Synthesis of ( R)-Muscone Synthesis of ( )-Musconechemistforchrist.de/Organische Chemie/Synthesis...
27
Synthesis of (R)-Muscone More resources available at www.chemistforchrist.de Synthesis of (R)-Muscone α (R) β O 15 14 1 2 3 (R) 4 5 O 6 7 8 15-membered-Cycle 13 12 11 10 9 (R) O Macrocycle, many degrees of freedom (freedom of rotation). Reaction are therefore rather intermolecular than intramolecular. A cycle with 15 members behaves more or less than a acyclic system. Variation at the configuration of C-3 influences strongly the odor character and the human olfactory threshold. R-Muscone has an extremely low threshold (0.027 ng/L) whereas S-Muscone has only a threshold of 3 ng/L and is therefore 100 times less intense than R-Muscone. R-Muscone was isolated by Walbaum in 1906 from musk pod obtained from the male musk deer Moschus moschferus,' and its structure was determined by Ruzicka in 1926. O O (CH 3 ) 2 CuLi + O O OEt OEt Dieckmann - Working under high dilution O O Br O Metathesis O O O Cl Negishi coupling Asymmetric Micheal addition Asymmetric hydrogenation O O O Isomerize to the α,β unsaturated species
Transcript of Synthesis of ( R)-Muscone Synthesis of ( )-Musconechemistforchrist.de/Organische Chemie/Synthesis...
Synthesis of (R)-Muscone
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Synthesis of (R)-Muscone
α
(R)β
O15
14
1
23(R)
45
O
6
7
8
15-membered-Cycle
13
12
11
10
9
(R)
O
� Macrocycle, many degrees of freedom (freedom of rotation). Reaction are therefore rather
intermolecular than intramolecular. A cycle with 15 members behaves more or less than a acyclic
system.
� Variation at the configuration of C-3 influences strongly the odor character and the human olfactory
threshold. R-Muscone has an extremely low threshold (0.027 ng/L) whereas S-Muscone has only a
threshold of 3 ng/L and is therefore 100 times less intense than R-Muscone. R-Muscone was isolated
by Walbaum in 1906 from musk pod obtained from the male musk deer Moschus moschferus,' and its
structure was determined by Ruzicka in 1926.
O
O
(CH3)2CuLi +
O
O
OEt
OEt
Dieckmann- Working under high dilution
O
O
Br
O
Metathesis
O O OCl
Negishicoupling
Asymmetric Michealaddition
Asymmetric hydrogenation
O O O
Isomerize to the α,βunsaturated species
Synthesis of (R)-Muscone
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Starting from large cycles:
Commercially available cheap cyclic systems:
Butadienedimerization
Butadienedimerization
8
Butadienetrimerization
12
500 ml, 20 €
500 g,40 €
OFluka 98
12 12
O
15
5 g,30 €
Synthesis by Tanaka et al: JCS Perkin I 1991, 1445 and Synlett 1994, 251
O
Br2
EtOH
OEtEtO
Br H3O
O
BrKOtBu
O
E/Z mixture(E = 95% + Z =5%)
Alternatives have been tried as well, due to a poor yield in the elimination of the bromide.
Elimination with Sulfur:
O O
SPh
15 15
O
SPh
15
O
H
O
SPh
15
OH
E > 99%
1) Br2, MeOH2) PhSNa, EtOH oxone
EtOHoxone = KHSO5
Pure trans compoundis obtained
CaCO3
benzene, reflux
Elimination with Selenium:
O
PhSe SePh
O
SePh
15 15
H2O2
O
SePh
15
O
H
O
SePh15
OH
E > 99% O
15Chiral Aminoalcohol
Me2CuLi
O
(R)
Muscone
Synthesis of (R)-Muscone
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� Simmons-Smith reaction, Org. React. 1973, 20, 1
Furukawa variant of the Simmons-Smith reaction Tet. Lett. 1966, 3353
Furakawa introduced Et2Zn instead of the Zn/Cu couple. Et2Zn is commercially available.
I IEt2Zn
I ZnI + EtI It's not a real carbene it is a carbenoid!
