0910 Sf Master Bloque1
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ASSIGNATURA 564520: Medicaments i nutrició / Drugs & nutrition Medicinal Chemistry (20h) Synthetic drugs (10h)-Part 1 MASTER ON DRUGS, COSMETICS AND FOOD QUALITY MASTER ON DRUGS, COSMETICS AND FOOD QUALITY Dr. Antonio Delgado Universitat de Barcelona October 2009
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Drug synthesis, Part 1
Transcript of 0910 Sf Master Bloque1
ASSIGNATURA 564520: Medicaments i nutrició / Drugs & nutrition
Medicinal Chemistry (20h)
Synthetic drugs (10h)-Part 1
MASTER ON DRUGS, COSMETICS AND FOOD QUALITYMASTER ON DRUGS, COSMETICS AND FOOD QUALITY
Dr. Antonio DelgadoUniversitat de BarcelonaOctober 2009
2
1. Introduction to drug synthesis: design and
strategies
2. Combinatorial synthesis: a high throughput
“hit-finding” strategy
3. Synthesis of single enantiomers
Synthetic drugs
3
Introduction to drug synthesis:Design and strategies
4
Drugs“Chemical compounds of known structure used for
therapeutic or diagnostic purposes”
Also commonly used for abused substances. Synonymous with medicine, pharmaceutical
Obtained by application of the principles and tactics of Organic Synthesis
Most of the drugs are synthetic organic compounds (carbon skeleton)
5
Common sources of drugs
• Total synthesis (around 70%)
• Isolation from natural sources (natural products)• Plants (alkaloids, enzymes, sugars….)• Animals (hormones, vaccines, enzymes,………• Algae, sponges, etc.
• Fermentation (antibiotics, amino acids, antibodies,
peptide hormones, etc.) • Chemical modification of natural products
(semisynthesis): steroids, β-lactam antibiotics, etc.
6
N
S CH3
CH3
O
H
COOH
HHN
bencilpenicilina(penicilina G)
O
penicilín acilasa
N
S CH3
CH3
O
H
COOH
HH2N
6-APA
COOH
ácido fenilacético
Semisynthesis
biotechnology
N
S
O
H2N
RCOOH/DCC*
O
CR Cl
O
CR N3
O
CR
O
CRO
base
base
N
S
O
HN
O
R
*DCC: N,N'-diciclohexilcarbodiimidaN C N
Et3N
7
• Construction of the carbon skeleton• Functional group transformations• Functional group protection• Stereochemical control (stereogenic
centers)
About synthetic sequences
Basic steps
8
About synthetic sequences Linear vs convergent synthesis
Linear synthesis
Convergent synthesis
AB ABC ABCD ABCDE
ABCDEF ABCDEFG ABCDEFGH
E
G
rendimiento de cada etapa 80%
rendimiento global:0,87 x 100 = 21%
A
B C D
F H
E G
AB EF GH
ABCD EFGH
ABCDEFGHrendimiento de cada etapa 80%
rendimiento global:0,83 x 100 = 51%
(80%)
(80%)
(80%)A B C D F H
CD
9
Construction of the carbon skeletonRetrosynthetic analysis
10
CH3
CH3C
OH
Nretrosíntesis
desconexión
CH3
CH3C
OH
N
sintones
CH3
CH3
O
reactivos
síntesis KCN
H
ReagentReal species
Synthon (“virtual”)Ionic or radical fragment arising from a disconnection
Construction of the carbon skeletonRetrosynthetic analysis:
Strategic disconnections and synthon generation
11
CE2
CX
PR2
OR
O
R
O
CH3Li / CH3MgBr
MgBr
NC CH2 CN
EtOOC CH2 COOEt
OR
O
R
O
Cl
Sintón Reactivo Sintón Reactivo
C1
CN
CH3
KCN
CH3Br
(CH3)3S Br
(CH3)2PCl
Equivalence between synthons and reagents
12
Reagents
MeR
O
N
R
O
HNNR
O
R
ON
NR
O
R
ON
Different disconnection approaches are possible for a single synthetic operation
Synthons
14
Guidelines for choosing a disconnection
15
Guidelines for choosing a disconnection
16
Transformación de grupos funcionalesQuimioselectividad
Una reacción quimioselectiva diferencia entre grupos funcionales identicos o de reactividad muy parecida
HO OH
MnO2
CH2Cl2, 2d OCHO
O OH
+
50% 25%
Ph
O
CHOBu4N BH(OAc)
Ph
O OH
PhH, 80ºC, 1d
3
17
Reacción no quimioselectiva
O
MeH
C N
CO2Me
LiAlH4, Et2O
-78ºC
OH
MeH
NH2
OH
18
Guidelines for choosing a disconnection
4
Two functional groups are involved in the same disconnection
Example of a 1,2-disconnection
19
Guidelines for choosing a disconnection
Example of a 1,3-disconnection
