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Metathesis Reactions
OO
OMeMe
OPMB
XX
OTBSLecture Notes
Key Reviews:
Metathesis in Complex Molecule SynthesisK.C. Nicolaou, S.A. Snyder, Classics in Total Synthesis II, Chapter 7.
Alkyne MetathesisM. Mori, Topics Organomet. Chem. 1998, 1, 133.
Enyne MetathesisS. T. Diver, A. J. Geissert, Chem. Rev. 2004, 104, 1317.
Olefin MetathesisK. C. Nicolaou, P. Bulger, D. Sarlah, Angew. Chem. Int. Ed. 2005, 44, 4490.
T. M. Trnka, R. H. Grubbs, Acc. Chem. Res. 2001, 34, 18.A. Furstner, Angew. Chem. Int. Ed. 2000, 112, 3140.
R. H. Grubbs, S. J. Miller, G. C. Fu, Acc. Chem. Res. 1995, 28, 446.
Alkene Metathesis Reactions:Background Material
[M]R1 R2
+R2
R1 +
J.-L. Herisson, Y. Chauvin, Makromol. Chem. 1970, 141, 161.
Alkene Metathesis Reactions:Background Material
[M]R1 R2
+R2
R1 +
[M]
R1
R1
M
[M]
R1R2
R2R1
R1
M
R2
J.-L. Herisson, Y. Chauvin, Makromol. Chem. 1970, 141, 161.
Alkene Metathesis Reactions:Background Material
Xn
[M]
X
[M]
n
Xn
Xn
n
RCM ROMP
ADMET
Versions of the olefin metathesis reaction:
RCM = ring-closing metathesisROM = ring-opening metathesis
ADMET = acyclic diene metathesis polymerizationROMP = ring-opening metathesis polymerization
ROM
Alkene Metathesis Reactions:Background Material
Xn
[M]
X
[M]
n
Xn
Xn
n
RCM ROMP
ADMET
ROM
norbornene
Alkene Metathesis Reactions:Background Material
RCM ROMP
ADMET
ROM
norbornene
[M]n
Alkene Metathesis Reactions:Background Material
Xn
[M]
X
[M]
n
Xn
Xn
n
RCM ROMP
ADMET
ROM
Alkene Metathesis Reactions:Background Material
[M]RCM
ROM
[M]
Alkene Metathesis Reactions:Applications in Industrial Processes
Phillips Petroleum Company, Hydrocarbon Process, 1967, 46, 232.
[W][W]
n
Me Me
Me
Me+ +
The Phillips triolefin process
The Norsorex process
[Mo]
ROMPROM
Note: Early industrial processes used weird mixtures of metals to initiate metathesis such asmolybdenum oxide on alumina combined with LiAlH4. They are still used today because they
are both cheap and effective for these particular polymers. In fact, 45,000 tons of the Norsorexnorbornene polymer are produced annually.
norbornene
Alkene Metathesis Reactions:Background Material
[M]R1 R2
+R2
R1 +
[M]
R1
R1
M
[M]
R1R2
R2R1
R1
M
R2
J.-L. Herisson, Y. Chauvin, Makromol. Chem. 1970, 141, 161.
Alkene Metathesis Reactions:What are Effective Initiators for the Process?
AcidsAlcohols, Water
AldehydesKetonesOlefins
Esters, Amides
Functionalgroupreactivity
1975 1980 1985 1990 1995 2000
W(CO)5Ph
R
R = Ph orR = OMe
(Katz, 1976)
W
Alkene Metathesis Reactions:What are Effective Initiators for the Process?
AcidsAlcohols, Water
AldehydesKetones
Esters, AmidesOlefins
AcidsAlcohols, Water
AldehydesKetonesOlefins
Esters, Amides
Functionalgroupreactivity
TiClAl
Cp
Cp
Me
Me
1975 1980 1985 1990 1995 2000
W(CO)5Ph
RTi
Cp
CpR = Ph orR = OMe
(Katz, 1976) (Tebbe andParshall, 1978)
W Ti
Alkene Metathesis Reactions:What are Effective Initiators for the Process?
AcidsAlcohols, Water
AldehydesKetones
Esters, AmidesOlefins
AcidsAlcohols, Water
AldehydesKetonesOlefins
Esters, Amides
AcidsAlcohols, Water
AldehydesOlefinsKetones
Esters, Amides
Functionalgroupreactivity
MoN
(F3C)2MeCO(F3C)2MeCO
Ph
MeMe
i-Pri-PrTiClAl
Cp
Cp
Me
Me
1975 1980 1985 1990 1995 2000
W(CO)5Ph
RTi
Cp
CpR = Ph orR = OMe
(Katz, 1976) (Tebbe andParshall, 1978)
(Schrock, 1990)
W Ti Mo
Alkene Metathesis Reactions:What are Effective Initiators for the Process?
