Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 1 of 11. Date: March 28, 2012

Chapters 14.8, 23-1,2, 5, and 7: Carbohydrates - Part II

II. Glycosides – A general term used to describe organic molecules covalently bound to carbohydrate molecules (through anomeric bonds).

(1) Formation of glycosides

C1-epimers; anomers; diastereomers

HO 6 HO 4 O O HO 5 2 1 HO 1 OH HO HO 3 anomeric carbon HO HO anomeric carbon α-anomer OH β-anomer

CH3OH, 0.7 % HCl, 10 °C (short time) Kinetic conditions (for this reaction)!

6 CH2OH CH2OH HO H HO H 5 H OCH + OH 3 OHO H O H 1 1 anomeric carbon 4 anomeric carbon 3 2 H OCH3 H H H HO H HO α-anomer β-anomer

methyl α-D-glucofuranoside methy β-D-glucofuranoside

CH3OH, 4 % HCl, rt Thermodynamic conditions!

HO 6 HO 4 O O HO 1 HO 5 2 1 + OCH3 HO HO 3 anomeric carbon HO anomeric carbon HO ~33% OCH3 β-anomer MAJOR PRODUCT α-anomer ~66% MINOR PRODUCT methyl α-D-glucopyranoside methyl β-D-glucopyranoside

In general, (5-membered) furanosides are formed preferentially under the kinetic conditions, whereas (6-membered) pyranosides are formed under the thermodynamic conditions, i.e., more stable. Five membered systems have a number of eclipsing interactions, thus less stable.

Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 2 of 11. Date: March 28, 2012

(2) Mechanism for the formation of anomeric glycosides

HO 6 When protonation occurs HO H 4 O on the anometic OH. O HO 5 2 1 OH HO O HO HO 1 H 3 HO HO β-anomer anomeric carbon lone pair-assisted ionization.

When protonation occurs HO on the ether oxygen atom. O HO H HO 1 O CH3 H H HO or HO lone pair-assisted HO O ionization. O H HO HO O H O H O CH3 H HO HO 1 or HO HO O CH3 H H HO H O HO O CH3 H H HO 1 HO OH HO HO O O H O CH3 CH stereochem. HO HO O 3 mixture HO 1 HO 1 O H O H H HO HO H H H H O CH3

lone pair-assisted ionization. H H HO rotation along HO O O the C1-C2 bond H HO 2 O CH3 HO H H HO HO 1 O CH3 1 O CH3 HO HO O H CH3 H H HO HO O O HO OCH HO H HO 3 HO HO HO H HO HO OCH3 O O HO 1 OCH HO H HO 3 HO HO HO β-anomer H α-anomer OCH3

Comments:

• The α-anomeric hemiacetal undergoes similar processes to produce a mixture of anomeric glycosides.

• Protonation on the lone pairs of the oxygen atoms other than the anomeric (i.e., C1-O) and ether ring oxygen ones does not lead to the ready elimination of the protonated hydroxyl groups due to the lack of the lone pair-assisted ionization.

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(3) Hydrolysis of the Glycosidic Linkages a. Lactose – milk sugar; disaccharide; reducing sugar (one hemiacetal group) anomeric anomeric HO 6' OH carbon OH OH 6 OH carbon HO 4 4' O 4 + O O 2' O H3O H 5' 5 2 + HO OH HO OH HO OH 3' 1' HO 1 HO 3 HO HO HO hemiacetal β-glycosidic D-galactose D-glucose β-D-lactose linkage (or bond) reducing sugar anomeric anomeric mixture mixture permethylation with NaOH (excess), (CH3)2SO4 (excess) or NaH (excess), CH3I (excess) All OHs except the anomeric OH methylated.

