Olefin Cross MetathesisOlefin Cross Metathesis
Christopher KendallChristopher KendallMarch 20, 2006March 20, 2006
The metathesis review: Handbook of Metathesis Grubbs, R. H., ed.; Wiley-VCH: Weinheim, 2003Metathesis in total synthesis: Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 4490
The nobel prize in chemistry, 2005The nobel prize in chemistry, 2005
“Considering the short time during which Grubbs’ and Schrock’s catalysts have been available, the breadth of applications, is truly remarkable.”
Prof. Per AhlbergNobel Committee for Chemistry
"for the development of the metathesis method in organic synthesis"
Yves Chauvin Robert H. Grubbs Richard R. Schrock
Commercial MetathesisCommercial Metathesis
cat. [Ru]=CHR
cat. PPh3
n n
x
polyDCPDhighly crosslinkedpolymer network
DCPDbp 170 °Cmp 33 °C
N
OS
OOBr
HN
O
OMe
O
ON
OS
OOBr
HN
O
OMe
O
O
NH N
HO
O
O
O
3-3.5 mol% H-Grubbs (~500 g)
[0.01 M] degassed toluene (2400 L),80 °C, 4-9 h
20.2 kg83% yield
~90% purity (dimerization)"produced almost 400 kg"
• Nicola, T.; Brenner, M.; Donsbach, K.; Kreye, P. Org. Proc. Res. Dev. 2005, 9, 513 (Boehring Ingelheim Pharma GmbH & Co. KG, Germany)• "We are confident that, soon, it will be even possible to use the RCM for market supply of pharmaceutical compounds on a multiton scale"• see also Faucher, A.-M. et al. Org. Lett. 2004, 6, 2901 and WO Patent 00/59929 (Boehringer Ingelheim Canada)
US Patent 6,525,125 (Materia Inc.):• 2000 g DCPD, 2.5 g Grubbs I (0.000002 mol%), 4 g PPh3, 60 g Ethanox 702 (antioxidant), 640 g glass microspheres• 9 h at 40 °C then 1 h at 140 °C• "an aluminum-faced sandwich panel utilizing this material as a core did not dent from the impact of a baseball fired from a cannon with ball velocities up to 180 mph"
19951996
19971998
19992000
20012002
20032004
2005
0
20
40
60
80
100
120
140
160
Articles cited on Web of Science,topic = “cross metathesis”
Olefin Cross Metathesis (CM)Olefin Cross Metathesis (CM)review in Handbook of Metathesis by Chatterjee, A. K. (chapter 2.8, Vol. 2 pp. 246-295)
review covering 1998-2002: Connon, S. J.; Blechert, S. Angew. Chem. Int. Ed. 2003, 42, 1900
Cross-metathesis methodologies have recently been shown to be highly effective in the synthesis of insect pheromones, polymer additives, and fine chemicals, i.e., valuable synthetic intermediates such as novel ,-unsaturated carbonyl systems.
Pederson, R. L. in Handbook of Metathesis Vol. 2 p 491
+
:
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 (%)
The mechanismThe mechanism
[Ru]=CHAr
R[Ru]
[Ru]
H
H
[Ru]
H H[Ru]
H
R
+
+
[Ru] CH2
Initiation
ProductiveCatalytic Cycle
• high catalyst loading means large amount of ArCH=CH2
• release of ethylene gas drives reaction• typical conditions: CH2Cl2, reflux
The CatalystsThe Catalysts
N
Mo
OO
CH3
F3C 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. Soc. 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.;Ziller, J. W.; Grubbs, R. H.
Angew. Chem. Int. Ed. 1995, 34, 2039
C43H72Cl2P2RuMol. 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. Lett. 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
RuCl
ClMesN NMes
H-Grubbs
Kingsburgy, Harrity, J. P. A.; Hoveyda, A. H.J. Am. Chem. Soc. 1999, 121, 791
C31H38Cl2N2ORuMol. Wt.: 626.62
Aldrich: 2 g / $899
O
aqua-Grubbs
Hong, S. H.; Grubbs, R. H.J. Am. Chem. Soc. 2006, 128, 3508
RuCl
ClMesN NMes
O
(OCH2CH2)nOCH3
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:
The functionalization of terminal olefinsThe functionalization of terminal olefins
RCl
10 mol% Grubbs II,CH2Cl2, reflux
R Cl RTMS
5 mol% Grubbs II,CH2Cl2, reflux
R TMS
3 equiv
Liu, B.; Das, S. K.; Roy, R. Org. Lett. 2002, 4, 2723 Thibaudeau, S.; Gouverneur, V. Org. Lett. 2003, 5, 4891
10 mol% Grubbs II,CH2Cl2, reflux
Demchuk, O. M.; Pietrusiewicz, K. M.; Michrowska, A.; Grela, K.Org. Lett. 2003, 5, 3217
P
O
R1R2
R3
P
O
R1R2
R3
2.5 equiv
R1 mol% Grubbs II, rt
Chatterjee, A. K.; Sanders, D. P.; Grubbs, R. H.Org. Lett. 2002, 4, 1939
R
bp 35-38 °C
CO2R2
2-5 mol% Grubbs II,benzene, rt
Smith, C. M.; O'Doherty, G. A. Org. Lett. 2003, 5, 1959
R1
OH
R1
OH
CO2R2R
5 mol% Grubbs II,CH2Cl2, reflux
Morrill, C.; Grubbs, R. H. J. Org. Chem. 2003, 68, 6031Morrill, C.; Funk, T. W.; Grubbs, R. H.