AcidsAlcohols, Water
AldehydesKetones
Esters, AmidesOlefins
AcidsAlcohols, Water
AldehydesKetonesOlefins
Esters, Amides
AcidsAlcohols, Water
AldehydesOlefinsKetones
Esters, Amides
Olefins Acids
Alcohols, WaterAldehydesKetones
Esters, Amides
Functionalgroupreactivity
MoN
(F3C)2MeCO(F3C)2MeCO
Ph
MeMe
i-Pri-PrTiClAl
Cp
Cp
Me
Me
1975 1980 1985 1990 1995 2000
W(CO)5Ph
RTi
Cp
Cp
RuCl
ClPCy3
PCy3 Ph
Ph
R = Ph orR = OMe
(Katz, 1976) (Tebbe andParshall, 1978)
(Schrock, 1990) (Grubbs, 1992)
W Ti Mo Ru
Alkene Metathesis Reactions:What are Effective Initiators for the Process?
RuPhCl
ClPCy3
PCy3 RuPhCl
Cl
PCy3
NN
Me
MeMe
Me
Me
MeMe
Me
t-Bu
OO Mo
Ni-PrMe
Me
t-Bui-Pr
PhMe
Me
Hoveyda andSchrock, 1998
Grubbs, 1995 Grubbs, 1999
RuPhCl
ClNN CyCy
Herrmann, 1998
NN CyCy
"a.k.a. Grubbs I" "a.k.a. Grubbs II"(first asymmetric
metathesis initiator)
Alkene Metathesis Reactions:An Initiator "Caught-in-the-Act" of Metathesis
M. L. Snapper and co-workers, J. Am. Chem. Soc. 1997, 119, 7157.
O
Ph
H
Me
RuPhCl
ClPCy3
PCy3CHCl3
O
Ph
H
Me
Ph
RuCl
Cl
PPh3
This finding of one displaced PPh3 ligand served as the key discovery leadingto the development of new ligands for ruthenium systems with different
reactivity profiles from the original catalysts.
Alkene Metathesis Reactions:What are Effective Initiators for the Process?
RuPhCl
ClPCy3
PCy3 RuPhCl
Cl
PCy3
NN
Me
MeMe
Me
Me
MeMe
Me
t-Bu
OO Mo
Ni-PrMe
Me
t-Bui-Pr
PhMe
Me
Hoveyda andSchrock, 1998
Grubbs, 1995 Grubbs, 1999
RuPhCl
ClNN CyCy
Herrmann, 1998
NN CyCy
"a.k.a. Grubbs I" "a.k.a. Grubbs II"(first asymmetric
metathesis initiator)
Note: For molybdenum systems, attaching more electron-withdrawing ligandsincreases metathesis activity. This trend is true for most late transition-metal initiators.
Ruthenium, however, is an exception. Both the Herrmann and "Grubbs II" systems improve upon"Grubbs I" by the attachment of bulky, and strongly basic (σ-donating) phosphine ligands.
Ring-Closing Olefin Metathesis:Applications in Synthesis
K. C. Nicolaou and co-workers, J. Am. Chem. Soc. 1996, 118, 10335.
O
O
O
O
O
O
O
OBn
OBnTBSO
Me
H H H H H
H H H H H H
H
TiClAl
Cp
Cp
Me
Me(4.0 equiv)THF, 25→65 °C, 5 h
Ring-Closing Olefin Metathesis:Applications in Synthesis
K. C. Nicolaou and co-workers, J. Am. Chem. Soc. 1996, 118, 10335.
O
O
O
O
O
O
O
OBn
OBnTBSO
Me
H H H H H
H H H H H H
H
O
O
O
O O
O
OBn
OBnTBSO
Me
H H H H H
H H H H H H
H
O
O
O
O O
O
OBn
OBnTBSO
Me
H H H H H
H H H H H H
H
TiClAl
Cp
Cp
Me
Me(4.0 equiv)