� Charette, Synlett 1995, 1197
Introducing the asymmetric variant of the Simmons-Smith reaction:
NR2
O
NR2
O
HO
HO
amide of tartric acid
OH
OH-is complexingthe Zn-Reagent
OHI ZnI
Ligand
Synthesis by Mash et al, JOC 1986, 51, 2721
Mash used chiral acetals to introduce a chiral center because the asymmetric version of Charette hasn't been
developed at that time.
O
O
ZnII
O
O
O
O Ph
PhZnII
O
O Ph
Ph
19:1 ds
OO
PhPh
H , H2O
O
Li, NH3
OO
prim radical,even though the sec. radicalwould be more stable this radical this radical is the one which seems to be preferred.
O
NH3 ort-BuOH
E.A. Mash: Another way to create the stereogenic center in the β-Position:
O
OR1
R2HO
HO
Synthesis of (R)-Muscone
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O O O O OO
OO
More important than 1,3 diaxial repulsions in the corresponding substituted cyclohexane, due to C-O bonds being shorter than C-C bonds
L.A.
OO L.A.
OO
L.A.O
O
Me
L.A.
H
Repulsion is getting smaller because the bond holding the two moieties together hasbeen broken.
OO Repulsion is getting greater because the
bond holding the two moieties together hasbeen transformed into a double bond.
L.A. OO
MeH
Prefered coordination
Disfavoured coordination
Therefore attacking the acetal with a nucleophile will cleave the bond pointing towards us rather the bond
pointing away from us.
OO
MeH
Nu
Nu
HOO
MeH
Nu
ee > 90%
OO
MeH
Nu
Nu
OO
Me
α
Hβ
Nu Creation of the stereogenic center in the β-position.
Synthesis of Sakai, JOC 1992, 57, 4300 and Chem. Comm. 1991, 1438
O Me2CuLi O Li
+ MeCu
More a Lithium-Enolatedue to HSAB-concept
E O
E
O
OEt
O
OEtMe2CuLi
O
OEt
O
OEt
O
OEt
O
H , H2O
O
Synthesis of (R)-Muscone
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Dieckmann reaction:
O
O
OR'
O
R'
O R
O
O
R'
O R
Idea: Why not link the 2 ends together by a chiral auxialiary.
OHOH
OO
O
R'
R
O
OHO
O
R'
RO
Take the same principle and apply it to the conjugated addition!
OO
O
R
O
Me2CuLi
attack from the backside is disfavoured bysteric hindrance
s-cis geometry
If an attack from the back should be favoured one only has to replace the ester group by an OH-group which
coordinates the Me2CuLi
OO
O
R
Li
Me Cu
Me Cu Me
Li
Me
from backside
OHO
O
Me
H
R
OO
O
R'
O
R2CuLi
OO
O
R'
O
R
Dieckmann OHO
O
R'
O
R
What about if R' and R were connected?!
1. PPh3
2. B
OH
O
O
Br
OH
OH
O
BrBr
OH
O
O
PPh3
H OEt
OO
OH
O
O
12
12
O
OEt
Even under high dilution conditionsonly the polymerized product is formed.
Synthesis of (R)-Muscone
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Solution of Nicolau JOC, 1979, 44, 4011
OH
O
O
PPh3
H S
OO
O
O
O12
N N S
O
H
H Et
OO
12
O
O
O
O
Me2CuLi
O
O
O
O
DieckmannOH
O
O
O
H3O
HO
O
O
- CO2
O
1514
1
23
45
O
6
7
8
13
12
11
10
9
Muscone
71% (High dilution)
52%, ee = 85%
Try to imitate an intramolecular reaction by forming a intramolecular hydrogen bond which brings the alcohol
and the ester close enough to react!
Synthesis of Oppolzer JACS, 1993, 115, 1593
Key step in the synthesis:
Zn+
R H
OCat*
R
OH
*
O HO HOSimmonSmithLi/NH3
HO
Introduction to Zn-Chemistry: Chemistry of RZnX and R2Zn
Revue: Knochel, Chem. Rev. 1993, 93, 2117
1849 1st
Zn-Organyl synthesized by Frankland
Liebigs Ann. Chem. 1849, 71, 171 and 213
I + Zn Et2Zn (Inert atmosphere at that time was H2)
Lacking reactivity RZnX and R2Zn were soon replaced by the more reactive Grignard reagents MgX-R.
