recent advances in selective olefin metathesis reactions · recent advances in selective olefin...

Recent Advances in Selective Olefin Metathesis Reactions

Jeffrey LipshultzGroup Meeting

MacMillan GroupJanuary 22, 2015

Ru

iPrO

NMesN

OONO

Ru

NMesMesN

OiPr

S

SCl

Cl

MoNDIPP

OCl

TBSOCl

NMe

Me

Me

MePh

Olefin Metathesis

Banks, R.L.; Bailey, G.C. Ind. Eng. Chem. Prod. Res. Dev. 1964, 3, 170.

Initial Discoveries

Heckelsberg, L.F.; Banks, R.L.; Bailey, G.C. Ind. Eng. Chem. Prod. Red. Dev. 1968, 7, 29.Herisson, P.J.-L.; Chauvin, Y. Makromol. Chem. 1971, 141 , 161.

■ Phillips Triolefin Process (1964)

■ Mo(CO)6•AlO2, WO3•SiO2

Me MeMe

■ Chauvin first proposed metallacyclobutane intermediate (1971)

■ Previously, coordinated quasicyclobutane was widely accepted intermediate

Calderon, N.; Chen, H.Y.; Scott, K.W. Tetrahedron Lett. 1967, 34, 3327.

WR

R'

WR

R'

WR

R'

WR

R'

WR

R'W

R

R'

Olefin Metathesis

Tsuji, J.; Hashiguchi, S. Tetrahedron Lett. 1980, 21, 2955.

Practical Developments

■ Ring-opening Metathesis Polymerization (ROMP)

■ Norsorex Process for polynorbornene (1980)

■ Ring-closing Metathesis (RCM)

■ First applied with in situ prepared W/Ti mixed catalysts

[W]R

R[W]

n

OO

RR

OO

18% yieldWCl6/Cp2TiMe2

Ohm, R.F. Chemtech 1980, 198.

Olefin Metathesis

Schrock, R.R.; DePue, R.T.; Feldman, J.; Chaverien, C.J.; Dewan, J.C.; Liu, A.H. J. Am. Chem. Soc. 1988, 110 , 1423.

Well-defined Catalysts

Gillion, L.R.; Grubbs, R.H. J. Am. Chem. Soc. 1986, 108 , 733.

■ Ring-opening Metathesis Polymerization with Tebbe's Reagent (1986)

■ Living Polymerization

■ First well-defined Tungsten alkylidene catalysts (1988)

■ Set the stage for detailed studies on structure and mechanism

n

Cp2TiCl

AlMe2

Cp2Ti

WNAr

tBu

RORO W

NAr

ORRO

ethylene

Cp2Ti

P

Olefin Metathesis

Schrock, R.R.; Hoveyda, A.H. Angew. Chem. Int. Ed. 2003, 42, 4592.

Nobel-Prize Winning Catalysts

Grubbs, R.H. Tetrahedron 2004, 60, 7117.

■ Development of stable Ru-carbene complexes (Grubbs)

■ Molybdenum and Tungsten alkylidenes (Schrock, Hoveyda)

Ru

PCy3

PCy3

Cl

Cl RuPh

PCy3

PCy3

Cl

Cl

Ph

PhNMesMesN

RuPhPCy3

Cl

Cl

NMesMesN

RuCl

Cl

OiPr

WNDIPP

DIPPODIPPO Mo

NDIPP

F6-tBuOF6-tBuO Ph

Me Me

MoN

tBu

F6-tBuOF6-tBuO

Ph

Me Me

Olefin MetathesisNobel-Prize Winning Catalysts

■ Nobel Prize in Chemistry award jointly in 2005

Prof. Yves Chauvin Prof. Robert Grubbs Prof. Richard Schrock

"for the development of the metathesis method in organic synthesis"

Olefin MetathesisTalk Breakdown

■ Part 1: Enantioselective (desymmetrizing) olefin metathesis

■ Part 2: Z-selective olefin metathesis

■ Early asymmetric catalysts utilizing chiral ligands (pre-2008)

■ Recent mechanistic understanding

■ Chiral-at-metal catalysts achieve new success (post-2008)

■ Early successes with MAP catalysts

■ The rise of carbometalated Ru catalysts

■ Bidentate anionic ligands unlock full potential of Ru catalysts

Olefin MetathesisEarly Asymmetric Catalyst Systems

Alexander, J.B.; La, D.S.; Cefalo, D.R.; Hoveyda, A.H.; Schrock, R.R. J. Am. Chem. Soc. 1998, 120 , 4041.

