Synthesis of (R)-Muscone Synthesis of (R)-Muscone

O
(R) (R) 3 4 5 6 8 7

O
1 2

15 14 12 13 11 9 10

O
(R)

15-membered-Cycle

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 + Br O O OEt

O OEt

Dieckmann - Working under high dilution Metathesis

Asymmetric Micheal addition

Cl Negishi coupling

Asymmetric hydrogenation

O Isomerize to the , unsaturated species

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Synthesis of (R)-Muscone Starting from large cycles: Commercially available cheap cyclic systems:
Butadiene dimerization

Butadiene dimerization

Fluka 98 8

Butadiene trimerization 12

12

12

15

500 ml, 20

500 g, 40

5 g, 30

Synthesis by Tanaka et al: JCS Perkin I 1991, 1445 and Synlett 1994, 251
O Br2 EtOH Br EtO OEt H3O Br O KOtBu 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 15 1) Br2, MeOH 2) PhSNa, EtOH O Ph S 15 O S oxone Ph EtOH oxone = KHSO5 H O CaCO3 15 benzene, reflux 15 Ph O OH S

E > 99% Pure trans compound is obtained

Elimination with Selenium:

O PhSe 15 SePh Ph Se 15 H E > 99%
O 15 Chiral Aminoalcohol Me2CuLi O

O H 2O 2 Ph

O Se

O 15

O OH 15 Ph Se

(R) Muscone

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Synthesis of (R)-Muscone Simmons-Smith reaction, Furukawa variant of the Simmons-Smith reaction Org. React. 1973, 20, 1 Tet. Lett. 1966, 3353

Furakawa introduced Et2Zn instead of the Zn/Cu couple. Et2Zn is commercially available.
I I Et2Zn 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:
O I OH OH-is complexing the Zn-Reagent ZnI Ligand OH HO HO O NR2 NR2 amide of tartric acid

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 I ZnI O O

Ph O O I ZnI 19:1 ds O NH3 or t-BuOH O Ph O O Ph

Ph H , H2O

OO Ph

Ph

O Li, NH3

prim radical, even though the sec. radical would be more stable this radical this radical is the one which seems to be preferred.

E.A. Mash:
R1 R2 O O

Another way to create the stereogenic center in the -Position:

HO HO

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Synthesis of (R)-Muscone

O O

O O

More important than 1,3 diaxial repulsions in the corresponding substituted cyclohexane, due to C-O bonds being shorter than C-C bonds

Prefered coordination O O L.A. O O L.A. L.A. H O O Me Repulsion is getting smaller because the bond holding the two moieties together has been broken.

Disfavoured coordination O L.A. O L.A. H O O Me Repulsion is getting greater because the bond holding the two moieties together has been transformed into a double bond.

Therefore attacking the acetal with a nucleophile will cleave the bond pointing towards us rather the bond pointing away from us.
Nu O O H Me Nu Nu O HO H Me ee > 90%

Nu O O H Me Nu Nu

O O H Me

Creation of the stereogenic center in the -position.

Synthesis of Sakai,
O Me2CuLi

JOC 1992, 57, 4300 and Chem. Comm. 1991, 1438

+ MeCu O Li E E O

More a Lithium-Enolate due to HSAB-concept

O OEt O OEt Me2CuLi

O OEt O OEt

O H , H2O O OEt

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Synthesis of (R)-Muscone Dieckmann reaction:

O O O O O R' O O R R' O R R'

Idea: Why not link the 2 ends together by a chiral auxialiary.

O OH OH O O O R R' O O OH R' O R

Take the same principle and apply it to the conjugated addition!

O O O O Me2CuLi R attack from the back side is disfavoured by steric 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
Me Cu Me Li O O O R from backside O H
O O O O O R2CuLi R' O O O O R' R Dieckmann O R' OH O R

Li O OH Me R

Me Cu Me

What about if R' and R were connected?!

O OH OH Br Br OH O O Br 1. PPh3 2. B O OH O PPh3 H
12

O OEt

Even under high dilution conditions only the polymerized product is formed.

OH O O

O OEt
12

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Synthesis of (R)-Muscone Solution of Nicolau JOC, 1979, 44, 4011

O OH O O PPh3 H
12

O S N O H O O O O Et
12

O N S

71% (High dilution) O O O Me2CuLi O

H O O HO - CO2 O O

O OH O O 52%, ee = 85%
15 14 1 2 3 13 11 9 5 6 7 8 10 12

O Dieckmann O O O

H 3O

Muscone

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:
O Zn + R H Cat*

*
HO Li/NH3

OH

HO

Simmon Smith

HO

Introduction to Zn-Chemistry: Chemistry of RZnX and R2Zn Revue: Knochel, Chem. Rev. 1993, 93, 2117 1849 1 Zn-Organyl synthesized by Frankland Liebigs Ann. Chem. 1849, 71, 171 and 213
I + Zn Et2Zn
st

(Inert atmosphere at that time was H2) Lacking reactivity RZnX and R2Zn were soon replaced by the more reactive Grignard reagents MgX-R.

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Synthesis of (R)-Muscone Reformatsky:

O O R Br Zn ZnBr O R R Br O Mg MgBr O R Br Br R OH R O R + R O Polymerization O R +

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, Wittig

German patent, 1936 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 ZnX2 Ar I Ar for example might be: O R I

or R Al

ZnX

Pd (cat.)

R Ar

can be functionalized

This would be impossible to do with Grignard reagents! Thiele: Transmetallation with Organo copper reagents
R CuLi + ZnBr R ZnBr

J. Organomet. Chem. 1968, 12, 225

1990, Knochel: Conjugated addition of a Zn-organyl to Cyclohexenone

O + BrZn CO2Et CuCN CO2Et O

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 but sp not very reactive R'O sp3 Zn R + R'' H R'' R O OH

Oxygen heteroatom attached to the Zn changes hybridization and makes it more reactiv.

Revues:

Noyori, Angew. Chem. Int. Ed. 1991, 30, 49 Soai, Chem. Rev. 1993, 93, 2117

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Synthesis of (R)-Muscone Enantioselective Addition to Aldehydes Oguni, TL 1984, 25, 2823

O Ph H + Et2Zn

*
NH2

OH Ph

OH H

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:
DAIB Ligand NMe2 OH 1% of catalyst loading is sufficient 99% ee

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:

OH Entry ee (Ligand) NMe2 OH ee (product) Ar

1 2

100% 50%

99% 91%

Usually the ee of the product is less or equal than the ee of the catalyst!
100% 91% ee Product
s Po iti L -E v -N

c ffe

t ec Eff a rvt t

e Lin g Ne

ati

fec -E f L N

50% ee Catalyst

100%

How can these results be explained?

HO R Zn R + sp Me2N sp3 R Zn N O 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).

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Synthesis of (R)-Muscone

R R Zn O N N O Zn Zn

N O R Ar O R Zn Ar O O N

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)
Possible combinations: R Zn O Zn N R O N 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 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.

occurring.

Preparation of Zn-Reagents according to Knochel:

O R Et2BH R Et2Zn BEt2 R ZnEt + Et3B R' H R R' OH

can't react with aldehydes!

Synthesis by Oppolzer et. al: JACS 1993, 115, 1593 Introductory information 1:
O 1) DIBAL-H 2) I2 I n-BuLi ZnBr R H R OH is used NMe2 stoichiometrically

HO

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Synthesis of (R)-Muscone Similar reaction asymmetrically:

sp2 (Cy)2BH B Cy = Cyclohexyl Cy Cy Et2Zn Zn sp3 Et R O H

1mol% sp2 is more reactive DAIB than the sp3 moiety and therefore is transfered faster.

OH ee > 95%

Introductory information 2: ZIP-Reaction, Abrams Can. J. Chem. 1984, 62, 1333

FG = functional group n FG n FG

Mechanism: H H B H CH3 H work-up CH3 H CH3 H CH3 BH H H B ~H H CH3 CH3

The driving force is the deprotonation of the sp-Proton to form a the corresponding anion (remember sp C-H 3 has a pka of only 25, whereas sp 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 HN Li NH + 1 eq. of t-BuOK H H H N H H C t-Bu H

The one equivalent of KOtBu has been added to deprotonate the actylene-derivative completely.

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Synthesis of (R)-Muscone Synthesis of Oppolzer:

2 eq. n-BuLi OH O C12H25-Br C12H25 O 1. KAPA 2. SWERN EtZn 12 1 mol% DAIB OH SimmonSmith ee = 92% 75% OH 1) SWERN 2) Li/NH3 82% O Et2Zn O Cy2B 12 HB(Cy)2 O 12 O

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".

HO H H H H R H H R OH H

HO H H H R

R OH H

favoured

1,3

minimized

disfavoured

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.

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Synthesis of (R)-Muscone Synthesis of Jasmone by Tanaka Use of heterocuprates:

O O

heterocuprate

Derived from camphor:

N O O Cu R N Me Li

stoich. use, 99% ee O

Me NH2 N

stoich. use, 91% ee Other Enantiomer

Kim, Tetrahedron Asymmetry. 2002, 13, 801

KIM: O O Ph L* + Me2Zn

O O

P N Ph

Pfaltz Synlett 2006, 1031 Pfaltz (Basel) was thinking of taking a more rigid dienone and thus getting better enantioselectivites (99% ee).
O OZn O O

L* + Me2Zn

Me

Me

H2 / Pd

Me

PFALZ: H N O N Ad

Slide-in unit: Creation of Lithiumenolates:

O Si Li Me OLi + Me4Si

Due to its hardness MeLi attacks the silicon atom and creates thus a Lithiumenolate. One Pot 1,4 Addition, Cyclopropanation.
O Et2Zn OZn Et2Zn, CH2I2 Et Et OZn TMSCl Et OTMS

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Synthesis of (R)-Muscone

OTMS

1. Br2 2. NaOAc, MeOH, 20C

Et

Et

Cyclopropane can be seen as a double bond (Reminder: Walsh Orbitals give Character rather than -Character) Br2 Br Br2 Br Br

Br

OAc Me3Si O Br Br Et Et O O Br OAc Et

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: Oxycope reaction:
O O

Org. React. 1975, 22, 1 "Comprehensive Org. Synthesis" 1991, 5, 785

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 7 O 15

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Synthesis of (R)-Muscone Second background information:

H2O, Cl2 OH Cl anti OH Cl R MgX O MgX H Cl H H O R MgX O MgX Cl intramolecular SN2 O

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
OH R 1. LiAlH4 2. H2O 1. LiAlH4 2. I2 R OH I R I AlR3 R AlR3 OH + R OH OH + R OH

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.
LiAlH 4 + AlCl3 AlH 3 + LiCl + AlHCl2

Corey found out that a mixture of LiAlH4 and NaOMe (which neutralizes AlCl3) leads to the formation of:
OH R 1. LiAlH4 R Al O 2. I2 R I OH

Whereas alanes as produced by the AlCl3 impurity give:

R3Al OH R 1. DIBAL-H R O

H
2. I2 I R OH

Al DIBAL-H

Note: The first 2 hydrides of LiAlH4 are very actively released, the others react much more sluggishly.

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Synthesis of (R)-Muscone
R R3Al O Cl Li R HO Cl LiAlH4 O AlR3 Cl sp>sp2>sp3 Facility of migration LiAlH4 R AlR3 R R3Al O R AlR3

O R CrO3

OH R H2O

OH

In case of Butenyne-Lithium we would have:

O Cl Li

HO Cl LiAlH4

OH CrO3

Li

O H2 O 14

O KH

OH

HO

Synthesis of Wenders:
Li O Cl O 1. 2. LiAlH4, NaOMe 3. CrO3 (Collins) O H2/Pd KH Oxy-Cope E/Z mixture O 1. 2. LiAlH4 3. H2O Li

*
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

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Synthesis of (R)-Muscone

Ni(0), Ln

Ni(II) -Allyl Species

Ni(0) Ni (II) Transition -metal COD

(II) Ni Ni(II) Depending on the Ligand:

bathtub-shape COD

Ni(II)

12 Ni(II) -Allyl Species

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.
(II)

Ni(II) Ni(II)

Can be written as:

Ni

Can be written as:

A nickel Allyl-p-complex attacking a propadiene (Allene):

Ni(II)

Propadiene instead of butadiene!