H CO 6' OCH OCH OCH 3 3 6 OCH3 H3CO 3 3 + 4 4' O 4 H3O O H O 5' 2' O 5 2 OCH + H3CO 3 H3CO OH H3CO OH 3' 1' H3CO 1 H CO 3 3 H3CO H3CO H3CO All glycosidic bonds 2,3,4,6-tetra-O- 2,3,6-tri-O- get hydrolyzed methyl D-galactose methyl D-glucose 4-OH is free. Thus, terminal sugar! the other sugar is Taken together, D-lactose must be: (D-galactose)-O-(D-glucose) attached at the attached to the C4-OH. C4-OH of D-glucose; O-β-D-galactopyranosyl-(1->4)-β-D-glucopyranose or β-D-Galp-(1->4)-β-D-Glcp. This reaction concept can be used for sequencing polysaccharides.

b. Sucrose (“Sugar”): disaccharide; non-reducing sugar (no anomeric hemiacetal nor hemiketals)

OH D-fructose 1 OH O CH OH 6 1 HO 2 HO HOH2C HO H O H O CH2OH HO 2 + HO H O 5 H3O OH 2 HO + 5 HO 3 4 OH CH OH HO 4 3 D-glucose 2 OH H6 OH H D-glucose α-glycosidic linkage (anomeric D-fructose to glucose β-glycosidic linkage to fructose mixture) (anomeric + mixture) OH H H Both of these are reducing sugars! D-glucose O HO HO α-glycosidic linkage HO to glucose Sucrose: 6 D D HOH2C HO O-β- -fructofuranosyl-(2<->1)-α- -gluco- H O β-glycosidic linkage pyranoside or β-D-Fruf-(2<->1)-α-D-Glcp 5 2 to fructose D-fructose 4 3 f: furanosyl; p: pyranosyl CH2OH OH H 1

Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 4 of 11. Date: March 28, 2012

III. The Anomeric Effect: The inherent preference of electronegative substituents (usually OR, SR or halogen atoms) for the axial position at the anomeric carbon; largest for halogen atoms.

See: Juaristi, E.; Cuevas, G. The Anomeric Effect; CRC Press: Boca Raton, FL; 1995.

Examples: (1) X O O X ______X = Cl ΔG° 1.8 kcal/mol Br 1.8

OCH3 0.9 OCH2CH3 0.8 SCH3 0.5 OH -0.3 ~ -0.1

NHCH3 -0.9

Note: OH

OH 11% 89%

ΔG°25°C = -1.24 kcal/mol

(2) HO 6 HO 4 O O HO 5 2 1 HO 1 OH HO HO 3 HO HO 36% OH 64%

ΔG°25°C = -0.34 kcal/mol

So, the inherent anomeric effect (AE) for an OH may be estimated to be:

AE (OH) = ΔG° (pyranose) - ΔG° (cyclohexane) = -0.34 – (-1.24) = 0.90 kcal/mol

Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 5 of 11. Date: March 28, 2012

Explanations for the Anomeric Effect

(1) Repulsive lone pair-lone pair interactions: axial Axial C -OCH equatorial Equatorial C1-OCH3 axial equatorial 1 3 (stabler) 5 O 2 5 O H 2 O 3 1 H 1 O CH H View through the equatorial 3 C1 - ring O bond H CH View through the 1,3-diaxial 3 interactions Stays away from the ring C1 - ring O bond portion, avoiding the steric repulsion.

repulsive lone pair-lone pair axial orbital interaction! axial C C2 H 1 Ring oxygen C2 O C1 equatorial C5 CH C5 3 O H repulsive Ring oxygen repulsive lone pair-lone pair equatorial lone pair-lone pair orbital interaction! orbital interaction! CH3

Only one bad interaction!! (2) The hyperconjugative orbital interaction concept axial Axial C1-OCH3 n σ∗ FMO interpretation (stabler) C1-OCH3 5 O H 2 1 ∗ anti-bonding orbitals σ C1-OCH3 axial O n CH3 hyperconjugative, stabilizing orbital interaction: the oxygen lone-pair electrons are delocalizing into the antibonding C1-O orbital (σ* orbital) of the axial C1-O bond.

This hyperconjugation should make the C1-O bond shorter and the C-X bond longer.

