Alkyne Metathesis - ChemistryMetathesis Reaction in Organic Chemistry Alkene metathesis Kürti, L....

Alkyne MetathesisCatalyst Development

and

Application in Total Synthesis

Meisam Nosrati

January 19th, 2011

Metathesis Reaction

Metathesis: Exchange of bonds between the two reacting chemicalspecies.

Mortimer, E. C.; General Chemistry, Sixth Edition 1986.

Ag NO3 (aq) + Na Cl (aq) Ag Cl (s) + Na NO3 (aq)

H Cl (aq) + Na OH (aq) H OH (l) + Na Cl (aq)

H3C

O

OH

+ O

O

ONa (aq)Na

+ O

O

OHH

H3C

O

ONa (aq)

2 2

(CO2 (g) + H2O (l))

Metathesis Reaction in Organic Chemistry

Alkene metathesis

Kürti, L. Czakó, B. Strategic Applications of Named Reactions in Organic Synthesis; Elsevier Academic Press: Burlington, MA 2005.

Alkyne metathesis

CatalystR1

R1R1

R1

R2

R2R2

R2

R2

R2R1

R12

R1 R1R1 R2

Catalyst

R2 R2

2

Enyne Metathesis

Nitrile Alkyne Cross Metathesis (NACM)

Kürti, L. Czakó, B. Strategic Applications of Named Reactions in Organic Synthesis; Elsevier Academic Press: Burlington, MA 2005.Geyer, A. M.; Gdula, R. L.; Wiedner, E. S.; Johnson J. A. M. J. Am. Chem. Soc. 2007, 129, 3800.

R2H2C

R1

CatalystR1 R2

CH2

R1 N R1N

R2R2

Catalyst

R2 N R2N

R1R1

Ring Closing Metathesis (RCM)

Hoveyda, H. A.; Cogen, A. D.; Xu, Z.; Houri, F. A.; J. Am. Chem. Soc. 1995, 117, 2943-2944.Fürstner, A.; Guth, O.; Rumbo, A.; Seidel, G. J. Am. Chem. Soc. 1999, 121, 11108.

Ring Closing Alkyne Metathesis (RCAM)

C CH2

C CH2

C

C+ H2C CH2

Catalyst

C C

C C

C

C+ C C

Catalyst

Alkyne Metathesis Reaction Mechanism

Katz, T. J.; McGinnis, J. J. Am. Chem. Soc. 1975, 97, 1592.

(RO)3M

R1

R1

R

(RO)3M

R

(RO)3M

R1

R1

R

R1

M(OR)3+ R1R

R1

R1

(RO)3M

R2

R2

R1

(RO)3M

R1

(RO)3M

R2

R2

R1

R2

M(OR)3+ R2R1

R2

R2

R1 R1

R1 R2

Catalyst

R2 R2

Catalyst:

2

Carbyne ComplexM = Mo, W R = Alkyl, Aryl(RO)3M

R

Katz, T. J.; McGinnis, J. J. Am. Chem. Soc. 1975, 97, 1592.Churchill, M. R.; Ziller, J. W.; Freudenberger, J. H.; and Schrock, R. R. Organometallics. 1984, 3, 1554.

Alkylidyne Mechanism Evidence

R

R(RO)3W

R

R

R

(RO)3W

(RO)3W

R

R

R

RR + (RO)3W RR +(RO)3W

W

Et

RORO OR

+ EtEt WRORO

ROEt

Et

Et R =

Crystals F3C

HF3C

RR

R

First Reports on Alkyne Metathesis

Pannella, F.; Banks, R. L.; Bailey, G. C.; Chem. Commun. 1968, 1548.A. Mortreux, M. Blanchard, J. Chem. Soc., Chem. Commun. 1974, 786.

Mortreux Catalyst

6.8 % WO3 on Silica

200 °C - 450 °C+

56% 23%

+ polymeric products

21%

Resorcinol : Mo(CO)66:1 10 mol %

160 °C+ Resorcinol:2

55% 23.5% 21.5%

OH

OH

Metallacycle Mechanism

Mortreux, A.; Coutelier, O. J. Mol. Catal. A. 2006, 254, 96.