■ Simple modification of the alcohol ligands on an Mo-catalyst generate chiral catalysts

MoNAr

Ph

MeMeOO

Me

Me

tBu

Me

Me

tBu

Mo*-1

MoNAr

Ph

MeMeRO

RO

Olefin Metathesis

La, D.S.; Alexander, J.B.; Cefalo, D.R.; Graf, D.D.; Hoveyda, A.H.; Schrock, R.R. J. Am. Chem. Soc. 1998, 120 , 9720.

Early Asymmetric Catalyst Systems

Alexander, J.B.; La, D.S.; Cefalo, D.R.; Hoveyda, A.H.; Schrock, R.R. J. Am. Chem. Soc. 1998, 120 , 4041.

■ Simple modification of the alcohol ligands on an Mo-catalyst generate chiral catalysts

■ Excellent stereochemical transfer to certain substrates

■ Kinetic resolutions and desymmetrizations

Me

Me tBu

Me

Me

tBu

OHOH

MoNAr

RTfO OTf

OMeMeO

MoNAr

Ph

MeMeOO

Me

Me

tBu

Me

Me

tBu

Mo*-1

OMe Me

3 mol% Mo*-1

C6H6, 22 °C, 6h

O

Me

MeH

86% yield93% ee

Olefin Metathesis

Zhu, S.S.; Cefalo, D.R.; La, D.S.; Jamieson, J.Y.; Davis, W.M.; Hoveyda, A.H.; Schrock, R.R. J. Am. Chem. Soc. 1999, 110 , 8251.


■ Other chiral diols could be utilized

■ Different chiral diols were optimal for different substrate classes

■ For example, 5 vs. 6 membered rings

MoNAr

Ph

MeMeOO

DIPP

DIPP

Mo*-2

OMe Me

O

Me

MeH

Mo*-183% yield99% ee

MoNAr

Ph

MeMeO

OMe

Me

tBu

Me

Me

tBu

Mo*-1


OMe Me

Me2Si O

MeH


Mo*-298% yield>99% ee

Me Me Me

Me2Si

Me

Olefin Metathesis

Zhu, S.S.; Cefalo, D.R.; La, D.S.; Jamieson, J.Y.; Davis, W.M.; Hoveyda, A.H.; Schrock, R.R. J. Am. Chem. Soc. 1999, 110 , 8251.


■ Simple proposed model

MoNAr

Ph

MeMeOO

DIPP

DIPP

Mo*-2

Weatherhead, G.S.; Houser, J.H.; Ford, J.G.; Jamieson, J.Y.; Schrock, R.R.; Hoveyda, A.H. Tetrahedron Lett. 2000, 41, 9553.

MoNAr

OO

DIPP

DIPP

O

Me

R

"The reason for the inefficiency of 1a in promoting the asymmetric formation of 7... is unclear."

Olefin Metathesis

Funk, T.W.; Berlin, J.M.; Grubbs, R.H. J. Am. Chem. Soc. 2006, 128 , 1840.


■ Chiral NHCs allow for asymmetric Ru catalysts

■ N-arenes are twisted, enforcing an open/closed geometry

Ru*-1: R=HRu*-2: R=iPr

Ru

NMesMesN

PhPCy3Cl

Cl

Ru

NN

PhPCy3Cl

Cl

PhPh

iPr

iPr

R

R

Seiders, T.J.; Ward, D.W.; Grubbs, R.H. Org. Lett. 2001, 3, 3225.

iPr pointed up,away from olefin

arene projected down,towards olefin

Olefin Metathesis

Funk, T.W.; Berlin, J.M.; Grubbs, R.H. J. Am. Chem. Soc. 2006, 128 , 1840.


