Académique Documents
Professionnel Documents
Culture Documents
Introduc)on
During
the
rst
half
of
the
20th
century
most
syntheses
were
developed
by
selec;ng
a
commercially
available
star;ng
material
having
a
structural
resemblance
to
the
target
molecule.
Synthe;c
planning
in
most
of
the
cases
was
strongly
dependent
on
an
assumed
star;ng
point.
A?er
World
War
II
the
synthesis
of
a
series
of
complex
molecules
was
achieved,
propelled
by
the
availability
of
more
powerful
conceptual
processes
for
the
synthesis
planning
and
by
the
use
of
new
synthe;c
methods.
For
instance
the
total
syntheses
of
vitamin
A
(O.
Isler,
1949),
cor;sone
(R.B.
Woodward,
R.
Robinson,
1951),
morphine
(M.
Gates,
1956),
penicillin
(J.C.
Sheehan,
1957)
and
chlorophyll
(R.
B.
Woodward,
1960)
were
achieved.
The
striking
leap
forward
was
recognized
by
the
award
of
the
Nobel
Prize
for
chemistry
to
R.
B.
Woodward
(1965)
and
later
to
E.
J.
Corey
(1990),
the
father
of
retrosynthe;c
analysis.
Forward
synthesis:
the
actual
synthesis
from
the
star;ng
materials
to
the
TM.
Disconnec5on:
the
reverse
opera;on
to
a
reac;on;
the
cleavage
of
bond
aording
synthons.
Synthon:
an
idealized
fragment,
most
o?en
a
ca;on
or
anion,
resul;ng
from
the
disconnec;on
of
a
bond
Synthe2c
equivalent
(Reagent):
compound
used
in
prac;ce
for
a
synthon.
With
the
same
assump;on
(90
%
yield
per
step)
a
convergent
synthesis
with
the
same
amount
of
steps
would
have
an
overall
yield
of
73
%.
Purely
convergent
synthesis
is
idealized,
for
all
syntheses
un;l
some
degree
are
linear.
Disconnec)on
approach
A
key
concept
in
Coreys
disconnec;on
approach
is
the
synthon.
A
synthon
is
a
conceptual
en;ty;
it
does
not
have
to
exist
as
a
chemical
structure,
but
can
be
reconducted
to
reagents
with
the
corresponding
polarity.
Example 1
Example 2
Example 3
1,3-bifunc)onal
compounds
Various
1,3-bifunc;onal
compounds
can
be
made
from
ketone
1.
Disconnec;on
of
bond
2-3
leads
to
synthons
which
have
synthe;c
equivalents
set
up
for
an
aldol
reac;on.
1,4-bifunc)onal
compounds
Disconnec;on
between
2-3
leads
us
to
synthons,
which
do
indeed
have
synthe;c
equivalents,
but
are
not
compa;ble.
Alterna;ve
disconnec;on
between
1-2
leads
to
a
1,4
addi;on.
1,5-bifunc)onal
compounds
Disconnec;on
between
2-3
aords
synthons
set
up
for
a
1,4
addi;on.
The
same
subs;tu;on
pajern
can
be
obtained
from
subs;tuted
cyclopentadiene
with
ozonolysis.
Amines
Many
natural
products
and
synthe;c
targets
contain
amine
func;onality;
some
general
ways
to
introduce
it
in
the
molecule
are
depicted
below.
Amines
can
arise
from:
halides
via
displacement
with
an
azide
and
Staudinger
reduc;on;
ketones
or
aldehydes
via
reduc;ve
amina;on;
reduc;on
of
a
nitro
compound
and
from
amides.
Ketones
Ketones
can
arise
from
alcohols
via
oxida;on,
Weinreb
amides
via
1,2
addi;ons,
or
alkenes
via
ozonolysis.
Olens
Olens
can
be
made
from
ketones
or
aldehydes
via
Wimg
and
related
reac;ons,
alkynes
(reduc;ons),
and
other
olens
via
metathesis
or
cross
couplings.
Various
transforma;ons
can
also
be
preformed
with
olens
such
as:
hydrobora;on-
oxida;on
sequence
to
aord
an
alcohol
which
can
be
transformed
into
a
ketone
or
carboxylic
acid;
epoxida;on
and
opening
with
a
nucleophile
aords
1,2
disubs;tuted
compounds;
Diels-Alder
reac;ons
which
aords
cyclic
compounds
and
also
reduc;on
to
aord
alkanes.
Synthesis:
3
-kainic
acid
-kainic
acid
1
is
a
potent
agonist
for
glutamate
receptors
in
the
nervous
system
and
is
widely
used
in
neuroscience
as
neurodegenera;ve
agent
modeling
epilepsy,
Parkinsonss
disease
and
Alzheimers
disease.
Retrosynthesis:
Synthesis:
4
Penicillin
V
Penoxymethylpenicillin
(Penicillin
V)
is
a
penicillin
an;bio;c
which
is
orally
ac;ve
against
Gram-nega;ve
bacteria.
Its
total
synthesis
was
accomplished
in
the
late
1950s
by
John
C.
Sheehan.
Retrosynthesis:
Synthesis:
5
Prostaglandin
F2
:
The
rst
total
synthesis
of
Prostaglandin
F2
and
Prostaglandin
E2
was
reported
by
E.
J.
Corey
in
1969
(J.
Am.
Chem.
Soc.
1969,
91,
5675)
and
has
become
an
all-;me
classic
in
the
total
synthesis
of
natural
products.
The
highly
stereoselec;ve
synthesis
of
the
ve-
membered
core
was
accomplished
using
transforma;ons
on
a
norbornene
system.
Retrosynthesis:
Synthesis:
6
Dil)azem
Dil;azem
is
a
calcium
channel
blocker
used
as
a
drug
for
the
treatment
of
angina
pectoris.
It
reduces
the
heart
rate
without
aec;ng
the
force
of
contrac;on.
The
ability
of
these
drugs
to
dilate
peripheral
blood
vessels
also
makes
them
agents
for
hypertension.
Retrosynthesis:
Synthesis: