1-glycals

Glycals are saccharide derivatives having a double bond between the anomeric carbon and the adjacent carbon atom. Formally, these derivatives are highly electron-rich enol ethers, which can undergo many reactions with high regioselectivity and stereoselectivity. 

Alternatively, Pd(0) adds oxidatively to the double bond of a glycal derivative resulting in the formation of a ir-allyl complex, which may react with carbon nucleophiles to give C-glycosides with a double bond between C(2) and C(3).26 A rt-allyl complex may also be formed starting from a Ferrier rearrangement product (2,3-unsaturated sugar derivative).22 

Pd-catalysed cross couplings to give C-glycosides that have a double bond between C(l) and C(2). 

The glycals, first reported by Fischer and Zach, were extensively investigated by Bergmann and Schotte. They are important intermediates for the interconversion of epimeric sugars and for the preparation of 2-deoxy-aldoses (Chapter II). 

The acetylated glycals result from the reductive removal of halogen and the neighboring acetate group from the acetylated glycosyl halides through 

For a review of the chemistry of the glycals, see B. Helferich, Advances in Carbohydrate Chem. 7, 210 (1952). 

Addition of the elements of water to the double bond of the glycals, by treatment with dilute sulfuric acid at low temperature, yields 2-deoxy- 

It is noteworthy that the 2-halo-2-deoxyaldoses, obtainable from the glycal dihalides by treatment with moist silver oxide, yield the normal osazones with phenylhydrazine 112), This elimination of halogen at carbon 2 by phenylhydrazine is reminiscent of the similar elimination of methoxyl (p. 458) and of the hydrofuran anhydro ring (p. 395). 

Over recent years, l,5-anhydro-2-deoxy-hex-l-enitols (more commonly called glycals) have proved to be useful starting points in the stereoselective synthesis of O-glycosides according to a variety of differing strategies. 

A reliable approach for the synthesis of 2-deoxyglycosides is through haloalkoxyl-ation of glycals followed by the subsequent reductive removal of the halide at C2. 

SCHEME 3.24 Dehydrative glycosylation promoted by Tf20/Ph2S0. 

SCHEME 3.25 Synthesis of a 2-deoxyglycoside using the glycal approach. AIBN, azobisisobutyronitrile. 

SCHEME 3.26 Approaches utilized for the synthesis of 2-amino-2-deoxyglycosides from glycals. 

SCHEME 3.27 Stereoselective control of glycosylation by using glycosyl epoxide. TBAF, tetrabutylammonium fluoride. 

Activated zlnc/silver-graphite, used in tetrahydrofuran, efficiently converts acetal-protected and acetylated glycofuranosyl and glyco-pyranosyl halides into glycals - at least on the modest scales (2.2 mmol ) reported. The method has particular potential value for preparing furanosyl glycal derivatives.  

The exocycllc alkene (1) has been prepared from the corresponding ketone by Wittig and Peterson oleflnation. When excess of the lithium salt of ethyl trimethylsllylacetate was used,the conjugated 

The chiral dlol (3) can be made by hydrogenation of tri-O-acetyl-D-glucal or of its isomer 1,4,6-tri-0-acetyl-2,3-dideoxy-a-D-erythro -hex-2-enopyranose (both, it is suggested, by way of the 3-deoxy- 

The factors, especially the solvent polarity, that influence the syn-addltlon of fluorine and acetylhypofluorite to D-glucal and its triacetate have been studied. A 95 5 ratio of 2-deoxy-2-fluoro-D-glucose to -D-mannose was obtained following reaction of the hypo- 

An improved method of oxidizing the allylic hydroxy group of D- 

For the first time, unsaturated compounds have been derived from ketoses. These are, however, few in number and, in this Chapter, are discussed together with the structurally analogous aldosyl derivatives a 4,5-unsaturated ketopyranosyl compound is thus, for example, treated along with the 3,4-unsaturated aldopyranoses (see p. 249). 1,2-Unsaturated ketopyranosyl compounds have 5,6-unsaturated aldopyranoses as their structural analogs (see p. 257), and 2-ketopyranoses having a double bond at C-2 are relatable to the glycals or to 4,5-unsaturated aldopyranoses they are arbitrarily dealt with under the latter heading (see p. 252). 

Several new methods, and improvements in existing methods, for introducing double bonds into carbohydrates have been reported (see pp. 201,215,219,232-234, and 255). 

