Advanced organic synthesis lect 2

Advanced Organic Synthesis
Chem 640
Dr. Nabila Al-Jaber

1431-1432


Latent Polarity. 9
Think about some of the reactions we've looked at for carbonyl compounds:

2

Let, 2/11-10-2010


3

Let, 2/11-10-2010


10. Latent polarity in bifunctional compounds
Consider a 1,3-disubstituted molecule, e.g.

Latent Polarities:
O

starting from C=O

OH

δ−

O

δ+

δ−

δ+

Ph

δ−

Ph

O

starting from CΟΗ
δ+
4

OH

Let, 2/11-10-2010

OH

δ−

δ+

Ph


δ−

δ−

O

OH

δ+

δ−

O

δ+

OH

Ph

Ph

≡

O

+

PhCHO

Thus
O

O

base

O

O

PhCHO

Cross Aldol

Ph

Acidic protne

H 3O+
O

OH

O

Na2SO 4
Ph

TM

TM2
5

Ph

- H2O

Let, 2/11-10-2010


δ−
R

δ−

δ−

O

O

δ−

δ+

δ+

δ−

O

δ−

δ+

O

R

R

R

O

e.g.

+
R

O

O

NaOH

∴

O

R

R
R

6

O

Let, 2/11-10-2010

R


But what about 1,4-disubstitution?
δ−

O

O

δ+

δ−

δ+

δ−

δ−

δ+

δ−

δ+
O δ−

O
O
O

synthons
O

O
O

+ base
7

Let, 2/11-10-2010

?

equivalents


O

O

≡

δ−
δ + Br

O
O

O

base

Br

O

O
8

Let, 2/11-10-2010


The German word UMPOLUNG, meaning polarity reversal is used to describe

the situation where the polarity in a compound is deliberately changed to facilitate a
particular reaction.
reacts with
nucleophiles

δ
−

example:

O

δ
+

H

HS

SH

cat. BF3·OEt 2

um

p

u
ol

ng

OH
SH

S
H

- H2O

S

S

acidic proton
(pKa ~ 32)

H

n-Butyllithium

Let, 2/11-10-2010

S

reacts with
electrophiles

S

δ
−

Li

δ
+


11. Strategy in retrosynthesis
1) Consider

different possibilities.
2) Try a number of disconnections and FGI's.
3) Try to keep the number of steps down, and stick to
known & reliable reactions.
4) In real life, a synthesis has to be economically viable.
5) Whenever possible, go for a convergent route rather
than a linear one, as this will lead to a higher overall
yield

10

Let, 2/11-10-2010


ABCDEF

ABCD

+

ABCDE + F
ABCD + E

EF

linear

convergent

.eg

AB + CD , E + F

ABC + D
AB + C

A+B ,C+D
A+B
Linear vs. convergent synthesis assume 80% yields (optimistic!)

11

Let, 2/11-10-2010


Linear:
step 1

A
AB
approx
overall yield: 80%

2

ABC
64%

3

ABCD
51%

4

5

ABCDE
40%

ABCDEF

...10

32%

A...K
...10%

...15

A......P
...3.5%

Convergent
:

A

AB
ABCD

C
E

CD

A...K

EF

80%
12

ABCDEF
G...K
L...P
64%

51%
Let, 2/11-10-2010

A......P
40%

32%


12. Aim for the greatest simplification
1. make disconnections towards the middle of the molecule
(this is more convergent anyway)
2. disconnect at branch points
3. use symmetry where possible
eg. (towards the middle)
O

O

O

Ph

O

Ph

O

∴

O

O

base
Ph

13

MVK

O
Ph

methyl vinyl ketone
MVK
Let, 2/11-10-2010


)

e g . (at branc he s
O

O

CO 2Et

CO 2Et

Ph

Ph

O
O

∴

?

CO 2Et
Ph

CO 2Et
Ph

NaOEt
Br
O
CO 2Et
Ph

14

Let, 2/11-10-2010

)e g . (lo o k fo r s ymme try
O

O

O
HO

HO

self -condensation
O
O

O

O

NaOEt

HO

− H2O

O

Let, 2/11-10-2010


Alternatively, potentially reactive groups can be protected or masked so

they don't react, eg. reduction of an ester in the presence of a ketone
OH

O
HO
CO2Me
Ph

O

O

CO2Me

cat. TsOH

Ph

Ketal
(stable to
bases and
nucleophiles)

O

Ph

H3O+
OH

LiAlH4
Et2O

O
Ph

O
OH

Note that protection strategy requires two extra steps (must be efficient);
better syntheses minimise the use of protecting groups.
16

Let, 2/11-10-2010


Sometimes it helps the retrosynthesis
if you add a functional group to facilitate bond formation
(Functional Group Addition, FGA).
An example of this is acetoacetic ester synthesis:
O

O

O

OEt

O

≡

:Thus

O

FGA

O

O
CO2Et

discon.

Bu

discon.
CO2Et

CO2Et

SM, Ethylaceto acetate
17

Let, 2/11-10-2010


The s ynthe s is the re fo re is
O

O
CO2Et

O

NaOEt
CO2Et

MeI
CO 2Et

Acidic proton
NaOEt
BuBr

O

O
Bu

− CO2

CO2H
Bu

TM
18

Let, 2/11-10-2010

H3O+
∆

O
CO 2Et
Bu


13. Ring Closing Reactions
Synthesis of carbocyclic molecules
Same approach as to acyclic systems. The probability
of reaction between two functional groups is higher if:
a) reaction is intramolecular (faster reaction)
b) the distance between the two groups is shorter

e.g. Intramolecular alkylation:

19

Let, 2/11-10-2010


e.g. Intramolecular alkylation:
EtO2 C

CO 2Et

EtO 2C

EtO2C

CO2 Et

CO2 Et

X

∴

EtO2 C

EtO2C

CO 2Et

NaOEt

NaOEt
EtO2C

CO 2Et

BrCH2CH2CH2CH2Br

Br

H 3O +
COOH

Cyclopentanoic acid
20

Let, 2/11-10-2010

heat

CO2 E
t


Intramolecular acylation eg. the Dieckmann cyclisation;
especially good for 5-membered rings:
O

O

CO2Et

CO2Et

O

∴

NaO
CO2 Et

OEt

NaOEt
CO 2Et

EtO2 C

21

- NaOEt

Let, 2/11-10-2010

CO2Et


Condensation:
O

O

O

OH

OH

1-(2-methylcyclohex-1-enyl)ethanone

∴

O

O

O

O

t-BuOK

- H2O

nonane-2,8-dione
acidic proton
22

Let, 2/11-10-2010

OH


14. Medium and Large Rings (8-11 membered and 12+)
Intramolecular reaction is less favoured with bigger rings.
Often, high-dilution conditions and slow addition can be
used to suppress intermolecular reaction and hence
promote ring closure.
O

eg.
MeO2C(CH2)7CO2Me

NaH

ester added over
nine days

(CH2)6
CO2Me

similarly
O

EtO2C(CH2)14CO2Et

"

(CH2)13
CO2Et

23

Let, 2/11-10-2010


15. Cycloaddition reaction (Diels-Alder)
Generic reaction (in retrosyntheic terms):
X

X

electron rich

eg

CO2Me

electron poor

CO2Me

concerted reaction
24

X = EWG
(CHO, CO2R, CN)

Let, 2/11-10-2010


Unsymmetrical Diels-Alder reactions:

R

R

R
R'

R'

+
R'

Minor product

Major product

R'

R

R

R

R'

+
R'

Major product

25

Let, 2/11-10-2010

Minor product