Olefin Metathesis and Use in Tandem Reactions
- The Work of Marc L.
Snapper
James Mousseau
Literature Meeting6 May 2008
1
Outline
2
Introduction to MetathesisHistorical backgroundDifferent types/catalysts
Applications in tandem reactionsMarc L. Snapper
Snapper ResearchTandem CopeTandem Olefin IsomerizationTandem Kharasch AdditionTandem CyclopropanationTandem Allylic Alcohol IsomerizationTandem OxidationTandem Wittig
3
Metathesis - Introduction
As applied to alkenes, refers to the transposition of the alkene carbon atoms so that two new alkenes are formed
Dates back to 1955
Very popular means of making C=C bonds
TiII
n
A. W. Anderson and N. G. Merckling, U. S. U.S. Patent 2,721,189 (October 18, 1955)
4
Metathesis - Introduction
Olefin metathesis has wide ranging applicability as evidenced by number of publications and citations
Results from Web of Science search on olefin metathesisAccessed 2 May 2008
5
Metathesis - 2005 Nobel Prize in Chemistry
To Pierre Chauvin, Robert Grubbs and Richard Schrock for “the
development of the metathesis method in organic synthesis”
6
Ring Opening Metathesis Polymerizations (ROMP)
n
ROMP
Thermodynamically favoured for smaller rings
Especially favoured for bridged systems
TiII
n
7
Acyclic Diene Metathesis (ADMET)
Used to polmerize certain terminal dienes to polyenes
Double bond formed can be E or Z
ADMETR
RR
n
Grubbs, R. H., et al. J. Am. Chem. Soc. 2006, 128, 15358-15359
8
Ring Closing Metathesis (RCM)
RCM
Reaction is driven by the loss of ethylene
Permits access of ring sizes that otherwise may be typically hard to make However if thermodynamically unfavourable polymerization may occur
OR
O
O
OR
O
O
Grubbs II (10 mol %)
DCM, 40 ºC
Nicolaou, K. C.., et al. Chem. Comm. 2006, 600-602
9
Enyne (EM) and Alkyne (AM) Metathesis
R2R1 R4R3
R2R1
R4R3
+
M R2 R3R1 +
R2 R3
R1M
R2 R3
R1M
M R1 R3R2 +
O
O
O
O
O
O
O
O
Furstner, A., et al. J. Am. Chem. Soc. 1999, 121, 9453-9454
Katz, T. J., et al. J. Am. Chem. Soc. 1985, 107, 737-738
10
Cross Metathesis (CM)
+
:
1:1
CM (%)
50
1:2 67
1:3 75
1:5 83
1:10 91
1:20 95
1:50 98
1:100 99
: CM (%)
Chris Kendall, Literature Meeting March 20 2006
CM works particularly well when one of the components is slows to dimerize
AcO CO2Me AcO CO2MeGrubbs II
DCM, r.t.+
Blechert, S., et al. Angew. Chem. Int. Ed. 2003, 42, 1900-1923
The key referenceThe key referenceChatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360
Type I
terminal olefins1° allylic alcohols, amines (protected), estersallyl halides, silanesallyl boronate esters, phosphonates, phosphine oxides, sulfidesstyrenes (no large ortho groups)
Type II
2° allylic alcohols, unptrotected 3° allylic alcoholsacrylates, acrylamides, acrylic acid, acrolein, vinyl ketonesvinyl epoxidesperfluorinated alkane olefinsstyrenes (large ortho substituents)
Type III
1,1-disubstituted olefinstrisubstituted olefins (non-bulky)4° allylic carbon3° allylic alcohol (protected)vinyl phosphonates
Type IV
vinyl nitro olefinstrisubstituted allylic alcohols (protected)
For Grubbs II:
Cross Metathesis (CM)
Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360Chris Kendall, Literature Meeting March 20 2006
12
Metathesis - Catalytic Cycle
Associative goes through 18e- cycle (ligand does not dissociate)
Two potential pathways were proposed
Grubbs, R. H., et al. J. Am. Chem. Soc. 1997, 119, 3887-3897
13
Metathesis - Catalytic Cycle
Dissociative 16e- pathway found to be dominant (~95%)
Grubbs, R. H., et al. J. Am. Chem. Soc. 1997, 119, 3887-3897
14
Metathesis - CatalystsN
Mo
OO
CH3F3C CF3
CH3
F3CF3C
H
C(CH3)2Ph
i-Pr i-Pr
Schrock I
Schrock, R. R.; Murdzek, J . S .; Bazan, G. C.;Robbins , J .; DiMare , M.; O'Reagan, M.
