carbohydrates (mcm chapt 25) · monosaccharides / simple carbohydrates: can not be hydrolyzed to...
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Carbohydrates (McM chapt 25)
Glucose: C6H12O6 = “C6(H2O)6”
Monosaccharides / Simple carbohydrates:Can not be hydrolyzed to simpler carbohydrates
D-shugars
H OHCH2OH
OH
H OHCH2OH
OH
(R) Glyceraldehyde / D-glyceraldehyde
H OHH OH
CH2OHH OH
OH
RiboseAldopentose
Aldehyde 5 C
CH2OHO
HO HH OHH OH
CH2OH
FructoseKetohexose
Ketone 6 C
Open and cyclic forms
H OHHO HH OHH OH
CH2OH
OH
Aldehyde
HOOH
OH
CH2OH
OHOH O
OHOH
OH
CH2OH
OH
H
Hemiacetal
HOOH
OH
CH2OH
OHOH
O
OHOH
HOHOHOH2C
α-D-glucopyranose
O
OHHOHOHOH2C
OH
β-D-glucopyranose
Monosaccharides - ReactionsFunctional groups: Alchohols, aldehydes/ketones, hemiacetals
React like ROH
O
O
OPyridine
H3COCO OCOCH3
O OCOCH3H3COCO
CH3IAg2O
OCH3 OCH3
O OCH3H3CO
OH OH
O OHHO
β-D-ribofuranose
OH OH
O OHHO
β-D-ribofuranose
CH3OHacid
OH OH
O OCH3HO
+
OH OH
O
OCH3
HO
hemiacetal acetalMethyl β-D-ribofuranoside
Glycoside
Stereoselectivity in glycoside syntheses
+
HOOH
OH
CH2OH
OHOH
O
OHOH
HOHOHOH2C
α-D-glucopyranose
Minor
β-D-glucopyranose
MajorH
O
OHHOHOHOH2C
O
OHHOHOHOH2C
Stereochemical info lost
R-OH
AB
O
OOH
HOHOHOH2C
Alkyl α-D-glucopyranoside
Major
O
OHHOHOHOH2C
O
Alkyl β-D-glucopyranoside
Minor
R
R
O
OHHOHOHOH2C
OH
The anomeric effect
O
O
OO
RR
No lone-pair repulsjonAxial subst
Lone-pair repulsjonequatorial subst subst
Stereoselective synthesis of β-glycisides - Koenigs Knorr react
OOAc
OAcAcOAcO
OAcHBr O
BrOAcAcOAcO
OAc
O
OAcOAcO
OAc
OH3C
O
OAcOAcO
OAc
OH3C
R-OH
OO
OAcAcOAcO
OAc
R
Reduction of carbonyl:
HO O
OHHO OH
OH
D-glukose
HO OH
OHHO O
OH
D-glukose
NaBH4 HO OH
OHHO OH
OH
D-glusitol(sorbitol)
Oxidative reactions:“Reducing shugars”: Easily oxidized (most often aldeh. - acid)
HO O
OHHO OH
OH
HO OH
OHHO O
OH
D-glucose
mild oxHO
CO2HOH
OHHO
OH
HO O
OHHO O
OHCH3 no ox. under mild cond
Not "reducing shugar"
Hemiacetal Aldehyde
Acetal •Tollens•Fehling•Benedict [old diabetes (glucose) test]
Tests (visual results)Not used in synthesis (preparative scale)
Ketoses as “reducing shugars”
CH2OHOHHOHHHHOO
CH2OH
Fructoseketo - tautomer I
Base
CH2OHOHHOHHHHOOH
enol - tautomer
HO
Base
CH2OHOHHOHHHHO
O H
OH
keto - tautomer II
mild ox
CH2OHOHHOHHHHO
O OH
OH
Synthetically useful oxidations
OH
OH
An aldose
Aldehyde
prim alchohol
HNO3
OHO
OHO
Diacid
Br2
H2O, pH 6
OHO
OH
Only aldehyde oxidized
Chain Lengthening and Shortening
OH
An aldose
HCN
CN
H OH 1) H2 / cat.2) Hydrol. imine
CH OH
H O
n C-atoms n+1 C atoms
H2N-OH
CH OH
H NOH- H2O
Strong base
Monosaccharides / Simple carbohydrates:Can not be hydrolyzed to simpler carbohydrates
Disaccharides
Complex carbohydrates: Disacch., polysacch.Can be hydrol. to monosacch. (cleav. of acetal / hemiacetal)
