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