STRATEGIES IN SYNTHESIS - University of...
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STRATEGIES IN SYNTHESIS Professor T. J. Donohoe MT 2006 6 Lectures: Tuesday at 10 am; Thursday at 9 am (weeks 6-8) DP: Lecture Theatre CO 2 H O O O O O OH Me Me H H Me Me OMe H HO Me Me Me H H Et HO 1 7 Monensin Kishi J. Am. Chem. Soc , 1979, 101, 259. A copy of this handout is available at: http://users.ox.ac.uk/%7Emagd1571/finalpage/teaching2.html
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Transcript of STRATEGIES IN SYNTHESIS - University of...
STRATEGIES IN SYNTHESIS
Professor T. J. Donohoe
MT 2006
6 Lectures: Tuesday at 10 am; Thursday at 9 am (weeks 6-8) DP: Lecture Theatre
CO2H
O O O
O
O
OH Me
MeH
H
Me
MeOMe
H
HO
Me
MeMe H H
Et
HO1
7
Monensin
Kishi J. Am. Chem. Soc, 1979, 101, 259.
A copy of this handout is available at:
http://users.ox.ac.uk/%7Emagd1571/finalpage/teaching2.html
2
Strategies in Synthesis
Synopsis 1) Introduction to synthesis: why do we want to synthesise molecules- what sort of molecules do we need to make? What aspects of selectivity do we need to exert to accomplish a good synthesis (chemo-, regio- and stereoselectivity) 2) Protecting group chemistry is central to any synthetic effort (examples) 3) Retrosynthesis- learning to think backwards (revision from first year). Importance of making C-C bonds and controlling oxidation state.
Umpolung 4) Examples of retrosynthesis/synthesis in action. 5) Handy hints for retrosynthesis Recommended books: General: Organic Chemistry (Warren et al) Organic Synthesis: The Disconnection Approach (S. Warren) Classics in Total Synthesis Volumes I and II (K. C. Nicolaou) The Logic of Chemical Synthesis (E. J. Corey)
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1) Why do we want to synthesise complex molecules?
O
O
AcO
OH
H
AcO
OH OO
O
O
OH
NH
O
Taxol
Strychnine
N
O
N
H
H
HO
SN
N
O
O
OEt
N
HN
O
NN
Sidenafil
4
In order to undertake the synthesis of a complex organic molecule, we need to control the following: 1) Carbon 2) Functional 3) Stereochemistry In order to control 1) and 2) Chemoselectivity
O
COOMe
Regioselectivity
Protecting group strategy
HO
OH
OH
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A) CHEMOSELECTIVITY
O
Using different tactics we can reduce each of the
a) H2, Pd-C. This reagent is sensitive to steric
O
b) Na, NH3, tBuOH (1 eq.)
O OO
H O
OH3O+
electron
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O
Q. What would happen if we added >2 eq. of tBuOH?
Na, NH3
2 eq.t B uOH?
c) NaBH4, CeCl3 (Luche reduction)
ONaBH4
O O
ONaBH4, CeCl3
O O
NaBH4 + MeOH B +
B
This process is promoted by
What does CeCl3 do to sodiumborohydride?
O Ce(III)
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B) REGIOSELECTIVITY
O O
OEt
pKa
NaOEt O O
OEt
O O
OEt
O
O O
OEt
LDA
LDA=
O O
OEt
LDA
O O
OEt
PhCH2Br
Dianion
How to influence regioselectivity by
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C) PROTECTING GROUPS (are essential to most syntheses)
R3SiCl
Et3NOH
OH OH
increasingR3SiCl
Me3SiCl
SiCl
SiCl
increasing
There are tactics for protecting the least and the most hindered groups.
N
O OtBu
TBSOTf
N
O OtBu
?
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RETROSYNTHESIS
The theory (Corey- Nobel prize
1) Think about reactions in reverse
A B
A BX
C D
2) Use disconnections to break down molecules
O
NH
O
NH
N
O
S
Make sure that your disconnections correspond to known and
3) Synthons: These are simply
There are two ways of analysing a single
A number shows the position of the charge relative to the
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O
NH
O
NH
N
O
S
You have to decide which synthon is realistic and
Remember the concept of UMPOLUNG is helpful (especially) with carbonyl groups:
1) Normal reactivity of the carbonyl group
O O
O
Ph
O
Ph
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2) Use UMPOLUNG to reverse the reactivity of the carbonyl group
O O
O
Ph
O
Ph
The hard part is choosing a particular disconnection (from several others) in a complex molecule.