20
Guidelines for choosing a disconnectionOther 1,3-disconnections
21
Guidelines for choosing a disconnection
1,4-disconnections
22
Construcción del esqueleto carbonadoControl de la regioselectividad
HBrMeBr
1.BH32. Br2Br
O
Me
MeNa MeO, MeOH MeOH, H2SO4
Me
MeOMe
OHMe
MeOH
OMe
Eligiendo los reactivos adecuados se puede preparar el regioisómero que interesa
REGIOISÓMEROS Compuestos que difieren en la disposición de los sustituyentes
23
OHH
quirón
ClO
H
(R)-epiclorhidrina
ClO
H
(S)-epiclorhidrina
OH
CH2OH
H
H OH
HO H
HO H
CH2OH
D-manitol
Chirons contain chiral information of the target compound
Construction of the carbon skeletonRetrosynthetic analysis: Chiron: the chiral version of a
synthon
24
Algo del chiral pool: concepto y ejemplos
El “chiral pool”
25
El “chiral pool”
26
El “chiral pool”
27
• Construction of the carbon skeleton• Functional group transformations• Functional group protection• Stereochemical control (stereogenic
centers)
About synthetic sequences
Basic steps
28
29
Reduction of carbonyl derivatives
30
The versatility of acyl chlorides
31
• Construction of the carbon skeleton• Functional group transformations• Functional group protection• Stereochemical control (stereogenic
centers)
About synthetic sequences
Basic steps
32
Protecting groups
33
R1
O
NHH
P
NH
O
O
R2H
Y
R1
O
NH2
HNH
O
O
R2H
YR1
O
NHH
P
NH
OH
O
R2H
elongación
desprotección NHPdesprotección COOY
Protecting groups in peptide synthesisDirectionality in peptide bond formation
34
Protecting groups in peptide synthesisReactivity control
ROH
O
NH2
H
RO
O
NH3
H
zwitterion
R1 O
O
NH3
H
R2 O
O
NH3
H
R1 OH
O
NHH
P
R1 X
O
NHH
P
protección NH2
activación COOH
R2 O
O
NH2
HY
R1
O
NHH
P
NH
O
O
R2H
Y
protección COOH
AA1 AA2
35
CH3
CH3
CH3 N3
O
Cl O
O
Cl O
O
R NH2
R NH2
R NH2
NH
O
O
R
NH
O
O
R
NH
O
O
RCH3
CH3
CH3
CH3
CH3
CH3 O
O
O
O
O CH3
CH3
CH3
R NH2
R NH2
R NH2
TFA
H2 Pd/C
piperidina
(R-NHBoc)
(R-NHZ o R-NHCbz)
(R-NHFmoc)
Carbamates: amine protecting groups in peptide synthesis
36
CH3 S
O
O
Cl
cloruro de tosilo
Ph3C Cl
cloruro de tritilo
CH3 S
O
O
NH
Ph3C NH R
R Na/NH3 líquido
HOAc 80%
R NH2R NH2
Br
bromuro de bencilo NH R H2/Pd-C
Other amine protecting groups
37
Br
R C OH
O
R C O
OHCl seco
R C O
O
CH3
CH3
CH3
CH3 C O
O
CH3
CH3
CH3
/HCH2CH3
CH3
/ H
R C OH
OTFA
H2 /Pd-C
Carboxylic acid protecting groups
38
OR
OOR
RO
SiH3C CH3
CH3
H3C CH3
(ROTHP)(ROTBDMS)
(ROBn)
R OH
OR
(ROBz)
O
Bu4NF H+
H2 / Pd- C
TBDMSCl
BnBr / base
DHP / H+
BzCl / piridina HO-
Hydroxyl protecting groups
39
Protecting groups
40
• Construction of the carbon skeleton• Functional group transformations• Functional group protection• Stereochemical control (stereogenic
centers)
About synthetic sequences
Basic steps
41
Control de los centros estereogénicos
Reacción estereoselectiva: Se forma mayoritariamente un estereoisómero. Según la naturaleza del diastereómero que se forme, la
reacción será diastereoselectiva o enantioselectiva
diastereoselectiva
CH3
O
H
CH3
OH
CH3 (3:1, eritro/treo)CH3Li
H
O
(R)-oxinitrilasa CN
OH
99% eeRto.: 95%
enantioselectiva
42
Stereospecificity and Stereoselectivity
43
Examples of stereospecific reactions
SN2 and E2 reactions
44
Examples of stereospecific reactions
Alkene halogenation
Alkene epoxidation
45
Stereoselective reactions can bediastereoselective or enantioselective
Diastereoselective: one diastereoisomer predominatesEnantioselective: one enantiomer predominates
diastereoselective
CH3
O
H
CH3
OH
CH3 (3:1, eritro/treo)CH3Li
H
O
(R)-oxinitrilasa CN
OH
99% eeRto.: 95%
enantioselective
46
A model to predict the diastereoselectivity in carbonyl additions:The Felkin-Ahn model
47
Diastereoselective synthesis
48
Diastereoselective synthesis
Preferred hydride attack
49
Diastereoselective synthesisMicroorganisms as chiral reagents:
double diastereoselection
