Medicinal Chemistry: An Overview

Course Outline
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

1
 Retrosynthesis
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+Y
a retrosynthetic
arrow

disconnection O
O

Ph Ph +
O Ph OH Cl Ph

target molecule proposed starting materials

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. 2

 Retrosynthetic Analysis

!  When doing retrosynthetic analysis, it is necessary to generate as

many possible precursors, hence different synthetic routes, as possible.

2nd precursor a
1st precursor A
2nd precursor b

2nd precursor c
target
1st precursor B
molecule
2nd precursor d

Elias James Corey

2nd precursor e Nobel Prize in Chemistry (1990)
1st precursor C "for his development of the
2nd precursor f
theory and methodology of
organic synthesis".

3
 Synthons & Reagents
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.

Retrosynthesis
Cl Cl

disconnection
Cl O Cl O + H2C CH3
CH3

synthons
Cl Cl

Cl OH Cl CH3 Br CH3 TsO CH3

Cl O H2C CH3

synthon reagent synthon reagents

Synthesis Cl
Cl
Br CH3
Cl OH Cl O
NaOH CH3 4
 Acetylsalicyclic Acid (Aspirin)
O
H3C
O
O

OH
Aspirin
(pain reliever; anticlotting agent)
Ball-and-Stick Model Space-filling Model
Retrosynthesis
O
OH OH
H3C
O
O
O
OH

OH
O
Synthesis H3C
O O
OH OH O
O O
NaOH H3C O CH3
CO2
OH OH
5
salicyclic acid aspirin
 Oseltamivir (Tamiflu)
Me

O CO2Et
Me

AcHN
NH2 Ball-and-Stick Model Space-filling Model
Oseltamivir is a neuraminidase inhibitor used for the treatment of influenza A and B viral infections.

Retrosynthesis

6
Synthesis of Intermediate 274

7
Synthesis of Oseltamivir

8
 Paclitaxel (Taxol)
O

O CH3
O NH O H3C O
OH
CH3
O
CH3
OH
H
HO
O O O
O
O
H3C

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. 9
 Paclitaxel (Taxol)
O

O CH3
O NH O H3C O
OH
CH3
O
CH3
OH
H
HO
O O O
O
O
H3C

10
Retrosynthesis of Taxol (1)

11
 Retrosynthesis of Taxol (2)

12
Synthesis of Hydrazone 11

13
Synthesis of Aldehyde 10

14
Racemic Synthesis of Intermediate 29

15
Resolution of Intermediate 29 &
Synthesis of Intermedate 33

16
Synthesis of Taxol

17
 Summary
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.

Next Lecture, 2016/02/18

Chemical Synthesis of Peptides

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