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The structures of title carbasugars (I) - (III) are verified by total synthesis, starting from D-mannitol and using a ring closing metathesis as key-step for installation of the cyclohexenyl core unit.

Transformation of cyclohexadienes (I) and (IX) to carbasugars (VIII) and (XII), resp., is described.

In order to prepare intermediates for the synthesis of ampelomins and deoxy-carbasugars reaction conditions are optimized for the stereoselective catalytic hydrogenation of methylcyclohex-2-ene derivatives (I) and (IV).

4,5-Dimethylenecyclohex-1-ene (I) is subjected to a photooxygenation reaction to introduce complex oxygen functionalities.

The key step for the synthesis of new carbasugars is reported wherein cyclobutanes with four contiguous asymmetric centers are generated with a high level of stereocontrol.

The importance of glycosidase inhibitors and especially the bicyclic molecules has led to design and assessment of many analogs of naturally occurring molecules. This review focuses on the synthesis and enzyme inhibitions of a few selected (synthetic or non-naturally occurring) molecules that have been reported in the last decade, which allow one to draw some connection between varying the structural features and their effect on glycosidase inhibitions. It is expected that further improvements based on these features could lead to improved inhibitors.

Fluoro-C-glycosides and fluoro-carbasugars are a particular subclass of hydrolytically stable glycomimetics that are expected to have different, hopefully improved properties thanks to the stereoelectronic features of the fluoroalkyl moiety. This review summarizes the studies devoted to the synthesis of such structures as well as the studies regarding their conformational behaviour and their potential as carbohydrate analogues.

A general approach to the stereoselective synthesis of 5a-carbasugars has been developed. The route mimics our palladium-catalyzed glycosylation/postglycosylation approach to carbohydrates in that it also utilizes a highly regio- and stereospecific palladium-catalyzed allylation and postglycosylation reaction sequence for the installation of either d- or l-cyclitols. This cyclitolization/postcyclitolization sequence was used for the enantioselective synthesis of a cyclitol analogue of SL0101, its d-sugar enantiomer, as well as several acetylation pattern analogues.

Readily available (R)-2,3-O-isopropylidene glyceraldehyde is used as starting material for the preparation of chiral dienes (I), (III), and (V) which undergo ring-closing metathesis to produce five-membered ring carbasugars.

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.

A quick arrival at chiral nonracemic cyclohexanoids is provided, which incorporates useful variability for large product diversity. Central to the construction is the exploitation of the dual nucleophilic character of an easily accessible triad of silyloxy diene synthons derived from the popular five-membered heterocycles furan, pyrrole, and thiophene. To assess the reliability of the procedure, the total synthesis of 1-deoxy-1-amino-pseudo-β-d-gulopyranose (10) (alias 1,2,4-tri-epi-validamine) is executed, in 12 steps and with a 17% overall yield, by starting with N-tert-butoxycarbonyl-2-[(tert-butyldimethylsilyl)oxy]pyrrole (1) and 2,3-O-isopropylidene-d-glyceraldehyde (2).

A novel fragmentation sequence has been executed within the norbornane system, involving C1–C7 bond scission, to extract a versatile, highly functionalized cyclohexanoid moiety. Its further evolution towards a range of carbasugars is described.

The norbornyl system has been recognized simply as a ‘locked’ carbasugar and a short, general approach to carbasugars and their new siblings, ‘confused’ carbasugars, from readily available 7-ketonorbornanes is reported.

As other monosaccharide mimics such as the azasugars and the carbasugars (with nitrogen and carbon atom, respectively, instead of oxygen atom in the ring) the thiosugars (with sulfur atom instead of oxygen atom in the ring) have gained importance in glycobiology and as potential drugs. Biological properties of monothiosaccharides are presented and the methods for their synthesis are reviewed and analyzed. Since the report of the synthesis of 5-thio-alpha-D-xylopyranose, the first example of thiosugars ever described, forty years of imaginative chemistry have produced a large number of monothiosaccharides and of analogs of biological interest. The preparative chemists have at their disposal a panoply of methodologies relying on pure chemical or on biochemical means, using carbohydrate or non-carbo hydrate precursors. Because the sulfur moieties can participate more readily than the corresponding oxygen moieties in heterolytical processes, the chemistry of the thiosugars and their analogs is more subtile and sometimes more delicate than that of the corresponding aldoses and alditols.

A stereodivergent approach to 5a-carba-d- and l-pyranoses has been applied to the preparation of 5a-carba-α-d-gluco-, 5a-carba-α-d-galacto-, and 5a-carba-β-l-gulopyranose pentaacetates. The strategy, by which a single precursor can be transformed into three different carbasugars, features a stereoselective reduction followed by deoxygenation of a key polyoxygenated methylcyclohexanone intermediate. The latter is readily available by 6-exo-dig radical cyclization of a d-mannose derivative.

A short, enantioselective synthesis of carbasugars 4a-carba-α- l-xylofuranose 15, 4- epi-validatol 16and their corresponding carboxylic acids 11and 12 is reported. These compounds were prepared via a four-step sequence of nucleophilic addition, ring closure (NARC), dihydroxylation and reduction.

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.

Nature utilizes simple C2 and C3 building blocks, such as dihydroxyacetone phosphate (DHAP), phosphoenolpyruvate (PEP), and the “active aldehyde” in various enzyme-catalyzed carbon−carbon bond formations to efficiently build up complex organic molecules. In this Perspective, we describe the transition from using enantiopure chemical synthetic equivalents of these building blocks, employing our SAMP/RAMP hydrazone methodology and metalated chiral α-amino nitriles, to the asymmetric organocatalytic versions developed in our laboratory. Following this biomimetic strategy, the DHAP equivalent 2,2-dimethyl-1,3-dioxan-5-one (dioxanone) has been used in the proline-catalyzed synthesis of carbohydrates, aminosugars, carbasugars, polyoxamic acid, and various sphingosines. Proline-catalyzed aldol reactions involving a PEP-like equivalent have also allowed for the asymmetric synthesis of ulosonic acid precursors. By mimicking the “active aldehyde” nucleophilic acylations in Nature catalyzed by the thiamine-dependent...

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

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.

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)

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.