An additional means of synthesizing glycal derivatives has been established as a consequence of an unexpected finding made during (1) R. J. Ferrier, Advan. Carbohyd. Chem., 20,67 (1965). 

A re-investigation of the reaction (conducted with methyllithium free from halide ion) which afforded the methylated derivative (1, R = Me, R = H), indicated that it proceeded by way of methyl 4,6-0-benzylidene-2-deoxy-2-C-methyl-a-D-altropyranoside (2, R= Me, R = H), because this compound [prepared by opening the corresponding 2,3-anhydroalloside with (methylsulfinyl)methyl carbanion, to give methyl 4,6-0-benzylidene-2-deoxy-2-C-[(methylsulfinyl) methyl]-a-D-altropyranoside (2, R = MeSOCH2, R = H), followed by reduction with Raney nickel], on treatment with methyllithium, also gave the C-methyl compound (1, R = Me, R = H).5 

More specifically, tri-O-acetyl-D-gulal has been isolated in low yield from the reaction of tri-O-acetyl-D-galactal and of 1,3,4,6-tetra-O-acetyl-2-deoxy-a-D-Jyxo-hexopyranose with boiling acetic acid (see p. 214), and 4,6-0-benzylidene-3-0-methyl-D-allal has been prepared by reductive desulfurization of 2-thio derivatives (see p. 225). 

Only occasionally are compounds with unsaturated carbohydrate components found in Nature. A well-known example is blasticidin S (3) which inhibits blast disease of rice,3 and a most unusual case is that of a 2,6-dideoxy-trisaccharide glycal (1,2-unsaturated cyclic compound) isolated from a plant in India.4 

Compounds of this category are vinyl ethers having double bonds between C-l and C-2 of pyranoid or furanoid aldose derivatives. Analogues with exocyclic C-l-C-2 double bonds in cyclic 2-ketoses are sometimes referred to as evo-glycals and are covered briefly in Section IV.3 isomers with C-2-C-3 unsaturation in 2-ketoses can be considered as C-l-substituted glycals and are referred to in Section II.3.a. Together the glycals and their derivatives constitute the most useful set of unsaturated carbohydrate derivatives for application in synthesis. 

The anomalous al suffix used in the trivial names of members of the family in all probability originated at the very beginning of their history from aldehydic impurities present in the original preparations in Emil Fischer s laboratory (see Section II.2.d.i). Compound 4, the D-glucose 

Similar chemistry involving glycosyl-Cr(III)-linked intermediates, produced from 0-acetylated glycosyl bromides or chlorides by treatment with [Cr(OAc)2 - H20]2 in the presence of EDTA, also results in the formation of 0-acetylated pyranoid glycals in high yields.14 

Otherwise, compound 30, and differently 0-substituted analogues, can be made efficiently from O-protected 2-deoxy nucleosides. Heating thymidine diether 29 in refluxing 1,1,1,3,3,3-hexamethyldisalazene in the presence of ammonium sulfate under an inert atmosphere gives 30 in 47% overall yield from the nucleoside. A notable feature of this approach is that thymidine itself can be converted directly to the unprotected parent of diether 30 with 80% efficiency.26 

5-Amino-5-deoxy-ido-furanosides are also obtainable from (2). 

The conformational equilibria of the peracetylated glycals derived from four hexoses and two pentoses have been calculated by use of a molecular mechanics programme and compared with those determined by X-ray crystallography and n.m.r. spectroscopy. For the pentose derivatives there are inconsistencies between the calculated and experimental results.  

Two complementary cycloaddition approaches have provided access 

Reagents l, Ltwfs acid, ii, Mn-(OAc)3 iii, No0H4- CCCI3 iv, AcjO Et3N 

Substitutions of the allylie hydroxy groups of L-rhamnal and L-fucal were favoured when acetyl chloride, N-ac tylimidazole, benzoyl chloride and N-benzoyllmldazole were used, and H0 60% yields of the 3-esters were obtainable. With acetic anhydride in pyridine the homoallyllc groups (0- ) were preferentially substituted. 3- - 

Spectral data on 24 derivatives of D-glucal and D-allal have been published, and the chemical shifts were discussed in terms of atomic charge densities.  

