Synthesis of β-Vetivone More resources available ... - ChemistforChrist

Synthesis of β-Vetivone
β-Vetivone
O
O Special Features:
- Spiro compound
- 2 vicinal stereocenters
β-Vetivone produces the pleasant odor characteristic of the essence of vetiver oil, which is of great value to the
perfume, soap, and cosmetic industries. Isolation of β-vetivone from plant sources is tedious, time-consuming
and low-yielding, which accounts for the high cost of this fragrant oiL
β-Vetivone is a Seqsuiterpene (15 C-Atoms)
Terpenes are a large and varied class of hydrocarbons, produced primarily by a wide variety of plants,
particularly conifers. Terpenes are derived biosynthetically from units of isoprene, which has the molecular
formula C5H8. The basic molecular formulae of terpenes are multiples of that, (C5H8)n where n is the number of
linked isoprene units. This is called the isoprene rule or the C5 rule. The isoprene units may be linked together
"head to tail" to form linear chains or they may be arranged to form rings. One can consider the isoprene unit
as one of nature's common building blocks. Isoprene itself does not undergo the building process, but rather
activated forms, isopentenyl pyrophosphate (IPP or also isopentenyl diphosphate) and dimethylallyl
pyrophosphate (DMAPP or also dimethylallyl diphosphate), are the components in the biosynthetic pathway.
O
O P O
O
O
P O
O
O P O
Dimethylallyl pyrophosphate Isopentenyl pyrophosphate
O
O
As chains of isoprene units are built up, the resulting terpenes are classified sequentially by size as
hemiterpenes, monoterpenes, sesquiterpenes, diterpenes, sesterterpenes, triterpenes, and tetraterpenes.
Hemiterpenes C5 consist of a single isoprene unit. Isoprene itself is considered the only hemiterpene, but
oxygen-containing derivatives such as prenol and isovaleric acid are hemiterpenoids.
O
HO
prenol
OH
isovaleric acid
Monoterpenes C10 consist of two isoprene units and have the molecular formula C10H16. Examples of
monoterpenes are: geraniol and limonene. +
HO
geraniol limonene
Sesquiterpenes C15 consist of three isoprene units and have the molecular formula C15H24. Examples of
sesquiterpenes are: farnesol. The sesqui- prefix means one and a half.
P O
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O
O

Synthesis of β-Vetivone
HO
farnesol
Diterpenes C20 are composed for four isoprene units and have the molecular formula C20H32. They derive from
geranylgeranyl pyrophosphate. Examples of diterpenes are cafestol, kahweol, cembrene and taxadiene
(precursor of taxol). Diterpenes also form the basis for biologically important compounds such as retinol,
retinal, and phytol. They are known to be antimicrobial and antiinflammatory.
Triterpenes C30 consist of six isoprene units and have the molecular formula C30H48. The linear triterpene
squalene, the major constituent of shark liver oil, is derived from the reductive coupling of two molecules of
farnesyl pyrophosphate. Squalene is then processed biosynthetically to generate either lanosterol or
cycloartenol, the structural precursors to all the steroids.
squalene
Polyterpenes consist of long chains of many isoprene units. Natural rubber consists of polyisoprene in which
the double bonds are cis. Some plants produce a polyisoprene with trans double bonds, known as guttapercha.
Correct structure elucidation by M.J. Marshall JACS 1967, 89, 2749 and 2750
First synthesis: M.J. Marshall JOC 1970, 35, 192
Possible synthesis of the starting material used by Marshall:
O O
Key-step reaction:
Base
stays axial to avoid A 1.2 strain
with OH
Excerpt from a textbook how the mechanism could go:
The Di-π-Methane rearrangement
3
hν
O
O
Me
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O
hν, dioxane
1,4 Dienes carrying alkyl or aryl Substituents on C-3 can be photochemically rearraanget to vinylcyclopropane
in a reaction that is called the Di-π-Methane rearrangement. When photolyzed 2,5-cyclohexadienones can
undergo a number of different reactions, one of which is formally the same as the di-π-methane
rearrangement.
O
O

Synthesis of β-Vetivone
O
Ph Ph
hν
O
Ph Ph
O
Ph Ph
Another proposal for the mechanism (ionic pathway):
KROPP, JACS, 1963, 85, 3779
O
O
hν, dioxane
hν, dioxane
O
O
Ph Ph
O O
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O
Ph Ph
AcOH, Ac 2O
H 2SO 4
In comparison with the desired molecule, following steps have to be done:
Get rid of C=O
O
Attach:
Introduce a C=O
Remember: This is chemistry from 1970, fancy reagents haven't been known then and benzene was still used
as a solvent!
O
O
O
O
O
O
Ph
H
Ph

