ERASMUS Intensive Program

SYNAPS: Synthesis and Retrosynthesis in the Chemistryof Natural Products

July 2011

NATURAL PRODUCT CHEMISTRY

Module 2 Retrosynthetic Approaches Towards the Synthesis of Natural Products

DEPARTMENT OF CHEMISTRYUNIVERSITY OF CRETE

Lifelong Learning Program – ErasmusHellenic National Agency LLP-Ι.Κ.Υ.

INTRODUCTIONBased on: S. Warren Organic Synthesis: The Disconnection Approach,

Wiley: New York, 1982

• Chemists synthesize compounds in just about every organic chemistry laboratory in the world.•  • Industrial chemists synthesize pharmaceuticals, polymers (plastics), pesticides, dye stuffs, food

colorings and flavorings, perfumes, detergents and disinfectants.•  • Research chemists synthesize natural products whose structure is uncertain, compounds for

mechanistic investigations, possible intermediate in chemical and biological processes, thousands of potential drugs used in medical practice, and even compounds which might themselves be useful for organic syntheses.

•  • Before and during these syntheses, groups of chemists sitting around blackboards or piles of

paper plan the work they are about to undertake. Possible routes are drawn out, criticized, modified again when the behavior of the compounds in the flask turns out to be different from what was expected, until finally success is achieved.

•  • The aim of this lecture is to show how this planning is done: to help you learn the disconnection

or synthon approach to organic synthesis. •  • This approach is analytical: we start with the molecule we want to make (the target molecule)

and break it down by a series of disconnection into possible starting materials.

Classifications in Synthetic Methodology Based on “Lecture Notes, Modern Organic Synthesis” by Dale L. Boger at The Scripps Research Institute, TSRI Press, La

Jolla, CA, 1999

Classifications in Synthetic Methodology 

Classifications in Synthetic Methodology

Retrosynthesis or Retrosynthetic Analysis

ROUTINE FOR DESIGNING A SYNTHESIS

• ANALYSIS 

1. Define the target molecule2. Recognize the functional groups in the target molecule3. Disconnect using as a guide methods corresponding to known reactions4. Repeat the Retrosynthetic Analysis till you reach available starting materials

• SYNTHESIS

1. Write down a synthetic scheme based in the Retrosynthetic Analysis adding reagents and reaction conditions.

2. If the synthesis fails, modify the synthetic scheme based on the failures/successes in the laboratory experiments.

SYNTHONS AND REAGENTS • During the retrosynthetic analysis of compound 2 the retrosynthetic cleavage (or

disconnection) leads to a nucleophile(-) and an electrophile (+). The correct alternative, based in known chemical transformations, is in this case leading to 3 and 4.

O

MeO

a

b

MeO

MeO

O

O

43

After the right choice has been made, the synthons may be converted retrosynthetically in to the corresponding reagents.

O

MeO

MeO

O

MeO

O

H

Cl

SYNTHONS REAGENTS

ONE GROUP DISCONNECTIONSBased on: S. Warren Organic Synthesis: The Disconnection Approach,

Wiley: New York, 1982

1.1   Carbonyl derivatives R(C=O)Xa . C a r b o n y l d e r i v a t i v e s R ( C = O ) X D e r i v e d f r o m t h e c o r r e s p o n d i n g c a r b o x y l i c a c i d s o r t h e i r d e r i v a t i v e s .

R C l

O> > >

R O R '

O O

R O R '

O

R N R ' 2

O

E x a m p l e : R e t r o s y n t h e s i s o f P o p a n i l , a w e e d k i l l e r u s e d i n t h e r i c e f i e l d s :

S y n t h e s i s :

HN

Cl

Cl

O

Cl

O+

NH 2

Cl

Cl

F G I

NO 2

Cl

ClCl

Cl

C- N C- N

Cl

Cl

NO 2

Cl

Cl

NH 2

Cl

Cl

H N O 3H 2 S O 4

H 2 , P d / C E tCOCl P R O P A N I L

a . A l c o h o l s , E t h e r s , A l k y l H a l i d e s a n d S u l f i d e s

RORRS R

RS H

R H a l

RX

ROH

R N u

R X = R B r o r R O T s o r R O M s

Cl

Cl

NO 2

Cl

Cl

NH 2

Cl

Cl

H N O 3H 2 S O 4

H 2 , P d / C E tCOCl P R O P A N I L

TWO GROUP DISCONNECTIONS

2.1. 1,1 Difunctionalized Compounds 2.1.1. Acetals

OMe

OMeOMe O + 2 MeOH

2.1.2. Cyanohydrines

OH

CNOH O + HCNCN+

2.1.3 Amino Acids: Strecker Synthesis

R

H

COOH

NH2NH2 O +

HCN

CN+

R

H

CN

NH2

NH3

FGI

TWO GROUP DISCONNECTIONS2.2 1,2-Difunctionalized Compounds 2.2.1 Alcohols

PhCl

PhOH PhMgBr

O+

Example

O

HN

O

C-O

OH

HN

O

OH

OH

NH2

O

O+

i. Carbonyl Compounds

NuR

O Nu- +R

OHal

R

O

Example: 2,4-D

Cl Cl

O COOH

Cl Cl

OHCl COOH

OH

Synthesis of 2,4-D

Cl COOH

OH Cl2, Fe

Cl Cl

OHNaOH

Cl Cl

O COOH

TWO GROUP DISCONNECTIONS

2.3 1,3-Difunctionalized Compounds 2.3.1 beta-Hydroxycarbonyl Compounds (Aldol Condensation)

OH

CHO

O

H

O

H

O

H+

 2.3.2        Unsaturated Carbonyl Compounds (Aldol and Dehydration) 

O2N

CHO

O2N

CHO

OH

O2N

CHO

CH3CHO+

Bull. Chem. Soc. Jap. 1952, 25, 54

TWO GROUP DISCONNECTIONS

2.3.3.      1,3-Dicarbonyl Compounds (Claisen-Type Reactions)

O O O O O

+

Example

PhO

Ph

O O

aba

b

Ph Ph

OEtO O

O

PhOEt

O

O

Ph

O

+

+

Pathway b is a self-condensation of ethyl phenylacetate.