(61%)Ring-closing metathesis
THF, 25→65 °C, 5 h
Ring-Closing Olefin Metathesis:Less Obvious Applications in Total Synthesis
K. C. Nicolaou and co-workers, Angew. Chem. Int. Ed. 1998, 37, 1874.
O OMe
TBSO
O OMe
TBSO
(15 mol %)
CH2Cl2,40 °C, 72 h
(90%)Ring-closingmetathesis
OMe
TBSOOH
OH
SPh
OMe
TBSOOPMB
SPh
FB
OMe
HOOBn
SPhC
OMe
OO
O
O
HOCl
ClOMe
Me
O
Me
OMe
NO2Me
Me
OMe
HO
OMe
OOH
OOMe
OHOMe
OO
OH
O
O
OO
OO O
OO
O OO
Me
OHMe HO OH
MeMeOE G
everninomicin 13,384-1A
HFC D A2A1B
RuPhCl
ClPCy3
PCy3
Ring-Closing Olefin Metathesis:Applications in Total Synthesis
A. H. Hoveyda and co-workers, J. Am. Chem. Soc. 1997, 119, 10302.
O
HN
O
Me Me (90%)
O
HN
O
Me Me
Me
AMe
OAcO MeOAc
NHCOCF3O
AcO MeOAc
NHCOCF3
(20 mol %)C6H6, 60 °C,
10 h
Ring-closing metathesis
O
HN
O
Me Me
Me
Sch38516
OHO MeOH
NH2
1. H2, Pd/C2. N2H4
(69%)
56
MoN
(F3C)2MeCO(F3C)2MeCO
Ph
MeMe
i-Pri-Pr
Note: Only the Schrock Mo initiator andthe second generation Grubbs initiator can
form tricyclic olefins via RCM.
A
Ring-Closing Olefin Metathesis:Applications in Total Synthesis
K. C. Nicolaou and co-workers, Angew. Chem. Int. Ed. Engl. 1996, 35, 2399.
O
O
HO
O
N
S
O
O
HO
O N
S
6 mM in CH2Cl2,25 °C, 12 h
Ring-closing metathesis
RuPhCl
ClPCy3
PCy3
In general, ring-closing metathesis provides predominantly E-alkenes, thoughthe actual distribution is subject to many factors: thermodynamic stability,
stereochemistry of the intervening chain, reaction conditions, etc.
(100% E-isomer)
Ring-Closing Olefin Metathesis:Applications in Total Synthesis
K. C. Nicolaou and co-workers, Angew. Chem. Int. Ed. 1997, 36, 166.
O
OOTBS
HO
O
N
S
O
OOH
HO
O
N
S
25 °C, 20 h
epothilone C
(85%, 1.2:1 Z:E)Ring-closing metathesis
TFA, CH2Cl2,0 °C, 3 h
(75%)(4.8:1.0 ratioof epoxideisomers)
(98%)
6 mM in CH2Cl2,
OO
MeF3CCH3CN/Na2EDTA
(2:1), 0 °C, 1 h
,
RuPhCl
ClPCy3
PCy3
O
OOTBS
HO
O
N
S
O
OOH
HO
O
N
SO
epothilone A
Ring-Closing Olefin Metathesis:Applications in Total Synthesis
K. C. Nicolaou and co-workers, Angew. Chem. Int. Ed. Engl. 1996, 35, 2399.
O
O
HO
O
N
S
O
O
HO
O N
S
6 mM in CH2Cl2,25 °C, 12 h
Ring-closing metathesis
RuPhCl
ClPCy3
PCy3
In general, ring-closing metathesis provides predominantly E-alkenes, thoughthe actual distribution is subject to many factors: thermodynamic stability,
stereochemistry of the intervening chain, reaction conditions, etc.
(100% E-isomer)
Ring-Closing Olefin Metathesis:Applications in Total Synthesis
S. J. Danishefsky and co-workers, J. Am. Chem. Soc. 1997, 119, 2733.D. Schinzer and co-workers, Angew. Chem. Int. Ed. Engl. 1997, 36, 523.
O
O
RO
X
N
S
various conditionsRing-closing metathesis
Y
R X YTBSTBSTBSTBS
HTBS
α-OTPS, β-Hα-OTPS, β-Hα-OTPS, β-H
OOO
α-OHα-OTESβ-OH
α-OTBSα-OHβ-OTBS
1:31:51:95:31:21:2
868081866588
Danishefsky
Investigator
TBS O α-OTBS 1.7:1Schinzer 94
T (°C) t (h)
222222
16CH2Cl2
C6H6C6H6C6H6C6H6C6H6C6H6
555555555555
25
Solvent Z:E Ratio Yield (%)
O
O
RO
X
N
S
Y
Schrock catalyst(Danishefsky)or "Grubbs I"
(Schinzer)
Ring-Closing Olefin Metathesis:Applications in Total Synthesis
S. J. Danishefsky and co-workers, J. Am. Chem. Soc. 1997, 119, 2733.
epothilone B
O
OOH
HO
O
N
SO
O
OOTBS
TBSO
O
N
S
C6H6, 55 °C, 2 hO
OOTBS
TBSO
O
N
S(20 mol %)
1. HF•py2. DMDO, -50 °C
(86%)(1:1 Z:E isomers)
Ring-closing metathesis
MoN
(F3C)2MeCO(F3C)2MeCO
Ph
MeMe
i-Pri-Pr
A
O ODMDO = (87% overall)
A
Question: what initiatorsare capable of formingtrisubstituted olefins
via ring-closing metathesis?
