Professor Philip Page
University of East Anglia at Norwich
Program Interreg IS:CE
Caen, 26-30 October 2009
"Synthesis of complex natural products"
Problems
The following scheme shows the synthesis of a key intermediate for prostaglandin synthesis by
Corey.
Cl
H3CO
H3CO
CN
OCH3
KOH
Cl
step 1
step 2
O
CN
m-CPBA step 3
O
O
O
H3CO
HO
I2/KI
OCH3
I
step 5
OH
(a)
NaHCO3/H2O
OCH3
step 4
O
O
OH
Step 1 involves a Diels-Alder reaction. With the aid of diagrams, show the mechanism and explain
the stereochemistry observed.
(b)
Indicate the mechanism of step 3 and explain the observed regiochemistry.
(c)
Step 5 involves an iodolactonization reaction. Indicate the mechanism using diagrams, and
account for the observed regiochemistry and stereochemistry.
The following scheme is taken from the synthesis of hirsutene by Curran.
O
O
PhSe
1. LDA, thf, –78 °C
PhSeCl
O
2. t-BuMe2SiCl
3. heat
step 1
OSi
O
O
CH2Cl2
step 2
H
step 3
THPO
THPO
CO2H
H
Li
O
O
step 4
H
H
I
H
Bu3SnH
AIBN, heat
H
(a)
H
step 5
H
H
Step 1 involves a sequence of reactions. Provide a mechanism for the heat-induced
rearrangement reaction. Indicate the type of rearrangement involved, and the structural feature required
for such rearrangements to take place.
(b)
Provide a mechanism for the reaction that takes place in step 2, and explain the stereochemistry
observed.
(c)
Suggest a reagent for the reaction shown in step 3, and provide a mechanism for the reaction.
Indicate the type of rearrangement involved.
(d)
Provide a mechanism for the reaction that takes place in step 4, and explain the stereochemistry
observed. Suggest a competing process that could occur.
(e)
Suggest a mechanism for the reaction that takes place in step 5.
The following scheme is taken from the synthesis of compactin by Grieco.
R
CO2Me
MeO2C
O
H
R
MeO2C
1. MCPBA
H
R
OH
2. MeOH
125 °C
step 1
O
step 2
O
PhS
SPh
step 3
1. Ph3P; DEAD; PhCO2H
2. NaOMe, MeOH
HO
H
R
LiAlH4
MeO2C
H
R
1. Ac2O, base
2. Me2CuLi
step 4
step 5
O
O
MeO2C
H
R
OH
O
step 6
KH, toluene, 110 °C
DEAD = CH3CH2OC(O)N=NC(O)OCH2CH3
OH
(a)
R
Explain with the aid of a diagram the stereochemistry observed in the Diels-Alder reaction in
step 1.
(b)
Step 2 involves a sequence of reactions. Provide a mechanism for the rearrangement reaction,
indicate the type of rearrangement, and explain the stereochemistry observed. The rearrangement is an
equilibrium process; indicate how the equilibrium is driven to give entirely the desired product.
(c)
Provide a mechanism for the reaction shown in step 3.
(d)
Explain why a cuprate reagent is used in step 4 rather than another type of organometallic reagent.
(e)
Provide a mechanism for the reaction shown in step 6.
The following scheme is taken from the synthesis of oestrone by Oppolzer.
O
1.
CuLi
2. Br
OSiR3
O
2
CO2Me
HO
MeO2C
step 1
steps 2-4
steps 5-6
OSiR3
OSiR3
SO2
I
NC
step 7
SO2
NC
heat
step 8
OSiR3
OH
1. MeLi
H
H
H
2. H3O
H
NC
H
3. CF3CO3H
4. H3O
H
HO
steps 9-12
(a)
Explain the stereochemistry observed in step 1.
(b)
Suggest reagents that could be used for the transformation shown in steps 2-4. Note that R3SI = t-
BuMe2Si
(c)
The anionic reagent shown in step 7 is generated by deprotonation of the parent sulfone with a
strong base. Suggest a suitable base and explain the regiochemistry of deprotonation.
(d)
Explain the processes occurring in step 8, show the mechanisms, and provide an explanation for
the observed stereochemistry.
(e)
Explain the reactions taking place in steps 9-12.
The following scheme is taken from the synthesis of prostaglandin F2a by Stork.
OMe
O
OH
CH3C(OMe)3
O
O
O
O
1
O
Heat, H+
step 1
O
O
O
O
O
step 2
MeO2C
MeO2C
1. Base
2. TsCl (1 equiv)
OTs
O
O
O
step 3
OH
O
O
O
O
MeO2C
MeO2C
H+/H2O
O
O
O
HO
step 4
O
OH
OH
step 5
O
O
HO
(a)
OH
Compound 1 was derived from D-glucose. What was the reason for incorporating the two different
types of diol protection in this molecule ? .
(b)
Suggest a mechanism for the generation of the methyl enol ether shown in step 1
(c)
Step 2 is an orthoester Claisen rearrangement. Explain the observed stereocontrol
(d)
Suggest a mechanism for removal of the carbonate protecting group shown in step 3 using
hydroxide anion.
