20060508 kt ch activation
TRANSCRIPT
C-H Activation in Natural Product Synthesis
Reviews:
Transition Metal: Shilov, Shul’pin Chem. Rev. 1997, 97, 2879Dyker ACIEE 1999, 38, 1698.
Mechanism: Bergman Acc. Chem. Res. 1995, 28, 154Stahl, Labinger, Bercaw ACIEE 1998, 37, 2180
Carbene-Induced: Davies Chem. Rev. 2003, 103, 2861
Stoichiometric: Jones Top. Organomet. Chem. 1999, 3, 9.
Catalytic: Fujiwara Acc. Chem. Res. 2001, 34, 633.Kakiuchi Top. Organomet. Chem. 1999, 3, 47.
Synthesis: Sames Science 2006, 312. 67
Kristy TranLeighton Group
May 1, 2006
C H C FG
Mechanisms of C-H Activation
Jones, W. D. Top. Organomet. Chem. 1999, 3, 9.
M R H MH
R
2M R H M R M H
M
X
H
R
M X R H
M
X
H
RM R M H
‡
R H MXH
RM X
Oxidative Addition
Radical Process (Rare)
Addition of Electrophiclic Metal Center (Concerted or Oxidative Addition)
Reversible Addition to an M=X Bond (Carbenoids)
Traditional vs C-H Activation
Godula, K.; Sames, D. “C-H Bond Functionalization in Complex Organic Synthesis” Science. 2006. 312. 67.
C-H activation offers new disconnection strategies which can rival traditional methods which requires manipulation of functional groups which are often relatively reactive and molecules which are unlike the target compound.
Simplifies synthetic approaches by using topologically obvious assembly
R1
O
H R3
OR2
R3
O
R2R1
OH
R1 R3
O
R2R3
O
R2R1
R1 XR3
FG
R2R3
FG
R2R1
H
NHN
HNNH
H2N
O NH2
O
NH2+
HO
(+)-Saxitoxin
Du Bois JACS 2006, 128, 3926
HO
C-H Activation in Natural Product Synthesis
HOOH
CO2H
O O
OOH
OH
CO2H
OH
(+)-Lithospermic Acid
Bergman, Ellman JACS, 2005, 127, 13496
Rhazinilam
Sames JACS 2000, 122, 6321
N
NH
O
OO O
MeOOMe
H
H
O
MeMe
(±)-Deguelin
Sames Org. Let. 2003, 5, 4053-5
OH
OMeOH
(+)-Imperanene
Davies Tetrahedron: Asymm. 2003, 14, 941
MeO
HO
OMeO
HO
O
OMeOH
(_)-α-Conidendrin
Davies Tetrahedron: Asymm. 2003, 14, 941-9
O
OO
O
O O
(_)-Hinokinin
Doyle JOC 1996, 61, 9146
O
(+)-α-Cuparenone
Taber JACS 1985, 107, 196-9
MeO
Me O
(+)-Estrone methyl ester
Taber JOC 1987, 52, 28
O
NMe
H
HOH
OH
(+)-morphine
White JOC 1997, 62, 5250-1
O
NMe
H
HOH
MeO
(+)-Codeine
White JOC 1999, 64, 7871-84
O
NH
O
NH
O
HNH
NH
H
OH
(_)-Ephedradine A (Orantine)
Fukuyama JACS 2003, 125, 8112-3
OH
N
O
Telocidin B4 Core
Sames JACS 2002, 124, 11856
NHOH
O
OH
HOHN+H2N
OH
HO OHO
Tetrodotoxin
Du Bois JACS, 2003, 125, 11510
Rhazinilam - Retrosynthesis
Johnson, J. A.; Sames, D., J. Am. Chem. Soc. 2000, 122, 6321-2.Johnson, J. A.; Ning, L.; Sames, D., J. Am. Chem. Soc. 2002, 124, 6900.
