Projections

1. Projections

2. More Reactions of Sugars • Reactions of OH group(s): • Esterification: • Ethers:

3. b) Ethers (con’t) • Acetals

4. c) Acetals (con’t)

5. These reactions are used for selective protection of one alcohol & activation of another (protecting group chemistry) 1° alcohol is most reactive protect first AZT

6. e.g, synthesis of sucrose (Lemieux, Alberta) • Can only couple one way—if we don’t protect, get all different coupling patterns • Yet nature does this all of the time: enzymes hold molecules together in the correct orientation, BUT the mechanism still goes through an oxonium ion (more on this later)

7. Selectivity of Anomer Formation in Glycosides • Oxonium ion can often be attacked from both Re & Si faces to give a mixture of anomers. • How do we control this?

8. This reaction provides a clue to how an enzyme might stabilize an oxonium ion (see later)

9. Examples of Naturally Occurring di- & oligo- Saccharides Maltose: 2 units of glucose a β sugar α glycoside 1,4-linkage Lactose (milk): galactose + glucose a β sugar β glycoside 1,4-linkage

10. Sucrose (sugar): glucose + fructofuranose a β sugar α glycoside 1,2-glycosidic bond α-1,6-glycosidic bond Amylopectin (blood cells): an oligosaccharide α-1,4-glycosidic bond

11. Structure Determination of Sugars • The following is an example to review & expand your knowledge of NMR • Consider the question of glycoside formation: See NMR spectra of both anomers: They are different-diastereomers have different spectra, but which is which?

12. -methyl glucopyranose

13. -methyl glucopyranose

14. These spectra are rich in independent information: • Chemical shift, : • Reveals functional groups (see chart) • Depends on inductive effects, # of EWGs &  bonds Inductive effects e.g. # of EWGs e.g. glucose– anomeric H is most downfield since 2 O atoms attached to C have more of an effect that 1 atom.  we can assign the anomeric proton in the both spectra of α and β methyl glucoside  bonds –alkenes, aromatics, C=O, etc

15. Integrals • NMR is quantitative e.g. glycosides—area under anomeric signal = 1; area under the signal at  3.3 = 3x bigger,  3 protons, must be a CH3 group • Multiplicity • Protons communicate their spins over 1, 2 or 3 bonds—reveals # of neighbors e.g. CH3-O group: a singlet, one line, no neighbors—nearst neighbor is 4 bonds away e.g. anomeric proton: a doublet, 2 peaks, one neighbor that is 3 bonds away (recall n neighbors, n +1 peaks) • Coupling Constant • Distance between peaks in a multiplet is J, coupling constant—depends on geometry

16. (con’t) • e.g. α glycoside: 2 peaks are 4.650-4.632 = 0.018 ppm apart spectrometer frequency = 200 MHz J = 0.018 ppm x 200 MHz = 3.6 Hz For the β-glycoside, J = 8.0 Hz • Different J values reflect different geometries:  H1 – C1 – C2 – H2 = 60° in α, = 180° in β J depends on geometry according to Karplus curve: At 60°, J is small 180°, J is large  J reveals the geometry, i.e., the stereochemistry of the glycoside dihedral H-X-X-H

17. But, looking at the spectra, note that the CHOH protons at C-2, C-3, C-4, C-5 & C-6 are all overlapping. •  hard to measure each J value—How to use NMR to get a complete structure?

18. What about a very complex case, i.e., sucralose, the sweetener in splenda: • Where are the chlorines? Which anomer is formed? Pyranose &/or furanose ring? A challenging structure—need advanced NMR methods