Ring-Closing Olefin Metathesis:Applications in Total Synthesis
J. Sun, S. C. Sinha, Angew. Chem. Int. Ed. 2002, 41, 1381.
epothilone B
O
OOH
HO
O
N
SO
O
OOTBS
TBSO
O
N
SO
RuPhCl
Cl
PCy3
NN MesMes
B
CH2Cl2, 45 °C, 48 h
RuPhCl
ClPCy3
PCy3
A
B
O
OOTBS
TBSO
O
N
SO
(30 mol %)
1. H2, Pd/C, EtOH2. TFA, CH2Cl2
(89%)(1:1 E:Z isomers)
Ring-closing metathesis
Ring-Closing Olefin Metathesis:Applications in Total Synthesis
S. F. Martin and co-workers, J. Am. Chem. Soc. 1999, 121, 866.
N
NHH
MeO OMe
O
O
N
NO
OMeMeO
H
O
H
Ring-closingmetathesis
(67%)(8:1, Z/E)
(13 mol %)CH2Cl2, Δ, 3 h
RuPhCl
ClPCy3
PCy3A
A
Ring-Closing Olefin Metathesis:Applications in Total Synthesis
S. F. Martin and co-workers, J. Am. Chem. Soc. 1999, 121, 866.
N
NHH
MeO OMe
O
O
N
NHH
MeO OMe
OH
O
N
NHH
O
OH
ON
N
NNH
OHHH
HH
(26%)
N
NO
OMeMeO
H
O
H
Ring-closingmetathesis
(67%)(8:1, Z/E)
(13 mol %)
manzamine A
1. KOH, MeOH, Δ2. O
Cl3(75% overall)
Ring-closingmetathesis
CH2Cl2, Δ, 3 h
(110 mol %),C6H6, Δ, 30 min;
then HCl
A
RuPhCl
ClPCy3
PCy3A
A
Ring-Closing Olefin Metathesis in Total Synthesis:Difficulty Predicting E-/Z- Product Distribution
K. C. Nicolaou and co-workers, Angew. Chem. Int. Ed. 2002, 41, 3276.
O O
p-BrBzO
Me
OMe
O
Me
O OMe
p-BrBzO
Me
O
O
Me
Me
Me
Me
Me
Me
Me
Me
Me
O O
p-BrBzO
Me
O
O
Me
MeMe
Me
Me
(32%)
(48%)
CH2N2
Ring-Closing Olefin Metathesis in Total Synthesis:Difficulty Predicting E-/Z- Product Distribution
K. C. Nicolaou and co-workers, Angew. Chem. Int. Ed. 2002, 41, 3276.
O O
p-BrBzO
Me
OMe
O
Me
O OMe
p-BrBzO
Me
O
O
Me
O
O
Me
Me
OMe
O
Op-BrBz
Me
Me
Me
Me
Me
Me
O
OMe
Me
O
O
Op-BrBz
MeMe
MeMe
Me
Me
Me
O O
p-BrBzO
Me
O
O
Me
MeMe
Me
Me
RuPhCl
Cl
PCy3
NN
Me
MeMe
Me
Me
Me
CH2Cl2,40 °C, 3 h
(86%)
(32%)
(48%)
CH2N2
CH2Cl2,40 °C, 3 h
(80%)
A
A
A
RCM
RCM
Note: Product distribution is kinetically controlled!
Ring-Closing Olefin Metathesis:Applications in Total Synthesis
A. Furstner, T. Muller, J. Org. Chem. 1998, 3, 424.
O
O
OHO
OMe
OHO
HO
HOO
OO
O
O
OHHOHOMe
O
O
MeMe
MeO
O
MeMe
tricolorin A
O
OH
O
OMe
OO
O
O
O
OOPh
O
OH
O
OMe
OO
O
O
O
OOPhO
OH
O
OMe
OO
O
O
OOPh
O
A (5 mol %)
CH2Cl2, 45 °C
H2, Pd/C,EtOH (77%)
Ring-closingmetathesis
Me
Me
Me
Me
RuPhCl
ClPCy3
PCy3A
Facilitating/Hindering Ring-Closing Olefin Metathesis:Long and Short Range Chelation
K.C. Nicolaou, S.A. Snyder, K.B. Simonsen, A.E. Koumbis, Angew. Chem. Int. Ed. 2000, 39, 3473.
