metal-catalyzed late stage c-h functionalization a powerful tool in total synthesis 3rd year seminar...
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METAL-CATALYZED LATE STAGE C-H FUNCTIONALIZATION
A powerful tool in total synthesis
3rd year seminarIoulia Gorokhovik 23.11.2011
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New challenges in total synthesis
In the last decades, development of new techniques and methods has enabled chemists to synthesize structures of increasing complexity.
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New challenges in total synthesis
Nicolaoou, K.C.; Aversa, R.J. Isr. J. Chem. 2011, 51, 359 – 377
Largest non polymericmolecule found in natureand most toxic non-peptide
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New challenges in total synthesis
Hendrickson, J. B. J. Am. Chem. Soc. 1975, 97, 5784.Gaich, T.; Baran, P.S. J. Org. Chem. 2010, 75, 4657–4673.
In the last decades, development of new techniques and methods has enabled chemists to synthesize structures of increasing complexity.
New challenge : «Aiming for the ideal synthesis »
Which “...creates a complex molecule...in a sequence of only construction reactions involving no intermediary refunctionalizations, and leading directly to the target, not only its skeleton but also its correctly placed functionality.” (Hendrickson, 1975)
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What is C-H activation ?
• Principle : Functionalization of unactivated C-H bonds
• Challenge :Find suitable catalysts and selectively functionalize one single C-H bond of a complex structure.
• Prof Robert Bergman, Berkeley :
"If you asked people ten years ago whether anyone would ever come up with a catalytic method to do this, they would have said no. I don't think it is outrageous to say that in five or ten years there will be commercial applications.“ (Nature 2006, 440, 390-391).
C FG1 C FG2
C FG1 C FG2 C C
Traditionnal approach : C-H activation approach
C H C FG
C H C FG C C
Godula, K.; Sames, D. Science, 2006, 312, 67-72.
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Why is it powerful for total synthesis ?• Complementary approach to classical transformations
• Access to multiple structural analogs : in theory any C-H bond could be functionalized
• Mild conditions : adapted for complex structure transformations
• «Green chemistry» : atom economy and reduction of waste
• Shorter routes to natural products, no need to functionalize the substrate and rapid complexity generation
Godula, K.; Sames, D. Science, 2006, 312, 67-72.Davies, H.M.L.; Manning, J.R. Nature, 2008, 451, 417-424.
O
HN
OH
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Outline
1. The beginnings of C-H activation
2. Coordination-directed metal insertion
3. Metal-catalysed carbene and nitrene insertion
C FG1 C FG2
C FG1 C FG2 C C
Traditionnal approach : C-H activation approach
C H C FG
C H C FG C C
Godula, K.; Sames, D. Science, 2006, 312, 67-72.
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THE BEGININGS OF C-H ACTIVATIONRadical intramolecular chemistry
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The principleX
Y HX
H
radical formation
H-transfer
XH
XH FG
radical trapping
Godula, K.; Sames, D. Science, 2006, 312, 67-72.Löffler, k.; Kober, S Berichte, 1909, 42, 3431.
Chemistry started and developed in the 1800’s by Hoffmann : study of halogenoamines.
First total synthesis using C-H activation : nicotine in 1909 by Löffler.
Known as the Hoffmann-Löffler-Freytag reaction.
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The Hoffmann-Löffler-Freytag reaction
N
NMeBr
N
NMe
N
NMeH
N
HNMeBr
N
NMe
radical formation H-transferradical trapping
nucleophilic substitution
nicotine
Löffler, K.; Kober, S Berichte, 1909, 42, 3431.
First total synthesis using C-H activation : nicotine in 1909 by Löffler.
Later used by E.J. Corey and recently by P. Baran.
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C-H FUNCTIONALIZATION BY DIRECTED METAL INSERTON
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The principle
R1 R2
HDG -H+
R1 R2
DG MLn
MLn
R1 R2
DG XX = C, O, N, Hal
1-2 1-2 1-2
DG = directing group
XR1
H
MLn
FG-R
XR1
MR
H
XR1
R
sp3 bonds
sp2 bonds
• Possible with sp2 and sp3 C-H bonds.• Use of heteroatomic functional group to direct the metallation of the desired C-H
bond
Godula, K.; Sames, D. Science, 2006, 312, 67-72.
