2000

06 CARBOHYDRATE CHEMISTRY

AGM Barrett

(A) "Open Chain" Carbohydrate Chemistry

Nomenclature; pentose, hexose, etc. aldose, ketose; chemistry of the carbonyl group: via oxidation of aldoses to - onicacids and - aricacids; reduction; hydrazone and osazone formation; thioacetalformation; homologation ( ascent) by the Kilianimethod; degradation ( descent) by the Weermanmethod; structural correlations by these methods

(B) Cyclisation of Carbohydrates - Hemiacetal Formation

(1) Mutarotationof D-glucose - αand βpyranose and furanose forms in equilibrium. Pyranose form is usually favoured with most hexoses. Anomeric Centre

(2) Glycoside Formation (Glycosidation) under kinetic control both αand βmethyl furanosidesare formed. Under thermodynamic control the αpyranoside is the major isomer. The anomeric effect is explained in terms of lone pair-lone pair repulsion, dipole-dipole interactions and by M.O. theory. Glycosidesare stable in neutral or basic solution but readily hydrolysed to the free sugar with dilute aqueous acid. Modern methods of glycoside synthesis: trichloroacetimidate activation.

(3) Reactions of Carbohydrates - Selective hydroxyl protection and neighbouring group participation

(a) Acetylationto give the αand βpyranose forms of the penta- acetate; preparation of α-glycosyl halides and their conversion to glycosidesand formation of glycals; reactions of glycals e.g. with dilute aqueous acid to give 2-deoxy-sugarsand with peracids to give epoxides

(b) Etherification

(i) MeI/NaH methyl ethers - difficult to remove

(ii) Benzyl ethers - cleaved by H ₂/Pd or Na/NH ₃

(iii) Silyl ethers - volatile for mass spectral studies, very readily cleaved by H ₃O⁺/ or KF/H ₂O, variable reactivity depending on bulk

(iv) Allyl ethers - acid stable, isomerisation with KO ^tBu or (Ph ₃P)₃RhCl to give acid labile vinyl ethers

(v) Triphenylmethyl ethers, "trityl" ethers - selective for primary OH. Removed by dilute acid

(c) Acetal and ketal formation - ketones prefer to form 5 membered ring ketals-1,2 diol protection. Aldehydes prefer to form 6 membered ring acetals-1,3 diol protection.

(d) Sulfonate esters - preparation and selectivity for primary hydroxyl; intermolecular nucleophilic displacement reactions and their problems; deoxygenation viafree radical chain reaction of xanthate esters with tri-n-buylstannane; intramolecular nucleophilic displacement reactions give ethers and epoxides (anhydro sugars); ring opening of epoxides and glycoside synthesis

(e) Keto sugars - best prepared by oxidation of alcohol with DMSO/Ac ₂O or DMSO/P ₄O₁₀; nucleophilic attack from the least hindered side

(f) Unsaturated sugars - the Corey-Winter Olefin synthesis (thiocarbonates + trimethyl phosphite); reduction of ditosylates with sodium iodide and zinc

(g) Amino sugars - tosylate displacement with azide followed by LiAlH ₄reduction; epoxide ring opening by ammonia; reduction of ketoximes with LiAlH ₄

(4) Use of Carbohydrates

(a) Fermentation

(b) Aminoglycosides are important in antibiotics e.g. erythromycin, streptomycin.

For a review of the preparation and reaction of aminoglycosides see: Topics in Antibiotic Chemistry Vol 1, p 1; Sammes, P.G., Ed.; John Wiley and Sons, 1977.

(c) In non-carbohydrate natural product synthesis carbohydrates belong to the "Chiral Pool" i.e. they are a very cheap source of starting materials for organic synthesis which contain chiral functionality.

Bibliography

Hanessian, S. Acc. Chem. Res. 1979, 12, 159.

Fraser-Reid, B. Acc. Chem. Res. 1975, 8, 192.

"Monosaccharide Chemistry" Hough, L. and Richardson, A.C. in "Comprehensive Organic Chemistry", Ed. Barton, D.H.R.; Ollis, W.D.; Haslam, E.; Pergamon Press, Oxford, 1979, vol. 5, p. 687-753.

"Synthsis of Glycosides" Schmidt, R.R. in "Comprehensive Organic Synthesis", Ed. Trost, B.M.; Fleming, I.; Winterfeldt, E.; Pergamon Press, Oxford, 1991, vol. 6, p. 33-64.

"Exploration with Sugars How Sweet it Was" Lemieux, R.U. American Chemical Society , Washington, D.C., 1990.

"Carbohydrate Chemistry" Kennedy, J.F. Claredon Press, Oxford, 1988.