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).
Synthesis of JASMONE
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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
Synthesis of JASMONE
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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)
Synthesis of JASMONE
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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 of JASMONE
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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 JASMONE
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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
Synthesis of JASMONE
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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
Synthesis of JASMONE
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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 of JASMONE
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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
Synthesis of JASMONE
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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.
Synthesis of JASMONE
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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.
Synthesis of JASMONE
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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
Synthesis of JASMONE
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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!
Synthesis of JASMONE
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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
Synthesis of JASMONE
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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
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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
Synthesis of JASMONE
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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.
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� 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
Synthesis of JASMONE
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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
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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
Synthesis of JASMONE
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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.
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