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Synthesis of JASMONE

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Synthesis of Jasmone

Reviews: Synth. Comm. 1974, 4, 265-287

Synthesis, 1973, 397-412

OO

Jasmolactone

O

CO2Me

Methyl-JasmonateThe syn compound has a strong smellOnly one enantiomer is active

O

Jasmone

Firmenich (Company in Geneva producing fragrances):

O

Hedrione

Ways to make a cis-Double bond:

90-95%H2 / Lindlar

R H

OWittig

R

R'

R'

PPh3

HBR2H

BR2

H

NiP2

H2

cis-Selectivity

85-90%

98-99%

98-99%

Diimine Reduction:

Usually gives an excellent Z/E ration (up to 99.9%)

Synthesis of N NH H :

EtO2C N N CO2Et

DEAD:H2O / NaOH

O2C N N CO2Na Na

H

HO2C N N CO2H- CO2

H N N HVery reactive!

Problem: intermediates and the diimine might be explosive (Not done in industry, largest scale might be 2 or 3

mmol).




Phauson-Khand reaction: Synthesis of cyclopentenones via [2+2+1] cycloaddition

Net-reaction:

O

RL

RS

RL

RS

RCo2(CO)8

CO comes from Co2(CO)8

R

R migh also end up here,mixtures are formed.

Mechanism:

RLRSCo2(CO)8

- 2 CO

RS

RL

Co(CO)3

Co(CO)3

R

RS

RL

Co(CO)2

Co(CO)3

To create afree coordinationsite

R

RS

RL

(OC)2CoCo(CO)3

R

Insertion in red bond

RS

RL

Co(CO)3

Co(CO)3

R

Insertion in red bond

CORS

RL

Co(CO)3

Co(CO)3

RO

Red. Elimination

RS

RL

Co(CO)3

Co(CO)3

RO

+ CO

O

R

RS RL

Co(CO)3

Co(CO)3

-[Co2(CO)6]

O

R

RS RL

Review: Angew. Chem. Int. Ed. 2005, 44, 3022

Aldolkondensation:

O O

OH

4

3

1

2

O

O

1,4 Dicarbonyl compound




O

O

R1

O

R1

O

R2

SS +

O

R2

1

O

R1

O

R2

ClR1

O

+

XMg

O OR2

Br

O OR2

O OR2

O

R2

O

O

R12

O

OBr R2

O

Nu

R2

O

Synthesis by S. Mann Synth. Comm. 1985, 15, 1147-1151

O

O O LiTo weak as a nucleophile?!

O

O N

made out of:

O+

NH

Enamine is a too weak nucleophile.

Solution: Hydrazone

O H2N NMe2N

NMe2

n-Bu LiN

NMe2

Li

very strong nucleophile(charge is not delocalized)




Chiral Hydrazones: Enders

NN

OMe

1.) n-BuLi

2.) E

3.) H3O , CuSO4

Is made out of prolineby reduction and protectionwith MeI

O

E

*

SAMP RAMP

NH

OMe AminoMethoxyPyrolidine

S or R

O

1 2

3

+O

O

O+

X

2

O1

NOMe

MeWeinreb-Amid

+

NO

OMg

XMg

R

X

H2 , Lindlar-Pd

3

O

O

+ Problem:E/Z IsomersPPh3

Wittig-Reaction

OCommercially available

Aledehyde reacts faster than the ketone!




Synthesis:

O

100%

H2N NMe2N

NMe2

1. n-BuLi2.

3. H2O + Cu(OAc)2

OO

OH

75%

Oxidationwith PCC

O

O

NaOH

70%

+

OO

O

2

1

O

10%90%

Enolate formed at Position: 2 1

1. O32. Me2S

O

Oelectron poor due to conjugation

Ph3P

NaOHto create the Ylide

O

44% yield

R

O

:Sterically hindered Base(Kinetically controlled deprotonation)

SiMe3

N

SiMe3LMDSLi

R

O

: Thermodynamically controlled deprotonation

EtO

O O

RBH4

EtO

O O

R

n-Bu Li

EtO

O O

R

What was deprotonatedlast will react first!

EtO

O O

R

E1

E2

E1

EtO

O O

R

E1E2

H3OO

R

E1E2

- CO2

For E1 = Br

For E2 = BrO




Synthesis of Larry Weiler Can. J. Chem. 1978, 56, 2301-2304

OEt

OO

1. Base2.

Br

OEt

OO 1. NaH2. n-BuLi

3.