O
OHHO
HO
OH
O
OHOHHO
O
OH
Maltose
1,4'-α-glycosideGlucose + glucose
1α 4'
O
OHHO
HO
OHO
OHOHHO
O
OH
Cellobiose
1,4'-β-glycosideGlucose + glucose
1β
4' O
OHHO
OH OHO
OHOHHO
O
OH
Lactose
1,4'-β-glycosideGalactose + glucose
1β
4'
hemiacetal aldehyde; "reducing shugar"
O
OHHO
HO
OH
O
Sucrose
1,2'-α-glycosideGlucose + fructose
1α 2'
O
OH
HO
OH
OH
No hemiacetal fuctionNot "reducing"
Milk intolerance
O
OHHO
OH OHO
OHOHHO
O
OH
Lactose
1,4'-β-glycosideGalactose + glucose
1β
4'
Not absorbet from intestinesAccumulation - diarrhea etc
Lactase
O
OHHO
OH OHO
OHOHHO
OH
Often missingadults
HOOH
galactase glucose
normal metabolism
No isomerisation:galactosemiaSevere milk intolerance (even kids)Mental retardation
Polysaccharides
CelluloseLong chains (>1000 monosachh.)H-bond between chainsStructural material - plantsβ-glycoside link., not digested humans
Starch: Amylose and amylopectin
O
OHHOO
OHO
OOH
HOO
OH
1β
4'O
OOH
HO
OH
O
OHHOO
OH
O
OHHO
O
OH1α 4'
O
OOHHO
O
OH
Amylose ca 20%
O
OHHOO
OH
O
OHHO
O
1α 4'
O
OOHHO
O
OH
O
OHHOO
OH
O
1α
6'
Branches(ca every 25. gluc.)
Amylopectin ca 80%
Energy storage plantsα-glycoside link., digested humans
Glycogen ≈ amylopectin, larger, more branchesEnergy storage animals
Synthesis Di- and Polysaccharides
Building from monosaccharides - Challenges•Regioselectivity•Stereoselectivity•Stability
O
HO
OH OHO
HO
OH OH
OHOH
Galactose Glycal from galComm. avail.
Cl Si
Base O
HO
OH O Si
O-silylationPrim OH
O
N N NN
Prot. as carbonate ester
O
O
OO Si
O
epoxidationi.e.mCPBA
O
O
OO Si
O
O
O
O
OOH
O
TBAF
ZnCl2
O
O
OO Si
O
OH
O
O
O
OO
1,6' β
Deprotection
O
HO
HOOH
OH
O
O
HO
HO
1,6' β
reduced, hydroxylated before deprotect
or couple again
Other carbohydrates
OH OH
O OHHO
β-D-ribofuranose
H OHOHH
H OHOH
H O
OH OH
ON
HO
N
O
NH2
RNA nucleosidei.e. cytidine
ribose
OH
O OHHOH H
OHHH OH
OH
H O
OH
ON
HO
N
O
NH2
DNA nucleosidei.e. deoxycytidine
Deoxyribose
(See also chapt 28)
N
N N
NNH2
O
ORHO
OP
O
OOH
P
OO
OHHO
N
OHO
O
NH2
N
N N
NNH2
O
ORHO
OP
O
OOH
P
OO
OHHO
N
OHO
O
NH2
NADH
H H
Nicotinamid adenine dinucleotide
NADR=H
R=Phosphate: NADP+, NADPH
N
N
N
NHH3C
H3C
O
OH OH
OHOHH
H
O P OO
OH
O
OHO O
HO OH
NN
N
N
NH2
FAD
N
HN
N
NHH3C
H3C
O
ORFADH2
Flavin adenine dinucleotide
DNA / RNA
OHO
OHOHOH
OH
Glucose
OCO2H
OHOOH
OH
UDP-Glucuronate
P P O
HO OH
N
NO
O
RXH
OCO2H
OHOHOH
X R
More hydrophilic metaboliteof RXH
Metabolism
N
N N
NNH2
O
OHHO
HO
Adenosine
O
O
O OH
CO2H
OH
HOOHHOOHO
O
OHNH2
OH
HO
OH
Amfotericin B(Legemiddel mot soppinfeksjon)
O
O
O
HOO
ON
HOHOHO
O
OO
OH
Erytromycin (Antibiotikum)
CO2H
H
O H
H
O
HO
O
OHCO2H
O
O
CO2HOH
HO
HO
Aglycone
GlycyrrhizinSaponin from liquorice (lakris) rootexpectorants (slimløsende) respir. tract infect.