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Syntheses of alkaloids rhazinilam, rhazinal and rhazinicine
Isolated in 1970 and 1998-1999.Promising starting point for the development of anti-cancer agents.Syntheses : Sames in 2000 and 2002
Trauner in 2005 and 2009 Gaunt in 2008
N
NH
O
N
NH
O
N
NH
O
CHO O
(-)-rhazinilam (-)-rhazinal (-)- rhazinicine
Banerji, A.; Majumder, P. L.; Chatterjee, A. G. Phytochemistry 1970, 9, 1491– 1493.Kam,T-S.; Tee, Y-M.; Subramaniam , G. Natural Product Letters, 1998, 12, 307-310.Kam, T.S.; Subramaniam, G.; Chen, W. Phytochemistry 1999, 51, 159.
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Total synthesis of (-)-rhazinilam
Le Floc’h, D.; Gouault, N.; David, M.; van de Weghe, P. ARKIVOC 2010, 247-259.Johnson, J.A.; Sames, D. J. Am. Chem. Soc. 2000,122, 6321-6322.
N
N
O
OMe
NH2
N
O
OMe
H2NNH O
N
RhazinilamH
Amino group close to the ethyl group : favorable scenario
Sames, 2002 : by selective platinium-mediated sp3 C-H insertion/β-H elimination
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Total synthesis of (-)-rhazinilam
Le Floc’h, D.; Gouault, N.; David, M.; van de Weghe, P. ARKIVOC 2010, 247-259.Johnson, J.A.; Sames, D. J. Am. Chem. Soc. 2000,122, 6321-6322.
N
NH O
N
Rhazinilam
N
O
OMe5 steps
NH2
Schiff base preparation
[Me2Pt(µ-SMe2)]2 stoechio.N
O
OMe
N Ph
NPt
TfOH- MeH
N
OOMe
N
Ph N
Pt+
N
OOMe
N
Ph N
Pt+H
70°C, 60h 90%
Racemic : auxiliary group containing a pyridine and a Schiff base Ph has a dramatic effect (decomposition with H)Use of a stoechimoetric amount of cationic Pt
isolated and cristallised
Sames, 2002 : by selective platinium-mediated sp3 C-H insertion/β-H elimination
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Total synthesis of (-)-rhazinilam
Le Floc’h, D.; Gouault, N.; David, M.; van de Weghe, P. ARKIVOC 2010, 247-259.Johnson, J.A.; Li, N.; Sames, D. J. Am. Chem. Soc. 2002,124, 6900-6903.
Sames, 2002 : by selective platinium-mediated sp3 C-H insertion/β-H elimination
Asymmetric : differentiation of the enantiotopic Et
Chiral auxiliary group containing an oxazoline and a Schiff baseUse of a stoechimoetric amount of cationic Pt
Bulkier R : better selectivity but lower conversionDiastereoselectivity : from 3:1 to 20:1
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Total synthesis of rhazinilam
Le Floc’h, D.; Gouault, N.; David, M.; van de Weghe, P. ARKIVOC 2010, 247-259.Bowie, A.L.; Hugues, C.C.; Trauner, D. Org. Lett. 2005, 7,5207-5209.
Trauner, 2005: by direct cross coupling reactionIdea :
N
NH
O
N
HN
O
IOO
OTs
H
COOMe
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Total synthesis of rhazinilam
Le Floc’h, D.; Gouault, N.; David, M.; van de Weghe, P. ARKIVOC 2010, 247-259.Bowie, A.L.; Hugues, C.C.; Trauner, D. Org. Lett. 2005, 7,5207-5209.
