C-H Activation in Natural Product Synthesis

C H C FG

Reviews:
Transition Metal: Shilov, Shulpin Chem. Rev. 1997, 97, 2879 Dyker ACIEE 1999, 38, 1698. Bergman Acc. Chem. Res. 1995, 28, 154 Stahl, Labinger, Bercaw ACIEE 1998, 37, 2180 Davies Chem. Rev. 2003, 103, 2861 Jones Top. Organomet. Chem. 1999, 3, 9. Fujiwara Acc. Chem. Res. 2001, 34, 633. Kakiuchi Top. Organomet. Chem. 1999, 3, 47. Sames Science 2006, 312. 67

Mechanism:

Carbene-Induced: Stoichiometric: Catalytic:

Synthesis:

Kristy Tran Leighton Group May 1, 2006

Mechanisms of C-H Activation

Oxidative Addition M R H R M H Radical Process (Rare) 2M R H M R M H

Addition of Electrophiclic Metal Center (Concerted or Oxidative Addition) R M X M X R H R M X Reversible Addition to an M=X Bond (Carbenoids) R M X R H M XH
Jones, W. D. Top. Organomet. Chem. 1999, 3, 9.

H M R H M H

Traditional vs C-H Activation

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.
O R
1

O H R2 R3 R1

OH

O R3

R2

O R1 R2 R3 R1 R2

O R3

H R1 X R2

FG R3 R1 R2

FG R3

Simplifies synthetic approaches by using topologically obvious assembly

Godula, K.; Sames, D. C-H Bond Functionalization in Complex Organic Synthesis Science. 2006. 312. 67.

C-H Activation in Natural Product Synthesis

O O
Me O
OH NMe

NMe MeO O H

O
O

H H OH

H OH

MeO
(+)--Cuparenone Taber JACS 1985, 107, 196-9

O (_)-Hinokinin

(+)-Estrone methyl ester Taber JOC 1987, 52, 28

(+)-morphine White JOC 1997, 62, 5250-1

(+)-Codeine White JOC 1999, 64, 7871-84

Doyle JOC 1996, 61, 9146

OH
N NH O Rhazinilam Sames JACS 2000, 122, 6321

OH HO
N O

OMe MeO H O H O

MeO HO

OH

O OH OH

HO HN
+

NH OH

O Me Me
OH

OMe (+)-Imperanene Davies Tetrahedron: Asymm. 2003, 14, 941

H 2N Tetrodotoxin

Telocidin B4 Core Sames JACS 2002, 124, 11856

()-Deguelin

Du Bois JACS, 2003, 125, 11510

Sames Org. Let. 2003, 5, 4053-5

OH

O MeO O HO
H HN O

H N H O O N H

CO2H HO OH CO2H OH O OH (+)-Lithospermic Acid Bergman, Ellman JACS, 2005, 127, 13496 OH O O

H2N HO HN HO N NH O

O NH2

OMe OH (_)--Conidendrin Davies Tetrahedron: Asymm. 2003, 14, 941-9

NH NH2+

N H (_)-Ephedradine A (Orantine) Fukuyama JACS 2003, 125, 8112-3

(+)-Saxitoxin Du Bois JACS 2006, 128, 3926

Rhazinilam - Retrosynthesis
N
MeO O N

NH O Rhazinilam
NH2

Member of Aspidosperma class of alkaloids Antitumor properties

Pro-S N

Selective dehydrogenation C-H bond activation

NO2 Br

Pyrrole Annulation

MeO N NH2

Pro-R
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.

Racemic Synthesis of C-H Activation Precursor

Br N NO2 Br DMF, 100C, 90% NO2 Pyrrole Annulation N 2 eq Ag2CO3 PhMe, reflux, 70% NO2 N

1. CCl3COCl 2. NaOMe, MeOH 3. H2 (1 atm), Pd/C 88% (3 steps)

N Pt N

O OMe N N

O O Ph , [PtMe2(-SMe2)]2 PhMe, rt NH2 N OMe

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

Selective C-H Bond Activation

MeO N N Ph Me Pt Me N TfOH, CH2Cl2 N -CH4 Ph Pt Me N TfO O MeO N O CF3CH2OH 70C, 60h, 90% (NMR) -CH4

MeO MeO N NH2 O 1. KCN (0.5M), CH2Cl2, H2O; 2. NH2OH, MeOH 60 % (4 steps) Ph N N

Pt H N

TfO

Johnson, J. A.; Sames, D., J. Am. Chem. Soc. 2000, 122, 6321-2. .

