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Applications in Natural Product Synthesis
Ruthenium Catalyzed Olefin Metathesis
Travis Schwantje
Supervisor: Dr. Louis Barriault
January 12, 2012
2
• A Brief History• Metathesis as a Synthetic Tool• Recent Advances in Metathesis Methodology
Outline
3
• 1955 – Initial discovery by Ziegler
• 1971 – Mechanism postulated by Chauvin
• 1990 – Schrock describes the first well-defined Mo catalyst
• 1993 – Ru catalyst system proposed by Grubbs
• 2005 – Grubbs, Schrock and Chauvin share Nobel Prize
An Abridged Timeline of Olefin Metathesis
4
Chauvin’s Mechanism[M]
R2
[M]
R2
[M]
R2
R1
R1
R1
[M]
R2
R1
[2+2]retro-[2+2]
R1
Hérrison, J-L, Chauvin, Y. Makromol. Chem. 1970, 141, 161-176
5
• A Brief History• Metathesis as a Synthetic Tool• Recent Advances in Metathesis Methodology
Outline
6
R1
R2
R1
R2
+
n
n
R1 R2
R3 R4
+
R1
R2
R3
R4
[Ru]
Ring-Opening MetathesisPolymerization (ROMP)
Acyclic Diene Metathesis(ADMET)
Polymerization
Ring-Closing Metathesis(RCM)
Cross Metathesis(CM)
Ene-Yne Metathesis
Types of Metathesis
Common Metathesis Catalysts
7
Grubbs 1st GenerationCatalyst
“Grubbs 1”
Grubbs 2nd GenerationCatalyst
“Grubbs 2”
Hoveyda-Grubbs2nd Generation Catalyst
“Hoveyda 2”
Grubbs, R. J. Am. Chem. Soc. 1996, 118, 100Grubbs, R. J. Am. Chem. Soc. 1999, 1, 953Hoveyda, A. J. Am. Chem. Soc. 2000, 122, 8168Blechert, S. Tet. Lett. 2000, 41, 9973
Ru
PCy3
PCy3Ph
Cl
ClRu
PCy3Ph
Cl
Cl
NN
Ru
O
Cl
Cl
NN
8
• First reported in 1980 by Villemin and Tsuji• Most common application of metathesis• Dozens of reviews
Ring Closing Metathesis
[Ru]+
Villemin, D. Tet. Lett. 1980, 21, 1715Tsuji, J. Tet. Lett. 1980, 21, 2955R. Grubbs (Ed.) Handbook of Metathesis: Volume 2. 2003, Wiley-VCHFogg, D. NATO. Scie. Peace.. Secu. 2010, 11, 129
X XMLn
kclosure
koligomerization
X
X
X
9
• Cyclopentenes
• Cyclohexenes
Ring Closing Metathesis - Carbocycles
O
CO2Me
BnO
1) Chiral asymmetricClaisen rearrangement
2) K-selectride
CO2Me
OHBnO
1 mol%Grubbs 2
0.05M DCE, 40C5h, 82%
CO2Me
OHBnO
83.7% over 2 steps95:5 dr, 99% ee
O
O
O
H
H
(-)-ecklonialactone B
Hiersemann, M. Synlett. 2007, 1683Mulzer, J. Angew. Chem. Int. Ed. 2008, 47, 6199
O
HO
8 mol%Grubbs 2
0.05M DCMreflux,90%
O
H1) NBS2) CrCl2
O(-)-perrillaldehydeO
NH
OOH
OH
HOOC
platencin
10
• Cycloheptenes
• Cyclooctenes
Ring Closing Metathesis - Carbocycles
