Cycloalkanes and Their Stereochemistry

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Carbohydrates

• Carbohydrate
• Broad class of polyhydroxylated aldehydes and
  ketones commonly called sugars
• Synthesized by green plants during photosynthesis
• Name derived from glucose
• Glucose was the first simple carbohydrate
  obtained in pure form
• Molecular formula of glucose, C6H12O6, was
  thought to be a hydrate of carbon, C6(H2O)6
• 50 of the dry weight of earths biomass
  consists of glucose polymers

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Carbohydrates

• Carbohydrates act as chemical intermediates by
  which solar energy is stored and used to support
  life on earth

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21.1 Classification of Carbohydrates

• Carbohydrates are classed as simple or complex
• Simple sugars , or monosaccharides
• Carbohydrates like glucose and fructose that
  cannot be converted into more simple sugars by
  hydrolysis
• Complex carbohydrates
• Made up of two or more simple sugars
• Sucrose is a disaccharide comprised of one
  glucose and one fructose
• Cellulose is a polysaccharide comprised of
  several thousand linked glucose units

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Classification of Carbohydrates

• Monosaccharides are classified as aldoses or
  ketoses
• -ose suffix designates a carbohydrate
• aldo- prefix identifies an aldehyde carbonyl
  group in the sugar
• keto- prefix identifies a ketone carbonyl group
  in the sugar
• Number of carbons indicated by the numerical
  prefix tri-, tetra-, pent-, hex-

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21.2 Depicting Carbohydrate Stereochemistry
Fischer Projections

• Fischer projections
• Suggested by Emil Fischer (1891)
• Method to project a tetrahedral carbon onto a
  flat surface
• Tetrahedral carbon represented by two crossed
  lines
• Horizontal lines come out of the page
• Vertical lines go back into page

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Depicting Carbohydrate Stereochemistry Fischer
Projections

• A Fischer projection of (R)-glyderaldehyde

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Depicting Carbohydrate Stereochemistry Fischer
Projections

• Rules for manipulating Fischer projections
• A Fischer projection can be rotated on the page
  by 180, but not by 90 or 270
• Only a 180 rotation maintains the Fischer
  convention by keeping the same substituent groups
  going into and coming out of the plane

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Depicting Carbohydrate Stereochemistry Fischer
Projections

• A 90 rotation breaks the Fischer convention by
  exchanging the groups that go into and come out
  of the plane
• A 90 or a 270 rotation changes the
  representation to the enantiomer

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Depicting Carbohydrate Stereochemistry Fischer
Projections

• A Fischer projection can have one group held
  steady while the other three rotate in either a
  clockwise or a counterclockwise direction
• Effect is to simply rotate around a single bond

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Depicting Carbohydrate Stereochemistry Fischer
Projections

• Three steps for assigning R,S stereochemical
  designations in Fischer projections
• Assign priorities to the four substituents in the
  usual way
• Place the group of lowest priority, usually H, at
  the top of the Fischer projection by using one of
  the allowed motions
• The lowest-priority group is thus oriented back
  away from viewer
• Determine the direction of rotation 1?2?3 of the
  remaining three groups and assign R or S
  configuration

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Depicting Carbohydrate Stereochemistry Fischer
Projections

• Carbohydrates with more than one chirality center
  are shown in Fischer projection by stacking the
  centers on top of one another
• By convention the carbonyl carbon is always
  placed at or near the top

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Worked Example 21.1Assigning R or S
Configuration to a Fischer Projection

• Assign R or S configuration to the following
  Fischer projection of alanine

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Worked Example 21.1Assigning R or S
Configuration to a Fischer Projection

• Strategy
• Follow the steps listed in the text
• Assign priorities to the four substituents on the
  chiral carbon
• Manipulate the Fischer projection to place the
  group of lowest priority at the top by carrying
  out one of the allowed motions
• Determine the direction 1?2?3 of the remaining
  three groups