Trauner, 2005, rhazinilam: by direct cross coupling reaction
N
NH
O
N
N
O
IOO
OTs3 steps MOM 10% mol Pd(OAc)2
K2CO3 47%
Me2NPCy3
10 mol%
N
N
O
[Pd]+
MOM
I-
N
N
O
Pd
MOM
-HI
N
N
OMOM
rhazinilam
-PdLn
Protective group crucial for the reaction
COOMe COOMe
COOMe
COOMe
H
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Total synthesis of rhazinal
N
NH
O
N
N
O
I
MOM 10% mol Pd(OAc)2 K2CO3 43%
Me2NPCy3
10 mol%
N
N
OMOM
rhazinal
CHOCHO CHO
H
N
OOEt
H
Pd(OAc)2 10 mol% tBuOOH
dioxane, AcOH, DMSO 45°C 69%
N
OEt
O
N
OOEt
I
CHO
Pd(OAc)2 6 mol%TBAB, TEA
acetonitrile, H2O 45°C 75%
N
OEt
O
Asymmetric versions of this Heck reactiongave low yields and ees.
OHC
Trauner, 2009, rhazinal: by direct cross coupling reaction
Bowie, A.L.; Hugues, C.C.; Trauner, D. Org. Lett. 2005, 7,5207-5209.Bowie, A.L.; Trauner, D. J. Org. Chem. 2009, 74, 1581-1586.Le Floc’h, D.; Gouault, N.; David, M.; van de Weghe, P. ARKIVOC 2010, 247-259.
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Total synthesis of rhazinicine
Le Floc’h, D.; Gouault, N.; David, M.; van de Weghe, P. ARKIVOC 2010, 247-259.Beck, E.M.; Hatley, R.; Gaunt, M.J. Angew. Chem. Int. Ed. 2008, 47, 3004-3007.
NH O
N
Rhazinicine
O
NH2
O
NO
OHoxidativecyclization
O2N
NMe3Si
OCOOEt
intermolecular C-H arylation
NBoc
SiMe3
NO2
I
H H
Gaunt, 2008 : by C-H borylation/Suzuki coupling and oxidative cyclization
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Total synthesis of rhazinicine
Le Floc’h, D.; Gouault, N.; David, M.; van de Weghe, P. ARKIVOC 2010, 247-259.Beck, E.M.; Hatley, R.; Gaunt, M.J. Angew. Chem. Int. Ed. 2008, 47, 3004-3007.Also in 2011 : Liao, X.; Stanley, L.M.; Hartwig, J.F. J. Am. Chem. Soc. 2011, 133, 2088-2091.
NMe3Si
NO2
I
Boc
1) 2mol% [IrCl(cod)]24mol% dtbpy, B2pin2 MW, 100°C
2) Suzuki conditions 78% one-pot
NMe3Si
Boc
NO2
O2N
NMe3Si
OCOOR
10mol% Pd(TFA)2
tBuOOBzDioxane/AcOH/DMSO30°C 53%
NH O
N
Rhazinicine
O
NO2
O
NO
OR
SiMe3
H
H
H
Gaunt, 2008 : by C-H borylation/Suzuki coupling and oxidative cyclization
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Synthesis of (+)-lithospermic acid
OH
HOO O
O
OH
COOH
COOH
OH
OH
(+)-lithospermic acid
Isolated in 1975. Active component of traditional herbs.Potent and nontoxic anti-HIV activity.Synthetic challenge : appropriate protecting group strategy required.
First synthesis : by Ellman and Bergman in 2005 by Yu in 2011
O’Malley, S.J.; Tan, K.L.; Watzke, T.; Bergman, R.G.; Ellman, J.. J. Am. Chem. Soc. 2005, 127, 13496-13497..
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Synthesis of (+)-lithospermic acid
OH
HOO O
O
OH
COOH
COOH
OH
OH
(+)-lithospermic acid
OMe
MeOOH
O
O
OMe
COOMe
COOMe
OMe
OMe
HO
OH
HOO O
OH
OH
COOH
rosmarinic acid
NR
O
OMe
OMe
OMe
MeOOC
H
H
Ellman and Bergman, 2005 : by C-H activation/hydroarylation
O’Malley, S.J.; Tan, K.L.; Watzke, T.; Bergman, R.G.; Ellman, J.. J. Am. Chem. Soc. 2005, 127, 13496-13497..
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Synthesis of (+)-lithospermic acidEllman and Bergman, 2005 : by C-H activation/hydroarylation
O’Malley, S.J.; Tan, K.L.; Watzke, T.; Bergman, R.G.; Ellman, J.. J. Am. Chem. Soc. 2005, 127, 13496-13497..