Rhazinilam
N
NH
O
N
OMeO
NH2
N
OMeO
NH2
Pro-S
Pro-R
NNO2
Br
Pyrrole Annulation
Selective dehydrogenationC-H bond activation
Member of Aspidosperma class of alkaloidsAntitumor properties
Racemic Synthesis of C-H Activation Precursor
Johnson, J. A.; Sames, D., J. Am. Chem. Soc. 2000, 122, 6321-2.Grigg, R.; Myers, P.; Somasunderam, A.; Sridharan, V. Tetrahedron 1992, 48, 9735
NNO2
Br
DMF, 100°C, 90%
NBr
NO2
2 eq Ag2CO3
PhMe, reflux, 70%
NO2N
1. CCl3COCl2. NaOMe, MeOH
3. H2 (1 atm), Pd/C 88% (3 steps)
NH2N
OOMe
Pyrrole Annulation
NPh
O
, [PtMe2(μ-SMe2)]2
PhMe, rt
NN
OOMe
NPt
Selective C-H Bond Activation
Johnson, J. A.; Sames, D., J. Am. Chem. Soc. 2000, 122, 6321-2..
TfOH, CH2Cl2
-CH4
N
OMeO
N
Ph N
Pt Me
N
OMeO
N
Ph N
Pt H
CF3CH2OH70°C, 60h, 90% (NMR)
-CH4
TfO
1. KCN (0.5M), CH2Cl2, H2O;2. NH2OH, MeOH
60 % (4 steps)
N
OMeO
NH2 TfO
N
OMeO
N
Ph N
Pt MeMe
Endgame of Razinilam
HOBT = 1-hydroxybenzatriazole hydrate (used in peptide synthesis to suppress racemization)PyBOP = Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphateJohnson, J. A.; Sames, D., J. Am. Chem. Soc. 2000, 122, 6321-2.
1.TFA, CH2Cl2, 75%
2. PyBOP, HOBT, iPr2NEt3. NaOH (aq, MeOH)
then HCl (aq), 80% (2 steps)
N
OMeO
NH2
Boc2O, DMAP, 76%1. OsO4, NaIO4
2. Ph3P=CHCO2tBu,
3.H2, Pd/C, 70% (3 steps)
N
OMeO
NHBoc
N
OMeO
NHBoc
O
t-BuO
Rhazinilam
N
NH
O
Teleocidin B4 Core
Dangel, B. D.; Godula, K.; Youn, S. W.; Sezen, B.; Sames, D., J. Am. Chem. Soc. 2002, 124, 11856-7.
OH
N
O
Telocidin B4 Core
Friedel-Crafts (racemic)
Alkenylation of unactivated alkyl Carbonylation of unactivated alkyl
Alkenylation of phenol
OMe
NH2 • HCl
Two tandem cycles of directed C-H bond functionalizations
Alkenylation of Unactivated Alkane
Dangel, B. D.; Godula, K.; Youn, S. W.; Sezen, B.; Sames, D., J. Am. Chem. Soc. 2002, 124, 11856-7.
OMe
NH2 • HCl2,6-dimethoxybenzaldehyde
Et3N, PhMe, 130°C
O
OMeMeO
H
OMe
N
OMe
MeO
OMe
N
OMe
O
PdCl2, NaOAc
HOAc, 100°C, 65 %
Me
PdCl
B(OH)2
Ag2O, DMF 90°C, 86 %
OMe
N
OMe
OMe
Schiff base protection retained.
In postion for second cycle of C-H activation/ C-C bond formation without interuption
Carbonylation of Unactivated Alkane
Dangel, B. D.; Godula, K.; Youn, S. W.; Sezen, B.; Sames, D., J. Am. Chem. Soc. 2002, 124, 11856-7.
OMe
N
OMe
OMe
OMe
N
OMe
OMe
PdCl2, NaOAc
HOAc, 70°C
Pd
1. CO, (40 atm), NaOAc, MeOH
2. Silica Gel, CHCl3, 65% (3 steps)
Cl
OMe
NH
O
6:1 cis:trans diastereomers
OMe
N
OMe
OMe
MeSO3H, CH2Cl2, 83%
Completion of Teleocidin B4 Core
Dangel, B. D.; Godula, K.; Youn, S. W.; Sezen, B.; Sames, D., J. Am. Chem. Soc. 2002, 124, 11856-7.
OMe
NH
O
BrBr
KOt-Bu, THF, 71 %
OMe
N
O
BrBBr3, CH2Cl2
96 %
OH
N
O
Pd(OAc)2, P(t-Bu)3, Cs2CO3
DMA, 57 %
Telocidin B4 Core
OH
N
O
Br
(+)-Lithospermic Acid
O’Malley, S.J.; Tan, K.L.; Watzke, A.; Bergman, R.G.; Ellman, J.A. J. Am. Chem. Soc. 2005, 127, 13496.