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Worked Example 21.1Assigning R or S
Configuration to a Fischer Projection

• Solution
• The priorities of the groups are (1) NH2, (2)
  CO2H, (3) CH3, and (4) H
• To bring the lowest priority (H ) to the top we
  might want to hold the CH3 group steady while
  rotating the other three groups counterclockwise

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Worked Example 21.1Assigning R or S
Configuration to a Fischer Projection

• Going from first- to second- to third-highest
  priority requires a counterclockwise turn,
  corresponding to S stereochemistry

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21.3 D,L Sugars

• Glyceraldehyde
• Simplest aldose
• One chirality center
• Two enantiomeric (mirror-image) forms
• Only dextrorotatory enantiomer ()-glyceraldehyde
  occurs naturally
• ()-Glyceraldehyde has the R configuration
• (R)-()-glyceraldehyde is also referred to as
  D-glyderaldehyde (D for dextrorotatory)
• (S)-()-glyceraldehyde in also known as
  L-glyceraldehyde (L for levorotatory)

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D,L Sugars

• Virtually all naturally occurring monosaccharides
  have the same R stereochemical configuration as
  D-glyceraldehyde at the chirality center farthest
  from the carbonyl group
• In Fischer projections most naturally occurring
  sugars have the hydroxyl group at the bottom
  chirality center pointing to the right
• Such compounds known as D sugars

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D,L Sugars

• L sugars have an S stereochemical configuration
  at the chirality center farthest from the
  carbonyl group
• OH group pointing to the left in Fischer
  projections
• An L sugar is the mirror image (enantiomer) of
  the corresponding D sugar
• D and L sugars can be either dextrorotatory or
  levorotatory
• D and L designations only specify the
  stereochemical configuration at the one chirality
  center farthest away from the carbonyl group

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21.4 Configurations of the Aldoses

• Aldotetroses are four-carbon sugars with two
  chirality centers and an aldehyde carbonyl group
• 22 4 possible stereoisomeric aldotetroses
• Two D,L pairs or enantiomers named erythrose and
  threose
• Aldopentoses are five-carbon sugars with three
  chirality centers and an aldehyde carbonyl group
• 23 8 possible stereoisomeric aldopentoses
• Four D,L pairs of enantiomers named ribose,
  arabinose, xylose, and lyxose
• All but lyxose occur widely
• D-Ribose is an important constituent in RNA
• L-Arabinose is found in plants
• D-Xylose is found in both plants and animals

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Configurations of the Aldoses

• Aldohexoses are six-carbon sugars with four
  chirality centers and an aldehyde carbonyl group
• 24 16 possible stereoisomeric aldohexoses
• Eight D,L pairs of enantiomers named allose,
  altrose, glucose, mannose, gulose, idose,
  galactose, and talose
• D-Glucose from starch and cellulose and
  D-galactose from gums and fruit pectins occur
  widely in nature

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Configurations of the Aldoses

• Configurations of D-aldoses
• -OH groups on right side (R) or left side (L) of
  the chain

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Configurations of the Aldoses

• Remembering the names and structures
• of the eight D aldohexoses
• Set up eight Fischer projections with the CHO
  group on top and the CH2OH group at the bottom
• At C5, place all eight OH groups to the right (D
  series)
• At C4, alternate four OH groups to the right,
  four to the left
• At C3, alternate two OH groups to the right, two
  to the left
• At C2, alternate OH groups right, left, right,
  left
• Name the eight isomers using the mnemonic All
  altruists gladly make gum in gallon tanks.
• (Structures of the four D aldopentoses Ribs are
  extra lean.

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Worked Example 21.2Drawing a Fischer
Projection

• Draw a Fischer projection of L-fructose.

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Worked Example 21.2Drawing a Fischer
Projection

• Strategy
• Since L-fructose is the enantiomer of D-fructose,
  look at the structure of D-fructose and reverse
  the configuration at each chirality center.

