Multi-step Organic Synthesis
Conversion of existing molecules into other useful molecules.
Pharmaceuticals
Natural sources: petroleum
natural gas
natural products
Polymers
→→→
Gasoline
Commercial sources
Textiles
Etc.
Etc.
•
Little molecules ----> big molecules
•
Synthesis of unnatural products
•
Modification of existing structures
•
Synthesis of rare and useful natural products
Example: Paclitaxel (taxol): anticancer drug and rare natural product
O
O
O
H
OH
H
H
N
H
O
O
O
H
OH
HO
Ph
H
O
O
O
O
O
Example #2: Synthesis of indynaprost from cyclopentadiene
into
HO2C
O
H
H
HO
Cyclopentadiene
8
HO
Indynaprost
(Experimental platelet aggregation inhibitor)
Lecture Supplement: Multi-step Organic Synthesis
Fundamental Synthesis Operations
⇒ C-C bond formation
⇒ functional group interconversions (FGI):
•
•
•
•
oxidation
reduction
substitution
elimination
•
•
addition
others
⇒ skeletal rearrangements
⇒ protection/deprotection
Keys to Doing Synthesis Problems
•
Use reactions you know (flash cards)
•
Keep an eye on the requirements of the problem: Can I solve the problem in one step
from where I am?
•
Think backwards: retrosynthesis (E.J. Corey, Harvard, Nobel Prize in Chemistry,
1990)
Retrosynthesis (Corey’s definition): “a problem solving technique for transforming the
structure of a synthetic target molecule to a sequence of progressively materials along a
pathway which ultimately leads to a simple or commercially available starting material
for chemical synthesis”
ü Practice
ü Practice
ü Practice
ü Practice
Sample Problem #1
H
O
from
Target molecule
Starting material
Hint: Unless otherwise specified, any other reagents can also be used.
Lecture Supplement: Multi-step Organic Synthesis
9
one step ???
Can the target molecule be made from the starting material
in one reaction?
Ph
H
O
Ph
Analysis: No change in carbon count
FGI: alkene → aldehyde
How to make an aldehyde?
• Alkene ozonolysis (alters carbon count)
• Oxidation of a primary alcohol (carbon count unchanged)
Hint: Flash cards may suggest reactions to carry out the desired FGI.
H
O
OH
oxidation
Ph
Ph
means: "thinking backwards"
"the molecule on the left could be made from the molecule on the
right by the reaction above the arrow"
Can the new target molecule (the alcohol) be made in one step from the starting alkene?
OH
hydroboration
Ph
Ph
Complete Retrosynthesis:
H
O
Ph
OH hydroboration
oxidation
Ph
Ph
Forward Direction:
• Fill in the reaction details
•
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Carefully check each step: stereochemistry, carbocation rearrangements, etc.
Lecture Supplement: Multi-step Organic Synthesis
H
O
oxidation
PCC
Ph
OH hydroboration
Ph
1. BH3
2. H2O2, NaOH
Ph
Or:
1. BH3
2. H2O2, NaOH
Ph
OH
PCC
Ph
H
O
Ph
Sample Problem #2
HO
CH3S
from
Ph
Ph
OCH2CH3
Can the target molecule be made from the starting material in one reaction?
Analysis: Target has three more carbons than starting material, but no new C-C bonds.
FGI: Alcohol → thioether
Alkene → ether
How to make an ether?
• SN2 with CH3 CH2 O• SN2 with RO- and CH3 CH2 I
• Alkoxymercuration
CH3S
Ph
Williamson
OCH2CH3
CH3S
Ph
OH
Can the target molecule be made from the new starting material in one reaction?
How to make an alcohol?
• SN2 with HO• Alkene hydration
• Nucleophilic addition to epoxide
CH3S
Ph
oxymercuration
OH
Lecture Supplement: Multi-step Organic Synthesis
CH3S
Ph
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Can the target molecule be made from the new starting material in one reaction?
How to make a thioether?
• SN2 with RS- (Must first convert OH into LG)
CH3S- SN2
CH3S
TsO
HO
TsCl
Ph
Ph
CH3S
oxymercuration
Ph
Complete Retrosynthesis
CH3S
Ph
Williamson
OCH2CH3
CH3S- SN2
Ph
TsO
OH
CH3S
Ph
HO
TsCl
Ph
Ph
Forward Direction
HO
pyridine
Ph
CH3S
Ph
TsO
TsCl
Ph
Ph
1. Hg(OAc)2, H2O
2. NaBH4
CH3S
1. NaH
OH
Na SCH3 CH3S
2. CH3CH2I
Ph
OCH2CH3
Shorter Forward Direction: Alkoxymercuration achieves the alkene → ether conversion in
just one step
HO
Ph
TsO
TsCl
pyridine
Ph
Na SCH3 CH3S
Ph
1. Hg(CF3CO2)2,
CH3CH2OH
2. NaBH4
CH3S
Ph
OCH2CH3
Hint: Thorough reaction knowledge increases flexibility and simplifies synthesis
problems. Some problems might not be doable without good mastery of reactions!
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Lecture Supplement: Multi-step Organic Synthesis
Sample Problem #3
C
N
into
O
Can the target be made in one step from the given starting material?
Analysis: New C-C bond between ring and nitriles
FGI: Alkene → ether + nitrile + another alkene, with trans stereochemistry
How to make a nitrile?
• SN2 with -CN and alkyl halide, alkyl sulfonate, or epoxide
How to make an ether?
• SN2 with RO• oxymercuration with ROH
• Williamson ether synthesis
Several routes to consider. Pick one and explore it! The trans relationship of the ether and
nitrile groups suggests an epoxide opening.
C
N
C
Williamson
O
N
-
CN (SN2)
O
OH
Can the new target molecule (the epoxide) be made from the original starting material
(alkene) in one step?
RCO3H
O
Complete Retrosynthesis
C
N
C
Williamson
O
N -CN (S 2)
N
O
RCO3H
OH
Forward Direction
CH3CO3H
C
O
KCN
CH3OH
OH
Lecture Supplement: Multi-step Organic Synthesis
N
1. NaH
2.
Br
C
N
O
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