ML
L
OO
OR
M
good chelation bad chelation
Ring-Closing Olefin Metathesis:Applications in Total Synthesis
A. Furstner, T. Muller, J. Org. Chem. 1998, 3, 424.
O
O
OHO
OMe
OHO
HO
HOO
OO
O
O
OHHOHOMe
O
O
MeMe
MeO
O
MeMe
tricolorin A
O
OH
O
OMe
OO
O
O
O
OOPh
O
OH
O
OMe
OO
O
O
O
OOPhO
OH
O
OMe
OO
O
O
OOPh
O
A (5 mol %)
CH2Cl2, 45 °C
H2, Pd/C,EtOH (77%)
Ring-closingmetathesis
Me
Me
Me
Me
RuPhCl
ClPCy3
PCy3A
Facilitating/Hindering Ring-Closing Olefin Metathesis:Long and Short Range Chelation
K.C. Nicolaou, S.A. Snyder, K.B. Simonsen, A.E. Koumbis, Angew. Chem. Int. Ed. 2000, 39, 3473.
ML
L
OO
OR
M
ON
NMeOMeO
ON
NMeOMeO
X
good chelation bad chelation
Example of bad chelation:
Lewis basic nitrogen
Ring-Closing Olefin Metathesis:Applications in Total Synthesis
A. I. Meyers and co-workers, Angew. Chem. Int. Ed. 2000, 39, 1664.
OS
O NH
NH
O
O N
O O
Mes
O Me
OS
O NH
NH
O
O N
OH OH
O Me
RuPhCl
ClPCy3
PCy3
griseoviridin
toluene, 100 °C
1.
2. PPTS(23% overall)Ring-closingmetathesis
Cascades of Metathesis Reactions:Applications in Total Synthesis
R. Stragies, S. Blechert, Tetrahedron 1999, 55, 8179.
O
TsN
SiMe Me
NTs
SiO
H
Me Me
NTs
OH
HNH
OH
H
(5 mol %)
TBAF, CH2Cl2-78→25 °C
(78%overall)
CH2Cl2, 25 °C, 4 hROM-RCM cascade
(–)-halosalin
1. H2, Pd/C2. Na/Hg, MeOH, K2HPO4, Δ(81% overall)
RuPhCl
ClPCy3
PCy3
Ring-Closing Olefin Metathesis:Applications in Total Synthesis
K. Kakinuma and co-workers, J. Org. Chem. 1998, 63, 4741.
Me Me Me Me
OOBn
O
Me Me Me MeH
(29 mol %)3.8 mM in CH2Cl2,45 °C, 42 h(79%, 7:1 E:Z)Ring-closing metathesis
Me Me Me Me
OOBn
O
Me Me Me MeH
RuPhCl
ClPCy3
PCy3
Ring-Closing Olefin Metathesis:Applications in Total Synthesis
K. Kakinuma and co-workers, J. Org. Chem. 1998, 63, 4741.
Me Me Me Me
OOBn
O
Me Me Me MeH
(20 mol %)108 mM in CH2Cl2, 25 °C, 9 h(81% based on recovered s.m.)Cross metathesis
O
OMe Me Me Me
Me Me Me Me
O
OMe Me Me Me
Me Me Me Me OBn
BnO
RuPhCl
ClPCy3
PCy3
Ring-Closing Olefin Metathesis:Applications in Total Synthesis
K. Kakinuma and co-workers, J. Org. Chem. 1998, 63, 4741.
Me Me Me Me
OOBn
O
Me Me Me MeH
(20 mol %)108 mM in CH2Cl2, 25 °C, 9 h(81% based on recovered s.m.)Cross metathesis
O
OMe Me Me Me
Me Me Me Me
O
OMe Me Me Me
Me Me Me Me OBn
BnO
O
OMe Me Me Me
Me Me Me Me
O
OMe Me Me Me
Me Me Me Me OH
HO
1. "Grubbs I" (20 mol %) 1.0 mM in CH2Cl2, 45 °C, 72 h2. H2, Pd/C, EtOAc
Ring-closing metathesis(34% overall)
RuPhCl
ClPCy3
PCy3
Cross Metathesis: A Reaction With A Slew of Potential Problems
R. H. Grubbs and co-workers, J. Am. Chem. Soc. 2003, 125, 11360
A B+
AA
AA
BB
BB
BA
AB
Six possible products; often all are formed.
