1 Sugar Chemistry & Glycobiology In Solomons, ch.22 (pp , ) Sugars are poly-hydroxy aldehydes or ketones Examples of simple sugars that may have existed in the pre-biotic world:

2 Most sugars, e.g. glyceraldehyde, are chiral: sp 3 hybridized C with 4 different substituents The last structure is the Fischer projection: 1)CHO at the top 2)Carbon chain runs downward 3)Bonds that are vertical point down from chiral centre 4)Bonds that are horizontal point up 5)H is not shown: line to LHS is not a methyl group

3 In (R) glyceraldehyde, H is to the left, OH to the right  D configuration; if OH is on the left, then it is L D/L does NOT correlate with R/S Most naturally occurring sugars are D, e.g. D-glucose (R)-glyceraldehyde is optically active: rotates plane polarized light (def. of chirality) (R)-D-glyceraldehyde rotates clockwise,  it is the (+) enantiomer, and also d-, dextro-rotatory (rotates to the right- dexter)  (R)-D-(+)-d-glyceraldehyde & its enantiomer is: (S)-L-(-)-l-glyderaldehyde (+)/d & (-)/l do NOT correlate with D/L or R/S

4 Glyceraldehyde is an aldo-triose (3 carbons) Tetroses → 4 C’s – have 2 chiral centres  4 stereoisomers: D/L erythrose – pair of enantiomers D/L threose - pair of enantiomers Erythrose & threose are diastereomers: stereoisomers that are NOT enantiomers D-threose & D-erythrose: D refers to the chiral centre furthest down the chain (penultimate carbon) Both are (-) even though glyceraldehyde is (+) → they differ in stereochemistry at top chiral centre Pentoses – D-ribose in DNA Hexoses – D-glucose (most common sugar)

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6 Reactions of Sugars 1)The aldehyde group: a)Aldehydes can be oxidized “reducing sugars” – those that have a free aldehyde (most aldehydes) give a positive Tollen’s test (silver mirror) b)Aldehydes can be reduced An alditol

Biological Redox of Sugars:

8 c)Reaction with a Nucleophile Combination of these ideas  Killiani-Fischer synthesis: used by Fischer to correlate D/L- glyceraldehyde with threose/erythrose configurations:

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10 Reactions (of aldehydes) with Internal Nucleophiles Glucose forms 6-membered ring b/c all substituents are equatorial, thus avoiding 1,3-diaxial interactions

11 Can also get furanoses, e.g., ribose: Ribose prefers 5-membered ring (as opposed to 6) otherwise there would be an axial OH in the 6-membered ring

12 Why do we get cyclic acetals of sugars? (Glucose in open form is << 1%) a)Rearrangement reaction: we exchange a C=O bond for a stronger C-O σ bond  ΔH is favored b)There is little ring strain in 5- or 6- membered rings c)ΔS: there is some loss of rotational entropy in making a ring, but less than in an intermolecular reaction:1 in, 1 out. ** significant –ve ΔS!  ΔG = ΔH - TΔS Favored for hemiacetal Not too bad for cyclic acetal

13 Anomers Generate a new chiral centre during hemiacetal formation (see overhead) These are called ANOMERS –β-OH up (technically, cis to the CH 2 OH group) –α-OH down (technically, trans to the CH 2 OH group) –Stereoisomers at C1  diastereomers α- and β- anomers of glucose can be crystallized in both pure forms In solution, MUTAROTATION occurs

14 Mutarotation

15 In solution, with acid present (catalytic), get MUTAROTATION: not via the aldehyde, but oxonium ion At equilibrium, ~ 38:62 α:β despite α having an AXIAL OH…WHY? ANOMERIC EFFECT We know which mechanism operates because the isotope oxygen-18 is incorporated from H 2 18 O

16 O lone pair is antiperiplanar to C-O σ bond  GOOD orbital overlap and hence stabilized by resonance form (not the case with the β-anomer) oxonium ion Anomeric Effect

17 Projections

18 More Reactions of Sugars 1)Reactions of OH group(s): a)Esterification: b)Ethers:

19 b) Ethers (con’t) c)Acetals

20 c) Acetals (con’t)

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

22 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 Mechanism still goes through an oxonium ion (more on this later)

23 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?

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

25 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

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