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Worked Example 21.2Drawing a Fischer
Projection

• Solution

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21.5 Cyclic Structures of Monosaccharides
Anomers

• Aldehydes and ketones undergo a rapid and
  reversible nucleophilic addition reaction with
  alcohols to form hemiacetals
• Monosaccharides undergo intramolecular
  nucleophilic additions
• The carbonyl and hydroxyl groups of the same
  molecule react to form cyclic hemiacetals

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Cyclic Structures of Monosaccharides Anomers

• Glucose exists in aqueous solution primarily in
  the six-membered, pyranose ring form
• Results from intramolecular nucleophilic addition
  of the OH group at C5 to the C1 carbonyl group
• The name pyranose is derived from pyran
• Pyran is the name of the unsaturated six-membered
  cyclic ether
• Pyranose rings have chairlike geometry with axial
  and equatorial substituents

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Cyclic Structures of Monosaccharides Anomers

• Pyranose rings are drawn placing the hemiacetal
  oxygen at the right rear
• OH group of hemiacetal can either be on the top
  or bottom face of the ring
• Terminal CH2OH group is on the top face of the
  ring in D sugars and on the bottom face of the
  ring in L sugars
• When an open-chain monosaccharide cyclizes to a
  pyranose ring form a new chirality center is
  generated at the former carbonyl carbon
• The two diastereomers are called anomers and the
  hemiacetal carbon atom is referred to as the
  anomeric center

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Cyclic Structures of Monosaccharides Anomers

• Two anomers formed by cyclization of glucose
• The molecule whose
• newly formed OH
• group at C1 is cis
• to the oxygen atom
• on the lowest chirality
• center (C5) in a Fischer
• projection is the
• a anomer
• The molecule whose
• newly formed OH
• group at C1 is trans
• to the oxygen atom
• on the lowest chirality
• center (C5) in a Fischer
• projection is the
• b anomer

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Cyclic Structures of Monosaccharides Anomers

• Some monosaccharides also exist in a
  five-membered cyclic hemiacetal form called a
  furanose
• D-Fructose exists in both the pyranose and the
  furanose forms
• The two pyranose anomers result from addition of
  C6 OH group to the C2 carbonyl
• The two furanose anomers result from addition of
  C5 OH group to the C2 carbonyl

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Cyclic Structures of Monosaccharides Anomers

• Both anomers of D-glucopyranose can be
  crystallized and purified
• Pure a-D-glucopyranose
• Melting point 146 C
• aD specific rotation 112.2
• Pure b-D-glucopyranose
• Melting point 148-155 C
• bD specific rotation 18.7

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Cyclic Structures of Monosaccharides Anomers

• When a sample of either pure anomer of
  D-glucopyranose is dissolved in water its optical
  rotation slowly changes and reaches a constant
  value of 52.6
• The specific rotation of a-D-glucopyranose
  decreases from 112.2 to 52.6 when dissolved in
  aqueous solution
• The specific rotation of b-D-glucopyranose
  increases from 18.7 to 52.6 when dissolved in
  aqueous solution
• This change in optical rotation is due to the
  slow conversion of the pure anomers into a 37
  63 equilibrium mixture and is known as
  mutarotation

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Cyclic Structures of Monosaccharides Anomers

• Mutarotation of D-glucopyranose
• Mutarotation occurs by a reversible ring opening
  of each anomer to the open-chain aldehyde
  followed by reclosure
• Mutarotation is catalyzed by both acid and base

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Worked Example 21.3Drawing the Chair
Conformation of an Aldohexose

• D-Mannose differs from D-glucose in it
  stereochemistry at C2. Draw D-mannose in its
  chairlike pyranose form.