■ Chiral NHCs allow for asymmetric Ru catalysts

■ Ru catalysts have similar limited substrate scope but increased tolerance

■ Projecting aryl group and axial ligand combine to enforce geometry

Ru*-1: R=HRu*-2: R=iPr

Ru

NMesMesN

PhPCy3Cl

Cl

Ru

NN

PhPCy3Cl

Cl

PhPh

iPr

iPr

OMe

Me

Me

Me

4 mol% Ru*-1

NaI, THF, 40 °C

O

Me

MeH Ru

NN

X

X

PhPh

iPr

iPr

64% yield90% ee

R

R

Me

Seiders, T.J.; Ward, D.W.; Grubbs, R.H. Org. Lett. 2001, 3, 3225.

O

MeMe

RH

Olefin Metathesis

Van Veldhuizen, J.J.; Gillingham, D.G.; Garbder, S.B.; Kataoka, O.; Hoveyda, A.H. J. Am. Chem. Soc. 2003, 125 , 12502.


■ Hoveyda explored BINOL-derived bidentate NHC ligands

■ Bidentate catalysts capable of ROCM, mild success with RCM

■ Additionally, catalyst is recoverable by chromatography (up to 98%)

Ru*-3: R=HRu*-4: R=Ph

Ru

MesN NMes

Cl

Cl

10 mol% Ru*-3

THF, 50 °C, 1h

60% yield>98% ee

Van Veldhuizen, J.J.; Garber, S.B.; Kingsbury, J.S.; Hoveyda, A.H. J. Am. Chem. Soc. 2002, 124 , 4954.

OiPr

Ru

MesN N

O

Cl

OiPr

R

OO O

Cy

OO O

Cy

Olefin Metathesis

Poater, A.; Monfort-Solans, X.; Clot, E.; Copéret, C.; Eisenstein, O. J. Am. Chem. Soc. 2007, 129 , 8207.

Theory Informs Synthethis

■ Theoretical studies identify desired reactivity could be achieved thru asymmetrically bound metal

Monfort-Solans, X.; Clot, E.; Copéret, C.; Eisenstein, O. J. Am. Chem. Soc. 2005, 127 , 14015.

MoNMe

MeXRO

1: X= OMe2: X= Et

0.8

-0.40.8

-13.7

3.4

0.6 0.6

5.6

0.60.9

4.2

3.0

5.6

-13.4

Me

MoNMe

XOR

MoNMe

MeXRO

MoNMe

XOR

MoNMe

X

RO

Me

MoNMe

X

RO

Me

MoNMe

X

RO

Me

MoNMe

X

OR

Me

MoNMe

X

OR

Me MoNMe

X

OR

Me

MoNMe

X

ORMe

relative rate = 18:1

Olefin Metathesis





MoNMe

MeXRO

1: X= OMe2: X= Et

0.8

-0.40.8

-13.7

3.4

0.6 0.6

5.6

0.60.9

4.2

3.0

5.6

-13.4

Me

MoNMe

XOR

MoNMe

MeXRO

MoNMe

XOR

MoNMe

X

RO

Me

MoNMe

X

RO

Me

MoNMe

X

RO

Me

MoNMe

X

OR

Me

MoNMe

X

OR

Me MoNMe

X

OR

Me

MoNMe

X

ORMe

olefins binds trans to better σ-donor

Olefin Metathesis





MoNMe

MeXRO

1: X= OMe2: X= Et

0.8

-0.40.8

-13.7

3.4

0.6 0.6

5.6

0.60.9

4.2

3.0

5.6

-13.4

Me

MoNMe

XOR

MoNMe

MeXRO

MoNMe

XOR

MoNMe

X

RO

Me

MoNMe

X

RO

Me

MoNMe

X

RO

Me

MoNMe

X

OR

Me

MoNMe

X

OR

Me MoNMe

X

OR

Me

MoNMe

X

ORMe

two metathesis events per new bond = double inversion

Olefin Metathesis

Sattely, E.S.; Meek, S.J.; Malcolmson, S.J.; Schrock, R.R.; Hoveyda, A.H. J. Am. Chem. Soc. 2009, 131 , 943.

State of the Art Chiral Catalysts

■ MonoAlkoxidePyrrolide (MAP) catalysts exhibit enhanced reactivity

■ Capable of previously inefficient reactions

Malcolmson, S.J.; Meek, S.J.; Sattely, E.S.; Schrock, R.R.; Hoveyda, A.H. Nature 2008, 456, 933.