Cl Cl O O 1 O 1 hyperconjudation Cl 1

Bond length comparisons: Cl Cl 1.39Å 1.82Å 1.43Å 1.39Å 1.82Å O 1 1 O Cl O O Cl 1 1.72Å 1.43Å 1.78Å

Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 6 of 11. Date: March 28, 2012

Reactions of Carbohydrates (1) Isomerization of sugars: usually in the presence of acid or base

epimer

open chain form "ene-diol"

ketose

HO 6 4 H 1 O O 6 HO 5 2 1 2 HO OH HO OH HO H 4 O 3 HO 3 HO HO H 5 1 HO 2 OH H OH 3 H OH C2-epimer of D-glucose H 1 O H 1 OH CH2OH 2 H OH 2 OH D-mannose HO 3 H HO 3 H H OH H OH H H OH H OH H OH 1 CH2OH CH2OH 6 2 O HOH2C HO 1 D-glucose 3 H O CH2OH "ene-diol" HO H 2 5 H OH 4 3 OH H OH OH H CH2OH D-fructose

Under base-catalyzed conditions H 1 O 6 2 HO OH HO 6 HO H 4 4 O O 3 HO 5 1 HO 5 2 1 D-glucose + HO H HO 2 OH HO OH (~69%) H OH 3 3 HO H OH C2-epimer of D-glucose CH2OH D-mannose (~1%) H 1 O + NaOH (0.04%) 2 H H OH H OH 3 H O, 35 °C 1 HO H 2 6 50 h 2 O HOH2C HO 1 H OH 3 H CH2OH HO H O 2 H OH 5 H OH OH CH2OH 4 3 H OH OH H D-glucose CH2OH D-fructose (~20%)

Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 7 of 11. Date: March 28, 2012

Mechanism: a b H 1 O H 1 O O H 1 OH b O H H HO 2 2 b 2 H OH H H a a OH O 3 3 3 HO H HO H HO H H OH Protonation at C2 glucose from the bottom face "ene-diol"

a H H 1 O 2 O HO H H 3 H OH H HO H 1 H OH 2 O Protonation at C1 3 1 mannose HO H 2 O H OH 3 H OH HO H D-fructose CH2OH

------+ Mechanism under H3O conditions H H O H 1 O H H H 1 O 2 H O 2 H OH 2 H OH HO 3 H HO 3 H

glucose H2O H H H 1 O H 1 O H 1 O Loss of H+ Protonation at C O H 1 H 2 C=O H 2 2 OH HO H HO H (fructose) 3 3 HO H HO H HO 3 H Protonation at C2 from the bottom face mannose

(2) Reducing sugars: Sugars that contain a hemiacetal or hemiketal, and are therefore in equilibrium with open form, are called “reducing sugars.”

Tollens test H 1 O O 1 O HO 2 H OH Ag2O H OH O HO 3 H NaOH/H2O HO H 0 HO 1 + Ag (silver mirror) HO OH H OH H OH HO H OH H OH

CH2OH CH2OH

2+ +1 Also, with Cu (CuSO4) [deep blue color]/NaOH [Benedict's reagent] Cu2O (Cu ) [red ppts] reducing sugar

Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 8 of 11. Date: March 28, 2012

(3) Oxidation reactions involving C1-OH or C1- and C6-OHs (a) Br2 in H2O oxidizes only aldoses HO O HO 1 HO OH HO HO HO OH Br + 3 H O HO OH + O 2 2 HO H3O HO O HO HO HO O OH HO HO - + H + 2 Br + 2 H3O Under the acidic conditions, HO this hydroxy acid closes to HO O form the six-membered lactone. note: Br2 + H2O HBr + HOBr

(b) HNO3 oxidation: HNO3 is a stronger oxidizing agent than Br2–H2O, oxidizing both the aldehyde group and the terminal –CH2OH of an aldose to the corresponding di-acid.

Both C and C ends get oxidized H 1 O 1 6 HO 1 O to COOH's. 2 H OH H 2 OH 3 HO H HNO3, Δ 3 HO H galactaric acid 4 4 HO H HO H (meso; optically H 5 OH H 5 OH inactive) 6 6 CH2OH O OH D-galactose (optically active)

(4) Both (hemiacetal) aldoses and (hemiketal) ketoses undergo reactions observed for aldehydes and ketones, respectively.

