recent advances in selective olefin metathesis...
TRANSCRIPT
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 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.
Early Asymmetric Catalyst Systems
■ 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
Mo*-277% yield89% ee
OMe Me
Me2Si O
MeH
Mo*-117% yield65% ee
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.
Early Asymmetric Catalyst Systems
■ 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.
Early Asymmetric Catalyst Systems
■ 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.
Early Asymmetric Catalyst Systems
■ 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.
Early Asymmetric Catalyst Systems
■ 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
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
olefins binds trans to better σ-donor
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
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
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
■ Utilizing an enantiopure monodentate alkoxide ligand generates chiral, diastereomeric catalyst
■ Enantioselective total synthesis of (+)-quebrachamine
Malcolmson, S.J.; Meek, S.J.; Sattely, E.S.; Schrock, R.R.; Hoveyda, A.H. Nature 2008, 456, 933.
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
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
■ Utilizing an enantiopure monodentate alkoxide ligand generates chiral, diastereomeric catalyst
■ Very limited scope
Malcolmson, S.J.; Meek, S.J.; Sattely, E.S.; Schrock, R.R.; Hoveyda, A.H. Nature 2008, 456, 933.
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
Malcolmson, S.J.; Meek, S.J.; Sattely, E.S.; Schrock, R.R.; Hoveyda, A.H. Nature 2008, 456, 933.
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.
First Z-selective Catalysts
■ Bulky aryloxide ligand of MAP complexes imparts excellent steric control
■ Size differential between aryloxide and imido substituent key factor
Malcolmson, S.J.; Meek, S.J.; Sattely, E.S.; Schrock, R.R.; Hoveyda, A.H. Nature 2008, 456, 933.
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.
First Z-selective Catalysts
■ Modifiable monodentate alkoxide and N-substituent allow for substantial catalyst diversity
■ Extension of ROCM chemistry to CM, including with enol ethers
Malcolmson, S.J.; Meek, S.J.; Sattely, E.S.; Schrock, R.R.; Hoveyda, A.H. Nature 2008, 456, 933.
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.
First Z-selective Catalysts
■ Modifiable monodentate alkoxide and N-substituent allow for substantial catalyst diversity
■ Extension of ROCM chemistry to CM, including with protected allylic amines
Malcolmson, S.J.; Meek, S.J.; Sattely, E.S.; Schrock, R.R.; Hoveyda, A.H. Nature 2008, 456, 933.
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.
First Z-selective Catalysts
■ 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.
First Z-selective Catalysts
■ 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.
Cyclometalated Ru Catalysts
■ 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.
Cyclometalated Ru Catalysts
■ 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.
Cyclometalated Ru Catalysts
■ 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
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 homodimerization
0.1 mol% CMR-4
THF, 35 °C
77% yield, >95% Z
HO OHHO
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 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.
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
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.
Optimized Cyclometalated Ru Catalysts
■ 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
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
■ 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
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
■ 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
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
■ 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.