4) Sometimes functional group interconversion on the target helps
Simple
FGI
More difficult
COOEt
Ph
FGI COOEt
Ph
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Even stereochemistry can be altered in this way.
OH
H
FGI
O
H
Some problems: How would you synthesise the following? (Hint: think about Diels Alder)
COOMe
COOMe
COOMe
COOMe
HO
HO
COOMe
COOMe
OAc
AcONHCOMe
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Synthesis 1) Eletriptan (Pfizer) Migraine
NH
N
SO O
NH
N
SO O
NH
N
SO O
NH
N
NH
N
NH
The synthesis:
NH
N
NNH
BrO
Cl
O OCH2Ph
+
NO
Cl
O OCH2Ph
N
O OCH2Ph
N
LiAlH4
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N
N
Mechanism for this step is:
NH
N
NH
N
NH
N
NH
N
NH
N
NH
N
NH
N
NH
N
NH
N
To finish the synthesis
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NH
N
BrS
NH
N
NH
N
Synthesis 2) Talaromycin B (Schrieber, Tetrahedron Letters, 1983, P4781)
OO OH
OH
O
O
1) Most substituents on each ring are
2) The only axially disposed groups are
3) The ANOMERIC
O
O
O
O
OH
OH
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Further disconnections are possible
OH
OH
OH
OH
Now only
OH
OH
The synthesis in full:
1) Preparation of the starting materials
OH OH
OAc2O
O O
OMgBr
O O
SOCl2
mech?O O
HCl, MeOH
O OO O
OMeMeO
H+
Putting these pieces together:
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O O
Cl
S S
BuLiO O
H2, Pd Cat.
O O
BuLi
A
A
O
OO
O
BH3
then H2O2, NaOH
O
OO
OOH
OHHO
HO
HgCl2
H2O
And finally,
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O
OTsCl
Me2CuLi
H3O+
OMeMeO
O
O
O
O
O
O
O
O
mechanism
19
Synthesis 3) Estradiol (Helvetica Chimica Acta, 1980, 63, 1703)
OH
H
HHHO
OH
H
HHO
OH
HHO
HO
OH
H
Now the synthesis.
O Othen
O
think about relative
The other half:
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SI2
Ag
SNaCN, (Ph3)4Pd
S
Pd
SNaCN
S
The end-game
SO
O
NaHS
O
O
then
OSi
IS
O
O
∆
H
HH
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And finally,
H
HH
MeLi H
HH
H+
quench
H
HH
H
HH
H
HH
Synthesis 4) Prostaglandin F2α (Journal of the American Chemical Society, 1969, P5675) E. J. Corey
HO
HO H
H
OH
CO2HWittig Reaction
and protection H
H
Reconnect Lactoland change oxidation state
P= protecting group
PO H
O
Wadsworth Emmons
PO H
O
O
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AND
PO H
O
O
O
PO
O
O
HO
OMe
O
O
MeOMeO
C
Problem:
The synthesis:
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MeOCH2ClClNC
MeO
KOH
MeO
O
TlOH
MeOCH2Cl
Why Tl?
MeO MeO MeO
MeO
MeO
O
MCPBA NaOH
OMe
then Ac2O
I2, NaHCO3
AcO
OMe
O
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mechanism of iodide reduction:
AcO
OMe
O
BBr3
AcO
O
AcO
O
P
O
C5H11
O
MeOMeO NaH
AcO
O
PCC
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Why do
P
O
C5H11
O
MeOMeO
P O
P O
Reduction of the C=O bond
AcO
O
O
NaBH4
AcO
O
O
(i) K2CO3
(i) TsOH
O
O
O
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O
O
ODIBAl-H Ph3P
CO2
O
O
O
How do you make the ylid?
Ph3PCO2
Why do non-stabilised
P P P
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Finally, to complete the synthesis:
H3O+
Some handy hints for retrosynthesis
1) Make the synthesis
Use convergent rather than
2) Use only disconnections corresponding to
AcO
O
O
3) Disconnect C-X bonds wherever possible (this includes RCO
SO
O
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4) Disconnect C-C bonds by using nearby functional groups or by
O O O O
Also, it makes more sense to disconnect in the middle
OH
Ph Ph
5) Disconnect back to readily recognisable
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Some problems to think about:
Disconnect the following and then devise forward syntheses:
OH
H
OMe
O
OO
O
N
Me2N
OH
O
COOH
Cl
NMe
HO
OMe