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Worked Example 21.3Drawing the Chair
Conformation of an Aldohexose

• Strategy
• First draw a Fischer projection of D-mannose
• Lay it on its side and curl it around so that the
  CHO group (C1) is toward the right front and the
  CH2OH group (C6) is toward the left rear
• Connect the OH at C5 to the C1 carbonyl group to
  form the pyranose ring
• In drawing the chair form raise the leftmost
  carbon (C4) up and drop the rightmost carbon (C1)
  down

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Worked Example 21.3Drawing the Chair
Conformation of an Aldohexose

• Solution

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Worked Example 21.4Drawing the Chair
Conformation of an Aldohexose

• Draw b-L-glucopyranose in its more stable chair
  conformation

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Worked Example 21.4Drawing the Chair
Conformation of an Aldohexose

• Strategy
• Its probably easiest to begin by drawing the
  chair conformation of b-D-glucopyranose
• Then draw its mirror-image L enantiomer by
  changing the stereochemistry at every position on
  the ring
• Carry out a ring-flip to give the more stable
  chair conformation
• Note that the CH2OH group is on the bottom face
  of the ring in the L enantiomer

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Worked Example 21.4Drawing the Chair
Conformation of an Aldohexose

• Solution

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21.6 Reactions of Monosaccharides

• Ester and Ether Formation
• Monosaccharides exhibit chemistry similar to
  simple alcohols
• Usually soluble in water but insoluble in organic
  solvents
• Do not easily form crystals upon removal of water
• Can be converted into esters and ethers
• Ester and ether derivatives are soluble in
  organic solvents and are easily purified and
  crystallized

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Reactions of Monosaccharides

• Esterification is normally carried out by
  treating the carbohydrate with an acid chloride
  or acid anhydride in presence of base
• All OH groups react including the anomeric OH
  group

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Reactions of Monosaccharides

• Carbohydrates are converted into ethers by
  treatment with an alkyl halide in the presence of
  base the Williamson ether synthesis
• Silver oxide (Ag2O) gives high yields of ethers
  without degrading the sensitive carbohydrate
  molecules

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Reactions of Monosaccharides

• Glycoside Formation
• Hemiacetals yield acetals upon treatment with an
  alcohol and an acid catalyst
• Treatment of monosaccharide hemiacetals with an
  alcohol and acid catalyst yields an acetal,
  called a glycoside

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Reactions of Monosaccharides

• Glycosides are named by first citing the alkyl
  group and then replacing the ose ending of the
  sugar with oside
• Glycosides are stable in neutral water and do not
  mutarotate
• Glycosides hydrolyze back to free monosaccharide
  plus alcohol upon treatment with aqueous acid
• Glycosides are abundant in nature
• Digitoxigenin used for treatment of heart
  disease

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Reactions of Monosaccharides

• Biological Ester Formation Phosphorylation
• Glycoconjugates
• Carbohydrates linked through their anomeric
  center to other biological molecules such as
  lipids (glycolipids) or proteins (glycoproteins)
• Constitute components of cell walls and
  participate in cell-type recognition and
  identification

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Reactions of Monosaccharides

• Glucoconjugate formation occurs by reaction of
  the lipid or protein with a glycosyl nucleoside
  diphosphate
• Glycosyl nucleoside diphosphate is initially
  formed by phosphorylation of monosaccharide with
  ATP to give glycosyl phosphate

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Reactions of Monosaccharides

• Reaction with UTP forms a glycosyl uridine
  5'-diphosphate
• Nucleophilic substitution by an OH (or NH2)
  group on a protein then gives the glycoprotein

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Reactions of Monosaccharides

• Reduction of Monosaccharides
• Treatment of an aldose or ketose with NaBH4
  reduces it to a polyalcohol called an alditol
• Reduction occurs by reaction of the open-chain
  form present in aldehyde/ketone
  hemiacetal equilibrium
• D-Glucitol, also known as D-sorbitol, is present
  in many fruits and berries and is used as a
  sweetener and sugar substitute

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Reactions of Monosaccharides