Endgame of Razinilam
MeO N NH2 O Boc2O, DMAP, 76% NHBoc MeO N O 1. OsO4, NaIO4 2. Ph3P=CHCO2tBu, 3.H2, Pd/C, 70% (3 steps)

N 1.TFA, CH2Cl2, 75% NH O Rhazinilam 2. PyBOP, HOBT, iPr2NEt 3. NaOH (aq, MeOH) then HCl (aq), 80% (2 steps)

MeO N NHBoc t-BuO O

HOBT = 1-hydroxybenzatriazole hydrate (used in peptide synthesis to suppress racemization) PyBOP = Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate Johnson, J. A.; Sames, D., J. Am. Chem. Soc. 2000, 122, 6321-2.

Teleocidin B4 Core
OH Friedel-Crafts (racemic) N Alkenylation of unactivated alkyl O Telocidin B4 Core Carbonylation of unactivated alkyl Alkenylation of phenol

Two tandem cycles of directed C-H bond functionalizations

OMe

NH2 HCl

Dangel, B. D.; Godula, K.; Youn, S. W.; Sezen, B.; Sames, D., J. Am. Chem. Soc. 2002, 124, 11856-7.

Alkenylation of Unactivated Alkane

H OMe MeO O OMe OMe OMe 2,6-dimethoxybenzaldehyde NH2 HCl Et3N, PhMe, 130C MeO N HOAc, 100C, 65 % PdCl2, NaOAc

OMe OMe N N O Me Ag2O, DMF 90C, 86 % Pd Cl O Me B(OH)2 OMe OMe

Schiff base protection retained. In postion for second cycle of C-H activation/ C-C bond formation without interuption
Dangel, B. D.; Godula, K.; Youn, S. W.; Sezen, B.; Sames, D., J. Am. Chem. Soc. 2002, 124, 11856-7.

Carbonylation of Unactivated Alkane

OMe OMe N O Me MeSO3H, CH2Cl2, 83% N O Me OMe OMe PdCl2, NaOAc HOAc, 70C

OMe OMe 1. CO, (40 atm), NaOAc, MeOH NH 2. Silica Gel, CHCl3, 65% (3 steps) O 6:1 cis:trans diastereomers N Pd Cl O Me OMe

Dangel, B. D.; Godula, K.; Youn, S. W.; Sezen, B.; Sames, D., J. Am. Chem. Soc. 2002, 124, 11856-7.

Completion of Teleocidin B4 Core

OMe Br Br NH O KOt-Bu, THF, 71 % N O OMe Br BBr3, CH2Cl2 96 %

OH OH Br N O Telocidin B4 Core Pd(OAc)2, P(t-Bu)3, Cs2CO3 DMA, 57 % N O

Dangel, B. D.; Godula, K.; Youn, S. W.; Sezen, B.; Sames, D., J. Am. Chem. Soc. 2002, 124, 11856-7.

(+)-Lithospermic Acid
CO2Me
10

CO2H O CO2H
20 21

HO OH

Global Deprotection and Esterification

MeO OMe CO2H

OH

OH OH

CO2H OMe O OMe Knovenagel Condensation & C20 Epimerization OMe

O OH

(+)-Lithospermic Acid

NR MeO2C H

Intramolecular Asymmetric Alkylation via catalytic Rh Catalyzed C H Bond Activation

_

O CO2H OMe O

OMe OMe

OMe

OMe

OMe

OMalley, S.J.; Tan, K.L.; Watzke, A.; Bergman, R.G.; Ellman, J.A. J. Am. Chem. Soc. 2005, 127, 13496.

Racemic Intramolecular Alkylation

CO2Me H O 1. CBr4, PPh3, 88% 2. n-BuLi then ClCO2Me, 93% OMe OMe OMe OMe OMe Isovanillin, Na, MeOH MeOH:Py (1:1), 120C, 59% OMe O OMe H O MeO2C H

Chiral catalysts could not be identified to give good enantioselectivites and/or yields

BnNH2 PhMe, seives, 110C, 99%

H H O CO2H OMe O OMe OMe 10 mol % [RhCl(coe)2]2 30 mol % FcPCy2, PhMe, 75C then HCl, H2O, 89 % 1:0 cis:trans

NBn MeO2C O OMe OMe OMe H

coe = cyclooctene; Fc-ferrocenyl OMalley, S.J.; Tan, K.L.; Watzke, A.; Bergman, R.G.; Ellman, J.A. J. Am. Chem. Soc. 2005, 127, 13496.

Chiral Amine Auxillaries

Ph Me NH2 Ph Et NH2 t-Bu Me Me NH2 NH2

Ph

CO2t-Bu NH2 NH2 NH2

O CO2H

N MeO2C H

10 mol % [RhCl(coe)2]2 30 mol % FcPCy2, PhMe, 75C then HCl, H2O OMe

OMe O OMe

88% yield 73% ee OMe OMe OMe 56% yield 99% ee after recrystallization

OMalley, S.J.; Tan, K.L.; Watzke, A.; Bergman, R.G.; Ellman, J.A. J. Am. Chem. Soc. 2005, 127, 13496.

Heptamethyl Lithospermic Acid

H O CO2H
20

CO2H CO2Me OMe OMe 73% ee Piperdine, C5H5N, 100C, 85% Knovenagel Condensation C20 epimerization OMe 10:1 anti:syn O OMe

OMe

HO2C

CO2H

O OMe

99% ee after recrystallization

CO2Me MeO OMe CO2Me OMe O OMe OMe O O MeO OMe

CO2Me OH

EDC, DMAP, CHCl3, 80%

OMalley, S.J.; Tan, K.L.; Watzke, A.; Bergman, R.G.; Ellman, J.A. J. Am. Chem. Soc. 2005, 127, 13496.

Global Deprotection and Lithospermic Acid

CO2Me MeO OMe CO2Me OMe O OMe OMe O O

I N Me3SnOH, ClCH2CH2Cl, 93% TMS neat, 100C, sealed tube, 35%

10

CO2H O CO2H
20

HO
I N TMS neat, 100C, sealed tube decompostiton

O OH

O OH

21

OH OH

(+)-Lithospermic Acid

OMalley, 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

Saxitoxin
H 2N HO HN HO N NH NH2
+

O NH O NH2

NH2+ Cyclodehydration H2N Reaction at C4 O

4

NH O O NH NH2 Carbodiimide Condensation H2N NH OH N3 N H SMe NR

NH

HO N H

(+)- Saxitoxin

NR

Chemical Weapon Designation: TZ Toxic, paralytic agent Selective voltage gated Na+ channel blocker
Me

O H2N O O Me S

O O

O HN S

O O

OH R C-H Amination/ Iminium Ion Nucleophilic Attack

Fleming, J. J.; Du Bois, J. J. Am. Chem. Soc. 2006, 128, 3926.

Rh-catalyzed Sulfamate Insertion

OH ClSO2NH2 O Me O Me DMA/CH3CN Me O O Me O H2 N S O O 2-4 mol % Rh2(esp)2 PhI(OAc)2, MgO Toluene, 40C O HN O Me O Me S O O

O S NH

Me Me O Me Me O O Rh O Rh Rh2(esp)2
Ph

H2N Me

1 mol % Rh2(esp)2 PhI(OAc)2, MgO Toluene, 40C

O HN Me S

O NH 1,3-diamine derivatives

H2N

O NSO3R

1 mol % Rh2(esp)2 PhI(OAc)2, MgO Toluene, 40C Ph

O HN NSO3R 1,2-diamine derivatives

R = CH2CCl3

Fleming, J. J.; Du Bois, J. J. Am. Chem. Soc. 2006, 128, 3926.

N,O-Acetals as Latent Iminium Ions Equivalents

O HN O Me O Me S O O TsO ZnX BF3OEt OTs N3 p-MeOC6H4CH2Cl, n-Bu4NI, K2CO3 CH3CN, 85 % O HN S O O 1. H2, Pd/CaCO3 /Pb, THF 2. NaN3, DMF, n-Bu4NI 90 % (2 steps) O HN S O O

OH

OH

O PMBN S

O O MeS NMbs Cl

O PMBN S

O O Me3P, THF/H2O OH Staudinger's Reaction N3

O PMBN S

O O

MbsN MeS N H

OH

iPr2NEt, CH3CN, 72% (2 steps) Mbs = p-MeOC6H4SO2 H2N

OH

Fleming, J. J.; Du Bois, J. J. Am. Chem. Soc. 2006, 128, 3926.

Synthesis of Acyclic Core of Saxitoxin

O PMBN S O O 1. Tf2O, Py, DMAP, CH2Cl2 2.NaN3, DMF, -15, MbsN MeS N H OH 70 % (2 steps) MbsN MeS N H N3 O PMBN S O O (NH4)2Ce(NO3)6, t-BuOH/CH2Cl2, 74 % MbsN MeS N H N3 O HN S O O

KOtBu, Cl2C=NMbs then (Me3Si)2NH

MbsN H2N NH OH aq. CH3CN, 70C, 95% MbsN MeS N H N3

MbsN O H2N N S

O O

MbsN MeS N H

N3

Fleming, J. J.; Du Bois, J. J. Am. Chem. Soc. 2006, 128, 3926.

Carbodiimide Condensation
MbsN H2N NH OH 1. Me3P, THF/H2O 2. AgNO3, Et3N, CH3CN, 65% (2 steps) MeS N H NH2 N NMbs MbsN H2 N NH OH

MbsN

N3

NMbs H2N NH OC(O)NH2 NH N H NMbs Cl3CC(O)NCO, THF/CH3CN -78; then K2CO3, MeOH, 82% H2 N

NMbs NH OH NH N H NMbs

Fleming, J. J.; Du Bois, J. J. Am. Chem. Soc. 2006, 128, 3926.

Alkene Ketohydroxylation & Cyclodehydration

NMbs H2N HO OsO4, BuOOH, NMbs NaHCO3 H2N NH OR NH N H NMbs 10 mol % OsCl3, Oxone, Na2CO3, EtOAc/CH3CN/H2O, 57% H2N O HO N H NMbs NH O NH NMbs O NH2 N NH NMbs HO HOHN NMbs NH2 O O NH2 N H NMbs NH
t

NMbs O O NH2 H2N HO NH HO N NMbs NH OH

NH

R = C(O)NH2

Fleming, J. J.; Du Bois, J. J. Am. Chem. Soc. 2006, 128, 3926.

Synthesis of (+)-Saxitoxin
NMbs HO HOHN N NH2 O O NH NMbs NH2 B(O2CCF3)2 CF3CO2H, 82% H2N HO HN N NH O O NH2

NH NH2+

H2N HO HN HO N NH O

O NH2 DCC, C5H5NHO2CCF3, NH NH2+ DMSO, 70%

(+)-Saxitoxin

Fleming, J. J.; Du Bois, J. J. Am. Chem. Soc. 2006, 128, 3926.

Tetrodotoxin
OH
OH

HO HO HN
+

O OH OH

Rh-nitrene C-H Amination

HO O

OH O O OH OH H2N OH "tetrodamine" HO HO O

OH OH OH H CO2H

NH OH

H2N Tetrodotoxin

Rh-carbene C-H Alkylation

Guanidium poison from the Japanese fugu Selective voltage gated Na+ channel blocker
HO HO HO D-isoascorbic Acid O O N2 OH O

O O H O O OTBS

PivO

Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510.

Synthesis of Rh-Carbene Precursor

O p-TolN2 HSO4 OH HO D-isoascorbic Acid HO O HO O O N OH N H Tol

HO HO

HO

OH O

D-Erythronic -lactone

Me2NH, MeOH, 0C, 97 %

Me O

Me O O NH2 OTBS
t

BuMe2SiCl,

Me O

Me O O NH2 OH 2,2-DMP, cat. TsOH, 90 % HO

OH

O NH2

Et3N, DMAP

OH

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.

Synthesis of Rh-Carbene Precursor Cont.

Me O O H Me2N Me OTBS O i-Bu2AlH, n-BuLi, THF/Hexanes H H O O Me Me OTBS O BnO O NaOAc, THF >10:1 Anti:Syn O O OBn Me O O BnO H O HO O O Me OTBS

t-BuCOCl, C5H5, THF, 85 % (3 steps)

Me O O N2 O PivO H O O Me OTBS (COCl)2, cat. DMF, THF then CH2N2, CH2Cl2, 63-70 % O

Me Me O HO H O PivO O O OTBS H2, Pd/C, THF, 88 % O

Me Me O BnO H O PivO O O OTBS

Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510.

Stereospecific Rh-Carbene C-H Insertion

Me O O N2 O PivO H Me OTBS 1.5 mol % Rh (HNCOCPh ) , 2 3 4 O O CCl4 O PivO O O Me Me OTBS O O

Me O O NH3BH3, CH2Cl2/MeOH 75% (2 steps) HO PivO Me OTBS O O

Stereospecific Rh-Carbene C-H Insertion No purification!