Synthesis of (R)-Muscone
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Reformatsky:
R
O
Br
Zn R
O
ZnBrR
O
Br
MgR
O
MgBr
R
O
Br
ROH
Br
R
O
R
O
O
R+ +
Polymerization
This reaction cannot be done with Mg, because due to its increased reactivity it would react with itself.
More ways to synthesize R-Zn:
R Zn
Hundsdiecker, German patent, 1936
Wittig Liebigs Ann. Chem. 1967, 702, 24
Resurrection of Zn-Chemistry
Negishi JACS, 1980, 102, 3298
Extended the scope of Zn-Chemistry to Crosscoupling reactions due to Zn-R being able to undergo
transmetallations unto Palladium.
R Li
R Al
orZnX2
R ZnXAr I
Pd (cat.)R Ar
can be functionalized
Ar for example might be:O
R
I
This would be impossible to do with Grignard reagents!
Thiele: Transmetallation with Organo copper reagents J. Organomet. Chem. 1968, 12, 225
RCuLi + ZnBr R
ZnBr
1990, Knochel: Conjugated addition of a Zn-organyl to Cyclohexenone
BrZn CO2EtCuCN
CO2Et
OO
+
Knochel showed that in principal Zn-organyls can imitate every reaction that Cu-organyls do!
Asymmetric addition of a Zn-Organyl to an aldehyde:
R Zn R
sp
not very reactive
but R'O
ZnR
sp3
Oxygen heteroatomattached to the Znchanges hybridizationand makes it more reactiv.
+
R'' H
O
R'' R
OH
Revues: Noyori, Angew. Chem. Int. Ed. 1991, 30, 49
Soai, Chem. Rev. 1993, 93, 2117
Synthesis of (R)-Muscone
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Enantioselective Addition to Aldehydes
Oguni, TL 1984, 25, 2823
Ph H
O
+ Et2ZnNH2
OH*
Ph H
OH
Aminoalcohol
Noyori JACS, 1986, 108, 6071
JACS, 1995, 117, 4832
Noyori determines the mechanism of the reaction and improves the enantiomeric excess (ee) in his study:
OH
NMe2
1% of catalyst loading is sufficient99% ee
DAIB Ligand
� Works well especially for ArCHO
� Hundreds of Aminoalcohol and Aminothiol Ligands have been synthesized that also yield products
with ee in the high 90's.
HO NMe2 HS NMe2
The DAIB Ligand shows a positive non-linear effect:
Ar H
OH
*ee (product)
OH
NMe2ee (Ligand)Entry
1
2
100%
50%
99%
91%
Usually the ee of the product is less or equal than the ee of the catalyst!
ee Catalyst
ee
Pro
du
ct
100%
100%
50%
91%
Positiv-N
L-Effect
Negativ-NL-Effe
ctLinear-Effe
ct
How can these results be explained?
R Zn R
HO
Me2N
+
spZn
N
OR
sp3 1 orbital is vacant at Zn
Therefore a dimer is formed so that the empty orbital can be filled by interaction with the dimer partner. (Can
be compared with AlCl3 or BH3 which also form dimers to get their electrons).
Synthesis of (R)-Muscone
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Zn
N
O
RZn
N
O
R
Zn
N
O
R
Ar O
Ar O
Zn
N
O
R
For a chiral catalyst like the complex formed with Noyori's DAIB catalyst several Dimer-combinations are
possible if the racemic mixture is used (R + S Monomer)
Zn
N
O
R
Zn
N
O
R
Possible combinations:
If the 2 (R) monomers form a dimer: (R,R)
If the 2 (S) monomers form a dimer: (S,S)
If the (S) and (R) monomer form a dimer: (S,R) or (R,S)
In this case the (R,S) dimer proofed to be the most stable and thus the least reactive (it is more or less
catalytically inactive). If for example we have a ee of the Ligand = 75% which corresponds to a mixture of e.g.
75% (R) and 25% (S) [or vice versa]. Then 25% of the (R) enantiomer and 25% of the (S) enantiomer would form
the "inactive" (R,S) complex. This means that 50% of pure (R) enantiomer remains and forms an active (R,R)
complex. So adding 1mol% of a Ligand with an ee of 75% is as effective as 0.5mol% of a Ligand with 100% ee.
