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Home , Aldose, Altrose, Anomer, Fischer projection, Furanose, Glyceraldehyde

Chapter 25:

hydrates of : general formula Cn(H2O)n

Plants: hν 6 CO2 + 6 H2O C6H12O6 + 6 O2

Polymers: large molecules made up of repeating smaller units (monomer)

Biopolymers: Monomer units: carbohydrates (Chapter 25) peptides and proteins (Chapter 27) amino acids nucleic acids (Chapter 28)

246

25.1: Classification of Carbohydrates. I. Number of units monosaccharides: one carbohydrate unit (simple carbohydrates) : two carbohydrate units (complex carbohydrates) : three carbohydrate units : many carbohydrate units

CHO H OH HO HO HO H HO HO O HO O H OH HO HO OH HO H OH OH

CH2OH HO HO HO O HO O HO HO O HO HO O HO HO HO O O O O O HO HO O HO HO HO O O HO HO HO OH O 247

126 II. Position of at C1, carbonyl is an : at any other carbon, carbonyl is a :

III. Number of three carbons: six carbons: four carbons: seven carbons: five carbons: etc.

IV. Cyclic form (chapter 25.6 and 25.7)

CHO CHO CHO CHO CH2OH H OH HO H H OH H OH O

CH2OH H OH H OH HO H HO H CH2OH H OH H OH H OH

CH2OH H OH H OH CH OH 2 CH2OH (triose) (pentose) (tetrose) (hexose) (hexose) 248 (aldohexose) (ketohexose)

25.2: Fischer Projections and the D-L Notation. Representation of a three-dimensional molecule as a flat structure. Tetrahedral carbon represented by two crossed lines:

horizontal line is coming vertical line is going back out of the plane of the behind the plane of the page (toward you) paper (away from you) substituent carbon (R)-(+)-glyceraldehyde

CHO CHO CHO H OH H OH H C CH2OH HO CH2OH CH2OH

(S)-(-)-glyceraldehyde

CHO CHO CHO HO H HO H HO C CH2OH H CH2OH CH2OH

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127 before the R/S convention, was related to (+)-glyceraldehyde

CHO CHO H OH HO H

CH2OH CH2OH

D-glyceraldehyde L-glyceraldehyde R-(+)-glyceraldhyde S-(-)-glyceraldhyde (+)-rotation = dextrorotatory = D (-)-rotation = levorotatory = L

D-carbohydrates have the -OH group of the highest numbered chiral carbon pointing to the right in the Fisher projection as in R-(+)-glyceraldhyde

For carbohydrates, the convention is to arrange the with the carbonyl group at the top for and closest to the top for . The carbons are numbered from top to bottom.

250

Carbohydrates are designated as D- or L- according to the stereochemistry of the highest numbered chiral carbon of the Fischer projection. If the hydroxyl group of the highest numbered chiral carbon is pointing to the right, the is designated as D (Dextro: Latin for on the right side). If the hydroxyl group is pointing to the left, the sugar is designated as L (Levo: Latin for on the left side). Most naturally occurring carbohydrates are of the D-configuration.

1 CHO 1 H 2 OH CHO 3 2 HO H H OH 3 H 4 OH HO H highest numbered highest numbered 5 HO 4 H "chiral" carbon H OH "chiral" carbon 5 CH2OH 6 CH2OH

D-Glucose L-

CHO HO H CHO H OH HO H HO H H OH highest numbered highest numbered H OH "chiral" carbon HO H "chiral" carbon CH OH CH2OH 2 251 L- glucose D-Arabinose

128 25.3: The Aldotetroses. Glyceraldehyde is the simplest carbohydrate (C3, aldotriose, 2,3-dihydroxypropanal). The next carbohydrate are aldotetroses (C4, 2,3,4-trihydroxybutanal).

aldotriose

CHO CHO H OH HO H

CH2OH CH2OH

D-glyceraldehyde L-glyceraldehyde

aldotetroses 1CHO 1 CHO 2 HO 2 H highest numbered H OH highest numbered 3 3 "chiral" carbon H OH HO H "chiral" carbon 4 4 CH2OH CH2OH D- L-erythrose

CHO CHO HO H H OH highest numbered highest numbered HO H "chiral" carbon H OH "chiral" carbon CH2OH CH2OH D-threose L-threose 252

25.4: Aldopentoses and Aldohexoses.