Tori, M. Bull. Chem. Soc. Jpn. 2006, 79, 1955Prunet, J. Chem. Eur. J. 2008, 14, 7314
O
OEt
O 30 mol% Grubbs 10.01M DCM, 50%
H
OH
(-)-tormesol
OHO
OHAcO O
HOBz
O
O
Ph
OH
(PhOC)HN
paclitaxel
O O
5 mol% Grubbs 2
80°C, 0.01M DCE5 min, quant. O O
1 mol% Grubbs 20.1M, DCM, 95%
O
OEt
O
11
• Cyclononenes
• Cyclodecenes
Ring Closing Metathesis - Carbocycles
Clark, J. S. Org. Biomol. Chem. 2008, 6, 4012Barrett, A.G.M. J. Am. Chem. Soc. 2006, 128, 14042
O
O
O
20 mol% Grubbs 1
0.004M DCM, reflux
O
O
O O
O
O
30% 47%
HO
OO O
HO O
OH
hydroxycornexistin
O
O O
O
O
ent-Clavilactone B
OMe
OMe O
O
O
OMe
OMe O
O
O
40 mol% Grubbs 2tetrafluorobenzoquinone (80 mol%)
0.00034M PhMe, 80°C, 65%
12
• Silicon
Ring Closing Metathesis - Heterocycles
O9
OH HOO 4
OTBS
O
O
+
TBSO
Evans, P.A. J. Org. Chem. 1998, 63, 6768Evans, P.A. J. Am. Chem. Soc. 2003, 125, 14702
O
HO
OOH OH OH
O
O
Mucocin12 steps (longest linear)13.6% overall yield
1) iPr2SiCl2, imidazole, 0°C to RT, 74%2) 1.8 eq Grubbs 1, 0.0016M DCE, 83%then deprotection, hydrogenation
OO1. Ph2SiCl2, 2,6-lutidine
2. 50 mol% Grubbs-1DCM, reflux, 74%
O OOSi
O
Ph Ph
OO OH TBAF OO O OHOOH
13
• Phosphorus
• Sulphur
Ring Closing Metathesis - Heterocycles
O PO
O
O 10 mol% Grubbs-2
0.005M DCM, 81%
O PO
O
O
Hanson, P.R. Org. Lett. 2005, 7, 3375Cossy, J. Tetrahedron 2006, 62, 9017
LiAlH4
65%
OHOH OH
1. R2CuLi, 84%
2. Red-Al 85% R
OHOH
S
N OH
1. DMAP, THF
2. Grubbs 2, 0.01M Ph70°C, 70% over 2 steps
SO2Cl
S
NS
O
O O
14
• Sulphur
Ring Closing Metathesis - Heterocycles
Extrusion of SO2
+ steps
S
N OH
NH
OMe
O
Originally proposed structureof Mycothiazole
S
NS
O
O O
Cossy, J. Tetrahedron 2006, 62, 9017
15
• Oxygen
Ring Closing Metathesis - Heterocycles
O Ph
R1
R2
n
n = 0,1,2R1 = H, MeR2 = H, Me
O Ph
R1R2
n5 mol% Schrock
C6H6, 75-93%
Fu, G. and Grubbs, R.; J. Am. Chem. Soc. 1992, 114, 5426Rutjes, F. Synlett. 1998, 192Grubbs, R. J. Org. Chem. 1998, 63, 864
O R1R
n
OR OMe
1. 5 mol% Grubbs-1DCM, rt, 4h, 74%
2. BF3•OEt2, R1-TMS42-65%
n n = 1,2
O
R4
R2
R3
R1
O
R4
R3
R2
R1
2-6 mol% Grubbs-1
DCM, rt or C6H6, 60°C0.2M, 2h, 79-99%
Mo
N
O
O
F3C CF3
F3CF3C
17
• Nitrogen
Ring Closing Metathesis - Heterocycles
N
Ph
Rn
N
Ph
R
n
4 mol% Schrock
C6H6, rt, 73-87%n = 1,2,3
Fu, G. and Grubbs, R. J. Am. Chem. Soc. 1992, 114, 7324Grubbs, R. J. Am. Chem. Soc. 1995, 117, 5855Van Maarseveen, J. Org. Lett. 2002, 4, 2673
OO
HN
N
O
Bn2N
NHBOC
N
OO
O
NH
Bn2N
NHBOC
5 mol% cat.
0.2M DCM, rt, 81%Ru
Cl
Cl
PCy3
PCy3
Ph
Ph
OH
CHO
O
O
BocN
n1. 5 mol% Grubbs-2 0.01M PhMe 60°C, 12h
2. H2, Pd|CN
O
Boc
On = 0-4
n
1. TFA
2. NaHCO3, EtOAc
OH
N
On
Yields over 7 steps:n = 0: 15%n = 1: 42%n = 2: 33%n = 3: 34%n = 4: 37%
21
• Peptidomimetics
Ring Closing Metathesis - Macrocycles
Reitz, A. Org. Lett. 2001, 3, 893Grubbs, R. J. Am. Chem. Soc. 1996, 118, 9606
S S
NHH2N CO2H
O
NHH2N CO2H
O
vs.
N
O
NH
OBocHN
O
OCBz(Br)
HN O
HN
O O
N
O
NH
OBocHN
O
OCBz(Br)
HNO
HN
OO
Pro CBz-Tyr
Pro CBz-Tyr30 mol% Grubbs-1
DCM, 0.004M40°C, 80%
22
• Selectivity is the key to controlling cross metathesis reactions– Regioselectivity of metathesis– Stereoselectivity of alkene formation
Cross Metathesis (CM)
R1
R2
[Ru] R1
R2+ +
23
For 2nd gen [Ru]: Type I Type II Type III Type IV
Homodimerization Fast Slow None None
Homodimers consumable?
Yes Somewhat N/A N/A
Reactivity High Medium Low None
Example
Regioselectivity in Cross-MetathesisHow do I control this reaction?
Grubbs, R.H. J. Am. Chem. Soc. 2003, 125, 11360
O
X
For 2nd gen.[Ru]
For 1st gen.[Ru]
NO2
R3
R2
R1
R4
R
R
R
R
R
OH
R
24
• What does this mean?– Mixing identical types = statistical mixture– Mixing different types = selective CM
Regioselectivity in Cross-MetathesisHow do I control this reaction?
Grubbs, R.H. J. Am. Chem. Soc. 2003, 125, 11360
R1 +
+
+
R1
R2 R2
R1
R2
[M]
R1R2
R1R1
R2R2
+
+
+
[M]
[M]
[M]
R2
R1R2 + R1
25
• E-selective– Steric bulk at allylic position
Stereoselective CM Reactions
Crowe, W. Tet. Lett. 1996, 37, 2117Grubbs, R. et al. J. Am. Chem. Soc. 2000, 122, 58
PhO3
+ SiR32 mol% Schrock
DME, rt72/77%
PhO3
SiR3
R = Me, 2.6:1 E/ZR = i-Pr, 7.6:1 E/Z
BzO7
OTBS
TBSO
5 mol% Grubbs-1
DCM, reflux89%
2 equivs.
+BzO
7
OTBS
10:1 E/Z
BzO +
OTBS
TBSO2 equivs.
5 mol% Grubbs-1
DCM, refluxBzO
OH
47:1 E/Z54% after TBAF deprotection
26
• E-selective– Electron-poor olefins
Stereoselective CM Reactions
Grubbs, R. J. Am. Chem. Soc. 2000, 122, 3783
R1O7
+
R2
O
O
5 mol% cat.
DCM, reflux
R1O7
R2
O
O
R1= TBS, Bz
R2 = H: 91%, E/Z: 4.5:1
= Me: 62%, E/Z > 20:1
RuCl
ClPCy3
NN MesMes
AcO3
+
R
O
HDCM, reflux
AcO3
R
O
H
R = H: 62%, E/Z: 1.1:1 = Me: 92%, E/Z > 20:1
5 mol% cat.