Other examples of C-1 substituted glycals are compounds (1) and (2) which have been obtained, respectively, by eliminations from tri-O-benzoyl-L-rhamno-pyranosyl nitrile and 2,3 4,5-di-0-benzylidene-L-sorbofuranose. The former product, on debenzoylation, gave a diol which could be oxidized to the conjugated enone or the 7-pyrone compound (2) was derived by use of butyl-lithium.  

Huynh-Dinh, C. Gouyette, and J. Igolen, Tetrahedron Lett., 1980, 21, 4499. 

5-Anhydro-4,6-0-benzylidene-2,3-dideoxy-D-eryt/iro-hex-l-enitol was among the products formed when methyl 4,6-0-benzylidene-3-deoxy-p-D-eryt/iro-hexo-pyranosid-2-ulose reacted with hydrazine hydrate in 2,2 -oxybis(ethanol) (see also p.l03). 5 

The chlorination of 2,3,4,6-tetra-0-benzoyl-2-hydroxy-D-glucal (138) has been mentioned in Chapter 7. Further work established that the 2-chloro-l,2-benz-oxonium salt formed on low-temperature (— 30 °C) chlorination of (138) is readily hydrolysed to the glycosulose (316), which readily eliminated benzoic acid to give the enolone (317 R = OBz) on heating with sodium hydrogencarbonate in wet toluene. The enolone (317 R = OBz) afforded a-haloenolones (317 R = Cl 

A wide range of glucal and alkyl 2,3-dideoxy-D-co t/rr -hex-2-enopyranoside derivatives have been reported in a study of the preparation of monosaccharide compounds containing two double bonds. 6-Sulphonyl esters of D-glucal could be converted into analogues with 6-deoxyalk-5-ene functionality by way of 6-deoxy-6-iodo intermediates, but corresponding methods did not lead to 2,3 5,6-di-unsaturated products.  

Irradiation of 3,4-di-O-acetyl-D-xylal in acetone-1,3-dioxolane afforded compounds (13)—(15) isolated in 29, 10, and 9% yield, respectively (together with 33 % unchanged starting material).  

Details of the reductive rearrangement of glyc-2-enopyranosides to give 3-deoxyglycal derivatives and acyclic vinyl ethers have been reported (see Vol. 4, p. 95). The work was extended to other allylic derivatives, and the reaction pathways were investigated by means of deuterium-labelling techniques. 

A reinvestigation of the acid-catalysed addition of methanol to D-glucal has shown that the products are methyl 2-deoxy-a-D-amWno-hexopyranoside, the furans (212) and (213), and the acyclic derivatives (214) and (215). An analogous 

On hydrolysis in refluxing aqueous p-dioxan, 3,4,6-tri-O-acetyl-D-glucal, 3,4,6-tri-O-acetyl-D-galactal, and 3,4-di-O-acetyl-D-arabinal were each converted into a 

The racemic glycals (219) reacted with NBS in the presence of alcohols to give 2-alkoxy-3-bromo-tetrahydropyrans, which yielded unsaturated glycosides (220) on dehydrobromination.  

The stereoselectivity of formation of l,2-dideoxy-l,2-dihalogeno-a-D-gluco-pyranose derivatives when bromine and chlorine are added to 3,4,6-tri-O-acetyl-and 3,4,6-tri-O-benzyl-D-glucal has been shown to be influenced both by the substituents and the polarity of the solvent. Similar results were observed for halogenomethoxylations. 

The reaction of 3,4,6-tri-O-acetyl-D-glucal with appropriately protected monosaccharide derivatives in the presence of boron trifluoride etherate has been used to prepare modified disaccharides (215)—(218) containing a S-(l - I)-, a- and j3-(l 2)-, a-(l 3)-, and a-(l 4)-linkages, respectively. Both the 

The photochemical addition of formamide to 2,3,4,6-tetra-C -acetyI-2-hydroxy-D-glucal is mentioned in Chapter 3.  

4-Di-O-acetyl-L-rhamnal (115) gave a mixture of (220) (60%), (221) (5%), and (222) (22%) when treated with sodium azide in acetonitrile in the presence of boron trifluoride etherate. The conversion of the epimeric 3-azides (220) into derivatives of L-acosamine and L-ristosamine is noted in Chapter 8. 