J. Am. Chem. S oc. 1990, 112, 3875
C30H35F12MoNO2
Mol. Wt.: 765.53Strem: 2 g / $699
Cy3P
RuH
PhPCy3
Cl
Cl
Grubbs ICl2(PCy3)2Ru=ChPh
Schwab, P .; France , M. B.;Zille r, J . W.; Grubbs , R. H.
Angew. Chem. Int. Ed. 1995, 34, 2039
C43H72Cl2P 2RuMol. Wt.: 822.96
Aldrich: 5 g / $332.50
RuPh
PCy3Cl
ClN N
Grubbs II(H2IMes)(PCy3)Cl2Ru=ChPh
Scholl, M.; Ding, S .;Lee , C. W.; Grubbs , R. H.
Org. Le tt. 1999, 1, 953
C46H65Cl2N2PRuMol. Wt.: 848.97
Aldrich: 2 g / $532
RuPh
NCl
ClMesN NMes
Grubbs III
Love , J . A.; Morgan, J . P .;Tmka, T. M.; Grubbs , R. H.
Angew. Chem. Int. Ed. 2002, 41, 4035
C38H40Br2Cl2N4RuMol. Wt.: 884.53
N
Br
Br
H
Ru
Cl
ClMesN NMes
H-Grubbs
Kingsburgy, Harrity, J . P . A.; Hoveyda , A. H.J. Am. Chem. S oc. 1999, 121, 791
C31H38Cl2N2ORuMol. Wt.: 626.62
Aldrich: 2 g / $899
O
aqua-Grubbs
Hong, S . H.; Grubbs , R. H.J. Am. Chem. S oc. 2006, 128, 3508
Ru
Cl
ClMesN NMes
O
(OCH2CH2)nOCH3
Chris Kendall, Literature Meeting March 20 2006
15
Metathesis - Tandem ReactionsO 5 mol% Grubbs II
40 °C, 12 h(89%)
O
neat 3 equiv 1 equiv
B
O
O
O
O
3 equiv
2 mol% Grubbs II,CH2Cl2, 40 °C
then PhCHO, rt(69%)
Ph
OH
O O
dr > 20:1
OH OH
O
3 equiv
5 mol% H-Grubbs ,1 a tm H2, 5 mol% P tO2,
CH2Cl2, rt, 15 h(50%)
O
O
PhPh
Grubbs, R. H., et al. J. Am. Chem. Soc. 2003, 125, 11360
Grubbs, R. H., et al. Angew. Chem. Int. Ed. 2002, 41, 807
Cossy, J., et al.Org. Lett. 2003, 5, 459
16
Marc L. Snapper
EDUCATION AND EXPERIENCE
UNION COLLEGE, Schenectady, New York 1976-1980 B.S., Chemistry/Biology
STERLING ORGANICS, Division of Sterling Drug, Rensselaer, New York 1980-1984 Research Chemist
STANFORD UNIVERSITY, Stanford, California 1984-1990 Ph.D., Organic Chemistry, Advisor: Professor Paul A. Wender
HARVARD UNIVERSITY, Cambridge, Massachusetts 1990-1993 NIH Postdoctoral Fellow, Advisor: Professor Stuart L. Schreiber
BOSTON COLLEGE, Chestnut Hill, Massachusetts 1993-1999 Assistant Professor of Chemistry 1999- Professor of Chemistry
HONORS AND AWARDS
1999-2001 Glaxo Wellcome Chemistry Scholar Award 1999-2000 Boston College Distinguished Research Award 1998-2001 Camille Dreyfus Teacher-Scholar Award 1998-2000 Alfred P. Sloan Research Fellowship 1998-1999 DuPont Young Professor Award 1997-1999 Lilly Grantee Award 1997-2000 National Science Foundation CAREER Development Award 1997-1998 Boston College Teaching Development Award 1996-1997 Boston College Faculty Fellowship 1995-1997 Massachusetts Breast Cancer Research Fellowship 1995-1996 Boston College Distinguished Junior Faculty Award 1990-1993 National Institutes of Health, NCI Postdoctoral Fellowship 1990-1991 Merck Postdoctoral Fellowship
17
Snapper Research
And obviously Tandem Metathesis!!!!!
18
Metathesis - Cope Rearrangement
Applied to the synthesis of +/- Asteriscanolide
9 step synthesis with the key step involving a tandem metathesis/Cope Rearrangement
Had previously done a similar transformation, but not in tandem
O
O
O
Snapper, M. L., et al. J. Am. Chem. Soc. 2000, 122, 8071-8072
O R2
HR1
H
Grubbs I
RO
TBSO
H
H
R2
R1
O
H
R1
R2
OTBSCope
200 ºC
57% - 72% 70% - 99%
Snapper, M. L., et al. J. Am. Chem. Soc. 1997, 119, 1478-1479
19
Metathesis - Cope Rearrangement
O
O
O
Snapper, M. L., et al. J. Am. Chem. Soc. 2000, 122, 8071-8072
O
O
CO2MeCO2Me
(OC)3Fe
NMe2
(OC)3Fe
O
OH
OO
O
O
O
O
O
O
O
(OC)3Fe(OC)3Fehv, Fe2(CO)6
50 ºC
LAH, BF3OEt2 Me2NCH2NMe2
H3PO4, AcOHMeINaH
Me3NOGrubbs II
PCC
Red-Al, CuBr BH3OEt2, PCC
20
Metathesis - Cope Rearrangement
O
O
O
Snapper, M. L., et al. J. Am. Chem. Soc. 2000, 122, 8071-8072
O
RuPh
PCy3Cl
ClN N
benzene, ethylene, 50 ºC, 10 h O
reflux
O
Key is a tandem reaction
Cope occurs under relatively mild conditions
Reason this occurs due to the absence of an alkyl group
O O R2
HR1
H
H
VS
21
RCM Metathesis - Olefin Isomerization
Snapper, M. L., et al. J. Am. Chem. Soc. 2002, 124, 13390-13391
Grubbs’ catalyst, in addition to metathesis, has been known to undergo hydrogenation
Occassionally noted that isomerization could interfere with metathesis
Explored the possibility of combining the two reactions
XRX X
RuPh
PCy3Cl
ClN N
RR [RuH]
22
RCM Metathesis - Olefin Isomerization
Snapper, M. L., et al. J. Am. Chem. Soc. 2002, 124, 13390-13391
Found that 95/5 N2/H2 was optimal hydride source
Unsure the the hydride - Ru species 22
XRX X
RuPh
PCy3Cl
ClN N
RR [RuH]
23
RCM Metathesis - Olefin Isomerization
Snapper, M. L., et al. J. Am. Chem. Soc. 2002, 124, 13390-13391
OBnOBn OBnOBnOBn
OR
4 1 0
OPh OPh
O O OOOPh Ph Ph Ph Ph
OPh OPh
65 %ee 65 %ee
24
RCM - Kharasch Addition
Snapper, M. L., et al. J. Am. Chem. Soc. 2005, 127, 16329-16332
Kharasch reaction is a radical atom transfer reaction
Earlier Snapper demonstrated that Grubbs I can promote the transformation
ClR
Cl
Cl AIBN Cl
Cl
R R1
R2
Cl
Cl
RR1
R2Cl
N Cl
RCl
R1
R2
Cl
Kharasch, M.S., et al. Science 1945, 102, 128
R1
R2 R2
R1
R3
Cl Cl Cl
R2
R1
R3
OGrubbs I
XS R3CCl3
H3O+