Conclusion:
a) A non-linear effect is usually observed if there is at least one aggregation occurring.
b) The non-linear effect is:
⊕ positive: If the R,S or the S,R dimer is the more stable one.
� negative: If the R,R or the S,S dimer is more stable.
Preparation of Zn-Reagents according to Knochel:
REt2BH
RBEt2
Et2ZnR
ZnEt + Et3B
can't react with aldehydes!
R' H
O
R R'
OH
Synthesis by Oppolzer et. al: JACS 1993, 115, 1593
Introductory information 1:
In-BuLi
1) DIBAL-H2) I2
ZnBrR H
O
OH
R
NMe2HOis used stoichiometrically
Synthesis of (R)-Muscone
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Similar reaction asymmetrically:
(Cy)2BH
Cy = Cyclohexyl
B
Cy
Cy Et2Zn
ZnEt
sp2 sp3
sp2 is more reactive
than the sp3 moiety
and therefore is
transfered faster.
R H
O
R
OH
*
ee > 95%
1mol%DAIB
Introductory information 2:
ZIP-Reaction, Abrams Can. J. Chem. 1984, 62, 1333
nFG
nFG
FG = functional group
H
H
HCH3
Mechanism:
H
H
CH3
B
BH H
H
CH3
B
H
CH3
~H
CH3
work-up
CH3
H
The driving force is the deprotonation of the sp-Proton to form a the corresponding anion (remember sp C-H
has a pka of only 25, whereas sp3 C-H Protons have a pka ~ 50).
Abrams introduced the use of the KAPA base: K Amine Propyl Amide
Proton source and base is incorporated in one molecule leading to an "intramolecular" protonation,
deprotonation.
NH N
H
H
H
H
H C
t-Bu
H
HNLi
NH+ 1 eq. of t-BuOK
The one equivalent of KOtBu has been added to deprotonate the actylene-derivative completely.
Synthesis of (R)-Muscone
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Synthesis of Oppolzer:
OH
2 eq. n-BuLi
O
C12H25-Br
O
C12H25
1. KAPA2. SWERN
O12
HB(Cy)2
O12
Cy2BEt2Zn
O12
EtZn
1 mol%DAIB
OH Simmon-Smith
OH 1) SWERN2) Li/NH3
O
ee = 92%75%
82%
One would expect that in the last step the ketone is reduced to the corresponding alcohol. A footnote in the
this paper faces this problem:
"The use of rigorously dried liquid ammonia was essential to prevent the reported concomitant reduction of
the carbonyl group".
OH
H
HR
H
R
HO
H
H
HO
H
H
H H
favoured disfavouredA1,3 minimized
OHH
H
RH
R
A1,3 not minimized
(might be around 2 kcal/mol,
see below!)
F. Johnson, Chem. Rev. 1968, 68, 375; Allylic Strain in Six-Membered Rings
R. W. Hoffmann, Chem. Rev. 1989, 89, 1841-1860.
Allylic 1-3-Strain as a Controlling Element in Stereoselective Transformations
Houk, Hoffmann, JACS 1991, 113, 5006.
Synthesis of (R)-Muscone
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Synthesis of Jasmone by Tanaka
Use of heterocuprates:
O
heterocuprate*
O
Derived from camphor:
O O
N
NCu
R Li
stoich. use,99% ee
O
NH2
stoich. use,91% ee
Me
N
Me
OtherEnantiomer
Kim, Tetrahedron Asymmetry. 2002, 13, 801
O
OP N
Ph
Ph
KIM:O
L* + Me2Zn*
O
Pfaltz Synlett 2006, 1031
Pfaltz (Basel) was thinking of taking a more rigid dienone and thus getting better enantioselectivites (99% ee).
N
O
N
H
Ad
PFALZ:
O
L* + Me2Zn
OZn
Me
O
MeH2 / Pd
O
Me
Slide-in unit: Creation of Lithiumenolates:
O SiLi Me
OLi
+ Me4Si
Due to its hardness MeLi attacks the silicon atom and creates thus a Lithiumenolate.
One Pot 1,4 Addition, Cyclopropanation.
