METAL-CATALYZED LATE STAGE C-H FUNCTIONALIZATION A powerful tool in total synthesis 3rd year seminar Ioulia Gorokhovik 23.11.2011

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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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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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


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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

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


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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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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


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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.


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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OH

HOO O

O

OH

COOH

COOH

OH

OH


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


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Synthesis of (+)-lithospermic acidEllman and Bergman, 2005 : by C-H activation/hydroarylation


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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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


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OH

HOO O

O

OH

COOH

COOH

OH

OH


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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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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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


12 steps, 11% yield



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.

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


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


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


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


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


45


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


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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

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METAL-CATALYZED LATE STAGE C-H FUNCTIONALIZATION A powerful tool in total synthesis 3rd year seminar Ioulia Gorokhovik 23.11.2011