Resorcinol : Mo(CO)66:1 10 mol %

160 °C+ Resorcinol:2

55% 23.5% 21.5%

OH

OH

R

R'

R

R'

M M

RR'

RR'

R

RR'

R'

RR'

R' R

M

M

R'

R'

R

R

MM

R

R

R'

R'

M = Active Metathesis Complex

In Situ Generation of Carbyne Complexes

Huc, V.; Weihofen, R.; Jimenez, M. I.; Oulié, P.; Lepetit, C.; Lavigne, G.; Chauvin, R. New J. Chem.2003, 27, 1412.

• No solid evidence to support the formation of carbyne complex

• No solid evidence to support metallacycle mechanism

Mo(CO)6 + ArOH Mo MoOAr

ArO

ArOArO

OArOAr

C6H5Cl, 135 °C

Mo(OAr)3Mo(OAr)3

Me

Ph

Mo(OAr)3

Mo(OAr)3Ph

Me

Ph

MeMo(OAr)3

Mo(OAr)3

Ph

Me

Mo(OAr)3

Mo(OAr)3

Ph Me21 , 25 - 50 °C

Ph Ph +

1MS 4 Å

+H3CO OCH3

First Step:

Second Step:

ArOH = Cl OH

Catalyst Development

Pschirer G. N.; Bunz, F. H. Tetrahedron Lett.1999, 40, 2481.Fürstner, A.; Guth, O.; Rumbo, A.; Seidel, G. J. Am. Chem. Soc. 1999, 121, 11108.

MeO

OMe

NC

Catalyst

Catalyst

Catalyst

MeO

OMe

NC

OMe

MeO

CN15%

72%

0%

Catalyst: 5 mol % Mo(CO)6, 140 °C, 1,2-Dicholorobenzene, 12-16h Cl OH

OO

OO

OO

OOCatalyst

p-Chlorobenzene as solvent,140 °C, 64%

Catalyst Development

Fürstner, A.; .Guth, O.; Rumbo, A.; Seidel, G. J. Am. Chem. Soc. 1999, 121, 11108.Fürstner, A.; Stelzer, F.; Rumbo, A.; Krause, H. Chem. Euro. J. 2002, 8, 1856.

Catalyst: 5 mol % Mo(CO)6, 140 °C, Chlorobenzene Cl OH

O

O

O

O

NH

OSi

PhPh

O

O7

7

DecompositionStarting material recoveredStarting material recovered

Alcohol:

PMBO

PMBO OCH3

OPMB

PMBO

PMBO OCH3

OPMB

Chlorobenzene, microwave heating,

150 °C, 5 min

Mo(CO)6, 1

OH

CF3

1 =Cyclophaneintermediate

Fischer Type Catalysts

Cr COCOOC

OC

CO

H3CO Ph

W COCOOC

OC

Cl

Ph

Fischer CarbeneComplex

Fischer CarbyneComplex

Nobelprize.org/nobel_prizes/chemistry/laureates/1973/fischer-lecture.pdf Fischer, O. E.; Maasaböl, A. J. Organomet. Chem. 1968, 12, P15.

(CO)5WCH3

OCH3+

O

OCH3H2N

Ether, 20 °C CH3OH(CO)5WCH3

HN

O

OCH3

(CO)5CrCH2

OCH3 90 °C, 1.5 h

Pyridine

H

HH3CO

H+ (C5H5N)Cr(CO)5

+

H

Alkyne Metathesis with Fischer Carbynes

Fischer, E. O., Kreis, C., Kreiter, C. G., Müller, J., Huttner, G. and Lorenz, H., Angew. Chem.Int. Ed. 1973, 12, 564.Nobelprize.org/nobel_prizes/chemistry/laureates/1973/fischer-lecture.pdfFischer, O. E.; Ruhs, A.; Plabst, D. Naturforsch. Z. Teil B 32B 1977,7, 802.

Cr COCOOC

OC

Br

Ph

2Hexane, 30 °C

1.5 h

Cr COCOOC

OC

Br

Ph

m/z = 178

Cr COCOOC

OC

Br

Ph

+ Cr COCOOC

OC

Br

40 °C+ +

Schrock Catalyst Development

McLain, J. S.; Wood, D. C.; Schrock, R. R. J. Am. Chem. Soc. 1979, 101, 4558.Wengrovius, H. J.; Sancho, J.; Schrock, R. R. J. Am. Chem. Soc. 1981, 103, 3932.

, Aromatic AlcoholMo COCOOC

OC

CO

CO

Schrock Catalyst: First highly efficient CarbyneComplex in Alkyne Metathesis.

Ta

CMe3H

tBuH2CtBuH2C

CH2tBuTa

tBuH2CtBuH2C

CH2tBu

WtBuH2C

tBuH2CCH2tBu tBuO

WOtBu

tBuO

Metathesis inactive Metathesis inactive

Metathesis inactive Metathesis activeSchrock Catalyst

W COCOOC

OC

Cl

Ph

Fischer CarbyneLow Oxidation State MetalPositive Carbyne Carbon

The Role of the Alkoxide Ligand

Churchill, M. R.; Ziller, J. W.; Freudenberger, J. H.; Schrock, R. R. Organometallics 1984, 3, 1554.Schrock, R. R. Polyhedron 1995, 14, 3177.

Inactive

Metathesis

Polymerization

Polymerization

MotBuOtBuO

OtBuMoiPrO

iPrOOiPr

MoMe3CCH2OMe3CCH2O

OCH2CMe3WtBuO

tBuOOtBu

+ R'R

MAr(R)OAr(R)O

Ar(R)OR

R'

M = Mo, WR = Me R' = MeR = Et R' = EtR = Et R' = PrR= Pr R' = Pr

rt

R' +

MAr(R)OAr(R)O

O(R)Ar

MAr(R)OAr(R)O

O(R)Ar

R

• Molybdenum complexes in general are less reactive than theirTungsten analogs.

• Molybdacyclobutadiene complexes are much prone to losealkyne than tungstacyclobutadiene complexes.

• Molybdenum catalysts are more likely to polymerize alkynes.Churchill, M. R.; Ziller, J. W.; Freudenberger, J. H.; Schrock, R. R. Organometallics 1984, 3, 1554.Schrock, R. R. Polyhedron 1995, 14, 3177.

The Role of the Alkoxide Ligand

Metallayclobutadiene

MetathesisMetathesis

Metathesis

Mo(2,6-iPrC6H3)O(2,6-iPrC6H3)O

O(2,6-iPrC6H3)

W(2,6-iPrC6H3)O(2,6-iPrC6H3)O

O(2,6-iPrC6H3)W(CF3)2CH3CO

(CF3)2CH3COOCCH3(CF3)2

Mo(CF3)2CH3CO(CF3)2CH3CO

OCCH3(CF3)2

Theoretical Calculations of Alkyne Metathesis

Me

Me(R)3M

Me

Me

Me

(R)3M

(R)3M

Me

Me

Me

M = W R = OMe, NMe2

M = Mo R = OMe, CH2F

Me

Zhu, J.; Gia, J.; Lin, Z. Organometallics 2006, 25, 1812.

• B3LYP level of Density Functional Theory, LanL2DZ basis set for W and Mo atoms , 6-31G basis setfor C, N, F, O and H.

MoMeOMeO

OMe

WMeOMeO

OMeWMe2N

Me2NNMe2

MoFCH2OFCH2O

OCH2F

Theoretical Calculations of W Carbyne Complexes

Zhu, J.; Gia, J.; Lin, Z. Organometallics 2006, 25, 1812.

WMeOMeO

OMe

[W]

[W]

[W]

[W]

[W]

[W] [W]

0.0

22.3

10.3

9.1 9.1

22.3

0.0

[W] = W(OMe)3

WMe2NMe2N

NMe2

Free energies in kcal/mol

[W] = W(NMe2)3

[W]

[W]

[W]

0.0

33.4

18.5

• B3LYP level of Density Functional Theory, LanL2DZ basis set for W and Mo atoms , 6-31G basis setfor C, N, F, O and H.

Theoretical Calculations of Mo Carbyne Complexes

MoCH3OCH3O

OCH3

[Mo] = Mo(OMe)3

[Mo]

[Mo][Mo]

0.0

30.3

21.5

[Mo]23.9

[Mo]

16.9

[Mo]

30.3

[Mo]

0.0

MoFCH2OFCH2O

OCH2F

Zhu, J.; Gia, J.; Lin, Z. Organometallics 2006, 25, 1812.

• B3LYP level of Density Functional Theory, LanL2DZ basis set for W and Mo atoms , 6-31G basis setfor C, N, F, O and H.

Free energies in kcal/mol

[Mo]

[Mo]

[Mo]

[Mo] [Mo]

0.0

15.9

5.5

15.9

0.0

[Mo] = Mo(OCH2F)3

Theoretical Calculations for W vs Mo Complexes

Zhu, J.; Gia, J.; Lin, Z. Organometallics 2006, 25, 1812.

[W]

[W]

[W]

[W]

[W]

[W] [W]

0.0

22.3

10.3

9.1 9.1

22.3

0.0

[W] = W(OMe)3

[Mo] = Mo(OMe)3

[Mo]

[Mo][Mo]

0.0

30.3

21.5

[Mo]23.9

[Mo]

16.9

[Mo]

30.3

[Mo]

0.0

Free energies in kcal/mol

MoCH3OCH3O

OCH3

WMeOMeO

OMe

• B3LYP level of Density Functional Theory, LanL2DZ basis set for W and Mo atoms , 6-31G basis setfor C, N, F, O and H.

Schrock Catalyst Scope

Vintonyak, V. V.; Maier, M. E. Org. Lett. 2007, 9, 655 –658.Funk, L. R.; Nilson, G. M. Org. Lett. 2010, 12, 4912.

PhCl, 80 °C, 3 h77%

N

N

O

OTIPS

Boc

HON

N

O

OTIPS

Boc

HO

25 mol %

OMe

MeO

TIPSO

O

O

ROODMB

WtBuO

tBuOtBuO

toluene, 85 °C91%

OMe

MeO

O

TIPSO

ODMB

O

TBSO

WtBuO

tBuOtBuO

20 mol %

Nakadomarin A intermediate

Cruentaren A intermediate

Schrock Catalyst Limitations

Fürstner, A.; .Guth, O.; Rumbo, A.; Seidel, G. J. Am. Chem. Soc. 1999, 121, 11108.Fürstner, A.; Muller, R.; Herrman, J.; Jean, L.; Bindl, M. Chem. Eur. J 2009, 15, 12310.Fürstner, A.; Alcarazo, M.; Hickmann, V. J. Am. Chem. Soc. 2010, 132, 11042.

OS

O

OO

NO

O

OO O

O

OO

O

OMe

MeO

TIPSO

O

O

OTHPTBSO

Thioethers

HeterocyclesUnsaturated Esters

Acetal Epoxide

Cruentaren A intermediate Ecklonialactone intermediate

tBuOW

OtButBuO

Schrock Catalyst

Trisamido Molybdenum Complexes

(tBuO)3W W(tBuO)3 + 2 (tBuO)3W

(tBuO)3W W(tBuO)3 + N (tBuO)3W + (tBuO)3W N

(tBuO)3W W(tBuO)3 + N N N.R.

Schrock, R. R.; Listemann, L. M.; Sturgeoff, G. L. J. Am. Chem. Soc. 1982, 104, 4291.Laplaza, C. E.; Cummins, C. C. Science 1995, 268, 861.Wu, X.; Tamm, M. Beilstein. J. Org. Chem. 2011, 7, 82.

MoN

NN

+ N N

MoN N

N

N

22

Fürstner, A.; Mathes, C.; Lehmann, W. C. J. Am. Chem. Soc. 1999, 121, 9453-9454.

Akyne Metathesis With Molybdenum TrisamidoComplexes

R21 , 10 mol %

CH2Cl2 (25 eq) / tolueneR R

R = H 60%R = CN 58%

RO

1 , 10 mol %

CH2Cl2 (25 eq) / tolueneR

OO

R

R = Me 59%R = THP 55%

2

MoN N

N+ Small Acetylenic molecule N.R.

1

MoN N

NCH2Cl2

Strongly endothermic reaction

1

Fürstner, A.; Mathes, C.; Lehmann, W. C. J. Am. Chem. Soc. 1999, 121, 9453-9454.Fürstner, A.; Mathes, C.; Lehmann, W. C. Chem. Euro. J. 2001, 7, 5299.

