Mitsunobu Reaction
(1934-2003)
Outline
„
General Information:
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The Mechanism:
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„
Who discovered this? What is the basic reaction?
What exactly happens and how?
Applications:
i) Variations of the method- where are certain conditions used and
why?
ii) What problem is solved by the reaction? What are the competing
methods?
iii) What are some examples of this reaction in total synthesis?
Oyo Mitsunobu
One of Japan’s eminent scientists
„
„
Gained importance due to it’s ability to invert the
stereochemistry of the –OH functional group
Allows for facile change of functionality via a
nucleophilic displacement
O
O
OH
R
R
R
1
2
PPh3
OH
R
O
DEAD
R
R
1
2
The Mechanism
O
O
O
2
N
H 3C
O
O
CH3
HO
:PPh 3
N
N
H3C
O
-
O
CH3
N
O
:PPh 3
O
+
DEAD
O
H
O
N
H 3C
O
O
N
:PPh 3
O
O
+
„
„
CH3
Diethyl azodicarboxylate (DEAD)
Triphenylphosphine
-
R
R
The Mechanism: Part II
O
H
O
N
H3C
O
O
CH3
N
:PPh3
-
O
R
O
H
O
+
1
R
1
-
R O
H
O
H
O
:PPh3
+
H3C
O
R
Ph
Ph
H
R
Ph
P
1
-
H
R
O
O
1
R
PPh3
1
+
R
H
CH3
R
1
R
O
OH
O
Ph
P
+
O
O
N
O
O
O
N
OH
RCOOH
Ph
O
Ph
1
R
The Mechanism: Part III
O
H
O
N
O
H3C
O
CH3
N
O
:PPh3
-
R
O
+
R
1
H
N
OH
H3C
O
O
H
O
+
PPh3
1
+
H
O
H
H
+
R
O
R
1
Ph3PO
O
N
H
R
O
R
H
O
H
O
CH3
i) (a) Variations of the Method
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Any nucleophile with
pKa under 15
‰
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„
Eg. Esters, alcohols,
aryl ethers, amine and
thioethers
Alternative
azodicarboxylate
Cl
CH2Cl2 solvent
Advantages to DEAD,
DIAD
‰
‰
Solid
Polarity of byproduct
significantly different
Lipshutz, B. H. et. al. Organic Letters. 2006, 8 No.22, 5069-5072
O
Cl
O
N
N
O
O
DCAD
i) (b) Where are certain conditions used
and why?
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Solid supported
reagents for better
product isolation
Solution: noncrosslinked polystyrene
with triphenylphosphine
Successful Mitsunobu
reaction with menthol,
2-(S)-octanol, ethyl-(S)lactate
Charette, A. B. et. al. J. Org. Chem. 2001, 66, 2178-2180
H3C
CH
y 3
x
O
PPh2
i) (b) continued…
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Sterically hindered alcohol and phenol
Reaction time reduced from 7 days to 15 minutes
Concentration 0.1M->3M
Sonic waves better mixing, generate free radicals
H3C
OH
HO
O
H3C
CH3
+
CH3
CH3
O
O
DIAD, PPh3
O
THF
H3C
O
70-75% yield
Lepore, S. D.; He, Y.. J. Org. Chem. 2003, 68, 8261-8263
CH3
CH3
ii) (a) Problems solved
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The Mitsunobu reaction is used to replace –OH by another group
with inversion of configuration.
R
O
P r o b le m : S tr o n g
bond
to
be
b ro ke n
H
2 Et
H
Nu
Nu
the reation we want
H 3C
p ro b le m :
a c id ic p r o to n
PPh
CO
+
Solution:
Strong bond formed
3
NH
N
Ph
Solution:
strong bonds formed
O
EtO
NH
CO
S o lu t io n :
w eak
bond
s a c r a f ic e d
3P
2 Et
NH
2C
ii) (a) Problems solved
„
Presents a method of inverting stereochemistry by
an SN2 displacement
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„
New method for easily changing the functionality of
the hydroxyl group
‰
‰
„
Beneficial for making sterically active compounds in
the pharmaceutical industry
Converts primary or secondary alcohols
New functional groups include esters, phenyl ethers,
thioethers etc.
