ERASMUS Intensive Program
SYNAPS: Synthesis and Retrosynthesis in the Chemistry
of Natural Products
July 2011
NATURAL PRODUCT CHEMISTRY
Module 2
Retrosynthetic Approaches Towards the Synthesis of Natural Products
DEPARTMENT OF CHEMISTRY
UNIVERSITY OF CRETE
Lifelong Learning Program – Erasmus
Hellenic National Agency LLP-Ι.Κ.Υ.
INTRODUCTION
Based on: S. Warren Organic Synthesis: The Disconnection Approach,
Wiley: New York, 1982
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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
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ANALYSIS
1.
2.
3.
4.
Define the target molecule
Recognize the functional groups in the target molecule
Disconnect using as a guide methods corresponding to known reactions
Repeat the Retrosynthetic Analysis till you reach available starting materials
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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
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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
O
a
MeO
MeO
4
3
b
O
MeO
After the right choice has been made, the synthons may be converted
retrosynthetically in to the corresponding reagents.
H
O
MeO
MeO
O
MeO
SYNT HONS
O
Cl
REAGENTS
ONE GROUP DISCONNECTIONS
Based on: S. Warren Organic Synthesis: The Disconnection Approach,
Wiley: New York, 1982
1.1 Carbonyl derivatives R(C=O)X
a. Carbonyl derivatives R(C=O)X
Derived from the corresponding carboxylic acids or their derivatives.
O
O
O
O
>
R
>
R
Cl
O
O
R'
>
R
OR'
R
NR' 2
Example: Retrosynthesis of Popanil, a weed killer used in the rice fields:
O
NO 2
NH 2
HN
O
FGI
+
C-N
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
C-N
Synthesis:
NO 2
HNO3
H2SO4
Cl
H2, Pd/C
Cl
Cl
NH 2
EtCOCl
Cl
Cl
Cl
PROPANIL
Cl
Cl
Cl
Cl
Cl
Cl
a. Alcohols, Ethers, Alkyl Halides and Sulfides
ROR
ROH
RSR
RX
RNu
RSH
RHal
RX= RBr or ROTs or ROMs
TWO GROUP DISCONNECTIONS
2.1.
1,1 Difunctionalized Compounds
2.1.1. Acetals
OMe
OMe
O
+
2 MeOH
OMe
2.1.2. Cyanohydrines
CN
OH
+ CN
O +
HCN
OH
2.1.3 Amino Acids: Strecker Synthesis
H NH 2
R COOH
FGI
H NH 2
R CN
HCN
NH 2 + CN
O +
NH 3
TWO GROUP DISCONNECTIONS
2.2
2.2.1
1,2-Difunctionalized Compounds
Alcohols
Cl
Ph
OH
Ph
PhMgBr
O
+
Example
H
N
H
N
C-O
O
NH 2
OH
OH
OH
O
O
+
O
O
i. Carbonyl Compounds
Nu
O
O
O
Nu-
+
Hal
R
R
R
Example: 2,4-D
O
COOH
Cl
Cl
Cl
OH
OH
COOH
Cl
Cl
Synthesis of 2,4-D
OH
OH
Cl 2, Fe
Cl
Cl
O
NaOH
Cl
COOH
Cl
Cl
COOH
TWO GROUP DISCONNECTIONS
2.3
2.3.1
1,3-Difunctionalized Compounds
beta-Hydroxycarbonyl Compounds (Aldol Condensation)
OH
O
O
+
CHO
H
H
2.3.2
O
H
a, b-Unsaturated Carbonyl Compounds (Aldol and Dehydration)
O2N
O 2N
O2N
+
CHO
CHO
OH
Bull. Chem. Soc. Jap. 1952, 25, 54
CHO
CH3CHO
TWO GROUP DISCONNECTIONS
2.3.3.