AcO3
+ O
RDCM, reflux
AcO3
O
R
R = Me: 95%, E/Z > 20:1 = Ph: 99%, E/Z > 20:1
5 mol% cat.
27
• E-selective– Electron-poor olefins
Stereoselective CM Reactions
Grubbs, R. Angew. Chem. Int. Ed. 2001, 40, 1277Grubbs, R. Synlett. 2001, 1034Grela, K. and Bieniek, M. Tet. Lett. 2001, 42, 6425
O
N +
5 mol% Grubbs-2
DCM, refluxR
R
N
O
R
R
9 examples, 39-100% yieldE/Z = 25:1 - 60:1
P
O
EtOEtO
R+5 mol% Grubbs-2
DCM, refluxP
O
EtOEtO
R5 examples, 77-97% yieldE/Z > 20:1
SO O
Ph R+5-10 mol% Grubbs-2
DCM, refluxS
O O
Ph R6 examples, 33-85% yieldOnly E isomer detected
• E-selective– Electron-poor olefins
Stereoselective CM Reactions
28
CHO(3 equivs)
5 mol% Hoveyda 2
DCM, RT, 36h79%
PMBO
OH
PMBO
OH
O
H 2 steps
PMBO
OH OAcCHO
(3 equivs)5 mol% Hoveyda 2
DCM, RT, 12h63%
PMBO
OH OAc
O
H
2 steps
PMBO
OH OAc OAcCOOEt
(3 equivs)5 mol% Hoveyda 2
DCM, RT, 24h61%
PMBO
OH OAc OAc
O
OEt
C1-C14 fragment of Amphidinol 37 steps, overall yield 17.5%
Bouzbouz, S. and Cossy, J. Org. Lett. 2001, 3, 1451
• E-selective– Electron-poor olefins
Stereoselective CM Reactions
29
HO
OH OAc OAc OH OH
OH
OH
OH OH
HOOH
O
HOH
OHO
HOH
HOH
OH
OH
HOOH
OH
Amphidinol C
Bouzbouz, S. and Cossy, J. Org. Lett. 2001, 3, 1451
PMBO
OH OAc OAc
O
OEt
30
• E-selective– Other useful functional groups
Stereoselective CM Reactions
Miyaura, N. Synlett. 2002, 128Grubbs, R. Angew. Chem. Int. Ed. 2002, 41, 3172Grubbs, R. J. Am. Chem. Soc. 2000, 122, 3783Lautens, M. Angew. Chem. Int. Ed. 2000, 39, 4079
BRO
OR R1
R2+5 mol% Grubbs-2
DCM, refluxB
RO
OR R1
R2 49-94%, E/Z 1:1 - 9:1
OR2+
5 mol% [Ru]
DCM, reflux
O
R
cat. BF3•Et2Oor Sc(OTf)3
RO
BRO
OR
R+5 mol% Grubbs-2
DCM, reflux
BRO
OR
R 64%, Only E isomer
31
• Z-selective
Stereoselective CM Reactions
Crowe, W. and Goldberg, D. J. Am. Chem. Soc. 1995, 117, 5162Fuchs, P. J. Am. Chem. Soc. 2006, 128, 12656
CN R+5 mol% Schrock
DCM, reflux CN
R 16 examples, 17-90% yieldcis:trans = 3:1 - 9:1
O 30 mol% Hoveyda 2
DCM, 120°C, uw5h, 62%
O
CN CN
NH2OH-HCl, NaOAcMeOH, MeCN50°C, 89%
NO
CN
NC
H
180°C, 3hNO
CN
CN
PhMe 95%
HN
OHHistrionicotoxin10 steps, 19.2% overall yieldor 9 steps, 16.5% overtall yield
32
• Multiple metathesis reactions can be linked together
• Ring-Opening-Cross Metathesis (ROCM)• Ring Rearrangement Metathesis (RRM)• Relay Metathesis
Cascade and Domino Metathesis
33