O OZn
Et
OZn
Et
Et2Zn, CH2I2Et2ZnTMSCl
OTMS
Et
Synthesis of (R)-Muscone
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OTMS
Et
1. Br2
2. NaOAc, MeOH, 20°C
O
Et
Cyclopropane can be seen as a double bond (Reminder: Walsh Orbitals giveπ Character rather than σ-Character)
Br2 BrBr
Br2Br
Br
O
Et
Br
Br
Me3Si
OAc
Et
Br
OH
OAc
Et
O
Synthesis of Muscone by Wender: JACS, 1983, 105, 3348
Literature for the methodology used by Wenders: Tet. Lett. 1981, 22, 2471
Tet. Lett. 1987, 37, 3967
JACS 1983, 105, 3348
1st Background information:
Revue Cope and Oxy-Cope reactions: Org. React. 1975, 22, 1
"Comprehensive Org. Synthesis" 1991, 5, 785
Oxycope reaction:
O O
As base usually KOtBu is used (O-Li bond is stronger, therefore O-K bond is higher in energy shifting the
equilibrium to the enolate. Crown ether (18-crown-6) is added to complex the K+ and give a highly basic OtBu
-
which is not stabilized by ion ion interactions. 6 electrons are shifting during in the TS, which is therefore
aromatic. Another aromatic system might be the following:
O O
Now imagine a 7 membered ring would be on the left side of the molecule and thus giving a 15 membered ring.
O O
157
Synthesis of (R)-Muscone
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Second background information:
OH
Cl
H2O, Cl2 R MgXO
Cl
MgX
intramolecularSN2
O
OH
Cl
R MgXO
Cl
MgX
anti
H
O
HH
In the second example the OMgX and the Cl are syn to each other and therefore a SN2 like displacement would
be impossible. Instead a hydride shift takes place and the Cl is kicked out by the H-.
Third background information:
Reduction of propargylic alcohols: Corey, JACS, 1967, 89, 4245
R
OH 1. LiAlH4
2. H2OR OH
1. LiAlH4
2. I2
R OH
I
+R OH
I
R OH
AlR3
+R OH
AlR3
Hydroalumination occurs in an antifashion (H transfered and Iodine are on opposite sides of the double bond).
The mixture of the 2 Products occurs due to impurities in the LiAlH4 like e.g. AlCl3.
LiAlH4 + AlCl3 AlH3 + LiCl + AlHCl2
Corey found out that a mixture of LiAlH4 and NaOMe (which neutralizes AlCl3) leads to the formation of:
R
OH 1. LiAlH4 R
OAl
2. I2 R
I
OH
Whereas alanes as produced by the AlCl3 impurity give:
R
OH 1. DIBAL-H R2. I2
R OH
R3Al
O
I Al
H
DIBAL-H
Note: The first 2 hydrides of LiAlH4 are very actively released, the others react much more sluggishly.
Synthesis of (R)-Muscone
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O
Cl Li R Cl
HO
R
LiAlH4Cl
O
R
AlR3
R3AlR
AlR3
O
sp>sp2>sp3
Facility of migration
R3Al
LiAlH4
R
AlR3
OH
H2O
OH
R
O
RCrO3
In case of Butenyne-Lithium we would have:
O
Cl Li Cl
HO
LiAlH4
OHO
CrO3
Li
HOOH
KH
O OH2O
14
Synthesis of Wenders:
O
Cl
1.Li
2. LiAlH4, NaOMe3. CrO3 (Collins)
O1.
Li
2. LiAlH43. H2O
KHOxy-Cope
O
E/Z mixture
H2/PdO
racemic
*
Synthesis of Muscone by Baker, JCS Chem. Comm. 1972, 802
� 2 steps
� Problem: Only 5% yield
Review: Nickel catalyzed oligormerisation Org React. 1972, 19, 115
Angew. Chem. Int. Ed. 1966, 5, 151
Synthesis of (R)-Muscone
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Ni(0), Ln Ni(II)
π-Allyl Species
Ni(0)Ni(II)
(II)Ni
Ni(II)
Depending on the Ligand:
COD
COD
bathtub-shape
Transition-metal
Ni(II)Ni(II)
π-Allyl Species
12
Di and Trimerization of Butadiene leads to inexpensive 8 and 12 membered macrocycles. COD as described in
the scheme is a well known Ligand for transition metalls.
Ni(II)
Ni(II)Can bewritten as:
Ni
(II)
Can bewritten as:
A nickel Allyl-p-complex attacking a propadiene (Allene):
Ni(II)
Propadiene instead of butadiene!
Ni(II)
π-Allyl Species
4
314
13
5 9
8
7
6
12
11
10
Ni(II)
2
1
red. Elimination 4
3
14
13
5 9
8
7
6
12
11
10
2
1
Now one carbon is still missing, this can be introduced by a CO-insertion:
Ni(II)+ CO
COinsertion
Ni
O
red.Elimination
O
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4
314
13
5 9
8
7
6
12
11
10
Ni(II)
2
1
4 8 124 4
COinsertion
4
314
13
5 9
8
7
6
12
11
10
Ni(II)
2
1
15
Ored.
Elimination
O
H2 / Pd
O
In a mixture with all kind of other possible isomers that might have occured.
5% Muscone was not isolated simply detected (most possibly by GC-MS). Even though the yield is very low (5%)
this might be nevertheless be interesting for industrial applications due to the starting material being
extremely cheap!
General approach to macrocycles:
In order to bring the 2 ends together in an intra rather than an intermolecular fashion it is extremely important
to work under high dilution conditions (~ 1g/l). High dilution methods are only applicable in the academic
realm. Industry could never afford wasting volume of reaction vessels or the huge quantities of solvent needed.
Synthesis of muscone by Nicolau: JOC, 1979, 44, 4011
O
(EtO)2P
O
O
H
K2CO3
high dilution(45-50%)
O
Me2CuLi
O
Muscone
SM
Synthesis of (R)-Muscone
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Synthesis of the starting material:
CO2Me
Methyloleate (C18)
Unsaturated fatty acid
O3
HO OHCO2Me
O
O
9
8
7
6
5
4
3
2
1
O
O O
C9 - (6 Carbons still missing)
MeO2CPPh3
9
8
7
6
5
4
3
2
1
O
O 10
11
Non stabilizide Anion!Leads to Z-configuration.
12
13
CO2Me14
P(OEt)2
O
EtO
O
9
8
7
6
5
4
3
2
1
O
O 10
11
Non stabilizide Anion!Leads to Z-configuration.
12
13
14
O
P(OEt)2
EtO O
O
H3O
- CO2
9
8
7
6
5
4
3
2O
10
11
12
13
14
O
P(OEt)2O
SM
SM1
SM2
Synthesis of SM1 and SM2:
O OHBr (dry) Br OBr
MeOH
OMe
O
Br
SM1
SM2
Br CO2Et
P(OEt)3Arbusow
(EtO)2P CO2Et
O
BaseP(OEt)2
O
EtO
O
R OMe
O
P(OEt)2
O
EtO
O
RO
OMe
-HOMe
P(OEt)2
O
EtO
O
RO
(EtO)2P
O
OEt
O
RO
(EtO)2P
O
OEt
O
RO
Not possible!
Reaction stopps here!
Synthesis by Tsuji et al: Bull. Chem. Soc. Jpn 1980, 53, 1417
Synthesis of (R)-Muscone
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O
O
O
15H2 / Pd
O
15
Muscone
SM
OPhAl
OPhAl
Acts as a soft Lewis acid (OPh was used to tune the Lewis acidityjust right)
high dilution(1-4 g)
Synthesis of the starting material:
1
161
16
O
O
Wacker oxidation
1
16
14
MgBr
Br
1
8
Br1
4
MgBr
The length of the starting material was chosen this waydue to being cheaper than other choices.
Slide-in unit: The Wacker oxidation Org. Synth. 1989, 67, 121
Oxidation of vinylgroups to methylketones.
RPdCl2 (cat.)
H2O, O2
CuCl2R
O
Instead of using Pd(II) in a stoichiometrically way a external oxidant (in this case air) is used to complete the
catalytic cycle. Oxygen present in air oxidizes Cu(I) to Cu(II).
H2O-II
CuCl2
II
CuClI
O2
0
PdCl2
II
Pd0
After the formation of the p-complex the best nucleophile present in the reaction mixture (H2O) is attacking the
alkene at the higher substituted end of the complex. Keto / Enol tautorimerization leads to the desired product.