Tetrahedron Lett. 2004, 45, 7733
BO
O
BO
O
R
R5 mol% Grubbs II,
CH2Cl2, reflux
Chatterjee, A. K.; Toste, F. D.; Choi, T.-L.; Grubbs, R. H.Adv. Synth. Catal. 2002, 344, 634
PhPh
R5 mol% Grubbs II,
CH2Cl2, reflux
Vasbinder, M. M.; Miller, S. J. J. Org. Chem. 2002, 67, 6240
R R
CO2Me
CO2Me
NHBoc NHBoc
G
G
G = Me:G = H:
The functionalization of terminal olefinsThe functionalization of terminal olefins
RSiCl3
0.5 - 5 mol% Grubbs II,CH2Cl2, reflux
RSiCl3
Pietraszuk, C.; Fischer, H.; Rogalski, S.; Marciniec, B.J. Organomet.Chem. 2005, 690, 5912
HO(CH2)nCN
4 mol% Grubbs III,20 mol% Ti(Oi-Pr)4,
CH2Cl2, reflux
HO(CH2)n
CN
Bai, C.-X.; Lu, X.-B.; He, R.; Zhang, W.-Z.; Feng, X.-J.Org. Biomol.Chem. 2005, 4139
2 equiv
E/Z = 1:2 - 1:4
5 mol% H-Grubbs,CH2Cl2, reflux
BouzBouz, S.; Simmons, R.; Cossy, J. Org. Lett. 2004, 6, 3465
R
R
OTBDPSOTBDPS
R1
3 equiv
R2
10 mol% Grubbs III,benzene, 70 °C
Z/E = 3:1 to >25:1
R1 R2
Kang, B.; Lee, J. M.; Kwak, J.; Lee, Y. S.; Chang, S.J. Org. Chem. 2004, 69, 7661
5 mol% H-Grubbs,CH2Cl2, reflux
Silva, F. A.; Gouverneur, V. Tetrahedron Lett. 2005, 46, 8705
R
Ar
OH O
Ar
OH O
R
R5 mol% Grubbs II,
CH2Cl2, reflux
R
Hoveyda, H. R.; Vezina, M. Org. Lett. 2005, 7, 2113
2 equivCN
CN
cm in natural product synthesiscm in natural product synthesisWang, Y.; Romo, D. Org. Lett. 2002, 4, 3231
Cl
CO2EtHO
4 steps CHOTIPSO
SPy
OTIPSTBDPSO
ZnCl2, CH2Cl2(68%)
TIPSO OO
TBDPSO
dr = 5:1
TMS
4 equiv
2.5 mol% Grubbs II,CH2Cl2, reflux
(80%)
TIPSO OO
TBDPSO
TMS
E/Z ~ 3:1
TiCl4
CH2Cl2, -78 °C(90%)
CO2H
TBDPSOH
H
TIPSO
3 steps CHO
TBDPSOH
H
TIPSO
2 equiv
2.5 mol% Grubbs II,CH2Cl2, reflux
(86%)
Me
O
O
P
O
EtOEtO
CHOO
OTBDPSO
H
H
TIPSO
Me
PO
EtOEtO
E/Z = 4:1
4 stepsO
OHO
H
H
HO
Me
(+)-brefeldin
NS
SPy
cm in natural product synthesiscm in natural product synthesisBouzbouz, S.; Cossy, J. Org. Lett. 2001, 3, 1451
O
HO
HO OH
HO
O
HO
Me
HO
OH
OH
HH
OHOHOH
OHHOOHOHOH
Me
OH
H
H
HOOH
OH
OH
510 14 20
30
40
50
60
65
amphidinol 3
CHO3 equiv
5 mol% H-Grubbs,CH2Cl2(70%)
OH
CHO
E/Z > 30:1
OHC
OR CHO3 equiv
5 mol% H-Grubbs,CH2Cl2(73%)
OAc
CHO
E/Z > 30:1
R = H R = OAc
OHOH
PMPO
CHO3 equiv
5 mol% H-Grubbs,CH2Cl2
OHOH
PMPO CHO OHCCHO
31% 43%
O
OO2N
CO2Et
5 mol% Grubbs,CH2Cl2, reflux
no reaction
Grubbs I: 55% SM rec'dGrubbs II: 62% SM rec'd
RuR2
O
R1
O
RRu
R2
O
R1
O- or - DEAD?