O
OMe
OMe
NBn
O
OMe
MeOOC
H O
O
OMe
COOMe
OMe
OMe
cis only
1.[RhCl(coe)2]2, L2. HCl, H2O
89%
No L* gave a good enough selectivity and yield
OMe
OMe
N
O
OMe
MeOOC
H
O
O
OMe
COOMe
OMe
OMe
1.[RhCl(coe)2]2 10 mol%FcPCy2 30 mol%
2. HCl, H2O 88%, 73%ee
OMe
OMe
H
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Synthesis of (+)-lithospermic acid
N
O
OMe
MeOOC
H
O
O
OMe
COOMe
OMe
OMe
1.[RhCl(coe)2]2 10 mol%FcPCy2 30 mol%
2. HCl, H2O 88%, 73%ee
after recrystallisation : 99%ee
OMe
OMe
H
OH
HOO O
O
OH
COOH
COOH
OH
OH
(+)-lithospermic acid10 steps, 5.9% yield
Ellman and Bergman, 2005 : by C-H activation/hydroarylation
O’Malley, S.J.; Tan, K.L.; Watzke, T.; Bergman, R.G.; Ellman, J.. J. Am. Chem. Soc. 2005, 127, 13496-13497..
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Synthesis of (+)-lithospermic acid
OH
HOO O
O
OH
COOH
COOH
OH
OH
(+)-lithospermic acid
OMe
MeOO
O
OMe
COOMe
COOMe
OMe
OMe
OH
HOO O
OH
OH
COOH
rosmarinic acid
O
H
OOMe
COOR*
OMeMeO
H
HN2
Yu, 2011: by C-H olefination/C-H carbene insertion
Wang, D.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 5767-5769..
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Synthesis of (+)-lithospermic acid
O
OMe
COOR*
OMe
OMe
H
OOMe
H
HN2
OH
OMe
O O
O
N
OMe
OMe
Rh2(S-DOSP)2 0.5 mol%DCM, 23°C, 2h
85%, dr 8:1
Yu, 2011: by C-H olefination/C-H carbene insertion
Wang, D.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 5767-5769..
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Synthesis of (+)-lithospermic acid
basic hydrolysis
O
OMe
OMe
OMe
HO
OK+Pd(OAc)2 5 mol%
Ac-Ile-OH 5 mol%O2 (1 atm)
KHCO3 (2 eq)tAmyl-OH, 85°C, 2h 93%
OMe
MeOO O
O
OMe
COOMe
COOH
OMe
OMe
OMe
MeOO
COOMe
O
(+)-lithospermic acid
12 steps, 11% yield
Yu, 2011: by C-H olefination/C-H carbene insertion
Wang, D.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 5767-5769..
O
OMe
COOR*
OMe
OMe
H
OOMe
H
HN2
OH
OMe
O O
O
N
OMe
OMe
Rh2(S-DOSP)2 0.5 mol%DCM, 23°C, 2h
85%, dr 8:1
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C-H FUNCTIONALIZATION THROUGH METAL CARBENOID/NITRENOIDC-C and C-N bonds formation
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The principle
Davies, H.M.L.; Manning, J.R. Nature, 2008, 451, 417-424. Davies, H.M.L.; Dick, A.R. Top. Curr. Chem. 2010, 292, 303-345.Davies H.M.L. Angew. Chem. Int. Ed. 2006, 45, 6422-6425.
Advantages :- Often the conditions are very mild- Catalyst very selective for diazo site : extremely tolerant of other functional groups- Catalyst very active : low loadings of catalyst (1 mol%)
HDG
MLn
GD
XDG
X
LnM LnM
Coordination-directed metallation
R1 R2
N2
R1 R2
MLn
HRa
RcRb
HRa
RcRb
R2R1
LnRh
Ra
RcRb
R2
R1H
Metal catalyzed carbene insertion
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The catalyst and the carbenoid
LnMEWG
R2
LnMEWG
H
L = EW chiral ligand, modulating the electophilicity hence reactivityEWG = necessary for sufficient reactivityR2 = can modulate reactivity and selectivity
Catalyst : Dirhodium(II) catalysts mostly used. Copper (I) complexes also effective. Other metals generate too stable carbenoids for C-H functionalization.
