L11 Metathesis HO - University of...
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Alkene Metathesis Grubbs II published The Catalysts Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.; DiMare, M.; O'Reagan, M. J. Am. Chem. Soc. 1990, 112, 3875 N Mo O O Me F3C CF3 Me F3C CF3 C(Me)2Ph i-Pr i-Pr H Schrock I Cy3P Ru PCy3 Ph Cl Cl Cl2(PCy3)2Ru=CHPh Grubbs I Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew. Chem. Int. Ed. Engl. 1995, 34, 2039 H (H2IMes)(PCy3)Cl2Ru=CHPh Grubbs II Ru PCy3 Ph Cl Cl N N Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953 Ru Ph Cl Cl NMes MesN N N Br Br (H2IMes)(3-Br-py)2Cl2Ru=CHPh Grubbs III Love, J. A.; Morgan, J. P.; Trnka, T. M.; Grubbs, R. H. Angew. Chem. Int. Ed. 2002, 41, 4035 Ru Cl Cl NMes MesN O Green Grubbs Kingsbury, J. S.; Harrity, J. P. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 791 Ru Cl Cl NMes MesN O Zhan-1B http://www.zannanpharma.com/ english/products/ S O O NMe 2 Hoveyda, A. H.; Zhugralin, A. R., "The remarkable metal-catalysed olefin metathesis reaction." Nature 2007, 450, 243-251. Dr. P. Wipf Page 1 of 5 10/7/2009
Transcript of L11 Metathesis HO - University of...
Alkene Metathesis
Grubbs IIpublished
The Catalysts
Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.; DiMare, M.; O'Reagan, M.J. Am. Chem. Soc. 1990, 112, 3875
N
MoOO
MeF3C CF3
Me
F3C CF3C(Me)2Ph
i-Pr i-Pr
H
Schrock I
Cy3P
Ru
PCy3
PhCl
Cl
Cl2(PCy3)2Ru=CHPh
Grubbs I
Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H.Angew. Chem. Int. Ed. Engl. 1995, 34, 2039
H
(H2IMes)(PCy3)Cl2Ru=CHPh
Grubbs II
Ru
PCy3
PhCl
ClNN
Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H.Org. Lett. 1999, 1, 953
RuPh
Cl
ClNMesMesN
N
N
Br
Br
(H2IMes)(3-Br-py)2Cl2Ru=CHPh
Grubbs III
Love, J. A.; Morgan, J. P.; Trnka, T. M.; Grubbs, R. H.Angew. Chem. Int. Ed. 2002, 41, 4035
RuCl
ClNMesMesN
O
Green Grubbs
Kingsbury, J. S.; Harrity, J. P. A.; Hoveyda, A. H.J. Am. Chem. Soc. 1999, 121, 791
RuCl
ClNMesMesN
O
Zhan-1B
http://www.zannanpharma.com/english/products/
SOO
NMe2
Hoveyda, A. H.; Zhugralin, A. R., "The remarkable metal-catalysed olefin metathesis reaction." Nature 2007, 450, 243-251.
Dr. P. Wipf Page 1 of 5 10/7/2009
The Nobel Prize in Chemistry 2005
Yves ChauvinInstitut Français du Pétrole, Rueil-Malmaison, France,
Robert H. GrubbsCalifornia Institute of Technology (Caltech), Pasadena, CA, USA and
Richard R. SchrockMassachusetts Institute of Technology (MIT), Cambridge, MA, USA
"for the development of the metathesis method in organic synthesis".
Ring-Closing Metathesis (RCM) and Ring-Opening Metathesis (ROMP)
• Introduction• RCM• Cross-Metathesis• ROMP
http://nobelprize.org/chemistry/laureates/2005/animation.html
[M]R1
R2
R2
[M]R1
R2R2
[M]
R2
R1
R2
[M]R1
OR1
[M]O
R1
R2
[M]
O
R1
R2
RCM-C2H4
ROM+C2H4
ROMP
M
n
ADMET-nC2H4
R1 R2
CM
-C2H4
R2
R1
R1
R1
R2
R2
Important types of metathesis reactions:
RCM = ring-closing metathesis
ROM = ring-opening metathesis
ROMP = ring-opening metathesis polymerization
ADMET = acyclic diene metathesis polymerization
CM = cross-metathesis
Dr. P. Wipf Page 2 of 5 10/7/2009
Ruthenium-Based Olefin Metathesis
The synthesis of ruthenium vinylcarbene complexes allowed the development of well-defined, late transition metal, low oxidation state complexes that catalyze olefin metathesis. Ruthenium carbene complexes are significantly easier to make and handle than the Schrock molybdenum complex.In addition to the metathesis of strained cyclic and exocyclic olefins, the remarkable functional group tolerance (alcohols, aldehydes, carboxylic acids) and stability toward air, water, and acid has made this class of compounds particularly attractive for practical applications (Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446).