Active Metathesis Species in the Reaction

MoN N

N CH2Cl2Mo

N NN

Cl

+

MoN N

N

H

1 2 3

MoN N

Ntoluene/CH2Cl2

5 min 80 °CAbruptly -20 °C

OCH3

+ Prepare a sample for Crystallography

Mo Mo

Cl

Cl

(tBu)ArN(tBu)ArN

NAr(tBu)NAr(tBu) Mo N

Cl

Cl

Ar(tBu)N

Ar(tBu)N

4 5

OO

OO

OO

OOCatalyst

Fürstner, A.; Mathes, C.; Lehmann, W. C. J. Am. Chem. Soc. 1999, 121, 9453-9454.Fürstner, A.; Mathes, C.; Lehmann, W. C. Chem. Euro. J. 2001, 7, 5299.Chisholm, H. M.; Folting, K.; Hoffman, M. D.; Huffman, C. J. J. Am. Chem. Soc. 1984, 106, 6794.

Active Metathesis Species in the Reaction

Mo

RO

RORO

R'2 Mo MoOR

OR

RO

ROOR

OR

R'R'

R = CH2t-Bu, R' = HR = i-Pr, R' = H, Me

MoN N

N

H

35 mol %, , toluene 80 °C, 38%

Catalyst Dimerization:

3

Fürstner, A.; Mathes, C.; Lehmann, W. C. Chem. Euro. J. 2001, 7, 5299.

Active species in Catalysis

• Halogenated Molybdenum complexes at different oxidationstate are able to catalyze metathesis reactions

Mo Mo

Cl

Cl

(tBu)ArN(tBu)ArN

NAr(tBu)NAr(tBu)

10 mol % , toluene 80 °C, 0%

MoN N

N

Cl

10 mol % , toluene 80 °C, 70%

Mo N

Cl

Cl

Ar(tBu)N

Ar(tBu)N

5 mol %, toluene, rt, 90%

MoN

NN

Br

10 mol %, toluene 80 °C, 79%

4 2

5

Fürstner, A.; Mathes, C.; Lehmann, W. C. Chem. Euro. J. 2001, 7, 5299.

Substitution on the Aromatic Rings

MoN N

OMe

OMeN

MeO MeOOMeMeO

Cl

10 mol %, , toluene, 80 °C, 51%

MoN N

F

FN

F FFF

10mol%, 25 equiv CH2Cl2, toluene, 80 °C, 79%

MoN N

N

Cl

10 mol % , toluene, 80 °C, 70%

MoN N

N

10 mol % , 25 equiv CH2Cl2, toluene, 80 ˚C, 81%

OO

OO

OO

OOCatalyst

Schrock Catalyst Limitations

Fürstner, A.; .Guth, O.; Rumbo, A.; Seidel, G. J. Am. Chem. Soc. 1999, 121, 11108.Fürstner, A.; Muller, R.; Herrman, J.; Jean, L.; Bindl, M. Chem. Eur. J 2009, 15, 12310.Fürstner, A.; Alcarazo, M.; Hickmann, V. J. Am. Chem. Soc. 2010, 132, 11042.

OS

O

OO

NO

O

OO O

O

OO

O

OMe

MeO

TIPSO

O

O

OTHPTBSO

Thioethers

HeterocyclesUnsaturated Esters

Acetal Epoxide

Cruentaren A intermediate Ecklonialactone intermediate

tBuOW

OtButBuO

Schrock Catalyst

Trisamido Molybdenum Catalyst Scope

Fürstner, A.; Mathes, C.; Lehmann, W. C. J. Am. Chem. Soc. 1999, 121, 9453-9454.

OS

O

OO

NO

O

OO

Thioethers

Unsaturated Esters

O

1, 10 mol %, CH2Cl2, Toluene, 80 °C, 84%

1, 10 mol %, CH2Cl2, Toluene, 80 °C, 88%

Heterocycles1, 10 mol%, CH2Cl2, Toluene, 80 °C, 83%

MoN N

N

Catalyst: 1

O8

Fürstner, A.; Muller, R.; Herrman, J.; Jean, L.; Bindl, M. Chem. Eur. J 2009, 15, 12310.Fürstner, A.; Alcarazo, M.; Hickmann, V. J. Am. Chem. Soc. 2010, 132, 11042.

