Metathesis Reactions Lecture Notes Key Reviews: M e t a t h e s i s i n C o m p l e x M o l e c u l e S y n t h e s i s K.C. Nicolaou, S.A. Snyder, Classics in Total Synthesis II, Chapter 7. A l k y n e M e t a t h e s i s M. Mori, Topics Organomet. Chem. 1998, 1, 133. E n y n e M e t a t h e s i s S. T. Diver, A. J. Geissert, Chem. Rev. 2004, 104, 1317. O l e f i n M e t a t h e s i s K. 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.
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Metathesis Reactions€¦ · 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
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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.
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?
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