H 1 O C N C N * H OH HO H HO 2 * * H OH H OH H OH O 3 HCN HO 1 HO H + HO OH HO H HO H H OH H2O HO H OH H OH H OH H OH H OH CH2OH CH OH CH OH 2 2

1 CH OH 2 1 1 CH OH CH OH HO 6 2 O 2 2 1 2 2 HO CH OH 3 H OH HO H H O 2 HO H 2 NaBH4 3 3 5 H OH HO H + HO H 4 3 OH CH OH-H O H OH 3 2 H OH H OH OH H H OH H OH CH2OH α-/β-D-fructofuranose CH2OH CH2OH D-fructose

Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 9 of 11. Date: March 28, 2012

(4) Reactions of hydroxyl groups and their derivatives

Selective reactions of anomeric OHs and their derivatives under acidic conditions (by an SN1 process) and glycoside formation of the anomeric bromide (by an SN2 process). (a)

K H CO H3CO H3CO 3 HBr O-CH Ph O O O 2 (gas) H CO H CO H3CO 1 3 1 3 H3CO H3CO H3CO 1 CH2Cl2 H3CO H3CO H3CO OCH3 Br SN1 Br

The α-bromide formed due mainly to the anomeric effect of Br. SN2 !

H3CO O H3CO O H3CO 1 CH2Ph H3CO + KBr (b) H3C O O O HO O O H3C O CH3 O H C O HO 1 (excess) 3 O 1 HO O H3C HO OH * O O O CH3 N O CH3 O HBr (gas) SN1 acetic acid OH (0 °C) more acidic HO H3C OH O K KOH, Δ O O O H C O 3 O H3C O 1 O H3C O O OH O O Br O S 2 H C O N 3 O O CH3 O 1 H3C O O O * CH3 + KBr O O O O H C O H3C O CH3 3 H3C NaOH-H O O CH3 H 2 N N N O R HO OH O HO 1 O HO OH O salicin R H C O 3 Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 10 of 11. Date: March 28, 2012

Summary of Carbohydrate Reactions

The reactions applied to carbohydrates are not new and have been covered in earlier chapters, but they often exhibit uniquely carbohydrate behaviors.

1. Base or acid-catalyzed isomerization between aldoses and ketoses via ene-diol intermediates, particularly the mechanism. 2. Reactions of aldoses/ketoses with those that react with an aldehyde or ketone C=O group such as

NaBH4/CH3OH and a primary amine, NH2R. 3. Acid-catalyzed reactions at the anomeric center of a carbohydrate, particularly the mechanism that involves the lone pair-assisted ionization.

4. Ether formation from ROH: R’X/NaH or (CH3)2SO4/NaOH

5. Acylation of ROH:

6. Selective reactions of a primary alcohol with electrophiles

For example,

For the deprotection of the trityl group [Ph3C-], mild acidic conditions such as aq CF3C(=O)OH are used.

7. Hydrolysis (with HO-) [see p 9 (b) of Carbo notes Part II] or methanolysis (NaOCH3/CH3OH) of esters such as acetates.

For example,

Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 11 of 11. Date: March 28, 2012

8. SN2 reactions of mesylate, tosylate, and triflate [OTf; trifluoromethanesulfonate, OS(O)2CF3] derivatives of primary and secondary hydroxy groups.

For example,

9. Acetal/ketal derivatives of diols and their hydrolysis.

For the formation of acetal/ketal derivatives, RR’C(OCH3)2 [such as Ph-CH(OCH3)2] is usually used especially when a sugar has 1-OR group, instead of an aldehyde [e.g., Ph-C(=O)H] or ketone [e.g.,

(CH3)2C=O]. This is to avoid the hydrolysis of 1-OR by the water generated as a result of acetal/ketal formation from a diol when a RR’C=O is used.

Preferred formation of acetals/ketals from 1,2-cis-diol

The acetal/ketal derivative of a trans-diol is considerably more strained compared with those formed from cis-diols.

When there is no cis-diol in the pyranose ring, the six-membered acetal/ketal involving 4- and 6-OH’s is formed.