The carbenoid has to be electrophilic enough to react with a C-H bond, but not too much for good regio and stereocontrol
Widely used in intramolecular reactions
LnMEWG
EWG
Highly electrophilic carbenoid formed
LnMEWG
EDG
Stabilised carbenoid : highly selective
Davies, H.M.L.; Manning, J.R. Nature, 2008, 451, 417-424. Davies, H.M.L.; Dick, A.R. Top. Curr. Chem. 2010, 292, 303-345.Davies H.M.L. Angew. Chem. Int. Ed. 2006, 45, 6422-6425.Davies H:M:L:, Beckwith, R.E.J. Chem. Rev. 2003, 103, 2861-2903.
More selective carbenoid
More reactive carbenoid
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Which C-H bond ?Electronic, steric and conformational effects Electronic effects : C-H activation prefered on sites where a partial positive charge is stabilized.
5-membered rings favored over other size rings, if no EDG or conformational effects.Equatorial C-H bonds favored
Davies, H.M.L.; Manning, J.R. Nature, 2008, 451, 417-424. Davies, H.M.L.; Dick, A.R. Top. Curr. Chem. 2010, 292, 303-345. Davies H.M.L. Angew. Chem. Int. Ed. 2006, 45, 6422-6425. Davies H:M:L:, Beckwith, R.E.J. Chem. Rev. 2003, 103, 2861-2903.
EDG EWG
CH3
1° C-H sterically favouredelectronically disfavoured
2° C-H sterically favouredelectronically favoured
2° C-H sterically favouredelectronically disfavoured
3° C-H sterically disfavouredelectronically favoured
0.011 0.66 1
N
1700
BocO
2700 28,000
Relative rates and sites of insertion of methyl phenyldiazoacetate into various substrates at RT
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Intramolecular C-H activation : the beginingUsed since the early 80’s
O
O
5 steps
29%
O
O
N2
COOMe Rh2(OAc)2
91%
O
O
COOMe
Symmetry destruction
5 steps 4%
O
COOMe
OPentenolactone E methyl ester
O4 steps
25% O
O
O
ON2
Rh2(OAc)2,33 mol%
43%
OO
O
O
9 steps 12%
Cane, 1984 :
Taber, 1984 :
Formation of 6-membered ring
H
H
Cane, D.E.; Thomas, P.J. J. Am. Chem. Soc. 1984, 106, 5295-5303.D. F. Taber, J. L. Schuchardt, J. Am. Chem. Soc. 1985, 107, 5289.
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Intramolecular C-H activation
O
O
ON2
EtOOC
Rh2(OAc)2
87% O
O
H
COOEtO
2 steps
H
angular triquinane
H
Recently :
Srikrishna, A.; Sheth, Vishal M.; Nagaraju, G Synlett, 2011, 16, 2343-2346.
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Intramolecular vs intermolecular C-H activation
Doyle, M.P.; Hu, W.; Valenzuela, M.V.; J. Org. Chem. 2002, 67, 2954.Davies, H.M.L.; Jin, Q. Tetrahedron Asymmetry , 2003, 14, 941.Davies, H.M.L.; Dick, A.R. Top. Curr. Chem. 2010, 292, 303-345.