TWO GROUP DISCONNECTIONS

2.4 1,4-Difunctionalized Compounds2.4.1   2.4.1      1,4-Dicarbonyl Compounds (Enolates and Halocarbonyls)

RR'

O

O

R

O

R'

O

BrR'

O

+

Example

O

Br

O

O

O

O

+

Practically the synthesis involves the Stork enamine

methodology.

O

NH

NBr

O N

O

H2O

O

O

G. Stork et. al. J. Am. Chem. Soc., 1963, 85, 207

TWO GROUP DISCONNECTIONS

• 2.4.2       Hydroxy Carbonyl Compounds (Enolates and Epoxides)

C6H13

O

OH

C6H13

O

OH

O+

TWO GROUP DISCONNECTIONS• 2.5 1,5-Difunctionalized Compounds• 2.5.1. 1,5-Dicarbonyl Compounds (Michael Reaction) 

H

O

Ph

O O

Ph

H

O+

There are two alternative disconnections in this case

R R'

O OR

O

R'

O

a b

R

O

R'

O

a

b

+

+

Sometimes the disconnection is easy to choose.

Example

O OCOOEt O

O

COOEt

O

EtO OEt

O

++

TWO GROUP DISCONNECTIONS

• 2.6 1,6-Difunctionalized Compounds

• 2.6.1. 1,6-Dicarbonyl Compounds (Ozonolysis of Cyclohexenes)

R

R

RR

O

O

Example

OMeOMeOMe

OO

OMe

OHO

3. Regioselectivity

3.1 Regioselective Alkylation of Ketones

R1 R2

OMe I

?

R1 R2

O

R1 R2

O

Me

Me The use of Activating Groups Analysis

O O

Br

O

X

Synthesis

CO2Et

O

EtO-Na+

PrBr

O

CO2Et

EtO-Na+

Br

O

CO2Et

1. OH-

2. H+3. Q

O

3. Regioselectivity3.2 Regioselectivity in Michael Additions

R1 R2

O

R1 R2

O

R1 R2

Nu- ?

HO Nu

Nu

Mechanistic Principles  1. Michael products are the thermodynamic products since the more stable C=O bond

is preserved and the weaker C=C bond reacts. 2. Direct addition is more easily reversed than the Michael addition. Therefore, the

more stable the Nucleophile the more the Michael addition is favored. 3. Kinetically the C=O carbon is the hard site and the beta carbon is the soft one.

Therefore, RLI, NH2-, RO-, H-, attack on the carbonyl and RMgBr, R3N, RS-, and stable carbanions tend to give the Michael type products.

 

3. Regioselectivity in Michael Reactions

Analysis O O O

Synthesis

Br1. BuLi

2. Cu(I)Cl)2CuLi

O

O

4. Chemoselectivity

4.1 The Problems:

1. Relative reactivity of two different Functional Groups

NH2

HO

Ac2OHN

OHO

2. Reaction of one of two identical Functional Groups

OH

HO

OMe

HO

base

Me I

3. Reaction of a group that may react again. S2- + RBr RS- + RBr RSR

4. Chemoselectivity

4.2 The solution to the problems: Guideline 1: When the two groups are of unequal reactivity, the more reactive can be made to react alone. Paracetamol: Analysis

HN

OHO

NH2

HO

NO2

HO HO

C-N FGI C-N

4. Chemoselectivity

Guideline 2: When a functional group may react twice, the

reaction is successful only when the first product is less

reactive that the starting material.

Analysis

O Cl

O

OH

Cl

O

Cl Synthesis

OH Cl

O

Cl O Cl

O

O O

O

The reaction does not proceed to a second step since the intermediate is stabilized by the resonance effect

4. Chemoselectivity

Guideline 3: The above cases could be solved by the use of protective groups.

R

COOHH2N O Cl

O

+ O

O R

COOHNH

Again, the intermediate is stabilized by the resonance effect

NO2 NO2

NO2

NO2

NH2HNO 3

H2SO4NaHSMeOH

90%

4. Chemoselectivity

Guideline 4: One of the two identical groups may react if the first product is less reactive than the starting material.

NO2 NO2

NO2

NO2

NH2HNO 3

H2SO4NaHSMeOH

90%

4. Chemoselectivity

Guideline 5: One of the two identical groups may react with one equivalent of reagent using the statistical effect.

HO OH HO O- HO OEtEtBrNa/xylene

I don’t think so!!!

4. Chemoselectivity

Guideline 6: Use a derivative of the two identical groups which can react only once.

COOH

COOH

O

O

O

COOMe

COOH

COOMe

COCl

SOCl 2Me OHAcOAc

Guideline 7: When the two groups are almost but not quite identical, avoid attempts to react only one of them.

4. Chemoselectivity

Guideline 7: When the two groups are almost but not quite identical, avoid attempts to react only one of them.