MoNDIPP

CMe2PhNN

MoNDIPP

CMe2PhNO

Me CF3

CF3 MAP-1

NH

N

NH

N1 mol% MAP-1

C6H6, 1 h

79% yield

previous best: 61% yield, 6h

Me

Me

Me

Me

Me

Me

Olefin Metathesis



■ Utilizing an enantiopure monodentate alkoxide ligand generates chiral, diastereomeric catalyst

■ Enantioselective total synthesis of (+)-quebrachamine


MoNDIPP

CMe2PhNN

MAP*-15:1 dr

NH

N

NH

N1 mol% MAP*-1

C6H6, 1 h

84% yield, 96% ee

Me

Me

Me

Me

MoNDIPP

OCl

TBSOCl

NMe

Me

Me

MePh

10 steps1 step to quebrachamine

Olefin Metathesis



■ Utilizing an enantiopure monodentate alkoxide ligand generates chiral, diastereomeric catalyst

■ Very limited scope


MoNDIPP

CMe2PhNN

MAP*-15:1 dr

Me

Me

Me

Me

MoNDIPP

OCl

TBSOCl

NMe

Me

Me

MePh

7 years later, this remains state of the art

NPh

MeMe

91% yield, 93% ee

HN

MeMe

89% yield, 67% ee

N

Me

98% yield, 92% ee

NPh

Me

86% yield, 93% ee

MeMe

Olefin MetathesisTalk Breakdown

■ Part 1: Enantioselective (desymmetrizing) olefin metathesis

■ Part 2: Z-selective olefin metathesis

■ Early asymmetric catalysts utilizing chiral ligands (pre-2008)

■ Recent mechanistic understanding

■ Chiral-at-metal catalysts achieve new success (post-2008)

■ Early successes with MAP catalysts

■ The rise of carbometalated Ru catalysts

■ Bidentate anionic ligands unlock full potential of Ru catalysts

Olefin Metathesis

Ibrahem, I.; Yu, M.; Schrock, R.R.; Hoveyda, A.H. J. Am. Chem. Soc. 2009, 131 , 3844.

First Z-selective Catalysts

■ Bulky aryloxide ligand of MAP complexes imparts excellent steric control

■ Size differential between aryloxide and imido substituent key factor


MAP*-23:1 dr

MoNAdm

OCl

TBSOCl

NMe

Me

Me

MePhMo

NDIPP

OCl

TBSOCl

NMe

Me

Me

MePh

MAP*-15:1 dr

Adm<DIPP → better kinetic control

Olefin Metathesis

Ibrahem, I.; Yu, M.; Schrock, R.R.; Hoveyda, A.H. J. Am. Chem. Soc. 2009, 131 , 3844.


■ Bulky aryloxide ligand of MAP complexes imparts excellent steric control

■ Size differential between aryloxide and imido substituent key factor


MAP*-23:1 dr

MoNAdm

OCl

TBSOCl

NMe

Me

Me

MePhMo

NDIPP

OCl

TBSOCl

NMe

Me

Me

MePh

MAP*-15:1 dr

OTBS

O

1 mol% MAP*-2

2 eq. styreneC6H6, 1h

5 mol% MAP*-1

10 eq. styreneC6H6, 1h

no observed product

O

OTBS

Ph

80% yield, 90% ee> 98% Z

Olefin Metathesis

Meek, S.J.; O'Brien, R.V.; Llaveria, J.; Schrock, R.R.; Hoveyda, A.H. Nature 2011, 471, 461.


■ Modifiable monodentate alkoxide and N-substituent allow for substantial catalyst diversity

■ Extension of ROCM chemistry to CM, including with enol ethers


MAP*-55:1 dr

MoNDMP

OBr

TBSOBr

NMe

Me

Me

MePhMo

NDIPP

OBr

TBSOBr

NMe

Me

Me

MePh

MAP*-35:1 dr

2.5 mol% cat.

MAP*-43:1 dr

MoNAdm

OBr

TBSOBr

NMe

Me

Me

MePh

C6H6, 2hOBu Ph

10 equiv.