OMe
TBDPSO
O
ON2
Rh2(4S-MPPIM)4 1 mol%DCM
68%, 93%ee
OMe
TBDPSO OO
5 more steps 42%
MeO
HO
OH
OH
OMe
(+)-imperanene
Doyle, 2002: intramolecular
Davies, 2002: intermolecular
OMe
TBSO
OTBS
OMe
N2 COOMe
Rh2(R-DOSP)4 1 mol%DMB, 50°C
43%, 91%ee
MeO
TBSO
COOMe
OTBS
OMe
2 more steps 87%
H
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Intermolecular C-H activation
Davies, H.M.L.; Manning, J.R. Nature, 2008, 451, 417-424. Davies, H.M.L.; Hansen, T.; Hopper, D.W.; Panaro, S.A. J. Am. Chem. Soc, 1999, 121, 6509-6510.Thai, D.L.T; Sapko, M.T.; Reiter, C.T.; Bierer, D.E.; Perel, J.M. J. Med. Chem. 1998, 41, 591-601.Prashad, M.; Kim, H.Y.; Lu, Y.; Liu, Y.; Har, D.; Repic, O.; Blacklock, TJ.; Giannousis, P. J. Org. Chem., 1999, 64, 1750-1753.Y. Matsumura, Org. Lett., 1999, 1, 175-178
N
Boc
H
N2 Ph
COOMe
+1. Rh2(S-biDOSP)2 1mol%
2. CF3COOH
52%, 86% ee
NH
Ph
HCOOMe
4 eq Threo-methylphenidate
Ritalin, treatment for Attention Deficit Hyperactivity DisorderSome previous syntheses :
8 steps for Perel's group, in 10-27% yield, 99% optical purity9 steps for Prashad's group, in 13% yield, 99% optical purity5 steps for Matsumura's group, in 6% yield, 99% optical purity
Only 2 steps by C-H activation, 52% yield, 86%ee
Davies, 1999:
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Intermolecular C-H activation
Davies, H.M.L.; Manning, J.R. Nature, 2008, 451, 417-424. Davies, H.M.L.; Stafford, D.G.; Hansen, T. Org. Lett. 1999, 1, 233-236.
Vinyl diazoacetates :
H
Possibility of cascade sequences : C-H activation/Cope rearrangement
Cl
Cl
N2 COOMe
Rh2(S-DOSP)4 1mol%
Hex, RT
Cl
Cl
RhCOOMe
H
60%, 99% ee
Cl
Cl
COOMe
Cl
Cl
NHMe
(+)-sertalineZolof t, antidepressant
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N2
COOMeMe
MeOOC
Me
H
Rh2(R-DOSP)4
Me
Me
Me
Me
H
Me Me
erogorgiaene
Me
HO
MeO
OH
MeMeH
colombiasin A
Me
O
MeOH
OH
MeHMe
elisapterosin B
HR
racemic
enantiodivergent C-H activation/Coperearrangement
R
Me
Me
H
Me Me
Elisabethatriene
biosynthesis biosynthesis
Isolated from gorgonian coralsVery promisiong biological activities
Many synthetic studies and sytheses already published
3 very challenging stereogenic centersNo convenient neighboring group to assist stereocontrol
Total synthesis of (-)-colombiasin A, (-)-elisapterosin B and (+)-erogorgiaene
Davies, H.M.L.; Walji, A.M. Angew. Chem. Int. Ed. 2005, 44, 1733-1735.Davies, H.M.L.; Dai, X.; Long, M.S. J. Am. Chem. Soc. 2006, 128, 2485-2490.Davies, H.M.L.; Manning, J.R. Nature, 2008, 451, 417-424.
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Existing strategies
Davies, H.M.L.; Dai, X.; Long, M.S. J. Am. Chem. Soc. 2006, 128, 2485-2490.
O
O
Me
R4O
R5
Me
H
Me
Me
MeO
MeOMe
OMe
O
OO
Pd(0)
Me
MeO
MeOMe
OMe
zH
Me
Nicolaou's strategy : Tsuji allylation : poor regiocontrol, wrong epimer obtained
Me
MeO
MeOR
OR
Rh2(R-DOSP)4
N2
COOMe
Me
MeO
MeOR
OR
MeOOC
Me
H
Davies's strategy : C-H activation/Cope rearrangement
Me
MeO
O
O
R1
R2
R3
Me
+[4+2]
O
O
Me
MeO
R2
R3
R1
H
Me
H
H
Kim and Rychnovsky's, Jacobsen's strategy : Diels Alder reaction : one center introduced prior to DA poor diastereoselectivity (improved by Jacobsen)
O
Me
H
Me
Me
H OOH
MetBuO
Harrowven's strategy : Starting from commercial monoterpene
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C-H activation/Cope rearrangement
Davies, H.M.L.; Dai, X.; Long, M.S. J. Am. Chem. Soc. 2006, 128, 2485-2490.