Synthesis of β-Vetivone
O
n-BuSH
Et 2O
H 2SO 4
O
BuS
AcO
AcO
O
H OMe
Base
O
HO
NaBH 4,
MeOH
Ac 2O,
NaOAc, Δ
Na 2CrO 4, AcOH
Ac 2O, 40°C
O
O
O
HO
BuS
HO
BF 3 . Et2O, rt
O
O
O
β−Vetivone
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O
HgCl 2, H 3O +
acetone
MeLi, Et 2O
- 35°C
O
O
O
O
hν, dioxane
, NaH
H OEt
benzene, MeOH
O
O
MeLi, Et 2O
- 35°C
1. Li, NH 3, Et 2O
2. CrO 3
A small amount of the isoprenyl
isomer is also formed:
Other disconnection approaches:
O O
Cl
O
or
HO
O
AcOH, Ac 2O
H 2SO 4
For the - charge there is no easy synthon
O
MnO 2
O

Synthesis of β-Vetivone
O O O
Problem:
1,4
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Br
Br
1,2
Enolate
O
1.2 or 1.4 attack, usually
the 1.2 attack is the major
one!
Maybe it is possible to block the 2 Position, so that it would mainly be an attack from the 4-Position:
SiMe 3
O
SiMe3 Problem:
Brook rearrangement
O
Ways to get a Enone that is substituted in the para-Position:
OTMS
Method No.1:
I OMe
R (Nucleophile)
+ Pd
R
OMe
Li, NH3 (Birch)
R
OMe
Method No.2:
Use of the Danishefsky Diene
OMe
TMSO
δ
OMe
δ
R
TMSO
Treatment with H 3O + leads to the most
stable conjugated enone.
OMe
OMe
R
H
H 2O
δ
H
H2O TMSO R Me R
O R
δ
Problem: Due HOMO of the 2 Donors being on the same side the upper reaction will not work but will rather
give the meta product. A possible solution would be to use a Dienophile with an EWG-group attached to it (e.g.
an ester).
O
R
R
H 3O
O

Synthesis of β-Vetivone
TMSO
OMe
δ
δ
CO 2R
TMSO
OMe
Method 3: Micheal addition of an enamine.
O
R
N
H
N
R
CO 2R
Synthesis by Storck: JACS, 1973, 95, 3414
O
LDA
O
OEt O
O
N
R
H
H 2O
O
2
R
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O
kinetic enolate
O
H
thermodynamic enolate
1
N
N
R
CO 2R
Idea of Storck: Create the kinetic enolate and place something at the para-Position that can be turned later on
into a ketone:
O
O
O
Synthesis of β-Vetivone by Storck
O
OEt
Me
O
β-Vetivone
O
H 3O
OEt
OEt
LDA
Me
HO
LDA
O
OEt
O
OEt
kinetic enolate
MeLi
O
2
R
R X
OEt R
OEt
O
Cl
Cl
OEt
O
O
OEt
6
Cl
O
LDA
HMPA
O
OEt
Cl
This Methyl group will
direct the attack of the
enolate.

Synthesis of β-Vetivone
Synthesis of starting material:
O
OEt
OEt
Cl
Cl
+
O
OH
OH
OEt
OEt
O
O
OEt
OEt
O
O
The last step didn't work due to following side reaction:
The fast ring closure is due to the a very reactive LG (Allylic chloride)
OH
New approach:
OH SO 2Cl
OH 2 eq. n-BuLi
OH
O
Cl
OH
LiAlH 4
O 2 eq. MsCl
O
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O
+
O
OH
OH
Reacts faster due to being
the less stabilized alcoholate
Yields are rather moderate but the dichloride could be obtained.
Revisiting dipolar, aprotic solvents
Me
O
S
Me
H
O
N Me
Me
DMSO DMF
Most important ones are DMSO and DMF
Cl
Cl
SO 2Cl
O
OMs
HMPA
LiCl
Cl
Cl
The allylic alcoholate
is not very reactive and
give is therefore quickly
Mesylated before
undergoing ring -
closure.
OMs
OMs
HMPA makes the Cl -
very nucleophilic.