Personal Experience:
cm in natural product synthesiscm in natural product synthesisBouzbouz, S.; Cossy, J. Org. Lett. 2001, 3, 1451
O
HO
HO OH
HO
O
HO
Me
HO
OH
OH
HH
OHOHOH
OHHOOHOHOH
Me
OH
H
H
HOOH
OH
OH
510 14 20
30
40
50
60
65
amphidinol 3
PMBO
OH CHO3 equiv
2.5 mol% H-Grubbs,CH2Cl2(79%)
PMBO
OH
CHO
E/Z > 50:1
1. allyl-Ti*, Et2O, -78 °C
2. Ac2O, pyridine(82%)
PMBO
OAc OAc
dr = 19:1
CHO3 equiv
5 mol% H-Grubbs,CH2Cl2(63%)
PMBO
OAc OAc
CHO
E/Z > 50:1
1. allyl-Ti*, Et2O, -78 °C
2. Ac2O, pyridine(74%)
PMBO
OAc OAc OAc
dr > 20:1
CO2Et3 equiv
5 mol% H-Grubbs,CH2Cl2(61%)
PMBO
OAc OAc OAc
CO2Et5
10 14
7 steps, 18% overall
cm in natural product synthesiscm in natural product synthesisKitamura, T.; Sato, Y.; Mori, M. Tetrahedron 2004, 60, 9649
10 mol% H-Grubbs,CH2Cl2, rt
(60%)
SMe
NH2HO2CNCbz
MeO2C
CH2=CH2
5 mol% Grubbs I,CH2Cl2, rt
(76%)
NCbz
MeO2C N
HN
O
O
HMe
BnO
CO2Et
N
HN
O
O
HMe
BnO
CO2Et
RhCl3·3H2O
EtOH, 110 °C(50%)
N
HN
O
O
HMe
BnO
CO2Et
N
HN
OH
O
HMe
OH
NH2
O
(+)-anthramycin (antitumor)
cm in natural product synthesiscm in natural product synthesisRandl, S.; Blechert, S. J. Org. Chem. 2003, 68, 8879
Ghosh, A. K.; Liu, C. J. Am. Chem. Soc. 2003, 125, 2374
OMe
OSESMe
O
ON
O
Bn
5 mol% Grubbs II,CH2Cl2, reflux
(96%)
Me
O
ON
O
Bn
OMe
OSES
E/Z = 1:1
O
O
H
Me
MeC3H7
OH
O
OH
Me
amphidinolide T1S
SiMe3O
O
OOSES
!!• first cycle: 60% yield + dimers• separate dimers and re-subject• second cycle: 36% yield
2 equiv
NHCbz
O
C4H9
O
5 mol% H-Grubbs,CH2Cl2, reflux
(89%)
O
C4H9
O
NHCbzH2 (1 atm)
10% Pd-C, MeOH(75%)
N
H
Me C4H9
1 equiv
cm in natural product synthesiscm in natural product synthesisSpessard, S. J.; Stoltz, B. M. Org. Lett. 2002, 4, 1943
O
O
O 1. toluene, 140 °C
2. CH2N2, Et2O(62%)
O
O
OMe
1. CH3CH=C(CH3)2, 10 mol% Grubbs II, 40 °C (58%)
2. NaOH, H2O, 90 °C (87%)
O
O
OH
O
OR
OH
OH
garsubellin A(R = COi-Pr)
NH
OBn
OTBS
O
5
10 mol% Grubbs II,CH2Cl2, reflux
no reaction
NCbz
OBn
OTBS
O
5
10 mol% Grubbs II,CH2Cl2, reflux
(58%)
NCbz
OBn
OTBS
O
5
1. H2 (1 atm), 10% Pd-C, 2% HCl/MeOH (60%)
2. TBAF, THF (90%) NH
OH
OH
O
9
(-)-prosophylline
Cossy, J.; Willis, C.; Bellosta, V.; Bouzbouz, S. J. Org. Chem. 2002, 67, 1982
cm in natural product synthesiscm in natural product synthesisFerré-Filmon, K.; Delaude, L.; Demonceau, A.; Noels, A. F. Eur. J. Org. Chem. 2005, 3319
Velder, J.; Ritter, S.; Lex, J.; Schmalz, H.-G. Synthesis 2006, 273
5 mol% Grubbs II
OR
RO OR
toluene, reflux
OR
OROR
RO OR
RO OR
RO OR
1 1 (83%) 18 63 19
1 10 94% precipitatedR = Me
R = H1 1 (87%) 17 60 23
1 10 89%resveratrol
1.5 1 76%CH2Cl2, reflux
B
A
A
A
A
A
B
Atom economy of cm vs. altenate reactionsAtom economy of cm vs. altenate reactions
MeO
OMe
OMe
1.5 equiv
MeO
OMe
OMe
270.3
1.5x164.2 + 134.2= 54.0%0.76 x
270.3
164.2 + 134.0= 90.6%
2 mol% Grubbs II,CH2Cl2, reflux
(76%)
Velder, J.; Ritter, S.; Lex, J.; Schmalz, H.-G. Synthesis, 2006, 273
MeO
OMe
P(OMe)2
O
OHC
OMe
1.1 equiv
KOH
18-crown-6, CH2Cl2(94%)
MeO
OMe
OMe
E/Z > 95:5
Kim, S.; Ko, H.; Park, J. E.; Jung, S.; Lee, S. K.; Chun, Y.-L. J. Med. Chem. 2002, 45, 160
Atom Economywith yield and stoichiometry
[theoretical maximum]
270.3
260.2 + 1.1x136.2= 62.0%
MeO
OMe
B
OMe
1.3 equiv
MeO
OMe
OMeBr
F HO
HO5 mol% PdCl2(PPh3)2,