• Oxidation of Monosaccharides
• Aldoses are easily oxidized to yield
  corresponding carboxylic acids called aldonic
  acids
• Oxidizing agents include
• Tollens reagent (Ag in aqueous NH3)
• Gives shiny metallic silver mirror on walls of
  reaction tube or flask
• Fehlings reagent (Cu2 in aqueous sodium
  tartrate)
• Gives reddish precipitate of Cu2O
• Benedicts reagent (Cu2 in aqueous sodium
  citrate)
• Gives reddish precipitate of Cu2O
• (All three reactions serve as simple chemical
  tests for reducing sugars)

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Reactions of Monosaccharides

• Fructose is a ketose that is a reducing sugar
• Undergoes two base-catalyzed keto-enol
  tautomerizations that result in conversion to a
  mixture of aldoses (glucose and mannose)

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Reactions of Monosaccharides

• Br2 is a mild oxidant that gives good yields of
  aldonic acid products
• Preferred over Tollens reagent because alkaline
  conditions in Tollens oxidation cause
  decomposition of the carbohydrate

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Reactions of Monosaccharides

• Aldoses are oxidized in warm, dilute HNO3 to
  dicarboxylic acids called aldaric acids
• Both the CHO group at C1 and the terminal CH2OH
  group are oxidized

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Reactions of Monosaccharides

• Enzymatic oxidation at the CH2OH end of aldoses
  yields monocarboxylic acids called uronic acids
• No affect on the CHO group

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21.7 The Eight Essential Monosaccharides

• Humans need to obtain eight monosaccharides for
  proper functioning
• All are used for synthesis of glycoconjugate
  components of cell walls

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The Eight Essential Monosaccharides

• Fucose is a deoxy sugar
• The OH group at C6 is replaced by H
• N-Acetylglycosamine and N-acetylgalactosamine are
  amide derivatives of amino sugars
• The OH group at C2 is replaced by an NH2 group
• N-Acetylneuraminic acid is the parent compound of
  sialic acids

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The Eight Essential Monosaccharides

• All eight essential monosaccharides all
  synthesized from D-glucose
• Galactose, glucose, and mannose are simple
  aldohexoses
• Xylose is an aldopentose

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21.8 Disaccharides

• Cellobiose and Maltose
• Disaccharides contain a glycosidic acetal bond
  between the anomeric carbon of one sugar and an
  OH group at any position on another sugar
• A glycosidic bond between C1 of the first sugar
  and the OH at C4 of the second sugar is a common
  glycosidic link called a 1?4 link

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Disaccharides

• Maltose consists of two a-D-glucopyranose units
  joined by a 1?4-a-glycoside bond
• Maltose is the disaccharide obtained by
  enzyme-catalyzed hydrolysis of starch
• Cellobiose consists of two b-D-glucopyranose
  units joined by a 1?4-b-glycoside bond
• Cellobiose is the disaccharide obtained by
  partial hydrolysis of cellulose

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Disaccharides

• Maltose and cellobiose are both reducing sugars
  because the anomeric carbons on the right-hand
  glucopyranose units have hemiacetal groups and
  are in equilibrium with the aldehyde forms
• Maltose and cellobiose also exhibit mutarotation
  of a and b anomers
• Maltose is digested by humans and is fermented
  readily by yeast
• Cellobiose cannot be digested by humans and is
  not fermented by yeast

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Disaccharides

• Lactose
• Lactose is a disaccharide that occurs naturally
  in human and cows milk
• Lactose is a reducing sugar and exhibits
  mutarotation
• Lactose contains a 1?4-b-link between C1 of
  galactose and C4 of glucose

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Disaccharides

• Sucrose
• Sucrose is ordinary table sugar and is among the
  most abundant pure organic chemicals in the world
• Sucrose is obtained from sugar cane (20 sucrose
  by weight) or from sugar beets (15 sucrose by
  weight)
• Sucrose is a disaccharide that consists of 1
  equivalent of glucose and 1 equivalent of
  fructose
• 11 mixture often referred to as invert sugar
  because the sign of optical rotation inverts
  (changes) during hydrolysis from sucrose (aD
  66.5) to a glucose/fructose mixture (aD
  -22.0)
• Honeybees have enzymes called invertases that
  catalyze the hydrolysis of sucrose
• Honey is primarily a mixture of sucrose, glucose,
  and fructose

