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Medicinal Chemistry: An Overview
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Lecture Date Topic 1 2015/12/17 General Aspects of Medicinal Chemistry 2 2016/01/07 General Biochemistry 3 2016/01/21 Principles of Chemical Synthesis 4 2016/02/04 Chemical Synthesis of Small and Complex Molecules 5 2016/02/18 Chemical Synthesis of Peptides 6 2016/04/07 Strategies for Discovery of Lead Compounds 7 2016/04/14 Structure Activity Relationship 8 2016/04/21 Spatial Organization, Receptor Mapping and
Molecular Modeling 9 2016/04/28 Pharmacokinetic Properties 10 2016/05/12 Legal and Economic Aspects of Drug Development
Course Outline
Retrosynthesis
2
Retrosynthesis is the process of working backwards from the target compound to readily available starting materials. The art of planning the synthesis of a target molecule is called retrosynthetic analysis.
Z X + Ya retrosynthetic
arrow
Ph O Ph
O
Ph OH Cl Ph
O
+
target molecule proposed starting materials
disconnection
Should the bond disconnections correspond to known reliable reactions? Disconnect next to the heteroatom for molecules joined together by an heteroatom Disconnect reactive groups first. Propose other disconnections.
! When doing retrosynthetic analysis, it is necessary to generate as many possible precursors, hence different synthetic routes, as possible.
targetmolecule
1st precursor A2nd precursor a
1st precursor B
1st precursor C
2nd precursor b
2nd precursor c
2nd precursor d
2nd precursor e
2nd precursor f
Retrosynthetic Analysis
3
Elias James Corey Nobel Prize in Chemistry (1990)
"for his development of the theory and methodology of
organic synthesis".
Synthons & Reagents
4
A synthon is an idealized fragment resulting from a disconnection while a reagent is a real chemical compound used in the synthesis. Synthons need to be replaced by reagents in the proposed synthesis.
Cl
OHClBr CH3
Cl
OCH3
ClNaOH
Synthesis
Retrosynthesis
Cl
OCH3
Cl
Cl
OCldisconnection H2C CH3+
synthons
Cl
OCl H2C CH3
Cl
OHCl
synthon reagent
Cl CH3 Br CH3 TsO CH3
synthon reagents
Acetylsalicyclic Acid (Aspirin)
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Retrosynthesis
Synthesis OH
NaOH
CO2
OH
OH
O
salicyclic acid
H3C O CH3
O O OH3C
O
OH
O
aspirin
OH3C
O
OH
O
OH
OH
OOH
Aspirin (pain reliever; anticlotting agent)
OH3C
O
OH
O
Ball-and-Stick Model Space-filling Model
Oseltamivir (Tamiflu)
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Oseltamivir is a neuraminidase inhibitor used for the treatment of influenza A and B viral infections.
Retrosynthesis
NH2
AcHN
O
Me
Me
CO2Et
Ball-and-Stick Model Space-filling Model
Synthesis of Intermediate 274
7
Synthesis of Oseltamivir
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Isolated from Pacific Yew tree Approved by the U.S. Food & Drug Administration in 1992 for treatment of several types of cancer, including breast cancer, lung cancer, and melanoma. An estimation: a 100-year old yew tree must be sacrificed in order to obtain 300 mg of Taxol, just enough for one single dose for a cancer patient. Obviously, synthetic organic chemistry methods that would lead to the synthesis of Taxol would be extremely useful.
Paclitaxel (Taxol)
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O
O
H3C OO
OH
OO
O
HO
NH
OH
OO
O
CH3
O
CH3CH3
H
H3C
Paclitaxel (Taxol)
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O
O
H3C OO
OH
OO
O
HO
NH
OH
OO
O
CH3
O
CH3CH3
H
H3C
Retrosynthesis of Taxol (1)
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Retrosynthesis of Taxol (2)
12
6
Synthesis of Hydrazone 11
13
Synthesis of Aldehyde 10
14
Racemic Synthesis of Intermediate 29
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Resolution of Intermediate 29 & Synthesis of Intermedate 33
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Synthesis of Taxol
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Summary
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Next Lecture, 2016/02/18
Chemical Synthesis of Peptides
The chemical syntheses of small and complex molecules are governed by similar principles. An extraordinary level of creativity is required for success in the chemical synthesis of a complex molecule. The synthesis of molecules is not a matured discipline.
