Disconnection approach to Synthesis

Illogical Two group disconnections I) 1,2-dioxygenated pattern

)-hydroxy carbonyl compounds B) 1,2-diols C) Illogical electrophiles

II) 1,4-dioxygenated pattern

A)1,4 Dicarbonyl compounds )-hydroxy carbonyl compounds

Disconnection approach to Synthesis - Illogical Two group disconnections

1,2-Dioxygenated pattern
) -hydroxy carbonyl compounds B) 1,2-diols C) Illogical electrophiles

-hydroxy carbonyl compounds

Retrosynthetic Analysis
H O Ph CO2H Ph O + Me
-

CO2H

CN

Synthesis
O Ph Me
-

CN H+ Ph

OH CN

NaOH H2O Ph

OH COOH

OH

CHO
CO2H CO2H
-CN

+ CO2H Br

1,3-diCO HCO2Et

+ CO2H

CO2H

Synthesis
1. EtOCH2(CO2Et)2 2.
Br

EtOCO2Et HCO2Et OH

3. etc. CHO CO2Et 1. CN 2. Hydrolysis CO2H CO2H

-

Ph Ph

OH OH OH

EtO2C OH

OH OHC

OH + CN-

Synthesis
CH2O CHO K2CO3 OHC OH 1. CN-

2. Hydrolysis

HO2C OH

OH

1. EtOH/H+ 2. PhMgBr

Ph Ph

OH OH OH

If the reaction between an aldehyde and cyanide is done in the presence of ammonia, the product is an -amino-nitrile:
NH3, CNR NH2 CH CN

RCHO

What is the intermediate being trapped by the cyanide ion?

NH3
NH2 NH2 CN R CH COOH

RCHO

RCH=NH
-

CH

CN

NH2 COOH

CNNH

CHO + NH3

Synthesis
NH3, CN-

NH2 COOH

CHO

This is the Strecker amino acid synthesis.

-hydroxy carbonyl compounds

Retrosynthetic Analysis
H O
+ A

O O

We need a reagent for an acyl anion synthon (A). Recall

Hg2+, H+ R H H2O R O

OH

O
O

Synthesis
1. Na, Liq NH3 2. acetone H OH Hg , H H2O O
2+ +

OH

OH

OH O

OH

OH

Synthesis
1. base, acetone

OH H H
2. base, acetone

O
Hg2+, H+ H2O

HO

The ether forms spontaneously from the tertiary alcohols in acid.

CHO
O O OH

O O

OH OH

Synthesis
1. Na, Liq NH3 2. acetone

OH

Hg2+, H+ H2O

OH O

CHO O O O OH

1,2-diols
Retrosynthetic Analysis
OH OH

wittig

Synthesis
O Mg-Hg benzene OH OH

OHOH Ph

FGI

O Ph
+

Ph3P+ Ph

Synthesis
Br Ph
Ph3P + PPh3 BuLi

Ph O

OsO4 or KMnO4

OHOH Ph

Ph

Illogical Electrophiles
O R O Ph O O Me
FGI

OH R

Br2

O Br R
+

O Ph OH Ph

O Br

Synthesis Since a-halo-carbonyl compounds are very reactive electrophiles, we can use a short cut:
O Ph
Br2 H
+

O Ph Br

NaOAc

O Ph O O Me

Illogical Electrophiles
The other main illogical electrophiles are epoxides, easily made from an olefin and per-acid, the usual one being m-chloroperbenzoic acid (MCPBA) a commercial product.
MCPBA

O R

What product would you get from this and sodium methoxide in methanol?

What product would you get from this and sodium methoxide in methanol?
O R
-

OR

MeOH R OMe

OH

OMe

OMe

In acid solution, the other regio isomer would be formed because the transition state has a partial positive charge on carbon stabilized by R:
+ OH

H O
(+)

R MeO

OH

R R
MeOH HOMe

PhCH2O

OH

FGI

Wittig

+ PhCH2O-

Synthesis
O
Ph3P=CH2 MCPBA

PhCH2OH Na

PhCH2O

OH

CO2H O O

CO2H HO H2OC
1,2-diO

H2OC

CH2CO2H +

1,5-diCO

Synthesis
O H+ O
-CH (CO Et) 2 2 2

acetone
hydrolysis decarboxylation H2OC O

EtO-

CN CNHO H2OC 1. NaOH, H2O 2. H+ O O

CO2H

Disconnection approach to Synthesis - Illogical Two group disconnections

1,4-Dioxygenated pattern
A) 1,4 Dicarbonyl compounds
) -hydroxy carbonyl compounds

1,4-Dicarbonyl compounds
Retrosynthetic Analysis
R O R O R A enolate anion O _ +
+

O R B "illogical" electrophile

O CO2Me

O
+

Br

CO2Me

Synthesis
O O + Br CO2Me CO2Me

The most acidic proton is the hydrogen next to the ester and the halide:
O Br H OMe O Br OOMe
-

Br O

CO2Me O

CO2Me

MeO-

To solve the problem:

We must use some means to make the ketone acts as the nucleophile in the initial condensation. One effective way is to convert it into an enamine.
H+ O R2NH R2NH H+
NR2

HO

+ NHR2

+ H2O

NR2

+ NR2
H

O CO2Me

O
+

Br

CO2Me

Synthesis
O NR2 Cl CO2Me

R2NH H+ + NR2 H+
CO2Me

O CO2Me

H2O

O O

Cl

Synthesis
O N H

Cl

O O

H+

O Br O O

EtO2C

EtO2C

Synthesis

Br2 HBr

EtO2C Br O
EtO-

EtO2C

-hydroxy carbonyl compounds

O Ph OH

O + O Ph

Synthesis
O R2NH H+ NR2 O H+/H2O OH Ph O Ph

O CO2Et OH O CO2Et O