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Disaccharides

• Sucrose is not a reducing sugar and does not
  undergo mutarotation
• Glucose and fructose are joined by a glycoside
  link at the anomeric carbons of both sugars, C1
  of glucose and C2 of fructose

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21.9 Polysaccharides and Their Synthesis

• Polysaccharides are complex carbohydrates in
  which tens or even thousands of simple sugars are
  linked together through glycoside bonds
• Only one free anomeric OH on end of long
  polymeric chain
• Not reducing sugars
• Do not exhibit noticeable mutarotation
• Cellulose and starch are the two most widely
  occurring polysaccharides

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Polysaccharides and Their Synthesis

• Cellulose
• Cellulose consists of several thousand D-glucose
  units linked by 1?4-b-glycoside bonds like those
  in cellobiose
• Used by nature to impart strength and rigidity to
  plants
• Used commercially as raw material for cellulose
  acetate (acetate rayon) and cellulose nitrate
  (guncotton) the major ingredient of smokeless gun
  powder

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Polysaccharides and Their Synthesis

• Starch and Glycogen
• Starch is a polymer of glucose found in potatoes,
  corn, and cereal grains
• Monosaccharide units are linked by
  1?4-a-glycoside bonds like those in maltose
• Starch is separated into two fractions
• Amylose accounts for about 20 by weight of
  starch
• Amylopectin accounts for about 80 by weight of
  starch
• Amylopectin is nonlinear and contains
  1?6-a-glycoside branches approximately every 25
  glucose units

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Polysaccharides and Their Synthesis
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Polysaccharides and Their Synthesis
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Polysaccharides and Their Synthesis

• Starch is digested in the mouth and stomach by
  a-glycosidase enzymes which catalyze the
  hydrolysis of a-glycoside links but leave the
  b-glycoside links in cellulose untouched
• Humans can digest potatoes and grains but cannot
  digest grasses and leaves
• Glycogen is a polysaccharide that serves as
  long-term storage of energy for the human body
• Glycogen contains both 1?4 and 1?6 links

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Polysaccharides and Their Synthesis

• Polysaccharide Synthesis
• Glycal assemble method
• A glycal is an unsaturated sugar with a C1-C2
  double bond
• The C6 OH group is protected as a silyl ether
  (R3Si-O-R)
• The C4 and C3 OH groups are protected as a
  cyclic carbonate ester
• Carbons C1 and C2 are epoxidized

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Polysaccharides and Their Synthesis

• Treatment of the protected glycal with another
  glycal containing a free C6 OH group in the
  presence of ZnCl2 yields a dissacharide
• The dissacharide can be epoxidized and treated
  with a third glycal to yield a trisaccharide
• Process is continued to prepare a polysaccharide

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Polysaccharides and Their Synthesis

• Lewis Y hexasaccharide
• Synthesized complex polysaccharide
• Tumor marker that is currently being explored as
  a potential cancer vaccine

Gal
Gal
GlcNAc
Glc
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21.10 Cell-Surface Carbohydrates and
Carbohydrate Vaccines

• Small polysaccharide chains covalently bound by
  glycosidic links to OH or NH2 groups on
  proteins act as biochemical markers on cell
  surfaces
• If human blood from one donor type (A, B, AB, or
  O) is transfused into a recipient with another
  blood type the red blood cells clump together, or
  agglutinate
• Agglutination results from the presence of
  polysaccharide markers on the surface of the cells

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Cell-Surface Carbohydrates and Carbohydrate
Vaccines

• Types A, B, and O red blood cells each have their
  own unique markers, or antigenic determinants,
  and type AB red blood cells have both A and B
  markers

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Summary of Reactions

• Summary of Carbohydrate Reactions