Aldopentoses: C5, three chiral carbons, eight stereoisomers

CHO CHO CHO CHO H OH HO H H OH HO H H OH H OH HO H HO H H OH H OH H OH H OH

CH2OH CH2OH CH2OH CH2OH

D-ribose D-arabinose D- D-

Aldohexoses: C6, four chiral carbons, sixteen stereoisomers

CHO CHO CHO CHO CHO CHO CHO CHO H OH HO H H OH HO H H OH HO H H OH HO H H OH H OH HO H HO H H OH H OH HO H HO H H OH H OH H OH H OH HO H HO H HO H HO H H OH H OH H OH H OH H OH H OH H OH H OH

CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH

D- D- D- glucose D- D- D- D- D-

253

129 Manipulation of Fischer Projections 1. Fischer projections can be rotate by 180° (in the plane of the page) only!

CHO CH2OH CHO CH2OH 180 ° H OH HO H 180 ° HO H H OH

CH2OH CHO CH2OH CHO (R) (R) (S) (S)

180° 180°

Valid Valid Fischer Fischer projection projection

254

a 90° rotation inverts the stereochemistry and is illegal!

90 ° CHO OH H OH ! OHC CH2OH

CH2OH H (R) (S)

90 °

This is not the correct convention 90° for Fischer projections

Should be projecting toward you Should be projecting away you

This is the correct convention for Fischer projections and is the

255

130 2. If one group of a Fischer projection is held steady, the other three groups can be rotated clockwise or counterclockwise. hold steady CHO CHO

H OH HO CH2OH

CH2OH H (R) (R)

CHO H HO H OHC OH hold steady CH2OH CH2OH (S) (S)

120° 120°

hold hold steady steady hold steady

120° 120°

hold hold 256 hold steady steady steady

Assigning R and S Configuration to Fischer Projections 1. Assign priorities to the four substitutents according to the Cahn-Ingold-Prelog rules 2. Perform the two allowed manipulations of the Fischer projection to place the lowest priority group at the top or bottom. 3. If the priority of the other groups 1→2→3 is clockwise then assign the carbon as R, if priority of the other groups 1→2→3 is counterclockwise then assign the center as S.

2 place at the top 4 CO2H H 1 H2N H 4 2 HO2C NH2 1 hold steady CH3 CH3 rotate other 3 3 three groups counterclockwise 1-2-3 counterclockwise = S

2 4 2 CO2H H CO2H 4 1 2 H NH2 1 H2N CO2H H2N CH3 CH3 1 3 CH3 H 3 3 4 1-2-3 clockwise = R 257

131 Fischer projections with more than one chiral center:

1 CHO CHO 2 HO H HO H 3 H OH H OH

4 CH2OH CH2OH Threose

2 CHO H 4 1 2 1 2 4 2 HO H OHC S OH 3 3 4 H OH 4 H OH 1 Hold Steady 1 3 CH2OH CH2OH 3 (2S, 3R)

4 H 4 H Hold Steady 2 1 2 1 2 2 S OHC OH OHC OH 3 3 4 H OH 1 1 HO CH2OH R 3 CH OH H 2 4 3 258

25.5: A Mnemonic for Carbohydrate Configuration. (please read)

25.6: Cyclic Forms of Carbohydrates: Forms.

O H+ + HO OR2 H , R2OH R2O OR2 + R2OH R1 H (Ch. 17.8) R1 H R1 H

acetal

O OH OR

H + H H H , ROH

OH O Ch. 25.13 O

cyclic hemiacetal mixed acetal ()

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132 In the case of carbohydrates, cyclization to the hemiacetal creates a new chiral center.

CHO * H OH H H O O H OH H H * + H H * H OH H H H OH CH2OH OH OH OH OH D-erythrose Converting Fischer Projections to Haworth formulas

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25.7: Cyclic Forms of Carbohydrates: Forms. H H 5 OH 5 H O H O OH H H 4 4 1 H H 1 H H 1 CHO HO HO H 2 2 H 3 H OH 3 3 HO OH OH OH H OH H H H H 1 new chiral 4 5 4 3 2 H OH HO CHO H center 5 H 5 H H H OH OH OH OH 5 H H O H OH H H H 4 H H 1 4 H H 1 D-ribose HO HO 2 OH 3 2 O 3 HO OH OH OH ribopyranose