Bn OBu

cat conv Z %

MAP*-3 47 >98

MAP*-4 37 >98

MAP*-5 85 9873% yield

substantial enol ether and α-olefin scope

Olefin Metathesis

Meek, S.J.; O'Brien, R.V.; Llaveria, J.; Schrock, R.R.; Hoveyda, A.H. Nature 2011, 471, 461.


■ Modifiable monodentate alkoxide and N-substituent allow for substantial catalyst diversity

■ Extension of ROCM chemistry to CM, including with protected allylic amines


MAP*-55:1 dr

MoNDMP

OBr

TBSOBr

NMe

Me

Me

MePhMo

NDIPP

OBr

TBSOBr

NMe

Me

Me

MePh

MAP*-35:1 dr

MAP*-43:1 dr

MoNAdm

OBr

TBSOBr

NMe

Me

Me

MePh

NBoc2

O O

BnO OBnOBn

OBn

C14H29

5 equiv.

8 mol% MAP*-4

C6H6, 22 °C, 5h, 1 torr

NBoc2

O O

BnO OBnOBn

OBnH29C14 85% yield

96% Z

HNO O

HO OHOH

OH

OHC14H29

OH

O

C25H51 4 steps, 74% yield

KRN7000

Olefin Metathesis

Kiesewetter, E.T.; O'Brien, R.V.; Yu, E.C.; Meek, S.J.; Schrock, R.R.; Hoveyda, A.H. J. Am. Chem. Soc. 2013, 135 , 6026.


■ BINOL-derived catalysts still find use for selective formation of Z-vinyl boronates via CM

■ Different N-substituent for differnt α-olefin coupling partners

MAP*-55:1 dr

MoNDMP

OBr

TBSOBr

NMe

Me

Me

MePhMo

NDIPP

OBr

TBSOBr

NMe

Me

Me

MePh

MAP*-35:1 dr

MAP*-43:1 dr

MoNAdm

OBr

TBSOBr

NMe

Me

Me

MePh

B(pin)5 mol% MAP*-5

5 equiv. vinyl-Bpin1 equiv. R

3 mol% MAP*-4

1 equiv. vinyl-Bpin5 equiv. Ar

B(pin)(pin)B

BuO B(pin)

60%, 97% Z

80%, 93% Z

B(pin)

R= OMe, 69%, 93% Z

R= CF3, 93%, 95% Z

R

Olefin Metathesis

Speed, A.W.H.; Mann, T.J.; O'Brien, R.V.; Schrock, R.R.; Hoveyda, A.H. J. Am. Chem. Soc. 2014, 136 , 16136.


■ Catalytic generation of Z-alkenyl boronate esters to enable a total synthesis

MAP*-55:1 dr

MoNDMP

OBr

TBSOBr

NMe

Me

Me

MePh

N

O OMe

O OH

MeMeMe

O

N

OMeO

O OOH

MeMeMe

disorazole C1

N

O OMe

I

O OTBSO

MeMeMe

N

O OMe

I

O OTBSO

MeMeMe

B(pin)10 mol% MAP*-5

7 equiv. vinyl-Bpin

91% yield, >98% Z

Olefin Metathesis

Flook, M.M.; Jiang, A.J.; Schrock, R.R.; Müller, P.; Hoeyda, A.H. J. Am. Chem. Soc. 2009, 131 , 7962.

Simpler MAP Catalysts

■ If sterics of the alkoxide vs. imide are determining factor, why use chiral alcohols?

■ Steric bulk of 2,6-Trip phenoxide ligand is sufficient for Z control

MAP*-43:1 dr

MoNAdm

OBr

TBSOBr

NMe

Me

Me

MePh

M= Mo, MAP*-6M= W, MAP*-7

MNAdm

O

NMe

Me

Me

MePh

TripTrip

MeO2C

MeO2C

2 mol% MAP*-6

MeO2C CO2Me

CO2MeMeO2C

>99% Z, >99% syndiotactic

Olefin Metathesis

Wang, C.; Yu, M.; Kyle, A.F.; Jakubec, P.; Dixon, D.J.; Schrock, R.R.; Hoveyda, A.H. Chem. Eur. J. 2013, 19 , 2726.