Ruthenium-Based Olefin Metathesis: Applications
N NH
N
N
H
OH
N
NCO2EtOPh
H CO2Me
N
NO
H CH2OBDPS
O
O
N
N
HCH2OBDPS
OO
O
N
NOPh
H CO2Me
O N
NOPh
H CO2Me
O
Manzamine A
B, 1equiv. rt, 5 days
30%
Pandit, THL 1994, 35, 3191
Martin, THL 1994, 35,691
A, benzene50°C, 63%
(Z only)
MoN
OO
F3CF3C
CF3F3C
Ph
A
RuPCy3
PCy3Cl
Cl
Ph
Ph
B
NO
N
OHNO
O
O
N SN
MeO
HN
CO2H
BILN 2061
Large-scale preparation of pharmaceutical candidates: Hepatitis C protease inhibitor BILN 2061 developed by Boehringer-Ingelheim
NO
HN
OHNO
O
O
CO2Me
SOO
Br
O
RuCl
Cl
P
toluene, 80 °C>400 kg scale
NO
HN
OHNO
O
O
CO2Me
SOO
Br
83%, >99% cis
Dr. P. Wipf Page 3 of 5 10/7/2009
Liverton, N. J.; Holloway, M. K.; Mccauley, J. A.; Rudd, M. T.; Butcher, J. W.; Carroll, S. S.; Dimuzio, J.; Fandozzi, C.; Gilbert, K. F.; Mao, S.-S.; Mcintyre, C. J.; Nguyen, K. T.; Romano, J. J.; Stahlhut, M.; Wan, B.-L.; Olsen, D. B.; Vacca, J. P., "Molecular modeling based approach to potent P2-P4 macrocyclic inhibitors of hepatitis C NS3/4A protease." J. Am. Chem. Soc. 2008, 130, 4607-4609.
NCl
Br
NBoc
CO2H
HO
N
OBr
NH
CO2Et•HCl
a) KOtBu, DMFb) HCl, EtOH, 65% (2 steps)
c) HATU, DIPEA, DMF, 74%
OHN
O
N
O
ONR
CO2Et
OHN
OCO2H
R = BrR = vinyl
d) Bu3SnCH=CH2, Pd(PPh3)4, toluene, 100 oC, 87%
e) Zhan catalyst, DCE, ~10 mM, 83% O
HN
O
N
O
O
N
CO2Et
f) H2, 10% Pd/C, EtOAc, quant.
double bondsingle bond
OHN
O
N
O
O
N
O
HNO
NH
SO
OO
NH
SO
H2N O
•HCl
g) LiOH, THF, MeOH, H2O
h) HATU, DIPEA, DMAP, DMF, 93%
+
RuCl
ClNMesMesN
O SOO
NMe2
MK-7009
Cross-Metathesis: Applications
Wipf, P.; Spencer, S. R. "Asymmetric total syntheses of tuberostemonine, didehydrotuberostemonine, and 13-epituberostemonine." J. Am. Chem. Soc. 2005, 127, 225-235.
H
H
NHOCO2Me
NH2
HO CO2H
NOCbz
H
H
CO2Me
Tuberostemonine
Tyrosine
HH
H
N
O
O
O O
H
8 2
O OH
HO
O
N
H
HNHO
H
H
Ph
OH
HO
N
H
H
Ph
OH
HO
O
N
RuCl2(=CHPh)(PCy3)2
PhSeCl, CH2Cl2
N
H
HO
H
HO
O
O
PhSe
Bu3SnCH2CH=CH2
N
H
HO
H
HO
O
N
N
H
HO
H
HO
O
O
Azepine Annulation via RCM
N,N-Dimethylacetamidedimethyl acetal
xylenes; 79%
CH2Cl2; 72%
-78 °C; 20% AIBN, toluene,100 °C; 42%
Dr. P. Wipf Page 4 of 5 10/7/2009
Cross-Metathesis: Applications
O OH
HO
O
N
H
H
Br OO
O
NCO2Me
O
H
H
Ph
NCO2Me
H
HO
N N
Ru
MesMes
PhPCy3
ClCl
O
O OO
N
H
HTBSO
NCO2Me
H
HO
N
H
HTBSO N
O
OMe
O
HO
N
H
HHO H
CH2Cl2; 92%
THF, -78 °C; 81%
1. PhSH, TEA2. (Ph3P)3RhCl, H2
3. DBU, THF; 76%
1. NaBH4, CeCl3; 75%2. TBS-Cl, Im.; 79%
3. MeONHMe•HCl, Me2AlCl; 94%
, LiDBB1. L-Selectride2. TsOH, MeOH
75%
Cross-Metathesis: Applications
O
HO
N
H
HHO H
N
O H
O
O OH
H
H
N N
Ru
MesMes
PhPCy3
ClCl
NHTr
O
Me2N
N
H
O OH
H
H
HN
O H
O
O OH
H
N NMes
Mes
RuO
ClCli-Pr
N,N-Dimethyl-acetamide
dimethyl acetal
xylenes; 79%
CH2Cl2; H2C=CH2;then Pd/C, H2, MeOH; 80%
1. PhSeCl, MeCN/H2O, 0 °C; 67%2. AIBN, allyltriphenyltin, 95 °C; 70%
3. LDA•HMPA, THF; MeI 76%
toluene; 85%
27 steps/1.1% yieldfrom Cbz-tyrosine
HH
H
N
O
O
O O
HTuberostemonine!
Why Carbene Ligands?
The nucleophilic carbenes are ‘phosphine-mimics’ and yet they are much more. They reside at the upper end of the Tolman electronic and steric parameter scales. From solution calorimetric studies, it became clear that nucleophilic carbenes (most of them) are better donors than the best donor phosphines.
Dr. P. Wipf Page 5 of 5 10/7/2009