6 CH OH 2 6 CH OH 5 2 OH 5 H O H O OH H H 4 4 1 1 OH H 1 OH H CHO HO HO H 2 3 2 H 3 H OH 6 H OH 3 H OH HO H HOH C H OH H 2 1 new chiral 5 2 H 4 OH HO 4 3 CHO center 6 CH2OH 6 5 CH2OH 5 HOH2C H H OH H OH OH 5 6 H H O H OH H H H 4 OH H 1 4 OH H 1 D-glucose HO HO 2 OH 3 2 O 3 H OH H OH glucopyranose 261

133 25.8: and the . The hemiacetal or hemiketal carbon of the cyclic form of carbohydrates is the anomeric carbon. Carbohydrate that differ only in the stereochemistry of the anomeric carbon are called . Mutarotation: The α- and β-anomers are in equilibrium, and interconvert through the open form. The pure anomers can be isolated by crystallization. When the pure anomers are dissolved in water they undergo mutarotation, the process by which they return to an equilibrium mixture of the .

HOH C 2 HOH C Cis OH 2 β-D-Glucopyranose (64%) HO HO O O (β-anomer: C1-OH and HO HO CHO OH CH OH are cis) HO HO 2 H OH H H HO H H OH HOH2C Trans α-D-Glucopyranose (36%) H HOH2C OH OH ( -anomer: C1-OH and HO HO α CH2OH O HO H HO CH2OH are trans) H D-glucose HO HO O OH 262

25.9: Ketoses. Ketoses are less common than aldoses

CH2OH CH2OH CH OH 2 CH2OH O O O O CH2OH HO H H OH H OH O HO H H OH H OH HO H H OH CH2OH H OH CH2OH CH OH 2 H OH H OH CH2OH CH2OH D- Dxylulose D-fructose D-sedohepuloase

Fructofuranose and Fructopyranose 1 6 CH2OH 6 6 CH OH OH 2 HOH C H OH HOH C O 2 O O 2 1 2 OH 3 5 4 3 2 5 H HO 2 HO H HO CH2OH 5 H HO 4 3 4 2 H CH OH H OH H OH H O H CH2OH 4 3 2 OH H 1 5 OH H 1 HOH2C H 6 furanose OH

1 H CH2OH 6 H 6 2 O OH 5 H H OH H H O OH 3 6 1 O HO H 5 2 H H 4 3 5 4 2 HOH2C CH2OH H HO 2 H HO H 4 OH OH OH H O HO HO CH2OH 5 4 3 CH2OH 3 H OH 1 1 6 HO H OH H CH2OH 263 pyranose

134 25.10: Deoxy . Carbohydrates that are missing a .

1 1 CHO CHO 2 H 2 OH H H HOH C OH HOH2C OH 3 2 O 3 O H OH H H H OH H H 4 4 H OH H H H OH H H H OH OH 5 OH 5 CH2OH CH2OH

D-ribose 2-Deoxy-D-ribose

1 1 CHO CHO 6 6 HO 2 H H HO 2 H H 3 5 3 5 O H OH H O OH H OH H OH CH OH CH3 4 4 2 4 4 H OH H HO 2 H OH H HO 2 5 H 5 H HO H HO 3 HO H HO 3 6 1 6 1 CH2OH OH H CH3 OH H L-Galactose 6-Deoxy-L-Galactose ()

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25.11: Amino Sugars. Carbohydrates in which a hydroxyl group is replaced with an -NH2 or -NHAc group

HOH2C HOH2C HO HO O O HO O OH HO C OH HN 2 HN CH H 3 H O O N-acetyl-D-glucosamine N-Acetylmuramic acid (GlcNAc or NAG) (MurNAc)

25.12: Branched-Chain Sugars. (Please read)

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135 25.13: . Acetals and ketals of the cyclic form of carbohydrates. O H+ + HO OR2 H , R2OH R2O OR2 + R2OH R1 H R1 H R1 H

hemiacetal acetal CHO H OH HOH C HOH C 2 2 HOH C HO H HO HO 2 O ROH O HO H OH HO HO + O OH H+ OR HO H OH HO HO H HO CH OH H H 2 OR pyranose Glycoside D-glucose (hemiacetal) (acetals) Note that only the anomeric hydroxyl group is replaced by ROH

266

25.14: Disaccharides. A glycoside in which ROH is another carbohydrate unit (complex carbohydrate). OH HO OH OH HO HO HO OH O O HO OH HO HO HO HO O O H OH O HO HO HO O O HO HO O O O HO HO O H H O HO HO OH OH HO OH HO OH HO (1,2'-glycoside) OH (1,4'-"-glycoside) (1,4'-!-glycoside) (1,4'-!-glycoside)