Cy3P
RuH
PhPCy3
Cl
ClClR3
Cl
ClCy3P
RuH
PhPCy3
Cl
Cl Cl
Cl
R3Cl
Snapper, M. L., et al. Tetrahedron 2004, 60, 7391-7396
25
RCM - Kharasch Addition
Snapper, M. L., et al. J. Am. Chem. Soc. 2005, 127, 16329-16332
R1R2
Cy3P
RuH
PhPCy3
Cl
Cl
R1R2 R1
Cl
R2
Cl
R3Cl
R3CCl3
+
R4
R1
Cl
R2
R3Cl
R4
Cl
Cy3P
RuH
PhPCy3
Cl
Cl
OH HNCCl3
O
CCl3OMe
O
n
n
nn
1. Cl3CCN, NaH 0 ºC
2. xylenes, 140 ºC
1. DIBAL2. I2, PPh3, imid3. CHCl3, BuLI
Reaction was performed on cyclic substrates
26
RCM - Kharasch Addition
Snapper, M. L., et al. J. Am. Chem. Soc. 2005, 127, 16329-16332
CCl3Cl
Cl
ClCl
Cl
Cl Cl ClCl
Grubbs
27
RCM - Kharasch Addition
Snapper, M. L., et al. J. Am. Chem. Soc. 2005, 127, 16329-16332
HNCCl3
O
HN
O
CCl3
Grubbs
Grubbs
HNCCl3
O
HN
O
CCl3
HN
HNO
Cl
Cl
Cl
O
Cl
Cl
Cl styrene
styrene
HN
HNO
Cl
Cl
O
Cl
ClPh
Cl
Cl
Ph
Double Kharasch could be performed generating bicyclic products with 3 adjoining double bonds
28
Enyne Metathesis - Cyclopropanation
Snapper, M. L., et al. J. Am. Chem. Soc. 2006, 128, 52-53
RuR
R1
RuR
R1
R1
R
N2
R
RuR
R1
Ru
RuR
R1
RuR
R1
Ru
R1
Ru R
R1
R R1
29
Enyne Metathesis - CyclopropanationEnyne Metathesis - Cyclopropanation
Snapper, M. L., et al. J. Am. Chem. Soc. 2006, 128, 52-53
TsNTsN
TsN
CO2Et
N2CO2EtEthylene
N2, 10 h 75 ºC75 ºC, 10 min
Grubbs I
TsN
NTs
N2CO2Et
N2, 10 h 75 ºC
Ethylene
Grubbs II
75 ºC, 10 minor r. t.
29
30
Enyne Metathesis - CyclopropanationReaction complimentary to that reported by Dixneuf
Snapper, M. L., et al. J. Am. Chem. Soc. 2006, 128, 52-53
NPG
MeO2CF3C +
N2
TMS Cp*RuCl(cod)
dioxane 100 ºC
N TMS
F3CCO2Me
PG
TsN
Cp*RuCl(cod)
dioxane 100 ºC
N2CO2Et
TsN
CO2Et
TsNTsN
TsN
CO2Et
N2CO2EtEthylene
N2, 10 h 75 ºC75 ºC, 10 min
Grubbs I
then
EtO2C
EtO2C EtO2C
EtO2C
Dixneuf, P. H., et al. Org. Lett. 2005, 7, 3741-3743
31
CM - Allylic Alcohol Isomerization
Snapper, M. L., et al. Org. Lett. 2006, 8, 2603-2606
R
OH
RRu
OHH
Ph
R
OH
Ph
Ru
H
R
OH
H
R H
O
Grubbs I
Grubbs I
Cy3P
RuH
PhPCy3
Cl
Cl
Quayle, P., et al. Synlett 2005, 572-576
Werner, H., et al. Organometallics 2003, 22, 1558-1560
32
CM - Allylic Alcohol Isomerization
Snapper, M. L., et al. Org. Lett. 2006, 8, 2603-2606
O
N
O
O
OH OH
N
O
N
O
OOO
OO
RR
O
R
O
R
X X
Ocat 1 or 2