Br

TMS

OEt

TMS

O O

Steric bulkhinders HydrogenationLindlar / Pd

TMS

OCO2Et

KF

H

OCO2Et

H3O

HgSO4

R H2SO4

HgSO4

R

OH

R

O

OCO2Et

O

NaOH

O

Jasmone

Synthesis of Welch JOC 1987, 52, 1440-1450

CO2Et

O

CO2Et

O

Cl

+

1. NaH2. n-BuLi

Cl

3.

OP(OEt)2

O

O

OP(OEt)2

O

CO2Et

NaOH

O

Jasmone




Additional information:

Reaction of Perkow: JACS 1955, 77, 2871

O

Cl Cl

P(OEt)3

∆

O

Cl

P(OEt)2

OPerkow:

O

Cl Cl

P(OEt)3

O

Cl

P(OEt)3

O

Cl

P(OEt)2

O

O

Cl

P(OEt)2

O

Et

Arbusow:

EtO PEtO

EtOR Br EtO P

EtO

O

R

EtO PEtO

O

R

BrEt

+ EtBr

HWE-Reagent (HWE = Horner-Wadsworth-Emmons)

Synthesis by McMurry

JOCS 1973, 38, 4367-4373

JACS 1971, 93 5309-5311

New approach to create the 1,4 diketone

R

O

S S

R

R

NO2

Hg(II)

1. NaOH2. H2SO4

Nef-reaction

R

O

S S

REEt

RE

NO2

R

O

Et

O

+

2

3 4

O

1

O

R

The conditions of the Nef-reaction are rather harsh:

NO O

H

NaOH

OH

NO O

H2SO4

conc.reflux

NHO OH

H2O

O




McMurrys attention was therefore drawn to a publication of Wildsmith, who used much milder conditions to

hydrolyze an oxime (which is not that far away from a nitro group):

Synthesis by Wildsmith TL 1971, 195-198

Utilisisation of TiCl3 for the Nef reaction: Tetrahedron Letters, 1971, 195-198

NOH

Oxime

TiCl3NH

1. 2. H2OO

McMurry was lucky, the reaction worked:

N

nitro

TiCl3N O

OHN

H

oxime imine

O O

Synthesis:

H baseHO Br

2 eq.HO

Lindlar Pd

HI

or:1. TsCl2. I

I

NaNO2

NO2

HO

NO2NH

OO

NO2

TiCl3

diglyme, ∆

MeO O OMe

O

ONaOH

O

Jasmone




Synthesis by Givaudan, Helv. Chim. Acta 1978, 61, 990-997

Br

H

Not a very good Electrophiledue to having a quite acidicProton in an allylic Position

Nu

undesiredside reaction

That's why he decided rather to use it as a nucleophile: MgBr

O

OH

O

That is present in a certain fraction in petrol refinery(The other compounds presentin the mixture are usually hydrocarbons and do therefore not react - pure Butin is very expensive)

n-Bu Li Li

OH

Lindlar-Pd,H2

Br

HBr

MgMgBr

OH

JONES-OX

Jones Reagent:CrO3, diluted H2SO4, acetone

O

NO2

NaOH

O

Conj. Addition

Nef-reaction1

O

2

3

NO2

4

O

NaOH

O

Jasmone

Synthesis of Jasmone by Stetter, Synthesis 1975, 379-380

Od1

NO2

Might be:

OR

CN

EtO

R

SS




Ph H

O

+ cat. KCNPh

O

OH

Phbenzoine

Ph H

O

+CN Ph H

O

CN

Ph

OH

CN

Ph

OH

CN

O

Ph

more acidicas the other

Ph

O

CN

OH

Ph+ Ph

O

OH

PhCN

cat.

R

O

HCN

R

O

H

CN

In the presence of:

R

OH

CN

O Will react much slower with CN , because theCarbonylfunction is stabilized by conjugation.

O

Conj. Add. RMe

OCN

OH

RMe

OCN

O

R 12

34 Me

O

O

Stetter: Biomimetic Reaction

Tetrahedron Letters, 1974, 4505-4508

Review: Org. React. 1991, 40, 407-496

Biomimetic: Means copied from nature.

Vitamine B1 (Thiamine)

HO

NH2

N+

SN

N

thiamine

Cl-Simplified by Stetter:

HO

PhN+

S

X

H

Thiazolium-Salt

Today also chiral versionsfor asymmetric reactions.