10 mol% PPh3,TBAF, THF, reflux
(86%)
0.94 x
F
288.3
261.1 + 1.3x152.0= 54.1%0.86 x
270.3
260.2 + 136.2= 68.2%
270.3
243.1 + 152.0= 68.4%
Eddarir, S.; Abdehadi, Z.; Ronaldo, C. Tetrahedron Lett. 2001, 42, 9127
MeO
OMeI
OMe
1.5 equiv
MeO
OMe
OMe
270.3
1.5x164.2 + 234.0= 43.3%0.77 x
270.3
164.2 + 234.0= 67.9%
Botella, L.; Najera, C. Tetrahedron 2004, 60, 5563
0.1 mol% catalyst,Cy2NMe, TBAB,
DMA/H2O (4:1), 120 °C(77%)
NOH
Me
Pd
Cl
HO2
catalyst
CM in pharmaceutical synthesisCM in pharmaceutical synthesisPederson, R. L.; Fellows, I. M.; Ung, T. A.; Ishihara, H.; Hajela, S. P. Adv. Synth. Catal. 2002, 344, 728
F
CHO
5 equiv
2.5 mol% H-Grubbs,CH2Cl2, reflux
(73%)
F
CHO
F
O
O
O
paroxetine (5-HT inhibitor)
PaxilTM
BzOCHO
31 equiv
5 mol% H-Grubbs,toluene, rt
(68%)
BzO CHO
BzOOH
NH NO
Ph
CO2H
(-)-ketorolac (NSAID)
AcularTM and ToradolTM
CM in pharmaceutical synthesisCM in pharmaceutical synthesisHsu, M. C.; Junia, A. J.; Haight, A. R.; Zhang, W. J. Org. Chem. 2004, 69, 3907
Grubbs I,CH2Cl2, reflux
O
O
O
O
O
O
NMe2
OHO
N
HN
OO
ABT-773
O
O
O
OH
O
O
NMe2
OBzOHN
OO
2 equivolefin
O
O
O
OH
O
O
NMe2
OBzOHN
OO
R
olefin mol% Grubbs I yield E/Z
N 10 71% > 95:5
25 75%
Ph 10 ?? > 95:5
> 95:5
C3H7 10 87% 1.8:1
• Grubbs II inferior to Grubbs I:
"Instead, its higher reactivity promoted homodimerization of the substrates"
OMeO2C
OO
OO 1.5 equiv
C10H21
5 mol% Grubbs I,CH2Cl2, 30 °C
(57%)OO
OO
C10H21
E/Z = 3.5:1
OO C13H27
CO2HMe
(-)-roccellaric acid
OO
CHO4 equiv
C8H17
5 mol% Grubbs I,CH2Cl2, reflux
(53%)27% SM rec'd
OO
CHO
C8H17
E/Z = 7:1
OO C11H23
CO2HMe
(-)-nephrosteranic acid
OO
CHO1.3 equiv(CH2)11CO2Me
2.5 mol% Grubbs I,CH2Cl2, reflux
(38%)56% SM rec'd
OO
CHO
(CH2)11CO2Me
E/Z = 7:1
OO C14H28CO2H
CO2H
(-)-protopraesorediosic acid
cm in natural product synthesiscm in natural product synthesisChlor, R. B.; Nosse, B.; Sörgel, S.; Böhm, C.; Seitz, M.; Reiser, O. Chem. Eur. J. 2003, 9, 260
Cm in library synthesisCm in library synthesisPlettenburg, O.; Mui, C.; Bodmer-Narkevitchy, V.; Wong, C.-H. Adv. Synth. Catal. 2002, 344, 622
7 mol% Grubbs I,CH2Cl2, reflux
(62-80%)
O
OAcAcO
AcOAcO O
4 equivR
O
OAcAcO
AcOAcO O R
hydrolysisand/or
hydrogenation
R = C6H13, C8H17, C10H21, C12H25, C14H29, C16H33,
CH2Ph, (CH2)2Ph, CH2OPh, CH2OBn
Centrone, C. A.; Lowary, T. J. Org. Chem. 2002, 67, 8862
OP
O
OOBn
BnO
BnO OBn
ORRO
20 mol% Grubbs II,CH2Cl2, reflux
(51-66%)
OP
O
OOBn
BnO
BnO OBn
OR
R = C7H15, C8H17, C9H19,
C10H21, C12H25, C16H33
OP
O
OO
HO
HO OH
OR
Rai, A. N.; Basu, A. J. Org. Chem. 2005, 70, 8228
O
PivOOPiv
PivOPivO
O
NHFmoc
OPMB
10 equivR
30 mol% Grubbs II,CH2Cl2, reflux
O
PivOOPiv
PivOPivO
O
NHFmoc
OPMB
R
R = C5H11, C7H15, C13H27, C15H31
Comin, M. J.; Parrish, D. A.; Deschamps, J. R.; Marquez, V. E. Org. Lett. 2006, 8, 705
5 mol% Grubbs II,CH2Cl2, reflux
2-5 equiv
RO
OEt
OOH O
OEt
OOH
R
CH2OBn 90%
Si(OEt)3 98% CO2Me 95%
CH2P(OEt)2 88%
O
1. TBS-Cl, imidazole, CH2Cl2
2. TsN3, Et3N, MeCN
O
OEt
OTBSO
R
N2
CuSO4
cyclohexane, 80 °C R
CO2Et
H
O
TBSO
CH2OBn 75% (2:1)
Si(OEt)3 62% (4:1) CO2Me 18% (1:1)
CH2P(OEt)2 95% (3.5:1)
O
OMeO2C
O
OO
O
AcO OAc
OAc
OAcR
10 mol% Grubbs II,toluene, 100 °C O
MeO2C
O
OO
O
AcO OAc
OAc
OAc
R
R = C3H7, C4H9, C6H13, C(CH3)3
O
OHC
MeO2C
O O