Trisamido Molybdenum Catalyst Scope

O

O

O

1 , 20-40 mol %, CH2Cl2, toluene, 50-89%2 Unsuitable

Ecklonialactone total synthesis

OMe

MeOTIPSO

O

O

OTHPTBSO

1 10 mol %, CH2Cl2, toluene, 80 °C, 87%2 Unsuitable

Cruentaren A intermediate

MoN N

N

Catalyst: 1tBuO

WOtBu

tBuO

2

Trisamido Molybdenum Catalyst Scope

Fürstner, A.; .Guth, O.; Rumbo, A.; Seidel, G. J. Am. Chem. Soc. 1999, 121, 11108.Fürstner, A.; Flügge, S.; Larionov, O.; Takahashi, Y.; Kubota, T.; Kobayashi.; I. J. Chem. Eur. J. 2009, 15, 4011.Fürstner, A.; Mathes, C.; Lehmann, W. C. J. Am. Chem. Soc. 1999, 121, 9453-9454.

N

O

R

1, 10 mol %, CH2Cl2, toluene, 80 °CR = H 0%, R=Me 72%2, 5 mol %, Chlorobenzene, 80 °CR = H 62%R = Me 72%

7RO

OOTBS

O O

1, 30 mol %, CH2Cl2, toluene, 80 °C, 84%

Amphidinolide V intermediate

MoN N

N

Catalyst: 1tBuO

WOtBu

tBuO

2

Silyloxy based Molybdenum Catalysts

Freudenberger, J. H.; Schrock, R. R. Organometallics 1986, 5, 398. Gdula, R. L.; Johnson, M. J. A. J. Am. Chem. Soc. 2006, 128, 9614.Wu, X.; Tamm, M. Beilstein. J. Org. Chem. 2011, 7, 82.

ROW

ORRO RO

WOR

RO

N

+

ROW

ORRO

N

ROW

ORRO

+

R =

R = C(CF3)(CH3)2

N

N

ROMo

ORRO

N

ROMo

ORRO + N

R = C(CF3)2Me, C(CF3)3

95 °C, 14.5 h

hexane

toluene

Metathesis inactive

Metathesis inactive

Metathesis active

Bindl, M.; Stade, R.; Heilmann, E. K.; Picot, A.; Goddard, R.; Fürstner, A. J. Am. Chem. Soc. 2009, 131, 9468.Heppekausen, J.; Stade, R.; Goddard, R.; Fürstner, A. J. Am. Chem Soc. 2010, 132, 11045.

Nitrido Molybdenum Silyloxy Based Catalysts

Mo

N

Ph3SiO

Ph3SiO

N

OSiPh3

Mo

NPh3SiO

Ph3SiO

OSiPh3

N

N

Air StableStable to be weighed in Air

Mo

N

NMe3SiO

Me3SiOSiMe3

SiMe3

1)Ph3SiOH (3 equiv), toluene, 80 °C

then Pyridine (5eq)81%

Mo

N

Ph3SiO

Ph3SiON

OSiPh3

1,10-Phenantroline, toluene/Et2O, 81%

Mo

NPh3SiO

Ph3SiO

OSiPh3

N

N

MnCl2, toluene, 80 °CAir Stable

Mo

N

Ph3SiO

Ph3SiOOSiPh3

Scope of Nitrido Silyloxy Based Catalysts

Smith, J. B.; Sulikowski, A. G.; Angew. Chem. Int. Ed 2010, 49, 1599.Funk, L. R.; Nilson, G. M. Org. Lett. 2010, 12, 4912.

20 mol %

PhMe, 80 °C, 16 h, 80%

N

N

O

OTIPS

Boc

HO

N

N

O

OTIPS

Boc

HOMo

N

Ph3SiO

Ph3SiO OSiPh3

N

Nakadomarin A intermediate

N

N

H

H

H

H

N

N

H

H H H

Ph3SiOH (3 equiv), toluene, 80 °C, 63%

Mo

N

NMe3SiO

Me3SiOSiMe3

SiMe3

Haliclonacyclamine CIntermediate

( 50 mol % Catalyst)

Scope of Silyloxy Based Carbyne Catalysts

Fürstner, A.; Micoine, K. J. Am. Chem. Soc. 2010, 132, 14064.Heppekausen, J.; Stade, R.; Goddard, R.; Fürstner, A. J. Am. Chem Soc. 2010, 132, 11045.