25.15: Polysaccharides. : glucose made up of 1,4’-β-glycoside linkages HO HO HO HO HO HO O O O O O O O O O O O O O HO HO HO HO HO HO HO HO HO HO HO HO H H H H H H : glucose polymer made up of 1,4’-α-glycoside linkages

HO HO H HO HO HO O O H H HO O O H H O O H O O O HO HO HO HO O O 267 HO HO HO HO HO O O HO HO HO

136 : OH O HO O H OH HO O HO O HO HO HO H HO O HO O O H H HO O O H H O O H O O O HO HO HO HO O O HO HO HO HO HO O O HO HO HO 25.16: Reactions of Carbohydrates. Glycoside formation is related to acetal formation. 25.17: Reduction of Monosaccharides. C1 of aldoses are reduced with sodium borohydride to the 1° alcohol (alditols) Reacts like A carbonyl CHO CH2OH HOH2C H OH H OH HO NaBH O HO H 4 HO H HO H OH H OH HO H OH H OH OH CH2OH CH2OH

D-glucose D-glucitol

268

CH OH CH OH Reduction of ketoses 2 CH2OH 2 O H OH HO H

HO H NaBH4 HO H HO H + H OH H OH H OH H OH H OH H OH CH OH 2 CH2OH CH2OH D-fructose D-glucitol D-mannitol 25.17: Oxidation of Monosaccharides. C1 of aldoses can be selectively oxidized to the carboxylic acid (aldonic acids) with

Br2 or Ag(I) (Tollen’s test). CHO CO2H H OH Ag(I) Ag(0) H OH HO H HO H H OH H OH N H 3 , H OH H OH H2O CH2OH CH2OH

CO2H HOH2C HOH2C H OH HO Br2 HO H2O O O HO H HO HO H OH HO HO H OH OH O CH2OH Reducing sugars: carbohydrates that can be oxidized to aldonic acids. 269

137 Oxidation of aldoses to aldaric acids with HNO3.

CHO CO2H H OH H OH HNO HO H 3 HO H H OH H OH H OH H OH

CH2OH CO2H Glucaric acid

Uronic Acid: Carbohydrate in which only the terminal -CH2OH is oxidized to a carboxylic acid.

CHO CHO H OH H OH HO2C [O] HO HO H HO H O HO H OH H OH H OH H OH HO OH CH2OH CO2H Gluronic acid

270

Reducing sugars: carbohydrates that can be oxidized to aldonic acids. HO HO HO HO HO HO HO HO HO O O HO O HO Ag(I) HO O O OH O OH + Ag(0) O HO HO HO HO HO H [O] HO OH HO HO HO OH O O reducing cellobiose and maltose end are

HO HO HO HO Ag(I) HO HO HO HO HO + Ag(0) O 4' O [O] HO HO HO O O O O OH O OH HO HO HO HO 1 HO H HO OH HO HO HO lactose OH O O (1,4'- -glycoside) reducing lactose is a ! end reducing sugar HO HO Ag(I) HO O HO No reaction HO 1 ! [O] 2' glucose O " O sucrose is not OH fructose sucrose HO a reducing sugar (1,2'-glycoside) No reducing end 271 OH

138 25.19: Cyanohydrin Formation and Chain Extension. Kiliani-Fischer Synthesis- chain lengthening of monosaccharides

272

Determination of carbohydrate stereochemistry

1) HCN CHO CO2H 2) H2, Pd/BaSO4 HNO , H OH 3 H OH 3) H2O heat H OH H OH CH2OH CO2H D-(-)-erythrose tartaric acid CHO H OH Killiani-Fischer synthesis CH2OH D-(+)-glyceraldehyde

CHO HNO , CO2H HO H 3 heat HO H H OH 1) HCN H OH CH2OH 2) H2, Pd/BaSO4 CO2H 3) H2O D-(-)-threose D-(-)-tartaric acid

273

139 1) HCN CHO CO2H 2) H2, Pd/BaSO4 3) H O H OH HNO3, H OH 2 heat H OH H OH H OH H OH CH OH 2 CO2H D-(-)-ribose ribonic acid CHO H OH Killiani-Fischer H OH synthesis