This proton is quite acidic!

NaOH

HO

Bn

N

SHO

Bn

N

S

This anion replaces the role of the CN that we saw in the reaction above.




Another way to see it is:

HO

Bn

N

S

A nucleophilic Carbene

This kind of carbenes are pretty important today:

N

N

Ar

Ar

The first carbene that was isolated, crystalized and characterized.Today there are many chiral versions available that are usedin asymmetric synthesis.

N

Very reactive species! Proneto nucleophilicattack.

N

N

Ar

Ar

N

N

Ar

Ar6-π Electron aromaticsystem, that's why the carbeneis so stable!

HN

Putting different charges on thesame carbon atom can also be away of representing a carbene!

Nu

Mesityl- Adamantyl-

N

N

Idea:Block the site proneto nucleophilic attackwith very bulky substituents.

N

N

N

N The 2 plane where the 2 mesitylsubstituents are lying in are perpendicular to each other.

The fact that carbenes can be used in catalysis as a Ligand is due to the fact that the 2 Electrons in the sp2

Orbital behave like lone pair and can thus donate electron density to the corresponding metal.

N

N

R

R

behaves like aDonor e.g.

RPR

R

Carbenes in catalysis are often named NHC-Ligands (N-Heterocyclic Carbenes) and offer many advantages

compare to their Phosphorous counterparts:

a) Environmentally more friendly (often non toxic)

b) Not sensitive to oxidation

c) Lower Molecular mass, for industrial purpose this means less gramms or kg of Ligand has to be added.




O

O

O

(with cat. Stetter reagent)+

+ DMFO

BrMg

Br

HO

(already discussedsee above)

For adding a formyl DMF is the best reagent (Adding the Weinrebamide would more complicated).

H OH

OSO2Cl2

H Cl

O

instableCO + HCl

H OH

ODCC

H

O

Me

HN

OMe

MeN

OMe

BrMg

H

O

R

Historically Formyl groups were added with the help of Orthoesters:

R MgX

EtO

Et

EtO

Et

in the presence of :

HC OEtOEt

OEtOrthoester

Heat > 35°Cand evaporatethe ether

R MgX

HC OEtOEt

OEt

OEt

OEt

H

Highly reactive,will react immediatelywith the grignardreagent.

R MgX

OEt

OEt

HR

H3O

H

O

R

Stetter chose to change the orthoester in makingone of the OEt group to a better leaving group aPhenol (OPh). This facilitates the reaction and it canbe done now at r.t.

HC OEtOEt

OEt+ PhOH HC OEt

OEt

OPh+ HOEt

Utilisation of mixed othoformiates: Chem. Ber. 1970, 103, 643

Synthesis of Stetter

MgBr H3OHC OEt

OEt

OPhOEt

OEt O

O10 mol%Thiazolium-Salt

4

O

3

2

1

O

O

Jasmone

NaOH




Different approach using Photo-reactions:

O

OO

Orotation ofC-C bond R

OH OHHIO4

R

OsO4

very difficultto synthesize

O

O

hν

O OH

O

O

hν

5

4 32

O1

O

H

Biradikal

1,5 H-ShiftOH

O O

OH

Problem:

O

OH BrMg

Does it come from above or below?

Answer: 50:50

OH

ROH

50 : 50

OH

ROH

Only this diastereoisomerwill react with HIO4, the othercannot react in a syn-fashion.

Synthesis by Büchi JOC 1966, 31, 977-978

O

Molecules with the same oxidation state:

N

O

O

Aminale

HN

NH

AcetaleImine

N

Enamine

OR

Enole / Enole-ether

O

O

Synthesis in 3 steps

OH

R

OH

Why not putting the 2 OHgroups together?O

R

To hydrolyze a furane is not that easy because it is aromatic, but it can be done!




O

n-Bu Li

O Li

Br

As discussed earlier not a good E but used anyway

OAcOH, H2SO4H2O

4

O

3

2

1

O

O

Jasmone

NaOH

Problem: under the very acidichydrolysis condition E/Z isomerizationtakes place! - 7% E Isomer is yielded

40%(3 steps)

one step

Synthesis of Jasmone by Hiyama, Bull. Chem. Soc. Jpn. 1980, 53, 169-173

(Electrocylic reactions)

In an electrocyclic reaction a ring is always broken or formed. Rings may, of course be formed by cycloadditions

as well, but the difference with electrocyclic reactions is that just one new σ bond is formed (or broken) across

the ends of a single conjugated π system.