HO OH
OH
OH
secologanin 1
Galan, M. C.; O’Conner, S. E. Tetrahedron Lett. 2006, 47, 1563
Cm in library synthesisCm in library synthesis
cm in natural product synthesiscm in natural product synthesisStatsuk, A. V.; Liu, D.; Kozmin, S. A. J. Am. Chem. Soc. 2004, 126, 9546
N
O
O
OBn
Me
1. 1.5 equiv cyclopropene, 10 mol% Grubbs II, benzene, 60 °C
2. 1M H2SO4, MeCN(63%)
NR2
OBn
Me
O
E/Z = 2:3
BnO
Me
OBn0.5 equiv
10 mol% Grubbs II,CH2Cl2, 35 °C
(68%)
BnO
Me
OBn
NR2
OBn
Me
OH2 (80 psi)
Pd(OH)2-C,EtOAc/MeOH (1:1)
(56%)
O
ON
O
O
Me
OHMe
NH
HN O Me
O
O O
H H
MeMe
OH
bistramide A
O
O
MeH
Me Me
Me
OHH
O O
cyclopropene
cm in natural product synthesiscm in natural product synthesisAlbert, B. A.; Sivaramakrishnan, A.; Naka, T.; Koide, K. J. Am. Chem. Soc. 2006, 128, 2792
OMe
Me
H
NH
OAcO Me
20 equivMe
CHO
5 mol% H-Grubbs,CH2Cl2, rt
(57%)
OMe
Me
H
NH
OAcO Me
CHO
Me
Ph3PCH3Br
t-BuOK,THF, 0 °C
(86%)
OMe
Me
H
NH
OAcO Me
Me
O OHMe
HOO
10 mol% H-Grubbs,ClCH2CH2Cl2, rt
(40%)
OMe
Me
H
NH
OAcO Me
Me
O OHMe
HOO
H
H
FR 901464
cm in natural product synthesiscm in natural product synthesisGhosh, A. K.; Gong, G. J. Org. Chem. 2006, 71, 1085
10 mol% Grubbs II,CH2Cl2, reflux
(82%)
O
OMe
O
MeOMOM
Me
Me
Me
CO2H
HO
Me
O
Me
OMOM
Me
Me
Me
cat. DMAP,CH2Cl2(77%)
DCC
O
Me
Me
OMOMO
O
Me
Me
AcO
Me
Me
OMOM
Me
Me CO2EtOTIPS
10 mol% Grubbs II,CH2Cl2, reflux
(86%)
O
O
2 equiv
Me
Me
OR
O
O AcO
OMOM
Me
Me CO2Et
E/Z = 11:1
CO2HHO
Me
O
MeOMOM
Me
Me
Me
2,4,6-Cl3C6H2COCl,i-Pr2NEt then
DMAP, benzene
O
OMe
O
MeOMOM
Me
Me
Me
(2S) 35%(2R) 12%
2S
O
OMe
O
MeOH
Me
Me
Me
2S
6R
amphidinolide W
cm in natural product synthesiscm in natural product synthesisWu, B.; Liu, Q.; Sulikowski, G. A. Angew. Chem. Int. Ed. 2004, 43, 6673
(d) TES-OTf, 2,6-lutidine, CH2Cl2, 0 °C 81%
(e) 24, isopropenyl pinacol boronic ester (18 equiv), CH2Cl2, reflux 30% (plus 30% rec'd 23)
(f) Pd(PPh3)4, TlOEt, THF/H2O (3:1) 60%
(g) HF-pyridine, THF, -5 °C 61%
cm in natural product synthesiscm in natural product synthesisYoshimura, T.; Fakushiji, F.; Kondo, S.; Wu, X.; Shindo, M.; Shishido, K. Org. Lett. 2006, 8, 475
10 steps
cm in natural product synthesiscm in natural product synthesisCrimmins, M. T.; Caussanel, F. J. Am. Chem. Soc. 2006, 128, 3128
8 steps
(a) Grubbs II, CH2Cl2, reflux: 68% + 10% Z isomer
cm in complex molecule synthesiscm in complex molecule synthesisLera, M.; Hayes, C. J. Org. Lett. 2001, 3, 2765
O NHO
HO
NH
OMe
O
5 steps
4 steps
O N
TBDPSO
NH
OMe
O
O NTBSO
O
NH
OMe
O
PO
MeO
20 mol% Grubbs II,CH2Cl2, 35 °C
(58%)
1.0 equiv
1.3 equiv
O N
TBDPSO
NH
OMe
O
O NTBSO
O
NH
OMe
O
PO
MeO
• also formed
O N
OTBDPS
NH
OMe
O
ON
TBDPSO
HN
OMe
O
(10%)
O N
TBDPSO
NH
OMe
O
Ph
(20%)
• 5 mol% Grubbs II: sluggish reaction of low conversion• excess metathesis partner: impractical
cm in complex molecule synthesiscm in complex molecule synthesisChen, G.; Schmieg, J.; Tsuji, M.; Franck, R. W. Org. Lett. 2004, 6, 4077
O
AcO
AcOAcO
OAc2.5 equiv
30 mol% Grubbs II,CH2Cl2, reflux
(61%)
O O
C14H29
NHBoc
O
AcO
AcOAcO
OAc
E/Z = 3:1
O
AcO
AcOAcO
OAc2.5 equiv
10 mol% Grubbs II,CH2Cl2, reflux,
CH2=CH2
(72%)
O O
C14H29
NHBoc
OAcO
AcOAcO
OAc
O O
C14H29
NHBoc
(no CH2=CH2: 27% yield)
O
HO
HOHO
OH
O
HN
OH
C14H29
OH
C25H51
O
KRN7000 (immunostimulant)