Ring-Opening-Cross Metathesis (ROCM) X [Ru]
R
X
R
R1
R11st gen. [Ru]
2-8 mol%
DCM or benzene,RT
+ R2
R1 R1
R2 R2 5 examples, 34-98% yield
stereochem of R1 retained
Blechert, S. Angew. Chem. Int. Ed. 1996, 35, 411Snapper, M. J. Am. Chem. Soc. 1997, 119, 1478
O
Pr H
H
1) X mol% Grubbs 1
R
O
Pr R
H4 examples49-65% overall
(1 equiv)
O
Pr
HR
or
O
Pr H
H
O
Pr H
Hor
R
R
34
Ring-Opening-Cross Metathesis (ROCM)
Kozmin, S. J. Am. Chem. Soc. 2004, 126, 9546
O O +N
OBnO
O
1) 10 mol% Grubbs-2 C6H6, 60°C
2) 1M H2SO4, MeCN
N
OBnO
O
O
(1.5 eq) 63% over 2 steps
10 mol%Grubbs-2 OBn OBn
N
OBnO
O
OOBn OBn
68%
O
ONH
OHN
OH
O O O
HO
Bistramide A15 steps (longest linear sequence)
35
• Formally a ROM + RCM cascade
Ring-Rearrangement Metathesis (RRM)
Blechert, S. Tetrahedron 1999, 55, 8179Phillips, A. Angew. Chem. Int Ed. 2008, 47, 8499
N
O
Ts
N
O
TsH
7 mol% Grubbs-1
DCM, RT97%
NH
OH
H
Si
Si
(-)-Halosine
O
2.5 mol% Grubbs 1H2C CH2
DCM, rt90% OH
H H
H
ONH
OHN
O
O
Aburatubolactam A
36
• Recent discovery by multiple groups:– Hoye group (U. Minnesota)– Piscopio group (Array Biopharma)– Lee Group (U. Wisconsin-Madison)
• “Tricks” catalyst into binding to unreactive olefins• Allows for high degree of control of catalyst reactivity• Entropically favoured
Relay Metathesis (RM)
Rn
relayR Ru
R
R
n
RCM or CMR
RR'
R'
R
R
[Ru]
Lee, D. Org. Lett. 2004, 6, 2035Hoye, T. J. Am. Chem. Soc. 2004, 126, 10210
37
Relay-Ring Closing Metathesis (RRCM)
Hoye, T. Angew. Chem. Int. Ed. 2010, 49, 6151
OH
CN O
CN
SiPh2
O
Et
O
Et
O
SiPh2
CN
45 mol% Grubbs-2DCM, 65°C
19%
OH
CN O
CN
SiPh2
O
Et
10 mol% Grubbs-2DCM, 65°C58%
O
Et
OH
O
O
HO
OH
OH
MeO OMe
HO
OMe
(+)-Peloruside A
38
Relay-Ring Closing Metathesis (RRCM)
Hoye, T. Angew. Chem. 2011, 123, 2189
OSi(i-Pr)2
O
O
O
MeO2C
MeO2C
TIPSOC12H25
15 mol% Hoveyda 2
DCM, reflux, 1.5h88%
OSi(i-Pr)2
O
O
O
TIPSOC12H25
3 steps
OH
OH
O
O
HOC12H25
HO O
O
(+)-gigantecin
39
• A Brief History• Metathesis as a Synthetic Tool• Recent Advances in Metathesis Methodology
Outline
40
• Accelerating Metathesis Reactions
New Conditions
Additive Yield
None 57%
CuI 98%OTBS
methyl vinyl ketone (3 equivs)2 mol% Grubbs 2
3 mol% additive0.1M Et2O, 35°C, 3h
OTBSO
Lipshutz, B. J. Org. Chem. 2011, 76,4697
OTBS
CN2 mol% Grubbs 2
3 mol% additive0.1M Et2O, 35°C, 3h
OTBS
CNAdditive
Conversion
None 30%
CuI 64%