Synthesis of β-Vetivone
HMPA Hexamethylphosphoramide
HMPA
Me 2N
Me2N Me2N P O
The most polar solvent that exists (Problem: might cause nasal cancers). HMPA is used as a solvent for
polymers, gases, and organometallic reagents. It usefully improves the selectivity of lithiation reactions,
because it breaks up the oligomers of lithium bases such as butyllithium. Because HMPA solvates cations so
well, while not solvating anions, it accelerates some difficult SN2 reactions. The basic oxygen atom in HMPA
coordinates strongly to Li + . Was used on a large scale as lubricant solvent in industry.
DMPU
DMPU
O
N N
DMPU is a cyclic urea sometimes used as a polar, aprotic organic solvent. D. Seebach showed that it is possible
to substitute the relatively toxic hexamethylphosphoramide (HMPA) with DMPU.
Synthesis of Asaoka Chem. Lett. 1988, 1225
Asaoka found a way to synthesize the enantiopure starting material (this will not be discussed here). The
strategy of the synthesis is pretty much the same as the one used by Stork:
Me 3Si
O
1) MeMgBr
5% CuX
2) TMS-Cl
The 1.4 addition is directed
mainly by the TMS-group
so that a single diasteroisomer
is formed.
Me 3Si
Analogous
to Peterson
Elimination
Cl
F
O
O
Me
TBAF
(Bu4N + F- )
Me
Me 3Si
MeLi
1. LDA
2. NCS
OTMS
Me
Me 3Si
OH
MeLi
Me
O
Me 3Si
PCC
Me
OLi
Me
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O
Allylic bromide
reacts faster than the
primary alkyl-bromide
attack from
upper side
Me
β-Vetivone
Br
Br
Me 3Si
The enolate here
would lead to a 7membered
cycle
-Disfavored-
NCS =
Me 3Si
7
O
O
N-Chloro-succinimid
Me
EtO , Na
EtOH
Na
1
Me
O
O
Br
5
Br
N Cl

Synthesis of β-Vetivone
The last step of the oxidation reaction with PCC we have already seen in the synthesis of JASMONE, here a little
reminder:
O
Thermodynamically more
stable due to being
a trisubstituted double
bond.
O
MeLi
Me
Jasmone
Synthesis of Posner JOC 1988, 53, 6031
MeO
O
S
O
O
MeTi(OiPr) 3
THF
Me CrO3, verd. H2SO4, Aceton
OH
Jones-Reagent
CrO 3
MeO
HO
Revisisiting: 1.4 Addition to chiral sulfoxides:
1.4 Addition to chiral sulfoxides:
µ O O
µ Decreasing Dipole-
R
S
Dipole interaction
R
O
S
R
O
Al (Hg)
created by reaction
of Al with HgCl 2
Chirality transfer on Carbon
OH
R
Al / Hg
O
S
O
S
Zn 2
O
OH
R
R
µ
Hydride
from above
O
R
S
O
µ
Cu-Organyl
will attack from
above!
R
DIBAL
ZnCl 2
O
O
S
tertiary alcohol,
H 2O is eliminated
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tertiary alcohol cannot be oxidized!
Me
O
S
O
Add metal
M = Zn, Ti
O
R
O
DIBAL
R
Raney-Nickel
EtOH
M
O O
S
Cu-Organyl
will attack from
below!
(Clayden, Greeves, Warren and Wothers, p.1266, reprint 2004, Oxford University press
O
S
Me
Me
O
O
51% yield
93% ee
Metal complexes
the oxygens and
attack leads to
the other isomer!
OH
R
Al / Hg
O R
S
O
Reduced
Dipol-Dipol
Interaction!
Hydride
from above
OH
R

Synthesis of β-Vetivone
Enolate can only
be formed here
O
O
This bond is the precursor
of the C=O bond
Methyl group is supposed to
direct the reactions to give
diasteromerically pure compounds.
Posner is using the same dihalide precursor as Storck (see above)
allylic bromide is
O
O
substituted faster
Br
KHMDS
Br
O
KHMDS
+
O
Mesitoylchloride
DMAP
Synthesis of Dauben
JACS 1975, 97, 1622
JACS 1977, 99, 7307
O
O
OH
O
Br
OH
1 eq.MeMgr
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O
Use of Mesitoylchloride prrevents the ketone from being attacked again by MeMgBr
to afford the corresponding tert-alcohol.
O
CrO 3 . 2Pyr
Ph 3P CH 2
Using the Fuchs (from Corey-Fuchs reaction) Synthon:
O
OH
Br
CH 2 O
O
1. CrO 3
2. SnCl 4
Oxidation to
aldehyde and
cyclisation
(no standard
chemistry)
O
O
K
O
O
LiAlH 4
PPh3 BF4
CO2Et - -
The Counterion BF4 is chosen because Cl and other halides often give very hygroscopic Salts and are often less
soluble.
CH 2
OH