1,3-Dicarbonyl Compounds (Claisen-Type Reactions)
O
O
O
O
O
+
Example
O
b
Ph
Ph
Ph
+
EtO
O
O
O
Ph
O
a
a
O
Ph
b
OEt
Ph
O
Pathway b is a self-condensation of ethyl phenylacetate.
O
+
O
TWO GROUP DISCONNECTIONS
2.4
1,4-Difunctionalized Compounds
2.4.1 2.4.1
1,4-Dicarbonyl Compounds (Enolates and a-Halocarbonyls)
O
O
+
R'
R
R'
Br
R'
R
O
O
O
Example
O
O
Br
+
O
O
O
Practically the synthesis involves the Stork enamine
methodology.
O
N
O
Br
O
N
N
H
G. Stork et. al. J. Am. Chem. Soc., 1963, 85, 207
H2O
O
O
TWO GROUP DISCONNECTIONS
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g-Hydroxy Carbonyl Compounds (Enolates and Epoxides)
2.4.2
O
O
O
+
C 6H13
C6H 13
OH
OH
TWO GROUP DISCONNECTIONS
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2.5
1,5-Difunctionalized Compounds
2.5.1. 1,5-Dicarbonyl Compounds (Michael Reaction)
O
O
O
O
+
H
H
Ph
Ph
There are two alternative disconnections in this case
O
O
R
a
b
a
O
O
+
R
R'
R'
b
O
O
+
R'
R
Sometimes the disconnection is easy to choose.
Example
O
COOEt
O
O
O
O
COOEt
O
+
+ EtO
OEt
TWO GROUP DISCONNECTIONS
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2.6
1,6-Difunctionalized Compounds
2.6.1. 1,6-Dicarbonyl Compounds (Ozonolysis of Cyclohexenes)
O
R
R
R
R
O
Example
OMe
O
OH
OMe
O
OMe
O
OMe
3. Regioselectivity
3.1 Regioselective Alkylation of Ketones
O
R1
O
R1
R2
R2
Me
Me I
?
O
R1
R2
Me
The use of Activating Groups
Analysis
O
O
O
X
Br
Synthesis
O
O
-
EtO Na
EtO-Na +
CO 2Et
PrBr
CO 2Et
Br
+
1. OH-
O
CO 2Et
2. H+
3. Q
O
3. Regioselectivity
3.2 Regioselectivity in Michael Additions
R1
R2
Nu
R1
R2
O
Nu- ?
O
R1
R2
HO
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
O
O
1. BuLi
Br
2. Cu(I)Cl
)2CuLi
4. Chemoselectivity
4.1 The Problems:
1. Relative reactivity of two different Functional Groups
NH 2
H
N
Ac2O
HO
HO
O
2. Reaction of one of two identical Functional Groups
OH
HO
OMe
base
Me I
HO
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
H
N
HO
NH 2
C-N
O
HO
NO2 C-N
FGI
HO
HO
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
O
Cl
O
OH
Cl
Cl
Synthesis
O
OH
Cl
O
Cl
O
O
Cl
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.
H2N
O
O
R
COOH
O
+
O
Cl
Again, the intermediate is stabilized by the resonance effect
NO 2
HNO 3
90%
NaHS
MeOH
H2SO4
NO 2
NH 2
NO 2
NO 2
R
N
H
COOH
4. Chemoselectivity
Guideline 4: One of the two identical groups may react if the first product is less
reactive than the starting material.
NO 2
HNO 3
90%
NaHS
MeOH
H2SO4
NO 2
NH 2
NO 2
NO 2
4. Chemoselectivity
Guideline 5: One of the two identical groups may react with one equivalent of
reagent using the statistical effect.
Na/xylene
HO
OH
HO
O-
EtBr
HO
OE t
I d on ’t th in k so!!!
4. Chemoselectivity
Guideline 6: Use a derivative of the two identical groups which can react only once.
O
COOH
AcOAc
Me OH
COOMe
SOCl 2
COOMe
O
COOH
COOH
COCl
O
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.