• Metathesis Reactions in Water?– Special catalysts required historically
• Another discovery by the Lipshutz group:
New Conditions
41Grubbs, R. J. Org. Chem. 1998,63, 9904Lipshutz, B. J. Org. Chem. 2011, 76,4379
Ru
P
P
Cy Cy
N
Cy Cy
N
Cl
Cl
Cl
ClPh
O3
O
O
O
O
OOMe
n = ca. 15
• Metathesis Reactions in Water?– Special catalysts required historically
• Another discovery by the Lipshutz group:
New Conditions
42Grubbs, R. J. Org. Chem. 1998,63, 9904Lipshutz, B. J. Org. Chem. 2011, 76,4379Lipshutz, B. J. Org. Chem. 2011, 76,4697
Ru
P
P
Cy Cy
N
Cy Cy
N
Cl
Cl
Cl
ClPh
O3
O
O
O
O
OOMe
n = ca. 15
-tocopherol
succinic anhydridePEG-750-M
“TPGS-750M”2% wt. solution – 100mL for $74.10 (Aldrich)
OTBS
2 mol% Grubbs 2
TPGS-750M/H2O (2.5 wt%)22°C
+
OTBSO O
without CuI - 74%with CuI - 93%
43
• Chiral Metathesis Catalysts– Several forms of chiral catalysts exist– Chiral NHC’s are popular among Ru
catalysts
New Catalysts
Hoveyda, A. J. Am. Chem. Soc. 2002, 124, 4954Collins, S. Organometallics 2007, 26, 2945 Blechert, S. Angew. Chem. Int. Ed. 2011, 50, 3299
NN Mes
Ru
OCl
Cl
NN Mes
Ru
PCy3
PhCl
Cl
NN
Ru
Ph Ph
i-Pri-Pr
i-Pr i-Pr
Ph
Cl
ClPCy3
N NMes
Ru
O
Cl
O
44
• First Z-selective Metathesis Catalyst– Effective in CM of alkenes, enol ethers,
ROCM
• Grubbs Z-selective Ru Catalyst– Highly reactive (<1 mol% loadings)– Adamantyl group critical for Z selectivity
New Catalysts
Hoveyda, A and Schrock, R. Nature 2011, 471, 461Grubbs, R. J. Am. Chem. Soc. 2011, 133, 8525Grubbs, R. J. Am. Chem. Soc. 2011 ASAP
NN Mes
Ru
OOO
NO
N
Mo
O
NPh
Br
BrTBSO
RR
45
New Catalysts
NN Mes
Ru
OOO
NO
N
Mo
O
NPh
Br
BrTBSO
RR
Hoveyda, A and Schrock, R. Nature 2011, 471, 461Grubbs, R. J. Am. Chem. Soc. 2011, 133, 8525Grubbs, R. J. Am. Chem. Soc. 2011 ASAP
46
New Catalysts
NN Mes
Ru
OO
R1
N
Mo
O
NPh
Br
BrTBSO
RR
Mo
N
Ar
R1N
R2OBr
TBSO
Br
R2
Hoveyda, A and Schrock, R. Nature 2011, 471, 461Grubbs, R. J. Am. Chem. Soc. 2012 (Accepted January 9, 2012)
R2
NN Mes
RuR1
O
O
R2
vs.
NN Mes
RuR1
O
O
R2
DE ≈ 4 kcal/mol
47
• Barriault Group– Daniel Newbury– Boubacar Sow– Gabriel Bellavance– Phillipe McGee– Francis Barabé– Mathieu Morin– Joel Marcotte– David Lapointe– Guillaume Revol– Patrick Levesque– Jason Poulin– Stephanie Lanoix– Geneviève Bétournay– Louis Barriault
Acknowledgements
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