Synthesis of β-Vetivone
Possible Synthesis:
EtO
Br
O
PPh 3
Br 2
For a simple system:
EtO
O
PPh 3
Br
O O
1. LDA
2.
O
EtO H
EtO
O
OEt
Diethylcarbonate
PPh 3
EtO
O
Br
O O
H
O
CO 2Et
EtO
PPh 3
O
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H
CO 2Et
O
H
PPh 3
NaH
Wittig
base
Br
O
Ph 3P
O
EtO
EtO
O
O
O
Br
O
H
PPh 3
CO 2Et
CO 2Et
H
PPh 3
PPh 3

Synthesis of β-Vetivone
For the real system:
EtO
O
1. Ac 2O
2, BF 3
by elimination
of the tert-alcohol
O
1. NaH
2.
O
EtO H
EtO
EtO
Synthesis of Büchi JOC 1976, 41, 3208
H
H
pKa = 15
base
O
O
OH
O
H
MeLi
NaH
EtO
This double bond formed
due to being the most stable
one (4 Subst instead of 3)
H
O
R H
EtO
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O
O
H
Only this enantiomer shown,
to explain diasteroselectivity
of the reaction.
O
OH
H
R
The Fuchs synthon comes in anti in regard to
the methyl group.
CO 2Et
- H 2O
PPh 3
CO 2Et
H 2 / Pd
EtO
EtO
O
Ph 3P
O
CO 2Et
O
Wittig
H
CO 2Et
This double bond
is more e - poor than the
other one (even though the
difference might not be that
big)
Fulvenes
Fulvenes can react as a micheal acceptor. The driving force of the reaction is the creation of an aromatic
system:
Nu
R
For example: Nu = R 2CuLi (Cuprates)
R
Nu
6 π-electron
System
R

Synthesis of β-Vetivone
Synthesis of the starting material:
O
5
Synthesis:
H
H
1
O
O
Rationale:
Pseudo 1,3 diaxial interaction
O
O O (Enolate of acetaldehye is very
difficult to create, either the use
of enamine chemistry or reacting
n-BuLi with THF might help).
O
n-BuLi
O
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Li
+
OLi
This is the reason why reactions including THF and n-BuLi
are often cooled down to -78°C.
O
O O
favored
(2 methyl are eq, ax)
+
disfavored
(2 methyl are ax, ax)
O
Ozonolysis + work up with
Me 2S
O
Me 2CuLi
O
1 single
diasteroisomer
is formed
The hydrogenation of only on of the double bonds in the furane ring proofed to be very difficult. The only
reagent found to do the job was Diimine:
Reminder of diimine reduction
Usually gives an excellent Z/E ration (up to 99.9%)
Synthesis of H N N H :
DEAD:
EtO2C N N CO2Et H 2O / NaOH
Na O2C N N CO2 Na
Very reactive! H N N H
HO2C N N CO
- CO
2H
2
Problem: Intermediates and the diimine might be explosive (Not done in industry, largest scale might be 2 or 3
mmol).
H
OH

Synthesis of β-Vetivone
OH
Might help to selectively
reduce one double bond
1) Ac 2O
2) NH=NH (Diimine)
Desymmetrizing the
the 5-membered cycle
Usual text-book chemistry of opening epoxides:
O
Nu
Nu
This might change quite a bit with sterically hindered nucleophiles:
OH
With Grignard reagents, X (e.g. Br) might turn out to be the nucleophile:
O
R Mg X
With BuLi Deprotonation might occur:
n-Bu Li
O O
This reaction was used by Büchi:
OH
O
nBuLi
X
OH
O
OH
The other H would
be too hindered to
deprotonate
OH
Example
OH
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O
O
O
O
O H
R Mg Br
OH
O
OH
O
X
PPh 3
Wittig
Br
OH
β−Vetivone