Mo

Ph

Ph3SiO

Ph3SiO

OSiPh3

OEt2

1,10-Phenantroline, toluene/Et2O, 81%

Mo

Ph

Ph3SiO

Ph3SiO

OSiPh3

N

N

MnCl2, toluene, 80 °CAir Stable

5 mol %

toluene, MS 5 Å, 80 °C, 95 %O

OTES OO O

OTESMo

Ph

Ph3SiO

Ph3SiO OSiPh3

OEt2

Lactimidomycin intermediate

Fürstner, A.; Alcarazo, M.; Hickmann, V. J. Am. Chem. Soc. 2010, 132, 11042.

Scope of Silyloxy Based Carbyne Catalysts

O

O

O

OO

O

Catalyst

Catalyst

WOtBu

OtBuOtBu

Mo

N

Ph3SiO

Ph3SiO OSiPh3

N

20-40 mol %, CH2Cl2/toluene, 50-89 %

Mo

Ph

Ph3SiO

Ph3SiO OSiPh3

OEt2

MoN N

N

Unsuitable

Unsuitable 5 mol %, toluene, 5Å ,80%

Ecklonialactone intermediate

Ring Closing Alkyne Metathesis (RCAM)in Natural Product total Synthesis

C CH2

C CH2

+ H2C CH2C

C H

HRCM C

C

H

H+

RCM

RCAM Z- selective olefin synthesis

C C

C C

C

C+ C C

RCAMLindlar

Reduction CC

H

H

Fürstner, A.; Guth, O.; Rumbo, A.; Seidel, G. J. Am. Chem. Soc. 1999, 121, 11108.

E-Selective Olefin Synthesis

(EtO)3SiH

(Cp*Ru[MeCN)]PF6

C C

C C

C

C+ C C

RCAM

C

C Si(OEt)3

H AgF

THF/MeOH

C

C H

H

Lacombe, F. Radkowski, K.; Günter, S.; Fürstner, A. Tetrahedron 2004, 60, 7315.

Ono, K.; Nakagawa, M.; Nishida, A. Angew. Chem. Int. Ed. 2004, 42, 2020.Funk, L. R.; Nilson, G. M. Org. Lett. 2010, 12, 4912.

RCM

RCAM

RuPhPCy3

PCy3Cl

Cl

20 mol %, CH2Cl2 reflux 24 h

N

N

O

H

O

ON

N

O

H

O

O

Z/E: 1:1.8 26%:46%

Nakadomarin A intermediate

Catalyst

PhCl, 80 °C, 3 h77%

20 mol %PhMe, 80 °C,

16 h, 80%

N

N

O

OTIPS

Boc

HON

N

O

OTIPS

Boc

HO

(tBuO)3W Mo

N

Ph3SiO

Ph3SiO OSiPh3

N

N

N

O

OH

Boc

HO

1) H2, Lindlar

2) TBAF, 80%Two steps

O

25 mol % OrCatalyst:

Nakadomarin Aintermediate

RCM

Nicolaou, K. C.; He, Y.; Vourloumis, D.; Vallberg, H.; Roschangar, F.; Sarabia, F.; Ninkovic, S.; Yang,Z.; Trujillo, J. I. J. Am. Chem. Soc. 1997, 119, 7960.

O

O O

HO N

S

OTBSO

O

N

S

OTBS

O

HO

O

O O

HO N

S

OH

RuPhPCy3

PCy3Cl

Cl

0.1 equiv, CH2Cl2, 25 °C, 20 h

CatalystCatalyst:

46% 39%Epothilone C intermediate

RCAM

Fürstner, A.; Mathes, C.; Grela, K.; Chem. Commun. 2001, 1057.

O

O O

TBSON

S

OTBS O

TBSO

N

S

OTBS

O

NMo

NN

10 mol%

toluene/CH2Cl2, 80 °C8 h, 80 %

Lindlar, H2, CH2Cl2,

O

O O

TBSON

S

OTBS

O

Quant

Epothilone C intermediate

Alkyne Activity in Metathesis Reactions

RCAM in the presence of Alkene

RCM in the presence of triple bond

Ono, K.; Nakagawa, M.; Nishida, A. Angew. Chem. Int. Ed. 2004, 42, 2020.Fürstner, A.; Micoine, K. J. Am. Chem. Soc. 2010, 132, 14064.