H2 (1200 psi), 5 mol % Rh_C, 2:1 CF3CO2H, MeOH

Me O O O HO Me2N O O H OPiv O Me Me 2,2-DMP, cat. p-TsOH, THF, 90 % Me2NH, THF, 83% O Me O

Me Me O OH OH

OPiv

Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510.

Formation of Bridge C5 Lactone

Me O O O HO Me2N O O H OPiv Me Me cat. (n-Pr4N)RuO4, NMO, 4 MS, CH2Cl2, 94% O Me2N O H OPiv Me O O O O Me Me Zn, TiCl4, CH2I2, cat PbCl2, THF, 72% Me2N O H OPiv Me Me O O O O Me Me Me Me

Ph2Se2, PhIO2, C5H5N, C6H5Cl, 100C, 70%

Me O HO O O O Me2N O
Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510. Olfination: Takai, J. Org. Chem. 1994, 59, 2668 Allylic Oxidation: Barton, Crich Tetrahedron 1985, 41, 4359

Me Me Me Me O 1. H2C=CHMgBr, CuI, THF 2. t-BuNH3BH3, DCE, 77 % (2 steps) Me2N O H OPiv O O O O Me Me Me

H OPiv

Formation of Bridge C5 Lactone Cont.

Me O O O O O Me2N O H OPiv Me Me 1. t-BuCO2H, C6H5Cl, 200C O 2. NaOMe, THF/MeOH 78 % (2 steps) O O OH H Me Zn, MeOH, 93 % Me O O O Me Cl3CC(O)NCO, CH2Cl2 Me Me

Me O O O O Cl O O O H NH2 O Me MeSO2Cl, C5H5N, DCE, 86 % HO O O Me O Me O

Me Me O O O H NH2 O Me O Me O3, then NaBH4, CH2Cl2/MeOH O O O

Me Me O O O H NH2 O Me Me

Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510.

Late Stage Stereospecific Rh-nitrene C-H Insertion

Me O O O O Cl O O O H NH2 O Me C2Cl2, 40C, Trace Me 5 mol % Rh2(OAc)4, PhI(OAc)2, MgO, Cl O O O NH O O Me Me O O O Me Me Me

Me O O O O Cl O O O H NH2 O Me C6H6, 65C, 77% Me 10 mol % Rh2(HNCOCF3)4, PhI(OAc)2, MgO, Cl O O O Me O

Me Me O O O NH O Me Me

Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510.

Endgame
Me O O O O Cl O O O NH O Me Me 1. NaSePh, THF/DMF, 77 % 2. m-CPBA, C5H5N, DCE, 55C 92% O O O O O NH Me Me O O O Me Me Me

Boc2O, Et3N DMAP, THF

Me O O O O O OH
Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510.

Me Me Me K2CO3, THF/MeOH, 84 % (2 steps) O O O O O O O O NBoc Me Me Me

O Me NHBoc

Synthesis of Tetrodotoxin
Me O O O O O OH O NHBoc Me Me H2O, 110C, 95% O OH O OH NHBoc Me OH OH OH

NBoc BocHN SMe , HgCl2, Et3N

MeCN/CH2Cl2, 80 % OH HO HO HN
+

OH OH O3, CH2Cl2/MeOH; Me2S; then aq CF2CO2H, 65 % O OH BocN OH O OH NH NHBoc

O OH OH

NHOH

H2N Tetrodotoxin

Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510.

Tetrodotoxin
OH HO HO HN
+

O OH OH

NH OH

H2N 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 Last night he and I ate fugu, Today I help carry his coffin.

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"

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 Teleocidin B4) but often stoichiometric in metal. Catalytic and Enantioselective C-H Activation (Lithospermic Acid) 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

N NH O Rhazinilam

OH
HO O

OH O OH OH NH OH

N O Telocidin B4 Core

HO HN
+

H 2N Tetrodotoxin

Sames JACS 2000, 122, 6321

Sames JACS 2002, 124, 11856

Du Bois JACS, 2003, 125, 11510

CO2H HO OH CO2H OH O OH (+)-Lithospermic Acid Bergman, Ellman JACS, 2005, 127, 13496 OH O O

H2N HO HN N NH O

O NH2

NH NH2+

(+)-Saxitoxin Du Bois JACS 2006, 128, 3926