Final Mitsonobu Presentation1 (1)

7/30/2019 Final Mitsonobu Presentation1 (1)

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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?


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Oyo Mitsunobu

Gained importance due to its ability to invert the

stereochemistry of the OH functional group Allows for facile change of functionality via a

nucleophilic displacement

R R1

OH

R2

OH

O

DEADPPh3

O

O

R R1

R2

One of Japans eminent scientists


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The MechanismO

CH3 O N

N

O

O CH3:PPh3

2

N-

O

O CH3

O

CH3 O N

:PPh3+

O

OH R

H

N

O

O CH3

O

CH3 O N

:PPh3+

O

O-

R

Diethyl azodicarboxylate (DEAD)

Triphenylphosphine

DEAD


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The Mechanism: Part IIH

N

O

O CH3

O

CH3 O N

:PPh3+

O

O

-

R

O

CH3 O NN

O

O CH3

H

H

O

O-

R

R1

O+

PPh3+

H

H

R1

OH

RCOOH

R1

P

O

O

Ph

Ph

Ph

R1

O

O

P

O R1

Ph

Ph

Ph

R

O

O

:PPh3+

R

R1

O-

H

R1

OH

H


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H

N

O

O CH3

O

CH3 O N

:PPh3+

O

O-

R

O

CH3 O N

N

O

O CH3

H

H

O

O

-

R

R1

O+

PPh3+

H

H

O

R O

R1

H

H

+ Ph3PO

H

R1

OH

H

The Mechanism: Part III


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i) (a) Variations of the Method Any nucleophile withpKa under 15

Eg. Esters, alcohols,

aryl ethers, amine andthioethers

Alternativeazodicarboxylate

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

NN

O

O

OCl

ClO

DCAD


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i) (b) Where are certain conditions used

and why?

Solid supported

reagents for betterproduct isolation

Solution: non-

crosslinked polystyrenewith triphenylphosphine

Successful Mitsunobu

reaction with menthol,2-(S)-octanol, ethyl-(S)-

lactate

Charette, A. B. et. al. J. Org. Chem. 2001, 66, 2178-2180

CH3

CH3

O

PPh2

x y


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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

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

OH

O

O

CH3

+ CH3

CH3

CH3

OHDIAD, PPh

3

THF

O

O

O

CH3

CH3

CH3 CH3

70-75% yield


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ii) (a) Problems solved The Mitsunobu reaction is used to replace OH by another group

with inversion of configuration.

R

O H

P r o b l e m : S t r o n gb o n d t o b eb r o k e n

p r o b le m :a c i d i c p r o t o n

+ H Nuthe reation we want

CH 3Nu

PPh 3

Solution:Strong bond formed

Ph 3 P O

N

N HCO 2 Et

S o l u t io n :w e a k b o n ds a c r a f i c e d

Solution:strong bonds formed

N H

N HCO 2 Et

EtO 2 C


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ii) (a) Problems solved

Presents a method of inverting stereochemistry byan SN2 displacement

Beneficial for making sterically active compounds inthe pharmaceutical industry

New method for easily changing the functionality ofthe 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.


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ii) (a) Problems solved

Mitsunubu Reaction

Better controlled The exact product is

known

Can control thestereochemistry

Ts

Not as easily controlled Several products

possible (elimination,

inversion etc.) Stereochemistry not

controlled

Mitsunubu vs. Ts for allowing oxygen to be a better leaving group


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ii) (b) Competing Methods

O

O- R

R1

O+

PPh3+

H

H R

1

OH

RCOOH

R1

P

O

O

Ph

Ph

Ph

R1

O

O

P

O R1

Ph

Ph

Ph

R

O

O

:PPh3+

R

R1

O-

The ratio of interconversion of intermediates depend onthe carboxylic acid pKa (or other nucleophile used) andthe solvent polarity

The rate of reaction is controlled by carboxylate (or othernucleophile) basicity and solvation.

The order of addition of reagents is very important forlimiting side reactions and achieving an appreciableamount of wanted product


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Ideal Order of Addition To Limit Byproduct Formation:

Dissolve the alcohol, thecarboxylic acid (or othernucleophile) and

triphenlyphosphine in THF (orother suitable solvent ex. Et2O)

Cool to 0 C using an ice bath

Slowly add the DEAD dissolved inTHF

Stir at room temperature forseveral hours.

If unsuccessful performing thebetaine may give better results

Add DEAD to triphenylphosphinein THF at 0 C

Add the alcohol and finally the acid


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iii) Examples in total synthesis

(+)-zampanolide synthesized inlaboratory of A.B. Smith

Tanaka and Higa reportedisolation, partial structureelucidation, and biologicalactivity of (-)-zampanolide

Key structural elementsinclude highly unsaturatedframework and uncommon N-acyl hemiaminal side chain

(-)-zampanolide shows

impressive cytotoxicity againstP388, HT29, A549, andMEL28 cell lines (IC50 1-5ng/mL)

J. Am. Chem. Soc. 123 (2001) 12426-12427

OH H

O O

O

NH

OH

(+)-Zampanolide

O


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iii) Example 1 continued

C8-9 (E)-olefin moiety constructed using Kocienski-modified Julia olefination

required PT-sulfone prepared from correspondingprimary alcohol via two-step protocol employingsequential Mitsunobou reaction and sulfide-sulfoneoxidation

J. Am. Chem. Soc. 123 (2001) 12426-12427


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iii) Example 2

enantioselective total synthesis ofent-WIN 64821 accomplished by

L.E. Overman and co-workers

compound representative memberof family ofC2-symmetricbispyrrolidinoindoline

diketopiperazine alkaloids WIN 64821 a competitive

substance P antagonist withsubmicromolar potency against

human NK1 receptor and also anantagonist of the cholecystokinintype-B receptor

J. Am. Chem. Soc. 123 (2001) 9465-9467


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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


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iii) Example 3

naturally occurring potentantitumor antibiotic (+)-duocarmycin A, its epimerand unnaturalenantiomers prepared byD.L. Boger et al.

Represents mostchallenging member ofclass

Properties derivedthrough sequence-selective alklyation ofduplex DNA

J. Am. Chem. Soc. 118 (1996) 2301-2302


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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


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iii) Example 4

first total synthesis oftricyclic marine alkaloid()-fasicularin completedby team of C. Kibayashi

Discovered by Patil and

co-workers fromMicronesian ascidian

Selective activityagainst DNA repair-

deficient organism andcytotoxic to Vero cells(IC50 = 14 g/mL)

6 13


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Example 4

secondary alcohol functionality inverted using

Mitsunobu protocol

resulting p-nitro benzoate readily hydrolyzed underbasic conditions

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

Final Mitsonobu Presentation1 (1)

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