BocN

N

O

H

O

Co2(CO)8

RuPh

PCy3Cl

Cl

NMesMesN

CH2Cl2 (1mM)reflux, 1.5 h, 83 %

25 mol %BocN

N

O

H

O

Co2(CO)8

Nakadomarin A intermediate

5 mol %

toluene, MS 5 Å, 80 °C, 95 %O

OTES OO O

OTESMo

Ph

Ph3SiO

Ph3SiO OSiPh3

OEt2

Lactimidomycin intermediate

Summary

• High oxidation state Tungsten and Molybdenum Carbynes are thecatalysts that has been used so far for Alkyne metathesis in thenatural product total synthesis.

• Metathesis activity of a carbyne comlplex highly depends on thecontrol of the lewis acidity of the catalyst, which can be optimized bythe electronic effects of ligands.

• The choice of a catalyst for Alkyne metathesis depends on itsfunctional group tolerancy.

• However, Alkyne Metathesis is much less used than AlkeneMetathesis in natural product total synthesis, it can be acomplementary approach to selectivity control of RCM reactions.

Acknowledgement

AdvisorsProf.Geiger, Prof.Borhan

ProfessorsProf.Maleczka, Prof.Odom, Prof.Jackson

Dr.Vasileiou

Best LabmatesRoozbeh, Ipek, Arvind, Carmin, Wenjing,Atefeh, Sarah, Kumar, Tanya, Mercy, Calvin,Camille, Aman, Nastaran, Susan, Rafida,Remi.

And You

Chuck-Harrold Mechanism

Chung, W. L.; Wu, Y.; Trost, M.; B.; Ball, T. Z. J.Am.Chem.Soc. 2003, 125, 11578.

Reductive Recycle strategy for TrisamidoMolybdenum complexes

Zhang, W.; Kraft, S.; Moore S. J. Am. Chem. Soc. 2004, 126, 309.

New Class of Carbyne catalysts

MoN N

N

Cl

Mo(CO)6

Mo

Ph

Ph3SiOOSiPh3Ph3SiOOEt2

tBuOW

OtButBuO

1

2

3

4

OO

OO

OO

OOCatalyst

73%4, 2mol%, toluene, rt, MS 5Å

70%3, 10mol%, toluene, 80oC

73%2, 5mol%, Cholorobenzene, 80oC

64%1, 5mol%, p-Chlorophenol(1eq),Cholorobenzene, 140oC

YieldCatalyst

Fürstner, A.; Guth, O.; Rumbo, A.; Seidel, G. J. Am. Chem. Soc. 1999, 121, 11108.Fürstner, A.; Mathes, C.; Lehmann, W. C. J. Am. Chem. Soc. 1999, 121, 9453-9454.Heppekausen, J.; Stade, R.; Goddard, R.; Fürstner, A. J. Am. Chem Soc. 2010, 132, 11045.

W NO

O

N

N

tBu

tBu

F3C

F3CF3C

F3C

Wu, X.; Tamm, M. Beilstein. J. Org. Chem. 2011, 7, 82.Lysenko, S.; Haberlag, B.; Daniliuc, G. C.; Jones, G. P.; Tamm, M. Chem. Cat. Chem. 2011, 3, 115.

Imidazoline-2-Iminato Tungsten Catalysts

Tri(tert-butoxy)silanolate-Supported TungstenBenzylidyne Complex

W OO

O

Si

Si

Ph

SiOtButBuO

OtButBuO

tBuO

tBuOtBuO OtBu

OtBu

Imidazoline iminato Tungsten vs Shrock catalyst

1

R = H

R = CH3

(tBuO)3W

W

CMe3

NO

O

NN

tBu

tBu

F3C

F3CF3C

F3C

R Hexane, rt350 mbar

R

RR = HR = CH3

Catalyst 1mol%

Beer, S.; Hrib, G. C.; Jones, G. P.; Brandhorst, K.; Grunenberg, J.; Tamm, M.Angew. Chem. Int. Ed. 2007, 46, 8890.