The types of pericyclic reactions are distinguished by the number of σ bonds made or broken.

Types of pericyclic reactions

Cycloadditions

∆∆∆∆σσσσ = 2

Sigmatropic rearrangements

∆∆∆∆σσσσ = 0

2 new σ-bonds are formed

... or broken

One new σ-bonds is formed as another is broken.

Electrocyclic reactions

∆∆∆∆σσσσ = 1

One new σ-bonds is formed

... or broken

Rules for electrocyclic reactions

All electrocyclic reactions are allowed

Thermal electrocyclic reactions involving (4n+2)π electrons are disrotatory:

one group rotates clockwise and one anticlockwise

Thermal electrocyclic reactions involving (4n)π electrons are conrotatory, in contrary reactions the two groups

rotate in the same way:

both clockwise both counterclockwise




The Nazarow reaction: Short revision

For more details see: Org. React. 1994, 45, 1-158

O

R R

O

hν (254 nm)

benzene

O

R RDisrotatory Conrotatory

AcOH, H3PO450°C

R R

O

R R

H

O

R R In its simplest form the Nazarow cyclization is the ring closure of a doubly α,β unsaturated ketone to give a

cyclopentenone.

O

R R

HO

R R

H OH

R

R

array of five p orbitalscontaining 4p electrons

empty

One of the five π orbitals involved is empty, so the cyclization is a 4π electrocyclic reaction and the orbitals

forming the new σ bond must interact antarafacially.

ππππ4a

O

R R

HOH

R

R

OH

HR R

OH

R R

O

R Rcyclopentenone

Usually the double bond is formed at the site which is higher substituted (thermodynamically more stable

product) to get the double bond at the less substituted site can also be done by introducing a silicon-

substituent:

O

TMS R

Lewis acid

O

TMS R

LA

Nazarow

O

TMS R

LA

Anion

O

R

H3O




Synthesis of Hiyama Bull. Chem. Soc. Jpn 1980, 53, 169-173

O

HCOOH,H3PO4

O

O

H

best nucleophilein the mixture

OH

OH

O

HO

HO

Difficult mechanism:Tautomerization,Isomerization,Eliminatation....For more details consultliterature given.

Some commercially available 5-memebered rings:

O O O

O

cyclopentane-1,3-dione

Is an important starting materialfor the industrial synthesis of steroids.

O O

O

O

is like other 1,3 diketonesin equilibrium with itsenol.

O OH

OH

O

The Keto-Enol Tautomerization can be seen in the 1H-NMR.

OH

O soft E

hard E

OH

O

E

O

O

E

Examples for E :

R I

EtO Cl

O

O

OO

,

Vinylogous Behaviour:

O

OH

OH

O

R

behaves like acarboxlic acid

pKa = 9-10

OH

O

This one also

Synthesis by Piers et al Can. J. Chem. 1982, 60, 1256-1263

O

O O




O

O

ClNaOH

O

O

Na O

O

Esoft

Br2, PPh3

Br

O

(due to Vinologous behaviour sameconditions can be used as for Carboxylicacids!)

Me2CuLi

Br

O

MeMe

O

Even easier:

O

O

EtOH, H

OEt

O

(due to Vinologous behaviour sameconditions can be used as for Carboxylicacids!)

This is a electron richdouble bond and thereforeMe2CuLi doesn't react nicelywith this molecule.

MeLi

OEt

OHMe

H

Me

O

Review on conjugated addition of Organocopper reagents: Org. React. 1972, 19, 1-113

Org. React. 1992, 42, 135-631

Revisit on Organocopper reagents:

Homocuprates (Gilman reagents): Me2CuLi, Bu2CuLi

e.g. Me2CuLi, Bu2CuLi

Mixed homocuprate: RCuR'Li

Mixed homocuprates are used in order not to waste halt of the Substituent R:

R MgX + CuCl2 R Cu + RCl + MgXCl

MeCuBuLi (Bu-Substituent is transfered), R Cu R'

Li

(The R substituent is transfered, alkynes are never

transfered!)

Heterocuprates: RCuXR'

e.g. -SPh, -OtBu (these substituents are never transfered)

R Li + CuSPh RCuSPhLi

R3CuLi2 (higher order cuprates)

Those were discovered by following experiment: MeLi and CuI were mixed in various rations and the Me-

Singlet in the 1H-NMR was observed: When mixing MeLi and CuI in a 3:1 ratio only a single species could be

seen.

