Glycosides

Glycosides

Glycosides have a substituent other than OH at the anomeric carbon.Usually the atom connected to the anomeric carbon is oxygen.

Example

Linamarin is an O-glycoside derived from D-glucose.

OOH

OHHO

HOHOCH2

OOCC

OHHO

HOHOCH2 CH3

N

CH3

D-Glucose

Glycosides

Glycosides have a substituent other than OH at the anomeric carbon.Usually the atom connected to the anomeric carbon is oxygen.Examples of glycosides in which the atom connected to the anomeric carbon is something other than oxygen include S-glycosides and N-glycosides.

Example

Adenosine is an N-glycoside derived from D-ribose

HOCH2

H

OHOH H

OHOHH

D-Ribose

HOCH2

H

NOH H

OHOHH

N

NH2

N

N

Adenosine

Example

Sinigrin is an S-glycoside derived from D-glucose.

OOH

OHHO

HOHOCH2

D-Glucose

OSCCH2CH

OHHO

HOHOCH2

CH2

NOSO3K

Glycosides

O-Glycosides are mixed acetals.

O-Glycosides are mixed acetals

H

OHO

CH O

CH2OH

hemiacetal

H

OROROH

acetal

Preparation of Glycosides

Glycosides of simple alcohols (such as methanol) are prepared by adding an acid catalyst (usually gaseous HCl) to a solution of a carbohydrate in the appropriate alcohol.

Only the anomeric OH group is replaced.

An equilibrium is established between the α and β-glycosides (thermodynamic control). The more stable stereoisomer predominates.

Preparation of Glycosides

HO

CH O

CH2OH

H OHH OH

HH OH

CH3OH

HCl

D-Glucose

OOCH3

OHHO

HOHOCH2

+

O

OCH3

OHHO

HOHOCH2

Preparation of Glycosides

OOCH3

OHHO

HOHOCH2

+

O

OCH3

OHHO

HOHOCH2

Methylβ-D-glucopyranoside

Methylα-D-glucopyranoside

(major product)

Mechanism of Glycoside Formation

HCl

carbocation is stabilized by lone-pair donation from oxygen of the ring

OOH

OHHO

HOHOCH2

••••

O

OHHO

HOHOCH2

+H

•• ••

Mechanism of Glycoside Formation

O

OHHO

HOHOCH2

+H

•• •• O••

H

CH3

••

OO

OHHO

HOHOCH2 •• ••

CH3

H

••++

O

OHHO

HOHOCH2

OHH3C ••

+

Mechanism of Glycoside Formation

OO

OHHO

HOHOCH2 •• ••

CH3

H

••+

+

O

OHHO

HOHOCH2

OHH3C ••

+

+

••

O

OCH3

OHHO

HOHOCH2 •• ••

••

–H+

••O

OCH3

OHHO

HOHOCH2

••

••

••

Disaccharides

Disaccharides

Disaccharides are glycosides.

The glycosidic linkage connects two monosaccharides.

Two structurally related disaccharides are cellobiose and maltose. Both are derived from glucose.

Maltose and Cellobiose

Maltose

Maltose is composed of two glucose units linked together by a glycosidic bond between C-1 of one glucose and C-4 of the other.The stereochemistry at the anomeric carbon of the glycosidic linkage is α.The glycosidic linkage is described as α(1,4)

O

HOCH2 HOCH2

OH

OHHOOHHO

HOO O1 4α

Maltose and Cellobiose

Cellobiose

Cellobiose is a stereoisomer of maltose.The only difference between the two is that cellobiose has a β(1,4) glycosidic bond while that of maltose is α(1,4).

O

HOCH2 HOCH2

OH

OHHOOHHO

HOO O1 4β

Maltose and Cellobiose

CellobioseMaltose

Cellobiose and Lactose

Cellobiose

Cellobiose and lactose are stereoisomeric disaccharides.Both have β(1,4) glycosidic bonds.The glycosidic bond unites two glucose units in cellobiose. It unites galactose and glucose in lactose.

O

HOCH2 HOCH2

OH

OHHOOHHO

HOO O1 4β

Cellobiose and Lactose

Lactose

Cellobiose and lactose are stereoisomeric disaccharides.Both have β(1,4) glycosidic bonds.The glycosidic bond unites two glucose units in cellobiose. It unites galactose and glucose in lactose.

O

HOCH2 HOCH2

OH

OHHOOHHO

HOO O1 4β

Polysaccharides

Cellulose

Cellulose is a polysaccharide composed of several thousand D-glucose units joined by β(1,4)-glycosidic linkages. Thus, it can also be viewed as a repeating collection of cellobiose units.

Cellulose

Four glucose units of a cellulose chain.

Starch

Starch is a mixture of amylose and amylopectin. Amylose is a polysaccharide composed of 100 to several thousand D-glucose units joined by α(1,4)-glycosidic linkages.Amylose is helical both with respect to the pitch of adjacent glucose units and with respect to the overall chain.