From microorganisms:
Macromolecules - Glycoproteins / Glycopeptides
Amino Acids, Peptides etc (McM chapt 26)
CO2H
R
H2N
L−α-aminoacids(S)
H2NHN N
HCO2H
R
O R'
O R''
Tripeptide C-terminalN-terminal
-Resolution of racemic mixt.
-Enantioselective synthesis
R
CO2H
HN COR
-NH2 potected as amide
H2, chiral catalyst CO2H
NH2
R
after deprotect.
20 essential AA, table 26.1
Synthesis
R
CO2H
HN COR
-NH2 potected as amide
H2, chiral catalyst CO2H
NH2
R
after deprotect.PRh
PPh
Ar
Ar
Ph
H2NHN N
HCO2H
R
O R'
O R''
Tripeptide C-terminalN-terminal
Determination of peptide structure - Sequensing
-NMR-MS-X-Ray
Chemical methods (only primary structure)-Edman Degradation: Removes - determines N-terminal AA -Carboxypeptidase: Cleaves of C-terminal AA
Peptide Synthesisala + gly ala-gly Not: gly-ala, ala-ala or gly-gly
N-term C-term
•Selectivity•Protecting groups•Solution chemistry•Solid phase / automatization
H2N CO2H
gly
ROH, H+
H2N COOR
Protected as ester
Nucleophile in amide bond forming step
H2N CO2H
ala
NH
O
O
O
O O
O
O
Protected as carbamate (BOC)
C NN
DCC
OOH
NH
O
OO
O
N
HN
Generated in situGood leaving group
NH
O
OO
O
N
HN
H2N COOR
NH
O
OO
HN
HN
HNO
COOR
Deprot.step(s)
H2NO
HN CO2H
Merrifield:
NH
O
OO
OH
BOC PolystyreneSolid phase
Cl+ N
H
O
BOCO
OBase 1) Excess reagents washed off
2) CF3CO2H cleav. of BOC H2NO
O
DCC
NH
O
BOCO
OH
NH O
OOH
N
O
BOC1) Excess reagents washed off2) CF3CO2H cleav. of BOC
NH O
OO
H2N
DCC
NH
O
BOCO
OHR
HF
NH O
OHO
H2N
Synthesis of: peptides,peptidomimetica; mimics bioactivity of a peptide
more stabe, better bioavail. etc.
O OHHO
N
Morfin
O
OHN
OH
H2N
OH
HN H
NO
OO
NH
HO
NH
O
O
S
Met-enkefalin
Tyr N-terminalhos opiopeptider
Asp-Arg-Val-tyr-Ile-His-Pro-Phe-His-Leu
Angiotensin I
N-term C-termACE
Asp-Arg-Val-tyr-Ile-His-Pro-PheAngiotensin II
+ His-Leu
N
OO
HN
O
NH O
HN
HN
N
O O
H2N NH2
Arg
+Zn2
S
H2N NH2
Arg
Zn2+
O
N
OO
Kaptopril i ACE
Peptide / ProteinProteins are larger and may also contain non-peptide parts, has a biological function
Functions:•Enzymes, biocatalysts, metabolism•Cell signaling; hormones (i.e. insulin), reseptors•Imune system; antibodies•Transport; hemoglobin etc•Structure; ie keratin (hair, nails etc)
Structure•Primary: AA-sequence
•Secondary: 3D structure of segment of the protein (α-helix, β-sheets etc)
•Tertiary: 3D structure of the whole protein
•Quartenary: 3D stucture of an agregate of several proteins
mammalian hemoglobine4 protein subunits, each with one heme
Protein crystallography KJM3350/4350 + Structure of biological macromolecules KJM5310
Insulin: 51 AA,Titin: 26.926 AA (in muscle tissue)
"a peptide is an amino acid molecule without secondary structure; on gaining defined structure, it is a protein."