RPdCl2 (cat.)
H2O, O2
CuCl2R
Pd Cl
ClH2O
R
OH
HPdCl
β-Hydride elimination
R
OH
Enol
R
O
Synthesis of (R)-Muscone
More resources available at
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Synthesis by Utimoto et al: Tet. Lett. 1978, 2310
Key reaction:
Cl
OMe3Si+ AlCl3
O
Obvious route:
Cl
O
O
15H2 / Pd
O
15
Muscone
TMS
high dilution Me2CuLi
O
15
Route chosen:
Cl
O
TMS
high dilution
52%
O
H2 / Pd
O
15
Muscone Starting material was made out of citronellol, the stereogenic centre is here already present in the right
configuration. Task for you: How can the starting material above be made from citronellol?
6
1
OH
Synthesis by Büchi et. al. : Helv. Chim. Acta 1979, 62, 2661
O
O
P(OEt)2
P(OEt)2
O
O
O OMe2CuLi
Only oncesee other
lecture
OH2 / Pd
O
20-25%
Problem:
The diketone starting material has lots of degrees of freedom and only 20-25% yield could be obtained for the
dienone. Therefore it was tried to make the diketone more rigid and thus give the system less opportunity to
move.
Synthesis of (R)-Muscone
More resources available at
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all trans(E,E,E)
Careful addition of1 eq. O3
O
O
P(OEt)2
P(OEt)2
O
O
O+
O
Me2CuLi
O
H2 / Pd
O
Muscone
Interesting observation: Only the Z-double bond reacts:
(Z,E,E)
Careful addition of1 eq. O3
Z
only the Z doublebond reacts
(Z,E,E)
O
O
50-55%
Takahashi for calculations and experiments: TL 1992, 33, 7561
Chem. Lett. 1997, 1291
Used computational methods to calculate on which points on the ring substituents have to be attached to
make the ring less flexible.
RONC
OR
NC
TsO OTs
CNRO
This double bond is essential for the rigidity!
Yields for Z-isomer: 37%
E-isomer: 64%
H2 / Pd
O
The calculations revealed that a E-double bond at the site shown make the system much more rigid and hence
reduce the degrees of freedom which usually causes a problem in the synthesis of macrocycles
Synthesis by Nicolaou et. al: JACS, 1998, 120, 5132
� Use of metathesis reaction
OO
metathesis
-
Synthesis of (R)-Muscone
More resources available at
www.chemistforchrist.de
3
2 1
54
6
O
Citronellal
Ru
PCy3
PCy3Cl
Cl PhGrubbs I
(first generation)
BrMg
13
2 1
54
6
OH
BrMg
10
BrBr
+
BrMg
The GRUBBS I catalyst doesn't work for gem-disubstituted olefins as the case in citronellal, therefore the
doublebond had to be cleaved and converted to a methylene-unit (which easiyl undergoes a metathesis
reaction.
OH
1. TMS-Cl2a. O32b. Me2S
O
OTMS
Wittig
OTMSRu
PCy3
PCy3Cl
Cl Ph
OTMS1. H+ or F-
2. Oxidation 3. Pd/H2
MUSCONE
In case of a protection of the OH group with TMS better yields were observed than without.
The GRUBBS II catalyst is able to carry the metathesis reaction out even with sterically hindered double bonds.
Ru
PCy3
Cl
Cl Ph
Grubbs II(2nd generation)
OH
NN
OH1. H2/Pd2. OX
O
1g/l High dilution76%
Even though this is a highly efficient route it has no industrial application due to the large amounts of solvent
needed for high dilution reactions.
Industrial Synthesis of Muscone
Synthesis using a C-3 and a C-12 builiding block
O
Cyclodecanone Cyclodecene
1212
Synthesis of (R)-Muscone
More resources available at
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12-membered macrocycles are inexpensive and therefore good starting materials for a industrial synthesis.
12 5
to break the bond that fuses the 2 rings together is not an easy task
Synthesis by Trost JACS 1980, 102, 5680
Before Trost was working on Pd (Allylic Substitution reactions etc.) he was doing a lot of works on sulfur
chemistry.