Reduction of Carbohydrates

Reduction of Carbohydrates

Carbonyl group of open-chain form is reduced to an alcohol.Product is called an alditol.Alditol lacks a carbonyl group so cannot cyclize to a hemiacetal.

Reduction of D-Galactose

α-D-galactofuranose

β-D-galactofuranose

α-D-galactopyranose

β-D-galactopyranose

CH2OH

H OH

HHO

HHO

H OH

CH O

CH2OH

H OH

HHO

HHO

H OH

CH2OH

D-Galactitol (90%)

reducing agent: NaBH4, H2O(catalytic hydrogenation can also be used)

Oxidation of Carbohydrates

Benedict's Reagent

Benedict's reagent is a solution of the citrate complex of CuSO4 in water. It is used as a test for "reducing sugars." Cu2+ is a weak oxidizing agent.A reducing sugar is one which has an aldehyde function, or is in equilibrium with one that does.A positive test is the formation of a red precipitate of Cu2O.

+ 2Cu2+RCH

O

5HO–+ + Cu2ORCO–

O

3H2O+

Examples of Reducing Sugars

Aldoses: because they have an aldehyde function in their open-chain form.Ketoses: because enolization establishes an equilibrium with an aldose.

CH2OH

C O

R

CHOH

C OH

R

CH

CHOH

R

O

oxidized by Cu2+

Examples of Reducing Sugars

Disaccharides that have a free hemiacetal function.

O

HOCH2 HOCH2

OH

OHHOOHHO

HOO O

Maltose

Examples of Reducing Sugars

Disaccharides that have a free hemiacetal function.

oxidized by Cu2+

O

HOCH2 HOCH2

OHHOOHHO

HOO OH

CH OMaltose

Glycosides are not reducing sugars

O

OCH3

OH

HOHO

HOCH2

Methyl α-D-glucopyranoside lacks a freehemiacetal function; cannot be in equilibriumwith a species having an aldehyde function

Oxidation of Reducing Sugars

The compounds formed on oxidation of reducing sugars are called aldonic acids.Aldonic acids exist as lactones when 5- or 6-membered rings can form.A standard method for preparing aldonic acids uses Br2 as the oxidizing agent.

Oxidation of D-Xylose

HO

H OH

H OH

H

CH O

CH2OH

Br2

H2O

D-Xylose

HO

H OH

H OH

H

CH2OH

CO2H

D-Xylonic acid (90%)

Oxidation of D-Xylose

HO

H OH

H OH

H

CH2OH

CO2H

D-Xylonic acid (90%)

OO

OH

OHHOCH2

O

O

OH

HOHO

+

Nitric Acid Oxidation

Nitric acid oxidizes both the aldehyde function and the terminal CH2OH of an aldose to CO2H.The products of such oxidations are called aldaric acids.

Nitric Acid Oxidation

CH O

CH2OH

H OH

H OH

H

H OH

HO HNO3

60°C

CO2H

H OH

H OH

H

H OH

HO

CO2H

D-Glucaric acid (41%)D-Glucose

Uronic Acids

CH O

CO2H

H OH

H OH

H

H OH

HO

D-Glucuronic acid

HOHO

OH

OH

HO2CO

Uronic acids contain both an aldehyde and a terminal CO2H function.

Cyanohydrin Formation and Carbohydrate Chain Extension

Extending the Carbohydrate Chain

Carbohydrate chains can be extended by using cyanohydrin formation as the key step in C—C bond-making.The classical version of this method is called the Kiliani-Fischer synthesis. The following example is a more modern modification.

α-L-arabinofuranose

β-L-arabinofuranose

α-L-arabinopyranose

β-L-arabinopyranose

CH2OH

HHO

HHO

H OH

CH O

Extending the Carbohydrate Chain

HCN

CH2OH

HO H

HHO

OHH

CN

CHOH

the cyanohydrin is a mixture of two stereoisomers that differ in configuration at C-2; these two diastereomers are separated in the next step

Extending the Carbohydrate Chain

CH2OH

HO H

HHO

OHH

CN

CHOH

CH2OH

HO H

HHO

OHH

H OH

CN

CH2OH

HO H

HHO

OHH

HO H

CN

+separate

L-Mannononitrile L-Gluconononitrile

Extending the Carbohydrate Chain

CH2OH

HO H

HHO

OHH

H OH

CN

L-Mannononitrile

H2, H2O

Pd, BaSO4

L-Mannose(56% from L-arabinose)

CH2OH

HO H

HHO

OHH

H OH

CH O

Likewise...