Other functional groups beside carboxylic acids may
also be used so long as their pKa is less than 15.
ii) (a) Problems solved
Mitsunubu vs. Ts for allowing oxygen to be a better leaving group
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Mitsunubu Reaction
Better controlled
The exact product is
known
Can control the
stereochemistry
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Ts
Not as easily controlled
Several products
possible (elimination,
inversion etc.)
Stereochemistry not
controlled
ii) (b) Competing Methods
The ratio of interconversion of intermediates depend on
the carboxylic acid pKa (or other nucleophile used) and
the solvent polarity
The rate of reaction is controlled by carboxylate (or other
nucleophile) basicity and solvation.
The order of addition of reagents is very important for
limiting side reactions and achieving an appreciable
amount of wanted product
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R
1
O
-
O
O
O
O
O
:PPh3
+
R
Ph
Ph
R
R
Ph
P
H
O
-
R
O
O
R
1
R
+
H
1
OH
O
Ph
P
+
PPh3
1
R
1
RCOOH
Ph
Ph
O
R
1
Ideal Order of Addition To Limit Byproduct Formation:
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Dissolve the alcohol, the
carboxylic acid (or other
nucleophile) and
triphenlyphosphine in THF (or
other suitable solvent ex. Et2O)
Cool to 0 °C using an ice bath
Slowly add the DEAD dissolved in
THF
Stir at room temperature for
several hours.
If unsuccessful performing the
betaine may give better results
‰
‰
Add DEAD to triphenylphosphine
in THF at 0 °C
Add the alcohol and finally the acid
iii) Examples in total synthesis
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(+)-zampanolide synthesized in
laboratory of A.B. Smith
Tanaka and Higa reported
isolation, partial structure
elucidation, and biological
activity of (-)-zampanolide
Key structural elements
include highly unsaturated
framework and uncommon Nacyl hemiaminal side chain
(-)-zampanolide shows
impressive cytotoxicity against
P388, HT29, A549, and
MEL28 cell lines (IC50 1-5
ng/mL)
J. Am. Chem. Soc. 123 (2001) 12426-12427
O
O
OH
O
O
N
H
H
O
(+)-Zampanolide
H
iii) Example 1 continued…
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C8-9 (E)-olefin moiety constructed using Kocienskimodified Julia olefination
required PT-sulfone prepared from corresponding
primary alcohol via two-step protocol employing
sequential Mitsunobou reaction and sulfide-sulfone
oxidation
J. Am. Chem. Soc. 123 (2001) 12426-12427
iii) Example 2
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enantioselective total synthesis of
ent-WIN 64821 accomplished by
L.E. Overman and co-workers
compound representative member
of family of C2-symmetric
bispyrrolidinoindoline
diketopiperazine alkaloids
WIN 64821 a competitive
substance P antagonist with
submicromolar potency against
human NK1 receptor and also an
antagonist of the cholecystokinin
type-B receptor
J. Am. Chem. Soc. 123 (2001) 9465-9467
iii) Example 2 continued…
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stereospecific incorporation of two C-N bonds achieved using
Mitsunobu reaction to convert two secondary alcohol
functionalities to corresponding alkyl azides with inversion of
configuration
azides subsequently reduced to primary amines and cyclized
to desired bis-amidine functionality
J. Am. Chem. Soc. 123 (2001) 9465-9467
iii) Example 3
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naturally occurring potent
antitumor antibiotic (+)duocarmycin A, its epimer
and unnatural
enantiomers prepared by
D.L. Boger et al.
Represents most
challenging member of
class
Properties derived
through sequenceselective alklyation of
duplex DNA
J. Am. Chem. Soc. 118 (1996) 2301-2302
Example 3
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last step of synthesis was elaboration of reactive
cyclopropane moiety carried out via a transannular
spirocyclization using Mitsunobu conditions
special case where Mitsunobu reaction used to create
new C-C bonds
J. Am. Chem. Soc. 118 (1996) 2301-2302
iii) Example 4
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first total synthesis of
tricyclic marine alkaloid
(±)-fasicularin completed
by team of C. Kibayashi
Discovered by Patil and
co-workers from
Micronesian ascidian
Selective activity
against DNA repairdeficient organism and
cytotoxic to Vero cells
(IC50 = 14 μg/mL)
6 13
Example 4
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secondary alcohol functionality inverted using
Mitsunobu protocol
resulting p-nitro benzoate readily hydrolyzed under
basic conditions
J. Am. Chem. Soc. 122 (2000) 4583-4592