important review articles and papers dealing with carbasugars, not discussed in the text, have been included in the final section of this account.

Recently, much attention has been focused on the glycosidase inhibitors under the premise that glycoconjugates such as oligosaccharides, glycolipids, and glycoproteins play pivotal roles in living systems. Glycosidase inhibitors possess interesting enzyme-specific inhibitory activities, therefore, they are expected not only to be tools to elucidate the mechanisms of living system manipulated by the glycoconjugates but also to be potential clinical drugs and insecticides by inducing the failure of glycoconjugates to perform their function: antiobesity drugs, antidiabetics, antifungals, and antivirals including substances active towards the human immunodeficiency virus [1, 2, 3, 4, 5, 6, 7]. Most of the glycosidase inhibitors are isolated from natural sources, and they possess interesting structures in their molecules. Some of them possess the highly functionalized and oxygenated cyclohexanes and cyclopentane rings; these are called cyclitols. Biochemically, the group of cyclitols is recognized as the pseudo compounds of sugars, and they show biological activities similar to those of sugars. On the other hand, chemically, such molecules are quite challenging targets for the synthetic studies. The most interesting and significant points in the synthesis of glycosidase inhibitors possessing cyclitols are the methods of the formation of the frameworks of the cyclitols and those for the introduction of the functional groups essential to generate their special, interesting biological activities. In recent years, a new generations of glycosidase inhibitors, e.g., cyclophelitol, allosamidin, mannnostatin, and trehazolin, were isolated, and the appearance of these natural product is helping to accelerate the development of the technologies needed to perform the aforementioned synthetic tasks. Herein, I will describe the update the progress in synthetic methodologies directed to the syntheses of these new generations of glycosidase inhibitors.

Recent applications of the "naked sugar" methodology are reviewed. General methods have been developed to transform enantiomerically pure 7-oxabicyclo[2.2.1]heptyl derivatives into rare monosaccharides, carbasugars, into a new doubly-branched imino-dideoxyalditol (iminosugar), into long-chain carbohydrates, C-disaccharides, imino-C-disaccharides and new polyhydroxylated quinolizidines. The methods allow to prepare both enantiomers of a given target with the same ease. Predictable high stereoselectivity of the reactions of the bicyclic chirons adds to the flexibility of the approach that can lead to a large molecular diversity.

A versatile, readily accessible triad of 2-enoxy silane synthons derived from furan, pyrrole, and thiophene is presented. These heterocycles, in reacting with carbonyl and carbonyl-related acceptors, act as vinylogous nucleophile modules, giving rise to diverse, functionality-rich, γ-substituted α,β-unsaturated carbonyl constructs. These, in turn, are invaluable platforms onto which further functional elements and chirality may be introduced. A couple of appealing applications—the variable construction of a repertoire of carbasugars and a library of annonaceous acetogenin segments—have been chosen to illustrate the viability of this vinylogous aldol approach.

This article focusses on the synthetic potential of selectively activated aldonolactones. These are obtained without using any protection group strategy, thus avoiding one of the less attractive features usually associated with polyhydroxylated compounds. The selectively brominated as well as the sulfonylated lactones are suitable starting materials for the preparation of hydroxylated and amino substituted pyrrolidines and piperidines, obtained by simple treatment with ammonia. Boiling in water transformed the activated lactones into hydroxylated tetrahydrofurans. Radical-initiated internal ring closure of brominated aldonolactones with unsaturation yields functionalized cyclopentanes regio- and stereospecifically. This results in the synthesis of optically pure carbasugars. Easy manipulation of the hydroxy groups in the cyclopentane-lactones obtained gives access to other hydroxy/amino substituted cyclopentanes.

The cis-dihydrodiol metabolite from methyl benzoate has been used as a synthetic precursor of carba-beta-L-galactopyranose, carba-beta-L-talopyranose and carba-alpha-L-talopyranose. The structures and absolute configurations of these carbasugars were determined by a combination of NMR spectroscopy, stereochemical correlation and X-ray crystallography.

Difluorinated cyclohexene diols (prepared from trifluoroethanol) can be elaborated to racemic analogues of phosphorylated sugars via regioselective protection and phosphorylation of the exposed C-1 hydroxyl group. Cis-diol protection was achieved using stannylene methodology, though the regioselectivity depended on the orientation of the methyl group at C-5. UpJohn dihydroxylation is effective with the phosphotriester in place and global deprotection to the tetrol monophosphates is efficient.

A new, efficient and highly diastereoselective approach for the synthesis of 1,2,3,5-tetraacetylcarba-α-D-lyxofuranose14 from D-ribose is reported via one-pot conversion of 5 to 1 using Tebbe reagent which involves a cascade reaction sequence of methylenation, cleavage of isopropyl group, carbocyclization and again methylenation.

A practical one-pot process involving a desymmetrizing hydroformylation with the aid of a chiral catalyst-directing group (CDG*), followed by a carbonyl ene cyclization provides a straightforward access to both enantiomers of the resulting cyclohexanediol; further divergent, highly selective and protecting group-free transformations furnish the carbocyclic analogues of four important 2,6-dideoxysugars.

Publisher Summary This chapter focuses on the chemistry of carbahexopyranoses and their derivatives. The first three carbasugars were synthesized by McCasland and coworkers. Two other carbasugars were prepared from myo -inositol and the remaining eleven carbasugars have been synthesized from the Diels–Alder adduct of furan and acrylic acid. Fifteen enantiomers have been synthesized among the thirty-two carbasugars theoretically predicted. D -Fructose is the sweetest sugar known in naturally occurring carbohydrates and its intense sweetness is produced only by β- D -fructopyranose. Carbaglycosylamines [2,3,4-trihydroxy-5-(hydroxymethyl)-1-cyclohexylamine] and related compounds are well known to exist as the components of antibiotic validamycin complex and carbaoligosaccharidic alpha amylase inhibitor. Carbadisaccharides are carbocyclic analogs of true disaccharides in which one or both of the hexose or pentose residues is(are) replaced with a carbasugar. Besides sweetness, a carbasugar may have biological activity owing to its structurally close resemblance to a true sugar. The chemistry of carba-sugars is a newly opened area ofchemistry and the biological effects of these compounds have not been well studied, except for (1) the equisweetness of D-carba-glucose, D-carba-galactose, and D-carba- fructose with the respective true sugars, (2) the antibiotic activity of α-D- carba-galactose, and (3) the inhibition of a D-glucose-stimulated insulin release by D-carba-glucose.

A short, stereoselective entry to carbasugars and shikimic acid from a readily available 7-norbornenone is reported.