Simpler MAP Catalysts

■ Application towards the total synthesis of nakadomarin A by Z-selective RCM

MAP*-8

WN

tBuArO

NMe

Me

M= Mo, MAP*-6M= W, MAP*-7

MNAdm

ArO

NMe

Me

Me

MePh

Cl Cl

NO

N

H

5 mol% MAP*-8

tol (1 mM), 8hN

O

N

H

63% yield, 94% Z

nakadomarin A

Olefin Metathesis

Endo, K.; Grubbs, R.H. J. Am. Chem. Soc. 2011, 133 , 8525.

Cyclometalated Ru Catalysts

■ CH activation leads to a surprisingly active and selective class of catalysts

Ru

NMesMesN

Cl

Cl

iPrO

2 PivOAgRu

NMesN

PivO

OPiv

iPrO

Me

MeMe

Ru

NMesNOPiv

iPrO

Me

Me-PivOH

CMR-1

Olefin Metathesis

Keitz, B.K.; Endo, K.; Herbert, M.B.; Grubbs, R.H. J. Am. Chem. Soc. 2011, 133 , 9686.


■ CH activation leads to a surprisingly active and somewhat selective class of catalysts

CMR-2

Ru

iPrO

N NMesOPiv

Ru

NMesNOPiv

iPrO

Me

Me

CMR-1

■ Highly promising levels of Z selectivity in CM and homodimerization

PhAcO OAc 5 mol% CMR-2

THF/H2O, reflux, 4hPh OAc 64% conv

87% Z

Endo, K.; Grubbs, R.H. J. Am. Chem. Soc. 2011, 133 , 8525.

(pin)B2 mol% CMR-2

THF, 35 °C, 4h

(pin)B B(pin) 74% yield>95% Z

Olefin Metathesis

Liu, P.; Xu, X.; Dong, X.; Keitz, B.K.; Herbert, M.B.; Grubbs, R.H.; Houk, K.N. J. Am. Chem. Soc. 2012, 134 , 1464.


■ Computational and mechanistic understanding elucidates important aspects of Z selective Ru catalysts

CMR-2

Ru

iPrO

N NMesOPiv

Olefin Metathesis

Liu, P.; Xu, X.; Dong, X.; Keitz, B.K.; Herbert, M.B.; Grubbs, R.H.; Houk, K.N. J. Am. Chem. Soc. 2012, 134 , 1464.


■ Side-bound transition state favors Z geometry over E geometry

steric clash withN-Mes methyl

Olefin Metathesis

Keitz, B.K.; Endo, K.; Patel, P.R.; Herbert, M.B.; Grubbs, R.H. J. Am. Chem. Soc. 2012, 134 , 693.

Optimized Cyclometalated Ru Catalysts

■ Swapping bidentate X ligands and varying arenes on NHC yielded ideal catalyst

Ar=Mes, CMR-3Ar=DIPP, CMR-4

■ Nitrate ligand proved to be key to unlocking full potential

Keitz, B.K.; Fedorov, A.; Grubbs, R.H. J. Am. Chem. Soc. 2012, 134 , 2040.

CMR-2

Ru

iPrO

NArN

OONORu

iPrO

NArN

OOtBu

Marx, V.M.; Herbert, M.B.; Keitz, B.K.; Grubbs, R.H. J. Am. Chem. Soc. 2013, 135 , 94.Rosenbrugh, L.E.; Herbert, M.B.; Marx, V.M.; Keitz, B.K.; Grubbs, R.H. J. Am. Chem. Soc. 2013, 135 , 1276.

■ Z-selective ROMP

O0.3 mol% CMR-3

THF, -20 °C O

80% yield, 91% Z

Olefin Metathesis







CMR-2

Ru

iPrO

NArN

OONORu

iPrO

NArN

OOtBu


■ Z-selective homodimerization

0.1 mol% CMR-4

THF, 35 °C

77% yield, >95% Z

HO OHHO

Olefin Metathesis







CMR-2

Ru

iPrO

NArN

OONORu

iPrO

NArN

OOtBu


■ Z-selective macrocyclic RCM

7.5 mol% CMR-3

DCE, 60 °C, 20 mTorr75% yield

94% Z

O

O

O

O

Olefin Metathesis

Cannon, J.S.; Grubbs, R.H. Angew. Chem. Int. Ed. 2013, 52, 9001.