CH2OH

HO H

HHO

OHH

HO H

CN

L-Gluconononitrile

H2, H2O

Pd, BaSO4

L-Glucose(26% from L-arabinose)

CH2OH

HO H

HHO

OHH

HO H

CH O

Epimerization, Isomerization, and Retro-Aldol Reactions of

Carbohydrates

Enol Forms of Carbohydrates

Enolization of an aldose scrambles the stereochemistry at C-2.This process is called epimerization. Diastereomers that differ in stereochemistry at only one of their stereogenic centers are called epimers.D-Glucose and D-mannose, for example, are epimers.

Epimerization

CH O

CH2OH

H OH

H OH

H

H OH

HO

D-MannoseD-Glucose

CH O

CH2OH

H OH

H OH

H

HO H

HO

Enediol

CH2OH

H OH

H OH

H

OH

HO

CHOH

C

This equilibration can be catalyzed by hydroxide ion.

Enol Forms of Carbohydrates

The enediol intermediate on the preceding slide can undergo a second reaction. It can lead to the conversion of D-glucose or D-mannose (aldoses) to D-fructose (ketose).

Isomerization

Enediol

CH2OH

H OH

H OH

H

OH

HO

CHOH

C

D-Glucose orD-Mannose

CH O

CH2OH

H OH

H OH

HHO

CHOH

D-Fructose

CH2OH

CH2OH

H OH

H OH

HHO

C O

Retro-Aldol Cleavage

When D-glucose 6-phosphate undergoes the reaction shown on the preceding slide, the D-fructose that results is formed as its 1,6-diphosphate.D-Fructose 1,6-diphosphate is cleaved to two 3-carbon products by a reverse aldol reaction.This retro-aldol cleavage is catalyzed by the enzyme aldolase.

Isomerization

D-Fructose1,6-phosphate

CH2OP(O)(OH)2

H OH

H OH

HHO

C O

CH2OP(O)(OH)2

aldolase

H OH

CH2OP(O)(OH)2

CH O

CH2OP(O)(OH)2

C O

CH2OH

Acylation and Alkylation of Hydroxyl Groups in

Carbohydrates

Reactivity of Hydroxyl Groups in Carbohydrates

acylationalkylation

Hydroxyl groups in carbohydrates undergo reactions typical of alcohols.

Example: Acylation of α-D-glucopyranose

O

OHOH

HOHO

HOCH2

+ CH3COCCH3

O O

5

pyridine

O

O

CH3COCH2

O

CH3CO

O

CH3CO

O CH3CO

OOCCH3

(88%)

Example: Alkylation of methyl α-D-glucopyranoside

O

OCH3

OH

HOHO

HOCH2

+ 4CH3I

Ag2O, CH3OH

O

OCH3

CH3O

CH3OCH3O

CH3OCH2

(97%)

Classical Method for Ring Size

Ring sizes (furanose or pyranose) have been determined using alkylation as a key step.

O

OCH3

OH

HOHO

HOCH2

OCH3

O

CH3O

CH3OCH3O

CH3OCH2

Classical Method for Ring Size

Ring sizes (furanose or pyranose) have been determined using alkylation as a key step.

O

OCH3

CH3O

CH3OCH3O

CH3OCH2

H2O

H+

(mixture of α + β)

O

OHCH3O

CH3OCH3O

CH3OCH2

Classical Method for Ring Size

Ring sizes (furanose or pyranose) have been determined using alkylation as a key step.

(mixture of α + β)

O

OHCH3O

CH3OCH3O

CH3OCH2

CH2OCH3

H OH

OCH3H

HCH3O

H OCH3

CH O

Classical Method for Ring Size

Ring sizes (furanose or pyranose) have been determined using alkylation as a key step.

CH2OCH3

H OH

OCH3H

HCH3O

H OCH3

CH O

This carbon has OHinstead of OCH3.Therefore,its O was theoxygen in the ring.

Periodic Acid Oxidation of Carbohydrates

Recall Periodic Acid Oxidation

Cleavage of a vicinal diol consumes 1 mol of HIO4.

CC

HO OH

HIO4C O O C+

Vicinal diols are cleaved by HIO4.

Also Cleaved by HIO4

Cleavage of an α-hydroxy carbonyl compound consumes 1 mol of HIO4. One of the products is a carboxylic acid.

CRC

OH

HIO4C O O C+

α-Hydroxy carbonyl compounds

O R

HO

Also Cleaved by HIO4

2 mol of HIO4 are consumed. 1 mole of formic acid is produced.

HIO4R2C O

R'2C O

+

Compounds that contain three contiguouscarbons bearing OH groups

HCOH

O

OH

R2C CH CR'2

OHHO

+

OHOCH2

HO

OH

OCH3

Structure Determination Using HIO4

Distinguish between furanose and pyranose formsof methyl arabinoside

HO

HO

OOH

OCH3

2 vicinal OH groups;consumes 1 mol of HIO4

3 vicinal OH groups;consumes 2 mol of HIO4