(e)
Give a mechanism for the hydrolysis of the cyclic acetal shown in step 4.
(f)
In step 5, there are three hydroxy groups that could react with the ester unit to provide a lactone
product. Suggest why only one product is observed.
The following scheme is taken from the synthesis of cholesterol by Woodward.
O
O
O
NaOH
heat
step 1
MeO
step 2
MeO
O
MeO
H
O
O
H
step 3
OH
H+/H2O
Ac2O/py
O
step 5
H
OAc
Zn
step 4
O
MeO
H
OH
H
OH
step 6
NaOMe
HCO2Et
O
step 7
step 8
O
H
O
OHC
H
HO
H
O
KOH
step 9
H
H
O
(a)
Draw a transition state for the Diels-Alder reaction in step 1 and explain the observed
stereocontrol.
(b)
Suggest a reagent to achieve the carbonyl group reductions shown in step 3.
(c)
Provide a mechanism for the reaction shown in step 4.
(d)
Suggest a mechanism for the reductive cleavage shown in step 6.
(e)
The reaction shown in step 7 is a Claisen condensation. Give a mechanism and explain the
purpose of including this step in the synthesis.
(f)
Suggest reagents for the reaction shown in step 8
(g)
Give mechanisms for the transformation shown in step 9
The following scheme is taken from the synthesis of reserpine by Woodward.
O
O
O
OH
H
H
heat
reduction
step 1
step 2
CO2Me
O
H
O
CO2Me
H
O
Br2
O
O
H
Br
O
H
H
NBS/H2O
HO
OMe
H
MeO
step 5
OMe
H
O
step 4
O
Br
H
O
O
oxidation
step 3
O
O
step 6
O
H
Br
H
OH
H
OMe
Zn/AcOH
O
OMe
H
O
step 7
O
O
O
(a)
O
Explain with the aid of a diagram the stereochemistry observed in the Diels-Alder reaction in step
1.
(b)
The carbonyl group reductions shown in step 2 are carried out using a hydride equivalent. Explain
the stereochemistry observed. Indicate the product of the alternative lactonization process, and indicate
why this does not occur.
(c)
Give a mechanism for the reaction shown in step 3, and explain the stereochemistry and
regiochemistry observed. How is this relevant to the reaction shown in step 5 ?
(d)
Explain with the aid of a reaction mechanism why retention of stereochemistry is observed in step
4.
(e)
Provide a mechanism for the reaction shown in step 7.
PG Problems: Sulfur and Related Chemistry
Suggest structures for the major products the following reactions. Identify any intermediates.
Explain the mechanism in each case and comment on any expected regioselectivity and stereoselectivity.
O
N
O
SPh
N
R
HO
O
Bu3P
H
BuLi, –78 C, TMEDA;
R
S
Ph
R
S
Ph
MeI
BuLi; warm;
MeI
DMSO
R
Br
NaHCO3
O–
S+
Ph
Ac2O
CO2H
OSiMe3
O–
S+
R
H
TMSOTf
+
iPr2NEt, –78 C
Ph
O–
S+
²
N
B
A
O
CO2Me
OH
1. BuLi
2. PhSCl
A
B
1. LDA
2. MeI
C
D
(MeO)3P
MeOH
OH
PG Problems 2: Sulfur and Related Chemistry continued
H
KOtBu
H
SO2
Br
THF, –15 °C
SO2Ph
1. BuLi
MsCl
A
2.MeO2C
Na/Hg
B
H
O
Base;
SO2Ph
CO2Me
CO2Me
OSitBuMe2
²
213 C
SO2
NC
O
O
Me2S+ CH2–
?
indicate products from both reactions
Me2S+ CH2–
?
O
1. base (2 equiv.)
2. Me3SiCl
NNHTs
OH
OH
1. (imid)2CS
2. R3P or
(MeO)3P
C
PG Problems: Silicon and Related Chemistry
Suggest structures for the major products the following reactions. Identify any intermediates.
Explain the mechanism in each case and comment on any expected regioselectivity and stereoselectivity.
SiMe3
SnCl4
MeO OMe
what principles of Si chem are illustrated here ?
1. BuLi
SiMe3
2. RX
what principle of Si chem is illustrated here ?
SiMe3
R
1. mCPBA
2. ²
SPh
what principle of Si chem is illustrated here ?
SiMe3
KH
BF3.Et2O
OH
1. Me3Si
MgCl
2. AcOH
O
H
C6H13
SiMe3
OsO4
MeOH
1. TsNHNH2
2. • 2 equiv BuLi
3. Me3SiCl
O
why are 3 equiv sometimes needed ?
PG Problems 4: Silicon and Related Chemistry continued
C6H13
SiMe3
1. DIBAL
2. MeLi
3. MeI
CO2H
SiMe3
Br2
PhCOCl
AlCl3
SiMe3
Br2
Ph
SiMe3
explain the observed double bond stereochemistry
R1
R2
O
TiCl4
SiMe3
OR
Cl
+
AlCl3
O
–60 C
SiMe3
why not use a Grignard reagent ?
Me3Si
O
Br2
Cl
–70 C
Cl
CO2H
CO2H
SiMe3
peracetic acid
Et2O, rt