HOOH
CO2H
O O
OOH
OH
CO2H
OH
(+)-Lithospermic Acid
Global Deprotection
and Esterification
MeOOMe
CO2Me
OH
OOMe
OMe
CO2H
OMe
CO2H
O
OOMe
OMe
CO2H
OMe
H
Knovenagel Condensation
& C20 Epimerization
NR
OMe
H
MeO2CH
OMeOMe
Intramolecular Asymmetric Alkylation
via catalytic Rh Catalyzed C_H Bond Activation
20
10
21
Racemic Intramolecular Alkylation
coe = cyclooctene; Fc-ferrocenylO’Malley, S.J.; Tan, K.L.; Watzke, A.; Bergman, R.G.; Ellman, J.A. J. Am. Chem. Soc. 2005, 127, 13496.
OH
OMeOMe
OMeOMe
CO2Me
1. CBr4, PPh3, 88%
2. n-BuLi then ClCO2Me, 93%
Isovanillin, Na, MeOH
MeOH:Py (1:1), 120°C, 59%
O
OMe
H
O
MeO2CH
OMeOMe
BnNH2
PhMe, seives, 110°C, 99%
NBn
OMe
H
O
MeO2CH
OMeOMe
10 mol % [RhCl(coe)2]230 mol % FcPCy2, PhMe, 75°C
then HCl, H2O, 89 %
1:0 cis:trans
O
OOMe
OMe
CO2H
OMe
H
Chiral catalysts could not be identified to give good
enantioselectivites and/or yields
Me
NH2
Ph Et
NH2
Ph Me
NH2
t-BuMe
NH2
CO2t-Bu
NH2
Ph
NH2 NH2
Chiral Amine Auxillaries
O’Malley, S.J.; Tan, K.L.; Watzke, A.; Bergman, R.G.; Ellman, J.A. J. Am. Chem. Soc. 2005, 127, 13496.
N
OMe
H
MeO2CH
OMeOMe
10 mol % [RhCl(coe)2]230 mol % FcPCy2, PhMe, 75°C
then HCl, H2O
O
OOMe
OMe
CO2H
OMe
H
88% yield 73% ee
56% yield 99% ee after recrystallization
Heptamethyl Lithospermic Acid
O’Malley, S.J.; Tan, K.L.; Watzke, A.; Bergman, R.G.; Ellman, J.A. J. Am. Chem. Soc. 2005, 127, 13496.
O
OOMe
OMe
CO2H
OMe
H
73% ee
99% ee after recrystallization
HO2C CO2H
Piperdine, C5H5N, 100°C, 85% OOMe
OMe
CO2Me
OMe
CO2H
10:1 anti:syn
MeOOMe
CO2Me
O O
OOMe
OMe
CO2Me
OMe
MeOOMe
CO2Me
OH
EDC, DMAP, CHCl3, 80%
Knovenagel CondensationC20 epimerization
20
Global Deprotection and Lithospermic Acid
O’Malley, S.J.; Tan, K.L.; Watzke, A.; Bergman, R.G.; Ellman, J.A. J. Am. Chem. Soc. 2005, 127, 13496.Minamikawa, J.; Brossi, A. Tetrahedron Lett. 1978, 19(34), 3085
HOOH
CO2H
O O
OOH
OH
CO2H
OH
(+)-Lithospermic Acid
20
10
21
Me3SnOH,
ClCH2CH2Cl, 93%
NTMS
I
neat, 100°C, sealed tube, 35%
MeOOMe
CO2Me
O O
OOMe
OMe
CO2Me
OMe
NTMS
I
neat, 100°C, sealed tube
decompostiton
Saxitoxin
Fleming, J. J.; Du Bois, J. J. Am. Chem. Soc. 2006, 128, 3926.
NHN
HNNH
H2N
O NH2
O
NH2+
HO
HO
(+)- Saxitoxin
Chemical Weapon Designation: TZ
Toxic, paralytic agent
Selective voltage gated Na+ channel blocker
NH
NH
NR
NHO
HO
NH2+
H2N
O NH2
O
N3
NH
SMe
NHH2N
OH
NH
NR
HN OS
O O
OHR
4
CyclodehydrationReaction at C4
Carbodiimide Condensation
C-H Amination/Iminium Ion Nucleophilic Attack
H2N OS
OOMe
Me
O O
Rh-catalyzed Sulfamate Insertion
Fleming, J. J.; Du Bois, J. J. Am. Chem. Soc. 2006, 128, 3926.