cm in complex molecule synthesiscm in complex molecule synthesisCho, Y. S.; Wan, Q.; Danishefsky, S. J. Bioorg. Med. Chem. 2005, 13, 5259
CM in Natural product modificationCM in Natural product modificationKarama, U.; Höfle, G. Eur. J. Org. Chem. 2003, 1042
O
O OH O
OH
O
HS
N
epothilone A
O3
O
O OH O
OH
O
H
O
O
O OH O
OH
O
H
O
O OH O
OHH
S
N
epothilone C
C2H4 (1 atm)
15 mol% H-Grubbs,CH2Cl2, rt
(76%)
O
O OH O
OH
S
NTBS-OTf
2,6-lutidine,CH2Cl2(80%)
HO2C
TBSO O
OTBS
S
N
OH
DCC, cat. DMAP, CH2Cl2(91%)
O
O OTBS O
OTBS
S
N1. 5 mol% Grubbs I, CH2Cl2, rt
2. TFA, CH2Cl2, 0 °C
O
O OH O
OH
O
H
S
N
16,17-alkyne epothilone A analogue
O
O OH O
OHH
S
N
O
O OH
H
S
NO
OH
(22%) (22%)
DMDO
CH2Cl2/acetone,-20 °C(32%)
NMe Me2,6-lutidine
CM in Natural product modificationCM in Natural product modificationSmith III, A. B.; Rucker, P. V.; Brouard, I.; Freeze, S. B.; Xia, S.; Horwitz, S. B. Org. Lett. 2005, 7, 5199
CM in Natural productCM in Natural productstructure determinationstructure determination
Tanaka, K.; Nakanishi, K.; Berova, N. J. Am. Chem. Soc. 2003, 125, 10802
O
(CH2)6CO2EtH
H
C5H11
OH
PGA1 ethyl ester
10 equiv
Ph
10 mol% Grubbs II,CH2Cl2, reflux
O
(CH2)6CO2EtH
PhH
C5H11
OH
Ph
85% 89%
• absolute configuration of allylic alcohols commonly determined by circular dichroism of corresponding benzoate• can be complicated by other chromophores
• PGA1 enone MAX 231 nm, allylic benzoate MAX ~ 230 nm• reaction "easily" run on 0.1 mg scale
Ene-yne cmEne-yne cmreview: Diver, S. T.; Giessert, A. J. Synthesis 2003, 466
OAc
SiMe3OAc
3 equiv
7 mol% Grubbs II,CH2Cl2, reflux
(71%)
AcO
SiMe3 OAc5 mol% Grubbs II,CH2Cl2, reflux
(74%)
OBz
CH3
4 equiv
OBz
CH3
Kulkarni, A. A.; Diver, S. T. J. Am. Chem. Soc. 2004, 126, 8110 Kim, M.; Park, S.; Maifeld, S. V.; Lee, D.J. Am. Chem. Soc. 2004, 126, 10242
R3
OR2
R1
C2H4 (60 psi)
20 mol% Grubbs II,CH2Cl2, rt
Smulik, J. A.; Diver, S. T. Org. Lett. 2000, 2, 2271
R1
10 equiv
R2R3R2O
R110 mol% Grubbs II,
CH2Cl2, rt,CH2=CH2 (1 atm)
R1 R2
Lee, H.-Y.; Kim, B. G.; Snapper, M. L. Org. Lett. 2003, 5, 1855
Ene-yne cmEne-yne cmRoyer, F.; Vilain, C.; Elkaïm, L.; Grimaud, L. Org. Lett. 2003, 5, 2007
Desired: RCEYM (ring closing ene-yne metathesis)
OTBS
O CO2Et
[Ru]
O
TBSO CO2Me
Result: Failure
Modification: RCEY-CM (tandem ring closing ene-yne / cross metathesis)
OTBS
X
3 equivR
10 mol% H-Grubbs,CH2Cl2, reflux X
TBSO R
RX = CH2
yieldX = Oyield
CO2Me 88% 67%
COMe 73% 68%
CHO 61% 65%
Ene-yne cm in natural product synthesisEne-yne cm in natural product synthesisKummer, D. A.; Brenneman, J. B.; Martin, S. F. Org. Lett. 2005, 7, 4621
20 mol% H-Grubbs,CH2Cl2, reflux
(83%)
OH
H O
O
(+)-8-epi-xanthatin
10 equivO
OH
H OMeO2C
OH
stepwise: Evans, M. A.; Morken, J. P. Org. Lett. 2005, 7, 3371
tandem cm reactionstandem cm reactionsO 5 mol% Grubbs II
40 °C, 12 h(89%)
O
neat 3 equiv 1 equiv
Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360
B
O
O
O
O
3 equiv
2 mol% Grubbs II,CH2Cl2, 40 °Cthen PhCHO, rt
(69%)
Ph
OH
O O
dr > 20:1
Goldberg, S. D.; Grubbs, R. H. Angew. Chem. Int. Ed. 2002, 41, 807
OH OH
O
3 equiv
5 mol% H-Grubbs,1 atm H2, 5 mol% PtO2,
CH2Cl2, rt, 15 h(50%)
O
O
PhPh
Cossy, J.; Bargiggia, F.; Bouzbouz, S. Org. Lett. 2003, 5, 459
