Olefin Metathesis and Use in Tandem Reactions - The Work of Marc L. Snapper James Mousseau Literature Meeting 6 May 2008 1

Olefin Metathesis and Use in Tandem Reactions

- The Work of Marc L.

Snapper

James Mousseau

Literature Meeting6 May 2008

1

Outline

2

Introduction to MetathesisHistorical backgroundDifferent types/catalysts

Applications in tandem reactionsMarc L. Snapper

Snapper ResearchTandem CopeTandem Olefin IsomerizationTandem Kharasch AdditionTandem CyclopropanationTandem Allylic Alcohol IsomerizationTandem OxidationTandem Wittig

3

Metathesis - Introduction

As applied to alkenes, refers to the transposition of the alkene carbon atoms so that two new alkenes are formed

Dates back to 1955

Very popular means of making C=C bonds

TiII

n

A. W. Anderson and N. G. Merckling, U. S. U.S. Patent 2,721,189 (October 18, 1955)

http://patft.uspto.gov/netacgi/nph-Parser?patentnumber=2721189

4

Metathesis - Introduction

Olefin metathesis has wide ranging applicability as evidenced by number of publications and citations

Results from Web of Science search on olefin metathesisAccessed 2 May 2008

5

Metathesis - 2005 Nobel Prize in Chemistry

To Pierre Chauvin, Robert Grubbs and Richard Schrock for “the

development of the metathesis method in organic synthesis”

6

Ring Opening Metathesis Polymerizations (ROMP)

n

ROMP

Thermodynamically favoured for smaller rings

Especially favoured for bridged systems

TiII

n

7

Acyclic Diene Metathesis (ADMET)

Used to polmerize certain terminal dienes to polyenes

Double bond formed can be E or Z

ADMETR

RR

n

Grubbs, R. H., et al. J. Am. Chem. Soc. 2006, 128, 15358-15359

8

Ring Closing Metathesis (RCM)

RCM

Reaction is driven by the loss of ethylene

Permits access of ring sizes that otherwise may be typically hard to make However if thermodynamically unfavourable polymerization may occur

OR

O

O

OR

O

O

Grubbs II (10 mol %)

DCM, 40 ºC

Nicolaou, K. C.., et al. Chem. Comm. 2006, 600-602

9

Enyne (EM) and Alkyne (AM) Metathesis

R2R1 R4R3

R2R1

R4R3

+

M R2 R3R1 +

R2 R3

R1M

R2 R3

R1M

M R1 R3R2 +

O

O

O

O

O

O

O

O

Furstner, A., et al. J. Am. Chem. Soc. 1999, 121, 9453-9454

Katz, T. J., et al. J. Am. Chem. Soc. 1985, 107, 737-738

10

Cross Metathesis (CM)

+

:

1:1

CM (%)

50

1:2 67

1:3 75

1:5 83

1:10 91

1:20 95

1:50 98

1:100 99

: CM (%)

Chris Kendall, Literature Meeting March 20 2006

CM works particularly well when one of the components is slows to dimerize

AcO CO2Me AcO CO2MeGrubbs II

DCM, r.t.+

Blechert, S., et al. Angew. Chem. Int. Ed. 2003, 42, 1900-1923

The key referenceThe key referenceChatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360

Type I

terminal olefins1° allylic alcohols, amines (protected), estersallyl halides, silanesallyl boronate esters, phosphonates, phosphine oxides, sulfidesstyrenes (no large ortho groups)

Type II

2° allylic alcohols, unptrotected 3° allylic alcoholsacrylates, acrylamides, acrylic acid, acrolein, vinyl ketonesvinyl epoxidesperfluorinated alkane olefinsstyrenes (large ortho substituents)

Type III

1,1-disubstituted olefinstrisubstituted olefins (non-bulky)4° allylic carbon3° allylic alcohol (protected)vinyl phosphonates

Type IV

vinyl nitro olefinstrisubstituted allylic alcohols (protected)

For Grubbs II:

Cross Metathesis (CM)

Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360Chris Kendall, Literature Meeting March 20 2006

12

Metathesis - Catalytic Cycle

Associative goes through 18e- cycle (ligand does not dissociate)

Two potential pathways were proposed


13

Metathesis - Catalytic Cycle

Dissociative 16e- pathway found to be dominant (~95%)


14

Metathesis - CatalystsN

Mo

OO

CH3F3C CF3

CH3

F3CF3C

H

C(CH3)2Ph

i-Pr i-Pr

Schrock I

Schrock, R. R.; Murdzek, J . S .; Bazan, G. C.;Robbins , J .; DiMare , M.; O'Reagan, M.