CMR-2

Ru

iPrO

NArN

OONORu

iPrO

NArN

OOtBu

■ Z-selective and chemoselective cross metathesis

1 mol% CMR-4

THF, rt, 5h

MeOH

7

1 equiv.

7 equiv.

5 equiv.

1 equiv.

45% yield, >95% Z

66% yield, >95% Z

OH7

Me

Olefin Metathesis

Chung, W.; Carlson, J.S.; Bedke, D.K.; Vanderwal, C.D. Angew. Chem. Int. Ed. 2013, 52, 10052.


■ Highly enabling technology for total synthesis of complex molecules

Ru

iPrO

NMesN

OONO

■ Vanderwal's synthesis of myltilipin A in 7 steps

Me OH1. Cl2, Et4NCl

2. DMPMe H

O

Cl

Cl

NaOH

;Br AlEt2Me

Cl

ClO

Br Cl1. Mg; DMF

2. CrCl2

30 mol%

32%, >95% Z

MeCl

ClO

Cl5

1. BF3, Et4NCl

2. Et4NCl3

51% yield (2 steps)

45% yield (3 steps)

Me Cl

Cl

Cl

OSO3-

Cl

Cl

Cl 3. SO3•pyr

58% yield (3 steps)

Olefin Metathesis

Hartung, J.; Dornan, P.K.; Grubbs, R.H. J. Am. Chem. Soc. 2014, 136 , 13029.

Enantiopure Carbometalated Ru Catalysts

■ Chirality at Ru center can be resolved by classical resolution

CMR*-3

■ Chiral-at-Ru CMR catalysts can provide excellent asymmetric induction

Hartung, J.; Grubbs, R.H. J. Am. Chem. Soc. 2013, 135 , 10183.

Ru

iPrO

NMesN

OONO

■ Z-selective enantioselective ROCM

1 mol% CMR*-3

THF, 23 °C

41% yield, 95% Z, 94% ee

Ru

iPrO

NMesN

I Ru

iPrO

NMesN

OO

MeO

Ph

separation of diastereomers

OBnOBn

NHBoc

NHBocOBnOBn7 equiv.

brand new technology, still developing

Olefin Metathesis

Nelson, J.W.; Grundy, L.M.; Dang, Y.; Wang, Z.-X.; Wang, X. Organometallics 2014, 33, 4290.

Bidentate Anionic LIgands■ Ruthenium catalysts with aryl thiolate ligand show promise for Z-selective CM

Ru

NMesMesN

Cl

Cl

iPrO

SKPh

Ph

PhRu

NMesMesN

ArS

Cl

iPrO

Occhipinti, G.; Koudriavtsev, V..; Tornroos, K.W.; Jensen, V.R. Dalton Trans. 2014, 43, 11106.

■ Very mild Z-selectivities, and only at low conversion

Occhipinti, G.; Hansen, F.R.; Tornroos, K.W.; Jensen, V.R. J. Am. Chem. Soc. 2013, 135 , 3331.

Me5

Me 5 Me5

0.25 mol% cat

THF, 40 °C

17% conv, 86% Z

■ Rate-limiting cyclobutane reversion, favors cis by ~ 1.2 kcal/mol

Ru

NMesMesN

ClSAr

R

R

Ru

NMesMesN

ClSAr

R

R

45% conv, 81% Z64% conv, 75% Z

Olefin Metathesis

Khan, R.K.M.; Torker, S.; Hoveyda, A.H. J. Am. Chem. Soc. 2013, 135 , 10258.