O
SPh
O
O
O
SPh
O
O
A Reversible Ring-opening reaction that is controlled by thermodynamics.
Synthon
Revue on these kind of synthons: Trost, Angew. Chemie. Int. Edition. 1986, 25, 1
Allylsilanes can be used under basic or acidic conditions.
Basic conditions:
Me3SiF E
Me3SiF
O
R
OH
R
The F- Ion is attacking the Silicon due to Si-F bonds being extremely strong.
Acidic conditions:
Me3Si
OTiCl4
R
Me3Si
αβ
O
R
TiCl4 OTMS
R
The activated Aldehyde is attacked by the Allylsilane to create a intermediate where the -Carbenium Iod is
stabilized through Hyperconjugation of the Silicon.
S
O
O
S
O
S
O
O
O
SulfonateSulfinateSulfoxide
Sulphur is a better nucleophile than oxygen, so in sulfinates the sulfur atom will atack the electrophile.
Synthesis of (R)-Muscone
More resources available at
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S
O
O
S
O
OE
The same is true in corresponding Phosphor analogues:
P
O
R P
R
OE
Phosphinite
Synthesis by TROST
O
2. Br23. PhSO2 Na
O
SPh
OO
1. Base
1. NaH2.
SiMe3Br
O
SO2Ph
SiMe3
O
Alternatively:
1. Base
2. S S PhPh
O
SPh
H2O2
O
SPh
OO
F
O
SO2Ph
O
SO2Ph
SiMe3O
SO2Ph
O
SO2Ph
work-up
1. H2/Pd2. Na/Hg Na2HPO4 (buffer?)
muscone
Na/Hg cleaves the C-SO2Ph bond.
Synthesis of (R)-Muscone
More resources available at
www.chemistforchrist.de
Synthesis of Muscone by Fehr (Firmenich) Helv. Chim. Acta 1983, 66, 2512
O
2.
1. LDA
Br
very reactive E+
(Allylbromide)
O1. PhSH AIBN (radical react.)
2. H2O2
O
SPh
Baeyer Villinger
O
O O+ H2O2
creating in situPeraceticacid
Oxidation of sulfur
O
SPh
O
O
O
Baeyer.V. higher subst.side
NaNH2O
SPh
O
O
O
12
O3
SPh
O
O
O
If it wouldn't bean ester, a driving force to cleave theC(1)-C(2) bond wouldbe missing rather theC(2)-C(3) bond wouldbe cleaved.
O
SPh
O
O
O
Na(Hg) O
OH
Polyphosphoricacid
made by mixingP4O10 with a little
water.
O
H2 / Pd
O
muscone
Even though the muscone isproduced in a racemic way, the other enantiomer doesn't smell very different but only much lessintense.
Synthesis of (R)-Muscone
More resources available at
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Eschenmoser Fragmentation (late 1960's)
The starting material is an epoxide of an α,β-unsaturated ketone. Ketone is reacted with tosylhydratzine to give
an alkyne.
O
H2O2, OH-
O
OTsNNH2
N
O
NH
Ts
MeO- Na+
in MeOH
N
O
N
Ts
N
O
N
Ts
O
fragmentation+
N2
S
Ar
O O
toluenesulfinate Important to note here: Sulfinate and especially N2 formation draws the equilibrium to the alkyne side. All the
bonds that break are parallel to one another, held anti-periplanar by two double bonds.
Application in the Synthesis of Muscone:
Büchi, Tet. Lett. 1976, 3585
O
Li
OLi
HO
HO
Polyphororic acid(made out of P4O10
+ a little H2O)
O
Mechanism for the second step:
HO
HO
- H2O
H
HO HO
- H
H
H2O
- H
HO
keto/enol
O
+H
HO
Nazarow
O
Synthesis of (R)-Muscone
More resources available at
www.chemistforchrist.de
This is a pretty general reaction sequence:
R+
O
H R1 R
OH
R1
H
R R1 R R1
H2O
R R1
OH
R R'
O
Modern Muscone Synthesis: Angew. Chem. 2007, 119, 1329 –1332
A very nice synthesis of (R)-muscone using enantioselective intramolecular Aldol Addition/Dehydration has
been published recently.
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