Me
MeO
OR
OR
N2
COOMe
Me
MeO
MeOR
OR
MeOOC
Me
HRh2(R-DOSP)4 2 mol%2,2-DMB, RT, 1.5h
Me
OMe
Me OR
OR
+
Me
MeOOC
Me
HH
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C-H activation/Cope rearrangement : Models
Davies, H.M.L.; Dai, X.; Long, M.S. J. Am. Chem. Soc. 2006, 128, 2485-2490.
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Me
MeO
OR
OR
N2
COOMe
Me
MeO
MeOR
OR
MeOOC
Me
HRh2(R-DOSP)4 2 mol%2,2-DMB, RT, 1.5h
Me
OMe
Me OR
OR
+
Me
MeOOC
Me
HH
5 steps
Me
Me
MeOOC
Me
HMe
Me
Me
H
Me Me
erogorgiaene4 additional steps
Me
MeO
MeOR
OR
MeOOC
Me
H
Me
HO
MeO
OH
MeMeH
colombiasin A14 additional steps
Me
O
MeOH
OH
MeHMe
elisapterosin B13 additional steps
C-H activation/Cope rearrangement
Davies, H.M.L.; Dai, X.; Long, M.S. J. Am. Chem. Soc. 2006, 128, 2485-2490.
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(-)-tetrodotoxin extracted from japanese fugu fish. Poison : very potent as a selective blocker of voltage-gated sodium ion channels.
Structure elucidated in 1964 by Woodward.First racemic total synthesis by Kishi in 1972 : about 30 steps
Second total synthesis in 2003 by Isobe : more than 60 steps 25 protecting group manipulations
A shorter version published in 2004.
Total synthesis by Du Bois : 32 steps 2 C-H functionalisations, 5 protecting group manipulations
OH
OO
OH
HO
OH
OH
HN NH+H2N
HO
(-)-tetrodotoxin
Total synthesis of (-)-tetrodotoxin
Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510-11511.
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Total synthesis of (-)-tetrodotoxin
OO
OHHO
HO
HOH
isoascorbic acid E315
O
PivO O
OTBS
O
N2H
O
ORh2(HNCOCPh3)4 1.5 mol%
further used without purification
O
PivO O
OTBS
O
O
O
9 steps
Stereospecif ic Rh-carbene C-H insertion
Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510-11511.
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Total synthesis of (-)-tetrodotoxin
14 steps
O
OO
O
O
Cl O
OH
O
NH2
Rh2(HNCOCF3)4 10 mol%
Stereospecif ic Rh-nitrene C-H insertion
O
OO
O
O
Cl O
O NH
O
PhI(OAc)2, MgO 77%
OH
OO
OH
HO
OH
OH
HN NH+H2N
HO
(-)-tetrodotoxin
7 steps
OO
OHHO
HO
HOH
isoascorbic acid E315
O
PivO O
OTBS
O
N2H
O
ORh2(HNCOCPh3)4 1.5 mol%
further used without purification
O
PivO O
OTBS
O
O
O
9 steps
Stereospecif ic Rh-carbene C-H insertion
Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510-11511.
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Rh-nitrene insertion
R O
H
O
NH2
O O
N
R HRhLn
O O
NH
R
Rh source
PhI(OAc)2, MgO
Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510-11511.Espino, C.G.; Du Bois, J. Angew. Chem. Int. Ed. 2001, 40, 598-600.Godula, K.; Sames, D. Science, 2006, 312, 67-72.
Used for C-N bond formation at an alkyl site.Pioneered by Breslow, and further developed by Du Bois. Detailed mechanism still unclear.
No second substituent to give flexibility, compared to carbenes.
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CONCLUSION
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C-H functionalization : a powerful tool in total synthesis
• Rapidly evolving field : many groups working on the development of new methods/conditions/catalysts.
Work to be done : improve regioselectivity and selectivity, reactivity…
• Many total syntheses already published, and more are appearing in the literature every year.
• C-H functionalization :
mild conditions => compatible with complex structures
rapid generation of complexity => interesting for complex molecules
no prefunctionalization needed => shorter syntheses
complementary approach => different strategies
green chemistry => appreciated nowadays
Soon C-H bonds will be seen as ubiquituous functional groups
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THANKS FOR YOUR ATTENTIONQuestions