17-44 h, 70 ºC
X = CHO or CH2OHR = H, Me
RuPh
PCy3Cl
ClN N
RuCl
ClMesN NMes
O
1
2
Ketones prevent over reduction
32
33
CM - Allylic Alcohol Isomerization
Snapper, M. L., et al. Org. Lett. 2006, 8, 2603-2606
ROHOH
R
O
Ru
Cl
ClMesN NMes
O
200 ºC, 7 h
+
34
Metathesis - Oxidation
Snapper, M. L., et al. Org. Lett. 2006, 8, 4759-4762
Plietker, B., J. Org. Chem. 2003, 68, 7123-7125
R2R1
R1
O
R2
OHRuCl3Oxone, NaHCO3-
R2R1
Ru
O
OOO
R1
R2O
ORu
O
O
R1
R2O
ORu
O
OO
R1
R2O
ORu
O
OO
R2
O-H
R1ORu
O+
O O
O
OS
-OO
O H
HSO5-
HSO4-
HSO5-
SO5-
HSO4-
R1
O
R2
OH
+
35
Metathesis - Oxidation
Snapper, M. L., et al. Org. Lett. 2006, 8, 4759-4762
R2R1
R1
OH
R2
OHRuCl3CeCl3, NaIO4
R1
R2O
ORu
O+
OO
LA
H2O
Ru
O
OOO
+R1
R2HO
HO
Mes
RuPh
PCy3Cl
ClN MesN
OHO
HO OH
oxone, NaHCO3
CeCl2, NaIO4
Plietker, B., et al. J. Org. Chem. 2005, 70, 2402-2405
36
Metathesis - Oxidation
Snapper, M. L., et al. Org. Lett. 2006, 8, 4759-4762
Mes
RuPh
PCy3Cl
ClN MesN
OHO O OH
+oxone, NaHCO3
R R R R
EtOAc/MeCN/H2ODCM
37
Metathesis - Oxidation
R1
R2
R1R2 R1
R2
OH
O
R1R2
O
OH
++oxone, NaHCO3
EtOAc/MeCN/H2O
Mes
RuPh
PCy3Cl
ClN MesN
DCM
Snapper, M. L., et al. Org. Lett. 2006, 8, 4759-4762
38
Metathesis - Oxidation
Snapper, M. L., et al. Org. Lett. 2006, 8, 4759-4762
Mes
RuPh
PCy3Cl
ClN MesN
OHHO
CeCl3, NaIO4
R R R
EtOAc/MeCN/H2ODCM
39
Metathesis - Oxidation
Snapper, M. L., et al. Org. Lett. 2006, 8, 4759-4762
R1
R2
R1R2 R1
R2
OH
OH
+oxone, NaHCO3
EtOAc/MeCN/H2O
Mes
RuPh
PCy3Cl
ClN MesN
DCM
40
CM - Wittig Olefination
Snapper, M. L., et al. Org. Lett. 2007, 9, 1749-1752
R O R
1) RhCl(PPh3) iPrOH, DPPBE2) TMSCHN2
3) TBAF
O
O N
CO2Et
N CO2Et
Ru(PPh)3, PPh3
N2CHCO2Et, DCM
N2CHCO2Et, PPh3 DCM
Lebel, H., et al. J. Am. Chem. Soc. 2004, 126, 320-328
Fujimura, O., et al. Tetrahedron 1998, 39, 625
41
CM - Wittig Olefination
Snapper, M. L., et al. Org. Lett. 2007, 9, 1749-1752
R2 R1
O R2
R1
OR2
R1
OR
O
Mes
Ru
PCy3Cl
ClN MesN
PPh3
N2CHCO2R+
42
ConclusionsAdvantages of tandem reactions are obvious
Economics
Environment
Time
Though individual reactions may not be interesting, finding methodology of combining them is
Still much work to be done on the development on tandem chemistry............. Nature’s still way ahead of us