5-membered rings (heteroatom n, o, s) · pdf file5-membered rings - electron rich ... pyrrole...
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![Page 1: 5-Membered rings (Heteroatom N, O, S) · PDF file5-membered rings - electron rich ... Pyrrole > thiophene > furan. 6-Membered rings (Heteroatom N) N ... Estrone in vivo HO H HH Estradiol](https://reader031.vdocuments.us/reader031/viewer/2022013120/5a9019387f8b9ac87a8e7ef8/html5/thumbnails/1.jpg)
Heterocycles (McM chapt 28)•Monocyclic or fused rings•Cont. one ore more ring atom ≠ C (normally O; N; S)•Aromatic, partly saturated or saturated ring(s)
5-Membered rings (Heteroatom N, O, S)
S
Thiophene
NH
Pyrrole
O
Thiophene
Other examples
N
NH
Imidazole
N
S
Thiazole
NH
Indole
NH
R'' NHR
R'R=HR'=CO2HR'''=H
Tryptophane
R=HR'=HR'''=OH
Serotonin R=AcR'=HR'''=OCH3
Melatonin
N
NH
N
N
NH2
Adenine(purine der.)
N
NH
H2N
R
R=CO2H: HistidineR=H: Histamine
N
S
N
NH3C
HO
H2N
CH3
Thiamin(Vit B1)
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X X X X X XX: S, Se
e- in d-orb.
Cyclopentadienyl anion
Thiophene
S
Criteria for Aromaticity (Hückel)(Monocyclic) ringPlanarNo of π-electrons in conjugation 4n+2 (n: 0, 1, 2,....)
S
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5-membered rings - electron rich - reactive i E-fil. Ar subst.
X+ E
XEH X
EH X
EH X E
X+ E
X
EH
X
EH
X E
React. in α-position generally preferredSelectivity not always goodReact.: Pyrrole > thiophene > furan
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6-Membered rings (Heteroatom N)N
Pyridine
Other examples
N
Quinoline
NN
Pyrimidine
N N
Pyridazine
Rare in nature
N
N
Pyrazine
NNH
NH2
O
Cytosine
N
Quinine
H3CO
HO
N
N
Ant pheremoneN N
HydralazineAntihypertensive drug
H2NHN
NH
H H
H H
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Pyridine as a base
N NH
+ H
NH
H H
H H
NH
H H
H H
H
pKa: 5.2
NH
pKa 0.4
NH
pKa 11.3
N
NH
pKa 7.1(≈amidine)
N
S
pKa 2.5
sp2 N less basic than sp3
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Electrophilic Reaction on Carbon: E-phil. Ar. Subs.
6-membered rings - electron deficient - ↓ reactivity
N
NE
N
HE
N
E
+ E
+ res. forms
•Both C and N may react•3/5 pos. most reactive C•Diazines less reactive•Sulfonation, Nitration, halogenatil•Not FC react.
N NH
NH
H NO2
N
NO2H / NO2 H / NO2
+ res. formsBenzo ring most reactiveMuch slower react. than naphthalene
N N N N N
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6-membered rings - electron deficient - reactive in Nu-fil. Ar subst.
N ClOMe
NOMe
Cl
+ res. form
N OMe
2 / 4 Pos. reactive; electron def. C, neg. charge partly on N in intermed3 / 5-Pos. much less reactive (benzenoid pos.)
Nucleophilic Aromatic Substitution
•SNAr
•SN1: Via arylic cation
•Benzyne
•SRN1: Involves radicals
•VNS: Vicarious nucl. Subst.
