Mitsunobu Reaction

(1934-2003)
Outline
„ General Information:
„ Who discovered this? What is the basic reaction?
„ The Mechanism:
„ 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
2 2
R OH O R
1
R R PPh3 DEAD

1
R R
 The Mechanism
O

O O
2 HO R
:PPh 3 -
N O CH3 N O CH3
H 3C O N H3C O N

O :PPh 3 O
+

DEAD O H O

N O CH3
H 3C O N -
O R

:PPh 3 O
+

„ Diethyl azodicarboxylate (DEAD)

„ Triphenylphosphine
 The Mechanism: Part II
O H O

N O CH3
H3C O N -
O R

:PPh3 O
+

O H
1 H
R
N O CH3
1 - OH
R O O H H3C O N

1
O H O R
O
O R O
1 Ph
- R OH
O R Ph Ph H O R
P
P + Ph
O Ph
1 RCOOH
:PPh3 Ph O R PPh3 O
1 + 1
+
R R
H
The Mechanism: Part III
O H O

N O CH3
H3C O N -
O R

:PPh3 O
+

O H
1 H
R
N O CH3
OH
H H3C O N

O H O

-
H O R
+
O
PPh3
1 +
R
H

O H
H

+ Ph3PO
R O
1
R
i) (a) Variations of the Method
„ Any nucleophile with
pKa under 15
‰ Eg. Esters, alcohols,
aryl ethers, amine and
thioethers O Cl
O
„ Alternative N N

azodicarboxylate Cl
O
O
„ CH2Cl2 solvent
DCAD
„ Advantages to DEAD,
DIAD
‰ Solid
‰ Polarity of byproduct
significantly different
Lipshutz, B. H. et. al. Organic Letters. 2006, 8 No.22, 5069-5072
i) (b) Where are certain conditions used
and why?
H3C
„ Solid supported x
CH
y 3

reagents for better

product isolation
„ Solution: non-
O
crosslinked polystyrene
with triphenylphosphine
„ Successful Mitsunobu
reaction with menthol, PPh2

2-(S)-octanol, ethyl-(S)-
lactate
Charette, A. B. et. al. J. Org. Chem. 2001, 66, 2178-2180
i) (b) continued…

„ 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
CH3
OH HO CH3 O
DIAD, PPh3
O
+ CH3
O
CH3
THF
CH3

O O
H3C H3C
70-75% yield

Lepore, S. D.; He, Y.. J. Org. Chem. 2003, 68, 8261-8263

 ii) (a) Problems solved
„ The Mitsunobu reaction is used to replace –OH by another group
with inversion of configuration.
R
the reation we want Nu
O H
+ H Nu
H 3C

P r o b le m : S tr o n g
p ro b le m :
bond to be
a c id ic p r o to n
b ro ke n

Solution:
Strong bond formed
PPh 3
Ph 3P O

Solution:
CO 2 Et NH strong bonds formed
NH EtO 2C
N
CO 2 Et NH

S o lu t io n :
w eak bond
s a c r a f ic e d
ii) (a) Problems solved
„ Presents a method of inverting stereochemistry by
an SN2 displacement
‰ Beneficial for making sterically active compounds in
the pharmaceutical industry
„ New method for easily changing the functionality of
the hydroxyl group
‰ 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

Mitsunubu Reaction Ts
„ Better controlled „ Not as easily controlled
„ The exact product is „ Several products
known possible (elimination,
„ Can control the inversion etc.)
stereochemistry „ 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
1 -
R O O
1
O R
O
O R O
1 Ph
- R OH
O R Ph Ph H O R
P
P + Ph
O Ph
1 RCOOH
:PPh3 Ph O R PPh3 O
1 + 1
+
R R
H
Ideal Order of Addition To Limit Byproduct Formation:

„ 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
„ (+)-zampanolide synthesized in
laboratory of A.B. Smith O
„ Tanaka and Higa reported O OH
isolation, partial structure O O
elucidation, and biological N
activity of (-)-zampanolide H
„ Key structural elements
include highly unsaturated
H H
framework and uncommon N- O
acyl hemiaminal side chain
„ (-)-zampanolide shows
impressive cytotoxicity against
P388, HT29, A549, and
MEL28 cell lines (IC50 1-5
(+)-Zampanolide
ng/mL)
J. Am. Chem. Soc. 123 (2001) 12426-12427
iii) Example 1 continued…

„ C8-9 (E)-olefin moiety constructed using Kocienski-

modified 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

„ 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…

„ 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

„ 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 sequence-
selective alklyation of
duplex DNA
J. Am. Chem. Soc. 118 (1996) 2301-2302
Example 3

„ 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

„ 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 repair- 6 13
deficient organism and
cytotoxic to Vero cells
(IC50 = 14 μg/mL)
Example 4

„ secondary alcohol functionality inverted using

Mitsunobu protocol
„ resulting p-nitro benzoate readily hydrolyzed under
basic conditions

J. Am. Chem. Soc. 122 (2000) 4583-4592