Sometimes, though, cross selectivity can be achieved in certain cases;E-/Z- control is still not as perfect as might be desired.
Cross Metathesis: A Reaction With A Slew of Potential Problems
R. H. Grubbs and co-workers, J. Am. Chem. Soc. 2003, 125, 11360
A B+
AA
AA
BB
BB
BA
AB
Six possible products; often all are formed.
Sometimes, though, cross selectivity can be achieved in certain cases;E-/Z- control is still not as perfect as might be desired.
Crossmetathesisproducts
The Total Synthesis of Laurefucin
with A. P. Brucks, D. S. Treitler, I. Moga, J. Am. Chem. Soc. 2012, 134, 17714.
OH
OH I2, NaHCO3
O
OH
IO
OH
I
+
(42%) (34%)
trans-3-hexene,Hoveyda-Grubbs II (78%)
O
OH
IMe
The Total Synthesis of Laurefucin
with A. P. Brucks, D. S. Treitler, I. Moga, J. Am. Chem. Soc. 2012, 134, 17714.
OH
OH I2, NaHCO3
O
OH
IO
OH
I
+
(42%) (34%)
trans-3-hexene,Hoveyda-Grubbs II (78%)
O
OH
IMe
Cross Metathesis: A Reaction You Have Seen Before
P. L. Fuchs and co-workers, J. Am. Chem. Soc. 2006, 128, ASAP.D. L. Hughes and co-workers, J. Org. Chem. 2004, 69, 1598.
Intramolecularnitrone [3+2]cycloaddition
MgBr1.
2. PCC, CH2Cl2
O
EtO HO
CN
CN
N
CN
CN
HON
CN
CN
HON
CN
CN
O
O CN
Michael addition
1,3-protonshift
H2NOH•HCl, NaOAc,MeOH/MeCN, 50 °C
RuCl
ClNN
Me
MeMe
Me
Me
Me
Oi-PrA
A
Olefin cross-metathesis
(62%)(91% overall)
Cross Metathesis:Applications in Total Synthesis
S. T. Diver, S. L. Schreiber, J. Am. Chem. Soc. 1997, 119, 5106.See also: The Billion Dollar Molecule by Barry Werth
N
O
O
HO
O
O
Me
Me
MeOOH
H
OOH
H
OMe
Me
OMe Me
Me
H
N
O
O
HO
O
O
Me
Me
MeOOH
H
OOH
H
OMe
Me
OMe Me
Me
H
N
O
O
OH
O
O
Me
Me
OMeOH
H
OHO
H
OMe
Me
OMeMe
Me
H
FK506 FK1012
CH2Cl2, 25 °C, 22 h
(58%)(1:1 E:Z isomers)Cross metathesis
RuPhCl
ClPCy3
PCy3
Cross Metathesis:Applications for Generating Potent Antiobiotics
D. H. Williams and co-workers, Angew. Chem. Int. Ed. 1999, 38, 1172.
O
HN NO
ONO
N
OHOH
HO
OHO
N
O2C
O
Cl
ClOOO
HOOH
OMeH2N
HOMe
OHO
MeMe
H2N Me
HNO
OH
NNH3
O
O
N O
O
Me
Me
HH
H
H
H HNH2
O
L-Lys-D-Ala-D-AlaVancomycin-susceptible bacteria
Cross Metathesis:Applications for Generating Potent Antiobiotics
D. H. Williams and co-workers, Angew. Chem. Int. Ed. 1999, 38, 1172.
O
HN NO
ONO
N
OHOH
HO
OHO
N
O2C
O
Cl
ClOOO
HOOH
OMeH2N
HOMe
OHO
MeMe
H2N Me
HNO
OH
NNH3
O
O
N O
O
Me
Me
HH
H
H
H HNH2
O
O
HN NO
ONO
N
OHOH
HO
OHO
N
O2C
O
Cl
ClOOO
HOOH
OMeH2N
HOMe
OHO
MeMe
H2N Me
HNO
OH
NNH3
O
O
O O
O
Me
Me
HH
H
H HNH2
O
L-Lys-D-Ala-D-Ala L-Lys-D-Ala-D-LacVancomycin-susceptible bacteria Vancomycin-resistant bacteria
Loss of onehydrogen bond
leads to a 1000-folddecrease in potency
Cross Metathesis:Applications in Total Synthesis
K. C. Nicolaou and co-workers, Chem. Eur. J. 2001, 7, 3824.
O
HN
NHO
OHN
ONH
OHOH
HO
NH2
O
O
HO
HN
O NH
OCl
H H H H
ClO
OO
HO OH
OH
OMe
HNHO Me
O
R2
OH
O
NHR1
n
vancomycin analogs
C15H25NMe3Br (2.2 equiv),H2O/CH2Cl2 (>95:5),
23 °C, 24 h(40-75%)
Cross metathesis
RuPhCl
ClPCy3
PCy3(20 mol %) vancomycin
dimers
Process when executed in the presenceof vancomycin's biological target is known
as dynamic combinatorial screening.