X Nu XNu
XNu
XNu
Nu
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Nucleosides, Nucleotides, Nucleic acids (DNA; RNA)
DNA bases
DNA Nucleosides
2-Deoxyribosides
RNA bases
HN
N
O
O
Thymidine
N
N
NH2
O
Deoxycytosine Deoxyadenosine
N
N N
NNH2
HN
N N
NO
H2NO O O O
OH OH OH OH
HO HO HO HO
Deoxyguanoosine
HN
NH
O
O
Thymin
N
NH
NH2
O
Cytosin Adenine
N
N NH
NNH2
Guanine
HN
N NH
NO
H2NHN
NH
O
O
Uracil
Cytosin Adenine Guanine
RNA Nucleosides
Ribosides
HN
N
O
O
Urinine
Cytosine
Adenosine
O
OH
HO GuanoosineOH
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Nucleotides
OO
XHO
B
P
OO
XO
B
P
OO
OHO
XO
B
OO
5'
3'
Double α-helix (DNA)A-T and G-C Base pairs
NN
O
O CH3
HN N
N HH
N
N
NN
O
N
N N
ON
N
H
NH
H
HH
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DNA
Procaryotes and eucaryotes
5'
5'3'
3'
Leading strandLagging strand
3' 5'
5' 3'
3' 5'
3'5'
Replication
Transcription
DNA polymerase
DNA
5'
5'3'RNA polymerase
DNA
5'
5'3'
3'5'
(+) stranded RNA
Translation
mRNA(+) stranded RNA
3'5'
Protein
3'5'
3'5'
Nucleotide sequence in DNA - genetic information
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DNA helicases: UnwindingDNA binding proteins: Prevents winding backDNA primase: formation of DNA/RNA primer (from free nucleosides in cell)DNA polymerase: Catalyse elongation of new strand (5’ - 3’)
Lagging strand:DNA ligase: Connects Okasaki fragments
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OO
O
T
P
OO
O
C
P
OO
OO
5'
3'Template strand
O O
OH
G
P
O O
O
A
P
OO
OO
5'
3'
New strandOO
O
T
P
OO
O
C
P
OO
OO
5'
3'Template strand
O O
OH
G
P
O O
OH
A
P
OO
OO
5'
3'
New strand
Next nucleotideGuanosine triphosphate
OPO
OO
O
OO
3'
DNA
5'
5'3' RNA polymeraseDNA
5'
5'3'
(+) stranded RNA3'5'
Uracil instead of thymine
Transcription: DNA - RNA
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Translation: RNA - Protein3 RNA bases coding for one AA (see Table 28.1)Protein synthesis occurs at ribosomes
mRNA(+) stranded RNA 5' 3'
50S
30S
Ribosom
Protein
NH3+
NH3+
CO2-
70S
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initiator tRNA
OH 3'
tRNA-Met
O SO
NH2
tRNA-fMet
O SO
HNO
mRNA30S ribosoe
O SO
HNO
3'mRNA
5'
30S initiator complex
AUG
50S ribosome
3'5' AUGU A C U A C AU C
U A C
O SO
HNO
U A C
Anticodon
Codon
3'
5'
fMet
U A C
A U G C G A G C U
3'
5'
fMet
U A C
A U G C G A G C U
Arg
G C U
3'
5' A U G C G A G C U
A-site
Arg
G C U
fMetRibosomewithP-site and A-site
3'
5'
U A C
A U G C G A G C U
Arg
G C U
fMet
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3'
5'
fMet
U A C
A U G C G A G C U
Arg
G C U
3'
5'
U A C
A U G C G A G C U
Arg
G C U
fMet
O SO
HNO
fMet
OHN
O
NH2Arg
NH
NH2 OH O
ONH
HN O
O
S
NH
NH2HN
Formyl groupProtection of N-terminal
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DNA / RNA Synthesis: Protecting groups and activating groups (cf. peptide synth)
OO
O
B
P
OO
O
B
OO
O
OO
HO
B
P
OHO
O
B
OON
NH3 / H2O[ox]
OO
O
B
P
OO
O
B
O
O
N
Phosphite Phosphate
acidcatalyst
OHO
O
BP
OO
O
B
O
O
NN
PO
O N
Phosphoramidite
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The Polymerase Chain Reaction (PCR, 1986)technique for quickly "cloning”(make many copies of) a particular piece of DNA in the test tube (rather than in living cells like E. coli).
primers: short oligonucleotides (ca 20 nucleotides) precisely complementary to the sequence at the 3' end of each strand of the DNA
DNA
5'
5'3'
3'
95 oC(denaturation)
5'
5'3'
3'
Addition of primers
5'
5'3'
3'
Taq polymeraseMg2+
Nucleoside-triphosphates
5'
5'3'
3'
Repeat cycle
4 copies
Repeat cycle
16 copies
ca 1011 copies in a few hours
Tac DNA polymerase: Heat stable enzymefrom Thermus aquaticus (bacteria)in hot springs Yellowstone Nat. Park
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Lipids (McM chapt 27)Naturally occuring, lipophilic comp.