Cyanocuprates (Lipshutz cuprates) R3CuCNLi2

2 RLi + CuCN R2CuCNLi2 (R2CuLi, LiCN) Cyanide (CN) acts as the 3rd R group in relation to the creation of higher order cuprates.




� The LiI that is created while reacting RLi and CuI is absolutely necessary for reactions to take place!

� The cuprates have a shape of a plane square, therefore reactions can done highly

diastereoseletive because cuprates are quite sensitive to sterical effects:

O

Cuprate

Example for an application of organocopper reagents: 1,4 Addition to Pyridinium-Salts

N

R'

R Cl

O

N

R'

R O

RMgX

R2CuLi

N

R'

R O

R

N

R'

R O

R

*

*

Construction of molecules that resemble natures NAD, NADH

Synthesis of Grieco JOC, 1972, 37, 2363-2364

Made out of:

, H

O

C

Cl Cl

Heating and destillationof cyclopentadiene

[2+2]O

ClCl

O

C

Cl Cl

Cl

O

Cl

ClCl Cl

O

Cl

ClH NEt3

Zn+

Made out of:

or

O

C

H H

stable

Not stable,reacts with itself:

OO

O

C

Cl Cl

[2+2]O

ClCl

O

ClCl CH2N2

Bayer Villinger

AcOH, H2O2

O

O

O




O

ODIBAL-H

O

OH

For a lactone the bestreducing agent to a lactoleis DIBAL-H, for an ester this might not work so well!

OH

O

Wittig

PPh3

OH

CrO3, verd. H2SO4, AcetonJones-Reagent

O

under the acidcconditions:isomerization

OH

O

H

Thermodynamically morestable due to being a trisubstituted double bond.

MeLi OH

Me CrO3, verd. H2SO4, AcetonJones-Reagent

Me

tertiary alcohol,H2O is eliminated

Me

tertiary alcohol cannot be oxidized!

Me

HO

Me

O

CrO3

Jasmone

The textbook Clayden, Greeves, Warren and Wothers (Oxford University press, p. 951, 2004 reprint) proposes

a different mechanism:

OR Li

OH

R

OH

ROCrO3

H

OH

R CrO3

H

O

R

CrO

OHO

[3,3] O

R

CrO

OHHO

H

H

(VI)

CrO3

(VI)orange

CrO3

(III)green

RO

+ Cr(IV) gives Cr(III) and Cr(VI) by disproportionation.

The first step is the formation of a chromate ester but this intermediate has no proton to lose, so it transfers

the chromate to the other end of the allylic system where there is a proton. The chromate transfer can be

drawn as a [3,3] sigmatropic rearrangement.

Very general method:

OR'

O

R

R'HO

OxH

R'

R

R R

OH

R' MgBr




Cope Rearrangement

1 2

Cope

1 2

CopeTechnique to enlarge cyclic systems

35

4

2

1

3 4

2

1

5

Synthesis of Descotes Synthesis 1975, 118-119

2

3

O

H1

4

5

6

O O

Jasmone2 steps as

explained above(Grignard, Oxidation)

2

3

H1

4

5

6 H

Z

CO2Et

CO2Et

YZnCH2

X

CO2Et

CO2Et

Simmons Smith

muchcheaper

EtO2C CO2Et

BrBr

+ + K2CO3

EtO2C CO2EtK2CO3 EtO2C CO2Et Br

Br EtO2C CO2Et

Br

K2CO3

EtO2C CO2Et

Br

intramolecularreaction

(ring closure)EtO2C CO2Et




Br

Br

+

CO2Et

CO2Et K2CO3

DMF CO2Et

CO2Et?

CO2Et

CO2Et

Br

SN2'

CO2Et

CO2Et

∆

150°C CO2Et

CO2Et?

Industrial Synthesis (Firmenich) Helv. Chim. Acta 1978, 61, 2524-2529

Br+ Br2 (hν) (heat in a radical fashion)

+Br

Br

BrBr

BrE/Z mixture

+

Br

Br

and..

O

via theenolate

O> 150°C

O

The Problem is that during the radical bromination epoxides are involved due to the presence of air and one

day the plant that produced Jasmone via this pathway was blown up and since then this reaction is not used

industrially anymore.

synthesis of jasmone - chemistforchristchemistforchrist.de/organische chemie/synthesis...

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