Advanced organic synthesis lect 2

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... ≡ O

Advanced Organic Synthesis

Chem 640

Dr Nabila Al-Jaber

njaber@ksu.edu.sa

1431-1432

9 Latent Polarity

Think about some of the reactions we've looked at for carbonyl compounds:

Let, 2/11-10-2010 3

10 Latent polarity in bifunctional compounds

Consider a 1,3-disubstituted molecule, e.g

O

PhOH

O

PhOH

But what about 1,4-disubstitution ?

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.

example:

H O

um po

lu ng

H

S S

Li

S S

reacts with electrophiles

acidic proton (pKa ~ 32)

OH

- H2O

Let, 2/11-10-2010

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

yield

Let, 2/11-10-2010 11

A step 1 AB 2 ABC 3 ABCD 4 ABCDE 5 ABCDEF 10 A K 15 A P

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)

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

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

Ph

CO2Me

Ketal

(stable to bases and nucleophiles)

O O

≡

O

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:

Thus

:

CO2Et Bu

The s ynthe s is the re fo re is

O

Bu

O

CO2Et Bu

CO2Et O

NaOEt BuBr

NaOEt

O

CO2H Bu

Acidic proton

TM

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:

EtO2C CO2Et EtO2C CO2Et EtO2C CO2Et

X

∴

EtO2C CO2Et

NaOEt BrCH2CH2CH2CH2Br

COOH

e.g Intramolecular alkylation:

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

EtO2C(CH2)14CO2Et (CH2)13

CO2Et

O

"

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.

eg.

similarly

15 Cycloaddition reaction (Diels-Alder)

Generic reaction (in retrosyntheic terms):

Unsymmetrical Diels-Alder reactions:

note that the 1,3-disubstituted product is the minor

product in both cases

16 Disconnections & Functional Group Interconversion in Aromatic Systems

Some reactions used in aliphatic systems don't apply for aromatic systems

(S N 1 and S N 2 reactions, for example, are extremely unfavourable for ArX

In planning synthesis of polysubstituted aromatics,

the order of reactions is important to ensure that the reagents are compatibleand to take advantage of the directing effect of existing substituents:

deactivating

(more)

(more) note that ortho/para- mixtures can be

*

17 Birch Reduction

Partial reduction of aromatic systems by (usually) sodium in liquid ammonia.

It's an example of dissolving metal reduction

Such methods used to be quite popular but most applications have been replace by modern hydride reagents

Dissolving metal reduction does still have it's uses thoughand the Birch reduction is one of them, (also recall the specific reduction of

alkynes totrans-alkenes).

The typical conditions involve liquid ammonia (bp −33 °C) and

sodium metal,in the presence of a proton source (usually an alcohol, EtOH).

18 Fusing Rings onto aromatic systems

The classical Hayworth naphthalene synthesis

The fused aromatic system is formed by dehydration of a tetralin intermediate, which is prepared from an existing benzene ring and succinic anhydride

O

+

O O

O

i) SOCl2ii) AlCl3

O

tetralone

R R

i) RMgx ii) H3O+

Dehydrogenation

Let, 2/11-10-2010

19 Blocking positions in aromatic rings

Functional groups that are introduced reversibly, or can be easily cleaved under mild condtions, can be used to access otherwise hard-to-make compounds

You have to know the terminology of

stereochemistry

a) Chiral, achiral compounds

.

b) Stereogenic, nonstereogenic centers

.

c) Enantiomers, diastereomers

.

d) Prochiral, prostereogenic

.

e) Enantiotopic, diastereotopic atoms and faces

f) Ways of drawing stereochemistry

ii For cyclic structures, cis and trans

iii threo and erythro (very old-fashioned