OH
OOMe
Me
H2N OS
OOMe
Me
O O
ClSO2NH2
DMA/CH3CN
HN OS
OOMe
Me
O O
2-4 mol % Rh2(esp)2
PhI(OAc)2, MgOToluene, 40°C
O
OORhRhOMe
Me
MeMe
Rh2(esp)2
H2N NHS
Me
O O
HN NHS
O O1 mol % Rh2(esp)2
PhI(OAc)2, MgOToluene, 40°C Me
1,3-diamine derivatives
1,2-diamine derivatives
PhNSO3R
OH2N
R = CH2CCl3
1 mol % Rh2(esp)2
PhI(OAc)2, MgOToluene, 40°C
HNNSO3R
O
Ph
N,O-Acetals as Latent Iminium Ions Equivalents
Fleming, J. J.; Du Bois, J. J. Am. Chem. Soc. 2006, 128, 3926.
HN OS
OOMe
Me
O O
ZnXTsO
BF3•OEt
HN OS
O O
OHOTs
1. H2, Pd/CaCO3 /Pb, THF
2. NaN3, DMF, n-Bu4NI 90 % (2 steps)
HN OS
O O
OH
N3
PMBN OS
O O
OH
N3
p-MeOC6H4CH2Cl, n-Bu4NI, K2CO3
CH3CN, 85 %
PMBN OS
O O
OH
H2N
Me3P, THF/H2O
Staudinger's Reaction
MeS Cl
NMbs
Mbs = p-MeOC6H4SO2
iPr2NEt, CH3CN, 72% (2 steps)
PMBN OS
O O
OH
NH
MeS
MbsN
Synthesis of Acyclic Core of Saxitoxin
Fleming, J. J.; Du Bois, J. J. Am. Chem. Soc. 2006, 128, 3926.
PMBN OS
O O
OH
NH
MeS
MbsN
1. Tf2O, Py, DMAP, CH2Cl22.NaN3, DMF, -15°,
70 % (2 steps)
PMBN OS
O O
N3
NH
MeS
MbsN
(NH4)2Ce(NO3)6,
t-BuOH/CH2Cl2, 74 %
HN OS
O O
N3
NH
MeS
MbsN
N OS
O O
N3
NH
MeS
MbsN
KOtBu, Cl2C=NMbsthen (Me3Si)2NH
aq. CH3CN, 70°C, 95%
MbsN
H2NNH OH
N3
NH
MeS
MbsN
MbsN
H2N
Carbodiimide Condensation
Fleming, J. J.; Du Bois, J. J. Am. Chem. Soc. 2006, 128, 3926.
NH OH
N3
NH
MeS
MbsN
MbsN
H2NNH OH
NH2
MbsN
H2N1. Me3P, THF/H2O
2. AgNO3, Et3N, CH3CN,
65% (2 steps)
NNMbs
•
NH
NH
NMbs
NH
OH
H2N
NMbs
Cl3CC(O)NCO, THF/CH3CN -78°;
then K2CO3, MeOH, 82%
NH
NH
NMbs
NH
OC(O)NH2
H2N
NMbs
Alkene Ketohydroxylation & Cyclodehydration
Fleming, J. J.; Du Bois, J. J. Am. Chem. Soc. 2006, 128, 3926.
NH
NH
NMbs
NH
OR
H2N
NMbs
R = C(O)NH2
NH
NH
NMbs
NHO
HO
NMbs
H2N
O NH2
O
10 mol % OsCl3, Oxone, Na2CO3,
EtOAc/CH3CN/H2O, 57%
OsO4, tBuOOH,
NaHCO3 NH
NH
NMbs
NHHO
O
NMbs
H2N
O NH2
O
NHN
HN
NMbs
O
O
NH2
NH2
NMbs
HO
NH
NNMbs
HO
NH
HOOH
H2N
NMbs
HO
Synthesis of (+)-Saxitoxin
Fleming, J. J.; Du Bois, J. J. Am. Chem. Soc. 2006, 128, 3926.