Dehydrochlorination of 2,3,5-tri-O-benzyl-a-D-arabinofuranosyl chloride using a molecular sieve gave the benzylated 2-hydroxyglycal (223). A mixture of three substituted furans, namely 2-[(isobutylthio)methyl]furan (224) and its 3-and 4-isobutylthio-derivatives [(225) and (226), respectively] was obtained when 2,5-anhydro-3,4-di-0-toluene-p-sulphonyl-D-xylose di-isobutyl dithioacetal (227) reacted with sodium iodide-zinc in DMF (the Tipson-Cohen reagent) at 150 C.  

Three O-acetyl-di-O-benzyl-D-galactals have been described, and the epimeric branched-chain compounds (1) and (2) have been made 

2-Hydroxy-D-glucal tetra-acetate is produced by thermolysis of acetylated D-gluco- or D-manno-orthoacetates in solvents such as 

Chlorobenzene, and aldopyranose peracetates with the 1,2-trans-confIguration likewise initially give products of 1,2-syn-ellmination of acetic acid when pyrolysed at 350°C in acetone. 

A simple method for converting glycal and 2-hydroxyglycal esters into unsaturated lactones involves treatment with m-chloroper- 

Syntheses Involving additions to glycal derivatives have included the following 2,6-dldeoxy-L-lyxo-hexose from di- -acetyl-L-fucal by addition of acetic acid or by methoxymercuration 2- 

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Methyl glycosides of 2 deoxy sugars have been prepared by the acid catalyzed addition of methanol to unsaturated sugars known as glycals... 

Unsaturated sugars are useful synthetic intermediates (11). The most commonly used are the so-called glycals (1,5- or 1,4-anhydroalditol-l-enes). In the presence of a Lewis-acid catalyst, 3,4,6-tri-0-acetyl-l,5-anhydro-2-deoxy-D-arabinohex-l-enitol [2873-29-2] commonly called D-glucal triacetate, adds nucleophiles in both kineticaHy controlled and thermodynamically controlled (soft bases predominately at C-3 and hard bases primarily at C-1) reactions (11,13). 

During an attempt to metalate a glycal with /-BuLi, it was discovered by deuterium labeling that a TBDMS ether can be deprotonated. °- ... 

Nitro-activated glycals and aromatic compounds are good acceptors for TMM-Pd chemistry. The nitroglycal (19) reacts with (1) to give a 2.4 1 ratio of products (20) and (21) in a combined yield of 69% (Eq. 2). Treatment of the less electron-rich... 

Clearly compound 26 (R = Ac) had undergone a reaction analogous to the glycal rearrangement. It has been demonstrated that the rearrangement of this compound also occurs at room temperature in acetic anyhydride in the presence of zinc chloride (34). Under these conditions, however, a further slower isomerization takes place and a third product, assigned the acetylated enone-hydrate structure 29, was isolated. As noted later this structure has been shown to be incorrect. 

Easily prepared from the appropriate monosaccharide, a glycal is an unsatu-rated sugar with a C1-C2 double bond. To ready it for use in potysaccharide synthesis, the primary -OH group of the glycal is first protected at its primary -OH group by formation of a silvl ether (Section 17.8) and at its two adjacent secondary - OH groups by formation of a cyclic carbonate ester. Then, the protected glycal is epoxidized. 

Glycal assembly method (Section 25.11) A method for linking monosaccharides together to sym thesis polysaccharides. 

Glycal assembly method, 1002 (4- )-Glyceraldehyde. absolute configuration of, 980 (-)-Glyceraldehyde, configuration of, 300... 

The glycal epoxide method turned out to be useful for the construction of complex 2-branched [3-aryl glycosides, which are salient features of the potent antibiotic vancomycin [75a]. Glycal epoxide glycosylation with sodium salts of indoles pro-... 

Scheme 8.41 Utilization of glycals and a-glycal epoxides in carbohydrate chemistry.

Evans developed a new method for the synthesis of [(-C-allylglycosides, based on BusSnOTf-mediated ring-opening of glycal epoxides with allylstannanes as nucleophiles [81a], This methodology has been efficiently used in the (3-stereoselective introduction of the side chain (C44-C51) of spongistatin 2 (Scheme 8.43) [81b,c]. 

A conceptually new direct oxidative glycosylation with glycal donors, employing a reagent combination of triflic anhydride and diphenyl sulfoxide, has recently been reported by Gin [83], This new 3-glycosylation method works very well with hindered hydroxy nucleophiles, including sterically shielded carbohydrate hydroxy systems, and can be run on large scales. 

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