7 6 8 6 7 8

5 13

10

red. Elimination

5 13

10

Ni(II)
3 2 14

11 12 2 1

3 12 14

11

-Allyl Species

Ni(II)

Now one carbon is still missing, this can be introduced by a CO-insertion:

O Ni(II) CO insertion Ni red. Elimination O

+ CO

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Synthesis of (R)-Muscone
7 6 8 6 7 8

5 13

10

12
3 2 1

CO insertion

5 13

10

14

11 12 2 1 15

14

11 12

Ni(II)

Ni(II) O red. Elimination

In a mixture with all kind of other possible isomers that might have occured.

H2 / Pd

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 H SM O O K2CO3 high dilution (45-50%) Me2CuLi Muscone O

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Synthesis of (R)-Muscone Synthesis of the starting material:

Methyloleate (C18) Unsaturated fatty acid CO2Me HO O
1 3 2 4 5 6 7 8 11 12 9 10 13

O3 OH PPh3 SM1 O O

O CO2Me

MeO2C CO2Me
14

O
1 2 3 4 5 6 7 8 9

Non stabilizide Anion! Leads to Z-configuration.

C9 - (6 Carbons still missing)

O EtO

O P(OEt)2 SM2

O
1 3 2 4 5 6 7 8 11 12 9 10

EtO
13 14

O H3O P(OEt)2 - CO2

5 4 6

7 8

9 10 13 11 12 14

P(OEt)2

Non stabilizide Anion! Leads to Z-configuration.

SM

Synthesis of SM1 and SM2:

SM1 O O HBr (dry) Br Br O MeOH Br O OMe SM2 Br CO2Et P(OEt)3 Arbusow

(EtO)2P O

CO2Et

Base EtO

O P(OEt)2 O R OMe

Not possible! O (EtO)2P O R O OEt

Reaction stopps here! O (EtO)2P O R O OEt EtO O O O P(OEt)2 R OMe -HOMe EtO O O O P(OEt)2 R

Synthesis by Tsuji et al: Bull. Chem. Soc. Jpn 1980, 53, 1417

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Synthesis of (R)-Muscone
O O Al OPh SM O high dilution (1-4 g) 15 H2 / Pd 15 O

Muscone Acts as a soft Lewis acid (OPh was used to tune the Lewis acidity just right)

Al OPh

Synthesis of the starting material:

O
16 1

Wacker oxidation
1

16

MgBr
4 1

Br
1

MgBr Br
4 1 1 16

The length of the starting material was chosen this way due to being cheaper than other choices.

Slide-in unit: The Wacker oxidation Org. Synth. 1989, 67, 121 Oxidation of vinylgroups to methylketones.
R PdCl2 (cat.) H2O, O2 CuCl2 R 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).
II II 0

PdCl2

CuCl2

O2

Pd

-II

CuCl

H2O

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.
H 2O R Cl Pd Cl R OH -Hydride elimination H PdCl R Enol OH R O

PdCl2 (cat.) H2O, O2 CuCl2

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Synthesis of (R)-Muscone Synthesis by Utimoto et al: Key reaction:

O Cl + Me3Si AlCl3 O

Tet. Lett. 1978, 2310

Obvious route:
O O Cl high dilution TMS 15 Me2CuLi 15 H2 / Pd 15 O O

Muscone

Route chosen:
O Cl 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?
1

OH
6

Synthesis by Bchi et. al. :

O P(OEt)2 O O O P(OEt)2 O

Helv. Chim. Acta 1979, 62, 2661

Me2CuLi Only once see other lecture

H2 / Pd

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.