J. Am. Chem. S oc. 1990, 112, 3875

C30H35F12MoNO2

Mol. Wt.: 765.53Strem: 2 g / $699

Cy3P

RuH

PhPCy3

Cl

Cl

Grubbs ICl2(PCy3)2Ru=ChPh

Schwab, P .; France , M. B.;Zille r, J . W.; Grubbs , R. H.

Angew. Chem. Int. Ed. 1995, 34, 2039

C43H72Cl2P 2RuMol. Wt.: 822.96

Aldrich: 5 g / $332.50

RuPh

PCy3Cl

ClN N

Grubbs II(H2IMes)(PCy3)Cl2Ru=ChPh

Scholl, M.; Ding, S .;Lee , C. W.; Grubbs , R. H.

Org. Le tt. 1999, 1, 953

C46H65Cl2N2PRuMol. Wt.: 848.97

Aldrich: 2 g / $532

RuPh

NCl

ClMesN NMes

Grubbs III

Love , J . A.; Morgan, J . P .;Tmka, T. M.; Grubbs , R. H.

Angew. Chem. Int. Ed. 2002, 41, 4035

C38H40Br2Cl2N4RuMol. Wt.: 884.53

N

Br

Br

H

Ru

Cl

ClMesN NMes

H-Grubbs

Kingsburgy, Harrity, J . P . A.; Hoveyda , A. H.J. Am. Chem. S oc. 1999, 121, 791

C31H38Cl2N2ORuMol. Wt.: 626.62

Aldrich: 2 g / $899

O

aqua-Grubbs

Hong, S . H.; Grubbs , R. H.J. Am. Chem. S oc. 2006, 128, 3508

Ru

Cl

ClMesN NMes

O

(OCH2CH2)nOCH3

Chris Kendall, Literature Meeting March 20 2006

15

Metathesis - Tandem ReactionsO 5 mol% Grubbs II

40 °C, 12 h(89%)

O

neat 3 equiv 1 equiv

B

O

O

O

O

3 equiv

2 mol% Grubbs II,CH2Cl2, 40 °C

then PhCHO, rt(69%)

Ph

OH

O O

dr > 20:1

OH OH

O

3 equiv

5 mol% H-Grubbs ,1 a tm H2, 5 mol% P tO2,

CH2Cl2, rt, 15 h(50%)

O

O

PhPh

Grubbs, R. H., et al. J. Am. Chem. Soc. 2003, 125, 11360

Grubbs, R. H., et al. Angew. Chem. Int. Ed. 2002, 41, 807

Cossy, J., et al.Org. Lett. 2003, 5, 459

16

Marc L. Snapper

EDUCATION AND EXPERIENCE

UNION COLLEGE, Schenectady, New York 1976-1980 B.S., Chemistry/Biology

STERLING ORGANICS, Division of Sterling Drug, Rensselaer, New York 1980-1984 Research Chemist

STANFORD UNIVERSITY, Stanford, California 1984-1990 Ph.D., Organic Chemistry, Advisor: Professor Paul A. Wender

HARVARD UNIVERSITY, Cambridge, Massachusetts 1990-1993 NIH Postdoctoral Fellow, Advisor: Professor Stuart L. Schreiber

BOSTON COLLEGE, Chestnut Hill, Massachusetts 1993-1999 Assistant Professor of Chemistry 1999- Professor of Chemistry

HONORS AND AWARDS

1999-2001 Glaxo Wellcome Chemistry Scholar Award 1999-2000 Boston College Distinguished Research Award 1998-2001 Camille Dreyfus Teacher-Scholar Award 1998-2000 Alfred P. Sloan Research Fellowship 1998-1999 DuPont Young Professor Award 1997-1999 Lilly Grantee Award 1997-2000 National Science Foundation CAREER Development Award 1997-1998 Boston College Teaching Development Award 1996-1997 Boston College Faculty Fellowship 1995-1997 Massachusetts Breast Cancer Research Fellowship 1995-1996 Boston College Distinguished Junior Faculty Award 1990-1993 National Institutes of Health, NCI Postdoctoral Fellowship 1990-1991 Merck Postdoctoral Fellowship

17

Snapper Research

And obviously Tandem Metathesis!!!!!