One-pot cm/intramolecular cycloadditionOne-pot cm/intramolecular cycloadditionHodgson, D. M.; Angrish, D.; Labande, A. H. Chem. Commun. 2006, 627
OO
t-BuO O
N2
R
5 mol% Grubbs II,CH2Cl2, reflux
O
t-BuO O
O
R
OO
t-BuO O
N2
R2 mol%
Rh2(OAc)4
rt O
R
t-BuO2C O
R = CO2Me, Cy, Ar43-80%
E/Z = 85:15 to >95:5
Tandem ene-yne cm/[4Tandem ene-yne cm/[4++2]cycloaddition2]cycloadditionMix, S.; Blechert, S. Org. Lett. 2005, 7, 2015
5 mol% H-Grubbs,benzene, 80 °C
(90%)
Ph
OTBS
CN
Ph
CN
H
OTBS
Tandem cm in natural product synthesisTandem cm in natural product synthesisQuinn, K. J.; Isaacs, A. K.; Arvary, R. A. Org. Lett. 2004, 6, 4143
Michaelis, S.; Blechert, S. Org. Lett. 2005, 7, 5513
C10H21
10 mol% Grubbs II,CH2Cl2, reflux
(65%)
OBn
O
O
OBn
C10H21
OO
H2 (? atm)
Pd-C, EtOH(82%)
OH
C10H21
OO
(-)-muricatacin
5 mol% H-Grubbs,CH2Cl2, reflux
(73%)
OTr
OH
O
H3C
OTBSOTr
OH
O
H3C
OTBS
OH
O
O
H3C
OTBS
O
5 mol% H-Grubbs
ClCH2CH2Cl, 80 °C(68%)
OH
O
O
H3C
OTBS
O OO
O
O
O
CH3
OH
H
(+)-phomopsolide C
Rom/cmRom/cmMihovilovic, M. D.; Grötzl, B.; Kandioller, W.; Snajdrova, R.; Muskotál, A.; Bianchi, D. A.; Stanetty, P.
Adv. Synth. Catal. 2006, 348, 463
1 mol% Grubbs I,CH2Cl2
X
O
X = CH2, O
R
X
O
RH H
R Yield E/Z Yield E/Z
X = CH2 X = O
CH2=CH2 4350 - -
CH3 40 3.5:1 40 3.5:1
C2H5 65 6:1 42 8.5:1
C4H9 50 7.5:1
Ph 61 > 95:5
50 1:2Ph
Weeresakare, G. M.; Liu, Z.; Rainer, J. D. Org. Lett. 2004, 6, 1625
10 mol% Grubbs II,CHCl3, 55 °C
BocN
Ts
5-15 equiv
R
NBoc
R
Ts
HN O
CO2H
Br
BnNC
furfural,BnNH2,
MeOH, rt(73%)
O NBnBnHN
OH
O
H
HN O
Br
Br
CsOH,THF, 0 °C
(79%)
O NBnBnHN
OH
O
H
N O
Br
Ph10 equiv
10 mol% Grubbs II,CH2Cl2, rt
(81%)
O
BnN
N
Ph
BnHN
O
O
HH
HO
Br
BnHN O
CO2H Br NC
furfural, BnNH2,MeOH, rt
(45%)
O NBnNH
OH
O
H
BnHN O
Br
Br
CsOH,THF, 0 °C
(77%)
O NBnN
OH
O
H
BnHN O
Br
Ph10 equiv
10 mol% Grubbs II,CH2Cl2, rt
(65%)
BnNN
O
HO
Br
H
Ph
O
NHBn
Rom/cm/rcmRom/cm/rcmOikawa, M.; Ikoma, M.; Sasaki, M. Tetrahedron Lett. 2005, 46, 5863
cm in natural product synthesis: ROM/CM/RCMcm in natural product synthesis: ROM/CM/RCMHart, A. C.; Phillips, A. J. J. Am. Chem. Soc. 2006, 128, 1094
ON
O O
Bn
TIPSO
10 mol% Grubbs II,CH2Cl2, reflux
(59%)
ON
O O
Bn
TIPSO HTIPSO
O
OO
O
3 equiv
4 mol% Grubbs II,CH2Cl2, reflux
(59%)
O H
H
OTIPS
OO
OE/Z = 2:1
14 steps
HN
O
MeH
H
cylindramide A
NH
OH
O
O
HO
H
My favourite example: rom/cm/rcmMy favourite example: rom/cm/rcmTakao, K.; Yasui, H.; Yamamoto, S.; Sasaki, D.; Kawasaki, S.; Watanabe, G.; Tadano, K. J. Org. Chem. 2004, 69, 8789
OOH
OTBDPS
5 steps OMe
OTBDPS
HOHO
3 steps Me
OTBDPSO
3 mol% Grubbs II
benzene, reflux(86%)
Me
OTBDPSO3 steps Me
OHO
Me
OO O
AcOH
H
(+)-mycoepoxydiene12 steps
OOH
OTBDPS
2 steps OMe
OTBDPS
2 equiv
2 mol% Grubbs I,benzene, rt then
10 mol% Grubbs II,benzene, reflux
Me
OTBDPSO
+ by-products
TBAF
THF(23%)
Me
OHO
4 steps
Alkyne cross metathesisAlkyne cross metathesisFürstner, A.; Grela, K.; Mathes, C.; Lehmann, C. W. J. Am. Chem. Soc. 2000, 122, 11799
Fürstner, A.; Mathes, C. Org. Lett. 2002, 3, 221review: Fürstner, A.; Davies, P. W. Chem. Commun. 2005, 2307
N
R1 MeR2
R2
10 mol% Mo[N(t-Bu)(Ar)]3,CH2Cl2/toluene, 80 °C
R1
R2N
N
Mo
Mo[N(t-Bu)(Ar)]3
Cl
OMe
Cl
CO2Me
62% 67%
CN
OMe OMe
OTHP
82% 68%
ClS
55%
