metal-catalyzed late stage c-h functionalization a powerful tool in total synthesis 3rd year seminar...
Post on 02-Jan-2016
223 Views
Preview:
TRANSCRIPT
METAL-CATALYZED LATE STAGE C-H FUNCTIONALIZATION
A powerful tool in total synthesis
3rd year seminarIoulia Gorokhovik 23.11.2011
2
New challenges in total synthesis
In the last decades, development of new techniques and methods has enabled chemists to synthesize structures of increasing complexity.
3
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
4
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)
5
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.
6
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
7
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.
8
THE BEGININGS OF C-H ACTIVATIONRadical intramolecular chemistry
9
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.
10
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.
11
C-H FUNCTIONALIZATION BY DIRECTED METAL INSERTON
12
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.
13
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.
14
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
15
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
16
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
17
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
18
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
19
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.
20
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
21
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
22
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..
23
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..
24
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
25
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..
26
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..
27
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..
28
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
29
C-H FUNCTIONALIZATION THROUGH METAL CARBENOID/NITRENOIDC-C and C-N bonds formation
30
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
31
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
32
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
33
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.
34
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.
35
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
36
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:
37
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
38
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.
39
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
40
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
41
C-H activation/Cope rearrangement : Models
Davies, H.M.L.; Dai, X.; Long, M.S. J. Am. Chem. Soc. 2006, 128, 2485-2490.
42
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.
43
(-)-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.
44
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.
45
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.
46
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.
47
CONCLUSION
48
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
49
THANKS FOR YOUR ATTENTIONQuestions
top related