CH2OH D-(-)-erythrose

CHO CO2H HO H HNO3, HO H heat H OH H OH 1) HCN H OH H OH 2) H2, Pd/BaSO4 3) H O CH OH 2 2 CO2H D-(-)-arabinose arabonic acid

274

1) HCN CHO CO2H 2) H , Pd/BaSO 2 4 H OH HNO3, H OH 3) H2O heat HO H HO H H OH H OH

CH2OH CO2H D-(+)-xylose xylonic acid CHO HO H Killiani-Fischer H OH synthesis

CH2OH D-(-)-threose

CHO CO2H HNO , HO H 3 HO H heat HO H HO H 1) HCN H OH H OH 2) H2, Pd/BaSO4 3) H2O CH2OH CO2H D-(-)-lyxose lyxonic acid

275

140 CHO CHO CHO CHO H OH HO H H OH HO H H OH H OH HO H HO H H OH H OH H OH H OH

CH2OH CH2OH CH2OH CH2OH D-ribose D-arabinose D-xylose D-lyxose

CHO CHO CHO CHO CHO CHO CHO CHO H OH HO H H OH HO H H OH HO H H OH HO H H OH H OH HO H HO H H OH H OH HO H HO H H OH H OH H OH H OH HO H HO H HO H HO H H OH H OH H OH H OH H OH H OH H OH H OH

CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH D-allose D-altrose D- glucose D-mannose D-gulose D-idose D-galactose D-talose

CO2H CO2H CO2H CO2H CO2H CO2H CO2H CO2H H OH HO H H OH HO H H OH HO H H OH HO H H OH H OH HO H HO H H OH H OH HO H HO H H OH H OH H OH H OH HO H HO H HO H HO H H OH H OH H OH H OH H OH H OH H OH H OH

CO2H CO2H CO2H CO2H CO2H CO2H CO2H CO2H

optically optically optically optically optically optically optically optically inactive active active active active active inactive active

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25.20: Epimerization, Isomerization and Retro-Aldol Cleavage.

O HO , OH HO , O H O From 2 H2O CH2CH3 CH2CH3 CH2CH3 C6H5 C6H5 C6H5 Ch 18.10 CH3 H CH3 H3C H

O OH O H H H C C C (R) (S) H OH OH HO , HO H HO , HO H HO H H2O HO H H2O H OH H OH H OH H OH H OH H OH

CH2OH CH2OH CH2OH D-glucose D-mannose

HO , H2O

CH2OH O HO H Fructose is a reducing sugar H OH (gives a positive Tollen’s test) H OH

CH2OH D-fructose

277

141 Retro- of carbohydrates

CH2OH CH2OH O O H O CH2OH H-B CH2OH HO H HO H H OH + O O H O H H O :B CH OH HO H CH2OH H OH 2 H OH CH2OH CH2OH D-Glyceraldehyde Dihydroxyacetone D-fructose

O H C CH2OH phosphoglucose phosphoglucose phosphofructo- H OH O isomerase 2- kinase O3POH2C O CH2OH HO H HO H HO H OH H OH OH H OH H OH 2- OH 2- CH2OPO3 CH2OPO3 !-D-fructofuranose- D-glucose-6-phosphate D-fructose-6-phosphate 6-phosphate

2- CH2OPO3 2-O POH C CH OPO 2- 3 2 O 2 3 O 2- aldolase aldolase CH2OPO3 CHO HO HO H O + H OH OH H OH 2- CH2OH CH2OPO3 OH H OH Dihydroxyacetone D-glyceraldehyde- 2- D-fructose- CH2OPO3 phosphate 3-phosphate 1,6-bisphosphate D-fructose- 1,6-bisphosphate 278 triose phosphate isomerase

25.21: Acylation and Alkylation of Hydroxyl Groups Acylation (ester formation): H3C O O O O HO O H3C O CH3 H C HO O 3 O HO OH O O HO O CH3 pyridine H3C O O O !-D-glucopyranose O CH3 Alkylation ( formation):

O H C HO H3CO Ag O, CH I H3CO + 2 3 H3O H CO H OCH3 HO O H CO 3 O HO 3 O H3CO OH H CO H3CO H 3 OCH3 H CO HO H CO 3 3 OH H OCH3 !-D-glucopyranose H OCH3 CH2OCH3

25.22: Periodic Acid Oxidation. The vicinal diols of

carbohydrate can be oxidative cleaved with HIO4. 279

142