•Wax, fat oils•Soaps•Phopholipids•Prostaglandins•Terpenoids•Stereoids
Wax, fat, oils: Derivatives of fatty acids (carboxylic acids)
O
OH
Ex saturated fatty acid: Stearic acid (C18)
O
OH
Ex unsaturated fatty acid: oleic acid (C18)
O
OH
linoleic acid (C18)
ΩΩ-6
Wax: esters between fatty acid and long chain alchohol
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Fat (solid), oil (liquid) - Soaps
Basic ester hydrol. - Saponifications
O
O Na
Hydrophilic headLipophilic tail
Ca 2+ - “Hard water” Ca(OCOR)2 (s)
Cationic soaps
O
O
OR
OR''
Triglycerides
NaOH (aq) OH
OH
OR
OR''
OR'
Glycerol
O
O
ONa
Na
Na
Soaps
HOOO
R'
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Phospholipids
Extracellular fluid
Intracellular fluid
Cell membranePassive diffusion: Small, lipophilic
O
O
OR
PO
Glycerophospholipids
OO
R'
R: saturated
R': unsatur.O
O (CH2)2NR3
R: H, Me
Diester Phosphoric acid
O PO
OO
R'O
O (CH2)2NR3
OO
R
Hydrophilic head
2 Lipophilic tails
Sphingomyelins
OHNH2OH
(CH2)12CH3
Sphingosine
O
NHCO(CH2)nCH3
OH
(CH2)12CH3
n: 16-24
PO
(CH2)2NH2R3O
coating of nerve fibers
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Prostaglandins etc
Subtypes COXCOX-1: Synth of essential prostagland.COX-2: Active only under inflamations
CO2H158
11 1420
Arachidonic acid
Cyclooksygenase(COX)5
15CO2H
O O
Prostglandin H2(PGH2)
Tromboxanes
Prostaglandines
Prostasyklines
Many different biolog. effectsInflamations, allergy responce
Inhib. by many pain killers
RofecoxibVioxx®
Avreg 2004
COX2/COX2: 35
SO
O
OO
COX2 inhibitorsCoxibes
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Prostaglandins etc
Subtypes COXCOX-1: Synth of essential prostagland.COX-2: Active only under inflamations
CO2H158
11 1420
Arachidonic acid
Cyclooksygenase(COX)5
15CO2H
O O
Prostglandin H2(PGH2)
Tromboxanes
Prostaglandines
Prostasyklines
Many different biolog. effectsInflamations, allergy responce
Inhib. by many pain killers
RofecoxibVioxx®
Avreg 2004
COX2/COX2: 35
SO
O
OO
COX2 inhibitorsCoxibes
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Terpenoids
O
Isopentenylpyrophosphate
(C-5)
P PO P PO
P
OOH
3 ATPOH
HO
OHOMevalonate(C-6)
N
N N
NNH2
OO
OHHO
PO
OHOP
O
OHOP
O
OHHO
ATP, Adenosine-5'-triphosphateP
C-10: MonoterpenesC-15: SesquiterpenesC-20: DiterpenesC-25: SesterterpenesC-30: Triterpenes
O
(+) Camphor α-Pinene β-Pinene
O
Isopentenylpyrophosphate
(C-5)
P PRearrange
O
Dimethylallylpyrophosphate
(C-5)
P P O P PH
O
trans-Geranylpyrophosphate
(C-10)
P P
OH
trans-Geraniol
OH
(-)−β-citronellol (-) Linalool
OH
OH(+)-α-Terpineol (-)-Menthol
HO
(+)-Carvone
O
OH
Thymol
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O
trans, trans-Farnesylpyrophosphate(C-15)
P P OPP+
tail to tail coupling
Squalene (C-30)
O
HO
Lanosterol
H
Squaleneepoxidase
Enzyme-Nu
H
HO H
H
Enz--Nu
H
Squalene epoxide cyclase
H
B All stereoids
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Stereoids
A B
C D1
2
34
5 678
910
1112
13
14 15
16
17 17β 17α
B / C og C / D always trans
10β
5α
A / B trans fused
10β
A / B cis fused
5α
Sex Hormones
H
HHO
Testosterone
OH
5α-reduktase H
HHO
5α-Dihydrotestosterone (5DHT)More active A-B ring transCis isomer inaktive
OH
H
H
HHOProgesterone
O
Many semisynth drugs in use (better bioavalabil.)
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HO
H
HH
O
Estrone
in vivo
HO
H
HH
Estradiol
OH
HO
H
HH
Estriol
OH
in vivo
(low activity)
(fast metabol)
OH
(low activity)
Used in drugs
HO
H
HH
OH
H K2 ekviv.
Ethinyl estradiol(only estrogen im P-pills)
Estrogens
Corticostereoids
Mineralcorticoid
O
H
H H
OOH O
OH
AldosteroneRegulation of elektrolyttic ballanceincrease re-uptake of Na (and hence H20)
GlucocorticoidH
H H
O
O
OH
HO OH
Hydrokortison
Effect on metabolism (karbohydrates, lipids, proteins)Antiinflammatoric
Numerous semisynth. analogs as drugsVarious antiinflam. activity, mineralcorticoid side effects