Ring-Closing Olefin Metathesis:Applications in Total Synthesis
A. B. Smith and co-workers, J. Am. Chem. Soc. 2001, 123, 5925.
Me
MeHO
Me
MeHO OH
HO OH
OH
(–)-cylindrocyclophane A
Me
MeTESO
Me
MeMeO OMe
MeO OMe
OTES
MeTESO
MeMeO OMe
(34 mol %)0.1 M in C6H6,1.25 h, 25 °C
(77%)Cross metathesis/
ring-closing metathesis
Me
MeHO
Me
MeMeO OMe
MeO OMe
OH
1. TBAF, THF2. H2, PtO2, EtOH
PhSH, K2CO3215 °C,
sealed tube(60% overall)
RuPhCl
ClPCy3
PCy3
Ring-Closing Olefin Metathesis:Applications in Total Synthesis
Me
MeMeO OMe
Me
MeO OMeMe
Me
Me
Me
MeMeO OMe
MeO OMe(34 mol %)
0.1 M in C6H6,1.25 h, 25 °C
(75-81%)
A. B. Smith and co-workers, J. Am. Chem. Soc. 2001, 123, 5925.
Ring-opening/cross metathesis/
ring-closing metathesis
RuPhCl
ClPCy3
PCy3
Ring-Closing Olefin Metathesis:Applications in the Synthesis of Designed Molecules
T. D. Clark, M. R. Ghadiri, J. Am. Chem. Soc. 1995, 117, 12364.
N NNNN
O
Me OO Me
NO H H
O
ONH
MeMe
O
O
NH
NN
N NNN
NN
O
O O
O O O
OO
H H H H
MeMeMeMe
N NNNN
O
Me OO Me
NO H H
O
ONH
MeMe
O
O
NH
NN
N NNN
NN
O
O O
O O O
OO
H H H H
MeMeMeMe
RuCl
ClPCy3
PCy3
Ph
PhCDCl3, 25 °C, 48 h
(65%)Cross metathesis/RCM (20 mol %)
Enyne Metathesis:Background and Principles of Selectivity
For a review, see: S. T. Diver, A. J. Geissert, Chem. Rev. 2004, 104, 1317.
0-4
[Ru]
0-4
Intramolecular enyne metathesis
0-4
[Ru]
0-4
[Ru]
0-4[Ru]
[Ru]-
Enyne Metathesis:Background and Principles of Selectivity
For a review, see: S. T. Diver, A. J. Geissert, Chem. Rev. 2004, 104, 1317.
0-4
[Ru]
0-4
R2R1
R1
R2
Intramolecular enyne metathesis
0-4
[Ru]
0-4
[Ru]
0-4[Ru]
[Ru] [Ru]
R1[Ru]
R1
Intermolecular enyne metathesis
[Ru]
[Ru]-
-R2 R2
R2
R2[Ru]
R1
R2
R2
Note the insertion into the terminal alkene; with ring sizes above 8,products looking like intermolecular enyne adducts result!
Enyne Metathesis:Selected Examples in Total Synthesis
T. R. Hoye and co-workers, Org. Lett. 1999, 1, 277.M. Mori and co-workers, J. Org. Chem. 1996, 61, 8356.
O
O
RuCl
ClPCy3
PCy3 Ph
Ph
O
O
OO
O
OCDCl3,50 °C24 h
Diels-Alderreaction
Enynemetathesis differolide
N
(40%)