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Synthesis of (R)-Muscone
O O Careful addition of 1 eq. O3 O + O P(OEt)2 all trans (E,E,E) O Me2CuLi P(OEt)2 O

Muscone

H2 / Pd

Interesting observation: Only the Z-double bond reacts:

O Z Careful addition of 1 eq. O3 only the Z double bond reacts (Z,E,E) (Z,E,E) 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.
OR NC TsO NC RO This double bond is essential for the rigidity! Yields for Z-isomer: 37% E-isomer: 64% OTs H2 / Pd RO CN 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
O O metathesis -

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Synthesis of (R)-Muscone
OH
6 3 2 4 5 1 6

O BrMg

1 10

3 2

4 5 1

Cl Cl Citronellal

PCy3 Ru PCy3 Ph Grubbs I (first generation)

BrMg

Br BrMg

Br +

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-Cl 2a. O3 2b. Me2S O 1. H+ or F2. Oxidation 3. Pd/H2 MUSCONE OTMS Cl Cl PCy3 Ru PCy3 Ph OTMS Wittig OTMS

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.
OH Grubbs II (2nd generation) N Cl Cl Ru PCy3 Ph N 76% OH 1. H2/Pd 2. OX O

1g/l High dilution

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

12

12 Cyclodecene

Cyclodecanone

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Synthesis of (R)-Muscone 12-membered macrocycles are inexpensive and therefore good starting materials for a industrial synthesis.
12

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 O

Ph

S O O

Ph

S 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:
F Me3Si E O F
-

OH R R

Me3Si

The F Ion is attacking the Silicon due to Si-F bonds being extremely strong. Acidic conditions:
O Me3Si TiCl4 R

Me3Si

R R O TiCl4 OTMS

The activated Aldehyde is attacked by the Allylsilane to create a intermediate where the -Carbenium Iod is stabilized through Hyperconjugation of the Silicon.
O S S O Sulfoxide Sulfinate O O S O O Sulfonate

Sulphur is a better nucleophile than oxygen, so in sulfinates the sulfur atom will atack the electrophile.

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Synthesis of (R)-Muscone
O S O S O O E

The same is true in corresponding Phosphor analogues:

R P O Phosphinite R P O E

Synthesis by TROST
O 1. Base 2. Br2 3. PhSO2 Na O O O S Ph 1. NaH 2. Br SiMe3 O SO2Ph SiMe3

Alternatively: O 1. Base 2. Ph S S Ph O S H2O2 Ph O O O S Ph

O SO2Ph

SiMe3 F

O SO 2Ph

O SO2Ph work-up

O SO2Ph

1. H2/Pd 2. Na/Hg Na2HPO4 (buffer?) muscone

Na/Hg cleaves the C-SO2Ph bond.

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Synthesis of (R)-Muscone Synthesis of Muscone by Fehr (Firmenich) Helv. Chim. Acta 1983, 66, 2512
S O 1. LDA 2. Br very reactive E+ (Allylbromide) Oxidation of sulfur O 1. PhSH AIBN (radical react.) 2. H2O2 O Ph

Baeyer.V. higher subst. side

Baeyer Villinger O + H2O2 O creating in situ Peraceticacid O Ph O S NaNH2 O O O O

If it wouldn't be an ester, a driving force to cleave the C(1)-C(2) bond would be missing rather the C(2)-C(3) bond would be cleaved.

O O S
3

Ph O

O Ph O S

O O
2 1

O Ph O S O O Na(Hg) O OH Polyphosphoric acid made by mixing P4O10 with a little water. H2 / Pd O Even though the muscone is produced in a racemic way, the other enantiomer doesn't smell very different but only much less intense. O

muscone

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Synthesis of (R)-Muscone Eschenmoser Fragmentation (late 1960's) The starting material is an epoxide of an ,-unsaturated ketone. Ketone is reacted with tosylhydratzine to give an alkyne.
Ts O H2O2, OHO O TsNNH2 O N NH MeO- Na+ in MeOH O N Ts N

Ts N N2 Ar O S O toluenesulfinate + O fragmentation O N

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: Bchi, Tet. Lett. 1976, 3585
HO O O OLi Li HO Polyphororic acid (made out of P4O10 + a little H2O)

Mechanism for the second step:

HO HO HO

HO H H - H2 O -H

H2O -H O Nazarow HO +H O keto/enol HO

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Synthesis of (R)-Muscone This is a pretty general reaction sequence:

R O + H R
1

OH R R1

H R R1 R R1 H 2O R1 OH

R O

R'

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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