NHN
HN
NMbs
O
O
NH2
NH2
NMbs
HOHO
NHN
HNNH
H2N
O NH2
O
NH2+
HOB(O2CCF3)2
CF3CO2H, 82%
NHN
HNNH
H2N
O NH2
O
NH2+
HODCC, C5H5N•HO2CCF3,
DMSO, 70%
(+)-Saxitoxin
HO
Tetrodotoxin
Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510.
NHOH
O
OH
HOHN+H2N
OH
HO OHO
Tetrodotoxin
Guanidium poison from the Japanese fugu
Selective voltage gated Na+ channel blocker
OHOH
OH
OH
H
O
OTBSO
O
O
PivO O
H
O
N2
H2NOH
O
OH
O OH
HO OHO
"tetrodamine"
HO
CO2HHO
OHO
HO
O
OHHO
D-isoascorbic Acid
Rh-carbene C-H Alkylation
Rh-nitrene C-H Amination
Synthesis of Rh-Carbene Precursor
Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510.Carrira, E. M.; Dubois, J. J. Am. Chem. Soc. 1994, 117, 8106.Cohen et al. J. Am. Chem. Soc. 1983, 105, 3661.
tBuMe2SiCl,
Et3N, DMAPNH2
O O
OTBS
O
MeMe
OHO
HO
O
OHHO
OHO
HO
O
OD-isoascorbic Acid
p-TolN2 HSO4
OHN
NTol
H
O
HO OH
O
D-Erythronic γ-lactone
Me2NH,
MeOH, 0°C, 97 %
NH2
OH O
OH
HO
NH2
O O
OH
O
MeMe
2,2-DMP,
cat. TsOH, 90 %
Synthesis of Rh-Carbene Precursor – Cont.
Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510.
Me2N O
OTBSH
OO
i-Bu2AlH, n-BuLi,
THF/Hexanes
OTBSO
OBnO
O O
O
OBn
O
HO O
H
O
BnO
OTBSO
O
O
PivO O
H
O
N2
t-BuCOCl, C5H5,
THF, 85 % (3 steps)
OTBSO
O
O
PivO O
H
O
BnOOTBS
OO
O
PivO O
H
O
HOH2, Pd/C,
THF, 88 %
(COCl)2, cat. DMF, THF then
CH2N2, CH2Cl2, 63-70 %
H O
OTBSH
OO
NaOAc, THF >10:1 Anti:Syn
MeMe
MeMe
MeMe
MeMeMe
MeMe
Me
Stereospecific Rh-Carbene C-H Insertion
Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510.
Stereospecific Rh-Carbene C-H InsertionNo purification!
OTBSO
O
O
PivO O
H
O
N21.5 mol % Rh2(HNCOCPh3)4,
CCl4
OTBSO
O
O
PivO O
O
MeMe
MeMe
OTBSO
O
O
PivO O
HO
NH3•BH3, CH2Cl2/MeOH
75% (2 steps)
MeMe
H2 (1200 psi), 5 mol % Rh_C,
2:1 CF3CO2H, MeOH
OHO
O
OHHO
O OPiv
2,2-DMP, cat. p-TsOH, THF, 90 %
Me2NH, THF, 83%
OO
HO
O Me
Me
OPivMe2N
O
HO
MeMe
MeMe
OO
HO
O Me
Me
OPivMe2N
O
HO
OO
HO
O Me
Me
OPivMe2N
O
O
cat. (n-Pr4N)RuO4, NMO,
4 Å MS, CH2Cl2, 94%
OO
HO
O Me
Me
OPivMe2N
O
Zn, TiCl4, CH2I2,
cat PbCl2, THF, 72%
Ph2Se2, PhIO2, C5H5N,
C6H5Cl, 100°C, 70%
OO
HO
O Me
Me
OPivMe2N
O
O1. H2C=CHMgBr, CuI, THF
2. t-BuNH3•BH3, DCE, 77 % (2 steps)
OO
HO
O Me
Me
OPivMe2N
O
HO
MeMe
MeMe
MeMe
MeMe
MeMe
Formation of Bridge C5 Lactone
Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510.Olfination: Takai, J. Org. Chem. 1994, 59, 2668Allylic Oxidation: Barton, Crich Tetrahedron 1985, 41, 4359
OO
HO
O Me
Me
OPivMe2N
O
O1. t-BuCO2H, C6H5Cl, 200°C
2. NaOMe, THF/MeOH 78 % (2 steps)
OO
O
O Me
MeH
O
OOH
Cl3CC(O)NCO, CH2Cl2
Zn, MeOH, 93 %
OO
O
O Me
MeH
O
OO
OO
O
O Me
MeH
HOO
OO
O3, then
NaBH4, CH2Cl2/MeOH
OO
O
O Me
MeH
ClO
OO
MeSO2Cl, C5H5N,
DCE, 86 %NH2
O
NH2
O
NH2
O
MeMe
MeMe
MeMe
MeMe Me
Me
Formation of Bridge C5 Lactone– Cont.
Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510.
Late Stage Stereospecific Rh-nitrene C-H Insertion
Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510.
OO
O
O Me
MeH
ClO
OO
5 mol % Rh2(OAc)4, PhI(OAc)2, MgO,
C2Cl2, 40°C, Trace
OO
O
O Me
MeClO
ONH2
O
ONH
O
MeMe
MeMe
OO
O
O Me
MeH
ClO
OO
10 mol % Rh2(HNCOCF3)4, PhI(OAc)2, MgO,
C6H6, 65°C, 77%
OO
O
O Me
MeClO
ONH2
O
ONH
O
MeMe
MeMe
1. NaSePh, THF/DMF, 77 %
2. m-CPBA, C5H5N, DCE, 55°C 92%
OO
O
O Me
MeO
OO
NH
O
OO
O
O Me
MeO
OO
NBoc
O
Boc2O, Et3N
DMAP, THF
OO
O
O Me
MeO
OOH
NHBoc
K2CO3,
THF/MeOH, 84 % (2 steps)
OO
O
O Me
MeClO
OO
NH
O
MeMe
MeMe
MeMe
MeMe
Endgame
Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510.
Synthesis of Tetrodotoxin
Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510.
OO
O
O Me
MeO
OOH
NHBoc
OHOH
OH
OHO
OOH
NHBoc
H2O,
110°C, 95%
OHOH
OH
OHO
OOH
NH
BocHN
NBoc
SMe , HgCl2, Et3N
MeCN/CH2Cl2, 80 %
BocN NHBoc
O3, CH2Cl2/MeOH; Me2S;
then aq CF2CO2H, 65 %NHOH
O
OH
HOHN+H2N
OH
HO OHO
Tetrodotoxin
MeMe
Tetrodotoxin
NHOH
O
OH
HOHN+H2N
OH
HO OHO
Tetrodotoxin
“It's bungee jumping for the indoorsy type; really, who cares what it tastes like as long as
you live to tell the tale.“ –Lonely Planet I cannot see her tonight.I have to give her up
So I will eat fugu.--Yosa Buson (Japanese Poet)
"I want to eat fugu, but I don't want to die"
Last night he and I ate fugu, Today I help carry his coffin.
…enough neurotoxin remains to produce a mellow, tingling glow – a flush and a drug rush. Remember, tetrodotoxin is
160,000 times more potent than cocaine. Eating fugu is an ancient and hallowed Japanese tradition,
but it's also a rush. No wonder the stuff is so popular.
--http://www.asiaandaway.com/travel_destinations/japan/tokyo/fugu-voodoo_61
Summary
• Selective C-H bond activation (Rhazinlam and TeleocidinB4) but often stoichiometric in metal.
• Catalytic and Enantioselective C-H Activation (LithospermicAcid) but with limited selectivity.
• Functional group tolerance (Tetrodotoxin and Saxitoxin)
• CH Activation process allows for new strageties in synthetic methods
And they lived happily ever after…
HOOH
CO2H
O O
OOH
OH
CO2H
OH
(+)-Lithospermic Acid
Bergman, Ellman JACS, 2005, 127, 13496
N
NH
O
Rhazinilam
Sames JACS 2000, 122, 6321
OH
N
O
Telocidin B4 Core
Sames JACS 2002, 124, 11856
NHOH
O
OH
HOHN+H2N
OH
HO OHO
Tetrodotoxin
Du Bois JACS, 2003, 125, 11510
NHN
HNNH
H2N
O NH2
O
NH2+
HO
(+)-Saxitoxin
Du Bois JACS 2006, 128, 3926