OMeO2C H N O
H
CO2Me
N OHO
MeH
H
O
stemomide
benzene,50 °C, 11 h
(87%)Enyne
metathesis
RuPhCl
ClPCy3
PCy3
Enyne Metathesis:Applications in Total Synthesis
M. D. Shair and co-workers, J. Am. Chem. Soc. 2002, 124, 773.
Me
TBSOOMe
Me
OTBS
MeO OTBS
Me
TBSO
TBSO H
Me OR
TBSO
OMe
Me
Me
OTBS
RO H
OMe
TBSO
Removableatropisomer
control element
R = TBS
Enyne Metathesis:Applications in Total Synthesis
M. D. Shair and co-workers, J. Am. Chem. Soc. 2002, 124, 773.
Me
TBSOOMe
Me
OTBS
MeO OTBS
Me
TBSO
TBSO H
Me OR
TBSO
OMe
Me
Me
OTBS
RO H
OMe
TBSO
Removableatropisomer
control element
Me
TBSOOMe
Me
OTBS
H2C=CH2,CH2Cl2,
40 °C, 21 h
(50 mol %)
(42%)
MeO OTBS
Me
OTBS
TBSO H
Enyne metathesis
H2C=CH2,toluene,
45 °C, 40 h(31%)
(40 mol %)
RuPhCl
ClPCy3
PCy3
RuPhCl
ClPCy3
PCy3
Enyne metathesis
R = TBS
Cascades of Metathesis Reactions:Applications in the Synthesis of Designed Molecules
R. H. Grubbs and co-workers, J. Org. Chem. 1998, 63, 4291.
-[H2C=CH2]Me
OTBDPS
(4 mol %)
Me
OTBDPS
Enyne metathesis
[Ru]C6H6, 25 °C, 4 h
RuPhCl
ClPCy3
PCy3
Cascades of Metathesis Reactions:Applications in the Synthesis of Designed Molecules
R. H. Grubbs and co-workers, J. Org. Chem. 1998, 63, 4291.
-[H2C=CH2]Me
OTBDPS
OTBDPS
(4 mol %)
(70%)
Me
OTBDPS
OTBDPS
Me [Ru]
Enyne metathesis
[Ru]
Enyne metathesisdomino sequence
C6H6, 25 °C, 4 h
RuPhCl
ClPCy3
PCy3
Ring-Closing Alkyne Metathesis:Applications in Total Synthesis
A. Furstner and co-workers, J. Am. Chem. Soc. 1999, 121, 9453.T. J. Katz, T. M. Sivavec, J. Am. Chem. Soc. 1985, 107, 737.
N
epothilone C
O
OOH
HO
O
N
S
O
OOTBS
TBSO N
S
MeMe
O
OOTBS
TBSO
O
N
S
O
A(10 mol %)
(80%)
1. H2, Lindlar cat.2. HF (79% overall)
A
Alkyne metathesis
toluene/CH2Cl280 °C, 8 h
MoNN
Alkyne Metathesis:Applications in Total Synthesis
A. Furstner and co-workers, Angew. Chem. Int. Ed. 2000, 39, 1234.
O
TBSO
MeO
O Me
Me
N
A
MoNN
A(10 mol %)
(73%)
1. H2, Lindlar cat.2. HF (74% overall)
Alkyne metathesis
toluene/CH2Cl280 °C, 16 h
O
TBSO
O
O
Me
O
HO
O
O
Meprostaglandin E-1,15-lactone
Ring-Closing Olefin Metathesis:How to Handle Long-Standing Problems
D. J. Dixon and co-workers, J. Am. Chem. Soc. 2009, 131, 16632.
N
NH
HRing-closingmetathesis
(62%)(1.7:1, Z/E)
(20 mol %)
nakadomarin A
CH2Cl2, Δ, 3.5 h
RuPhCl
ClPCy3
PCy3O
N
NH
H
O
Ring-Closing Olefin Metathesis:How to Handle Long-Standing Problems
D. J. Dixon, R.R. Schrock, A. H. Hoveyda and co-workers, Nature 2011, 479, 88.
N
NH
HRing-closingmetathesis
(63%)(15.6:1, Z/E)
(5 mol %)
nakadomarin A
toluene, rt, 8 h
O
N
NH
H
O
WN
ON
Cl Cl
Ar Ar
Ring-Closing Olefin Metathesis:Deploy Judiciously
D. J. Dixon, R.R. Schrock, A. H. Hoveyda and co-workers, Nature 2011, 479, 88.
OO O OH
Ring-Closing Olefin Metathesis:Deploy Judiciously
D. J. Dixon, R.R. Schrock, A. H. Hoveyda and co-workers, Nature 2011, 479, 88.
OO O OH
Ring-Closing Olefin Metathesis:Deploy Judiciously
D. J. Dixon, R.R. Schrock, A. H. Hoveyda and co-workers, Nature 2011, 479, 88.
OO O OH
Ring-Closing Olefin Metathesis:Applications in Total Synthesis
A. I. Meyers and co-workers, Angew. Chem. Int. Ed. 2000, 39, 1664.
OS
O NH
NH
O
O N
O O
Mes
O Me
OS
O NH
NH
O
O N
OH OH
O Me
RuPhCl
ClPCy3
PCy3
griseoviridin
toluene, 100 °C
1.
2. PPTS(23% overall)Ring-closingmetathesis