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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.
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