Bidentate Anionic LIgands■ Utilizing dithiolate (bidentate) ligands proves to be key for control

Ru

NMesMesN

Cl

Cl

iPrO

■ Design principle: tie back small anionic ligands, allow for bulky NHC to control

SNaNaS

Ru

NMesMesN

OiPr

S

SSNa

NC

NaS

CNRu

NMesMesN

OiPr

S

S

CN

CN

DT-1 DT-2

DT-2

Olefin Metathesis



Ru

NMesMesN

Cl

Cl

iPrO

■ Excellent reactivity and perfect selectivity for ROMP

SNaNaS

Ru

NMesMesN

OiPr

S

SSNa

NC

NaS

CNRu

NMesMesN

OiPr

S

S

CN

CN

DT-1 DT-2

0.1 mol% cat

DCM, rt, 1h

DT-1: 90% yield, >98% ZDT-2 : 93% yield, >98% Z

0.1 mol% cat

DCM, rt, 24h

DT-1: 75% yield, >98% ZDT-2: 75% yield, >98% Z

Olefin Metathesis



Ru

NMesMesN

Cl

Cl

iPrO

■ Z-selective ROCM are also highly efficient

SNaNaS

Ru

NMesMesN

OiPr

S

SSNa

NC

NaS

CNRu

NMesMesN

OiPr

S

S

CN

CN

DT-1 DT-2

1 mol% DT-2

THF, rt, 1h92% yield

97% ZOHOH Ph

20 equiv.PhHO

HO

Koh, M.J.; Khan, R.K.M.; Torker, S.; Hoveyda, A.H. Angew. Chem. Int. Ed. 2014, 126 , 1999.

2 mol% DT-2

DCM, rt, 2hOHOH X

10 equiv.XHO

HO

X= OBu, 95%, 98% ZX= SEt, 80%, 92% Z

Olefin Metathesis



Ru

NMesMesN

Cl

Cl

iPrO

■ Computational support for simple stereochemical model

SNaNaS

Ru

NMesMesN

OiPr

S

SSNa

NC

NaS

CNRu

NMesMesN

OiPr

S

S

CN

CN

DT-1 DT-2

Olefin Metathesis

Koh, M.J.; Khan, R.K.M.; Torker, S.; Yu, M.; Mikus, M.S.; Hoveyda, A.H. Nature 2015, 10.1038/nature14061.

Bidentate Anionic LIgands■ Limited in ability to perform CM with allyl alcohols - only can do ROCM efficiently

Ru

NMesMesN

OiPr

S

SPh HO OH Ph OH

3 mol%

9h, 50% conv42% yield, 98% Z

■ No further conversion implies decomposition of catalyst...

Ru

NMesMesN

S

S

H

R1

R

Ru

NMesMesN

R1

S SR

■ 1,2 shift likely deactivates catalyst

■ strong σ-donor (NHC) = large trans inf

■ large trans inf = electron rich apical S

■ electron deficient groups on S-arene?

Olefin Metathesis

Koh, M.J.; Khan, R.K.M.; Torker, S.; Yu, M.; Mikus, M.S.; Hoveyda, A.H. Nature 2015, 10.1038/nature14061.

Bidentate Anionic LIgands■ More stable dithiolate catalysts allow for broader substrate scope

Ru

NMesMesN

OiPr

S

SPh HO OH Ph OH

5 mol%

9h, 84% conv71% yield, 96% Z

■ Excellent scope - extremely broad functional group tolerance

Cl

ClDT-3

OH

4h, 72% conv64% yield, 96% Z

OH

4h, 86% conv80% yield, 94% Z

OH

4h, 85% conv70% yield, 96% Z

OH

12h, 85% conv70% yield, 98% Z

OH

8h, 72% conv63% yield, 92% Z

OH

4h, 77% conv68% yield, 98% Z

Ph

HO

MeOOH

Ac

O

8

O

HO3

O

NNHMoc

Olefin MetathesisWhat's Next?

■ Current State-of-the-Art:

Ru

NMesMesN

OiPr

S

SCl

Cl

Z-selectiveenantioselective

MoNDIPP

OCl

TBSOCl

NMe

Me

Me

MePh

decomposes readily

very poor generality

■ What's coming in the next 5 years?

Ru

iPrO

NMesN

OONO

broader scope for ee?

Is kinetic E-selecitivity possible?

Olefin MetathesisUseful references

■ Marx, V.M.; Rosebrugh, L.E.; Herbert, M.B.; Grubbs, R.H. Top. Organomet. Chem. 2014, 48, 1.

■ Hoveyda, A.H. J. Org. Chem. 2014, 79, 4763.

■ Fürstner, A. Science, 2013, 10.1126/science.1229713.

recent advances in selective olefin metathesis reactions · recent advances in selective olefin...

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