C4H9TBSO H
H
Cl
O
46%
C4H9TBSO H
H
CO2Me
O
43%
TBSO H
HO
C5H11
OTES
CO2Me
51%
MeSO2Ph
10 mol% Mo[N(t-Bu)(Ar)]3,CH2Cl2/toluene, 80 °C
(71%)
SO2Ph
Alkyne cross metathesisAlkyne cross metathesisSashuk, V.; Ignatowska, J.; Grela, K. J. Org. Chem. 2004, 69, 7748
Ar Me
2 equiv
5 mol% Mo(CO)6,1 equiv 2-FlC6H4OH,
C6H5Cl, reflux (135 °C)
Ar Et
Ar Yield
Ph 96%
3-CF3C6H4 81%
2-MeOC6H4 70%
speculation Mo(CO)6R R
ArOH
135 °CMo(OAr)3R
Mo(O) Mo(VI)
Asymmetric cmAsymmetric cmVan Veldhuizen, J. J.; Garber, S. B.; Kingsbury, J. S.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 4954
Gillingham, D. G.; Kataoka, O.; Garber, S. B.; Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 12288
O
O
O
R
10 mol% Cat A*,THF, 50 °C
O
H H
O O
RR Yield (%) ee (%)
Ph 71 80
C5H11 57 > 98
c-C6H11 60 > 98
OPh
2 mol% Cat B-I*(68%)
OPhH H
98% ee
OPh
5 mol% Cat B-Cl*(70%) OPh
H H
96% ee
H
OBn
5 equiv
2 equiv OBn
RuX
NMesN
OO
R
Cat A*: R = H, X = ClCat B*: R = Ph
Schrock, R. R.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2003, 42, 4592
Shawn Collins, Literature Meeting, October 4, 2004
Full Story:
Cm improvement: catalyst loadingCm improvement: catalyst loadingForman, G. S.; Tooze, R. P. J. Organomet. Chem. 2005, 690, 5863
Check Forman 2005 Organomet page ??
0.1 mol% Grubbs II,50 °C, 2 h
24% conversionE/Z = 13:1
2 equivMeO2C
C8H17 C8H17MeO2C
0.1 mol% Grubbs II,0.5 equiv p-cresol
50 °C, 2 h100% conversion86% isolated yield
E/Z = 35:1
2 equivMeO2C
C8H17
50 mmol scale
p-cresol
MeHO
Cm improvement: reaction timeCm improvement: reaction timeBargiggia, F. C.; Merray, W. V. J. Org. Chem. 2005, 70, 9636
H-Grubbs,CH2Cl2, microwave
CO2Me
(EtO)2P
OO
(EtO)2P
OO
CO2Et
H-Grubbs(mol%)
Temperature Time Yield NoteMethyl Acrylate(Equivalents)
4 10 100 °C 15 min 79%
1.1 10 100 °C 15 min 65% 1 min: 66% yield
1.1 5 100 °C 15 min 81%
1.1 1 100 °C 15 min 50%
1.1 10 150 °C ~ 45 sec 72% "1 sec" in publication
1.1 10 60 °C 15 min 51% no "mirowave" effect
4 10 reflux 6 h 80% thermal conditions
Catalyst delivery vehicle in CmCatalyst delivery vehicle in CmHansen, E. C.; Lee, D. Org. Lett. 2004, 6, 2035
OAc
PhBnO
OBn
10 mol% Grubbs II,CH2Cl2, rt
(37%)
OAc
Ph
OBn
E/Z = 1:20
[Ru]BnO +
OAc
Ph
OAc
Ph OBnO
OBn
10 mol% Grubbs II,CH2Cl2, rt
(63%)
OAc
Ph
OBn
E/Z = 1:4
AcO
Ph O
[Ru]O OAc
Ph[Ru]
R
OAllyl
ROBn
NET
6 steps
OH
O
O
OH
TBSO
H H8
+
O
O
O
TIPSO
Me
HOH H
OH
O
11 steps
1. xs (i-Pr)2SiCl2, imidazole, CH2Cl2 (74%)2. Grubbs (1.8 equiv), ClCH2CH2Cl, reflux (83%)
O
TBSO
H HO
O
O
TIPSO
Me
H HO
SiO
i-Pr i-Pr
1. HF, MeCN, CH2Cl2 (91%)2. TsNHNH2, NaOAc, DME/H2O, reflux (95%)
O
HO
H HO
H HOH HO
O
O
OH
Me
!!
• 50 mg scale• 70 mg catalyst
A temporary silicon-tethered rcmA temporary silicon-tethered rcmEvans, P. A.; Cui, J.; Gharpure, S. J.; Polosukhin, A.; Zhang, H.-R. J. Am. Chem. Soc. 2003, 125, 14702
summarysummary
• Cross Metathesis increasingly used as disconnection late in natural product total synthesis
• Useful tool for library synthesis, especially in biochemical-type applications
• “Ideal” reaction: a catalytic method for a highly efficient (re: atom economy) C-C bond forming reaction
• Improvement still possible in catalyst loading, stoichiometry, reaction time/temperature, selectivity, …