18

Metathesis - Cope Rearrangement

Applied to the synthesis of +/- Asteriscanolide

9 step synthesis with the key step involving a tandem metathesis/Cope Rearrangement

Had previously done a similar transformation, but not in tandem

O

O

O

Snapper, M. L., et al. J. Am. Chem. Soc. 2000, 122, 8071-8072

O R2

HR1

H

Grubbs I

RO

TBSO

H

H

R2

R1

O

H

R1

R2

OTBSCope

200 ºC

57% - 72% 70% - 99%


19


O

O

O


O

O

CO2MeCO2Me

(OC)3Fe

NMe2

(OC)3Fe

O

OH

OO

O

O

O

O

O

O

O

(OC)3Fe(OC)3Fehv, Fe2(CO)6

50 ºC

LAH, BF3OEt2 Me2NCH2NMe2

H3PO4, AcOHMeINaH

Me3NOGrubbs II

PCC

Red-Al, CuBr BH3OEt2, PCC

20


O

O

O


O

RuPh

PCy3Cl

ClN N

benzene, ethylene, 50 ºC, 10 h O

reflux

O

Key is a tandem reaction

Cope occurs under relatively mild conditions

Reason this occurs due to the absence of an alkyl group

O O R2

HR1

H

H

VS

21

RCM Metathesis - Olefin Isomerization


Grubbs’ catalyst, in addition to metathesis, has been known to undergo hydrogenation

Occassionally noted that isomerization could interfere with metathesis

Explored the possibility of combining the two reactions

XRX X

RuPh

PCy3Cl

ClN N

RR [RuH]

22



Found that 95/5 N2/H2 was optimal hydride source

Unsure the the hydride - Ru species 22

XRX X

RuPh

PCy3Cl

ClN N

RR [RuH]

23



OBnOBn OBnOBnOBn

OR

4 1 0

OPh OPh

O O OOOPh Ph Ph Ph Ph

OPh OPh

65 %ee 65 %ee

24

RCM - Kharasch Addition


Kharasch reaction is a radical atom transfer reaction

Earlier Snapper demonstrated that Grubbs I can promote the transformation

ClR

Cl

Cl AIBN Cl

Cl

R R1

R2

Cl

Cl

RR1

R2Cl

N Cl

RCl

R1

R2

Cl

Kharasch, M.S., et al. Science 1945, 102, 128

R1

R2 R2

R1

R3

Cl Cl Cl

R2

R1

R3

OGrubbs I

XS R3CCl3

H3O+

Cy3P

RuH

PhPCy3

Cl

ClClR3

Cl

ClCy3P

RuH

PhPCy3

Cl

Cl Cl

Cl

R3Cl

Snapper, M. L., et al. Tetrahedron 2004, 60, 7391-7396

25



R1R2

Cy3P

RuH

PhPCy3

Cl

Cl

R1R2 R1

Cl

R2

Cl

R3Cl

R3CCl3

+

R4

R1

Cl

R2

R3Cl

R4

Cl

Cy3P

RuH

PhPCy3

Cl

Cl

OH HNCCl3

O

CCl3OMe

O

n

n

nn

1. Cl3CCN, NaH 0 ºC

2. xylenes, 140 ºC

1. DIBAL2. I2, PPh3, imid3. CHCl3, BuLI

Reaction was performed on cyclic substrates

26



CCl3Cl

Cl

ClCl

Cl

Cl Cl ClCl

Grubbs

27



HNCCl3

O

HN

O

CCl3

Grubbs

Grubbs

HNCCl3

O

HN

O

CCl3

HN

HNO

Cl

Cl

Cl

O

Cl

Cl

Cl styrene

styrene

HN

HNO

Cl

Cl

O

Cl

ClPh

Cl

Cl

Ph

Double Kharasch could be performed generating bicyclic products with 3 adjoining double bonds

28

Enyne Metathesis - Cyclopropanation


RuR

R1

RuR

R1

R1

R

N2

R

RuR

R1

Ru

RuR

R1

RuR

R1

Ru

R1

Ru R

R1

R R1

29

Enyne Metathesis - CyclopropanationEnyne Metathesis - Cyclopropanation


TsNTsN

TsN

CO2Et

N2CO2EtEthylene

N2, 10 h 75 ºC75 ºC, 10 min

Grubbs I

TsN

NTs

N2CO2Et

N2, 10 h 75 ºC

Ethylene

Grubbs II

75 ºC, 10 minor r. t.

29

30

Enyne Metathesis - CyclopropanationReaction complimentary to that reported by Dixneuf


NPG

MeO2CF3C +

N2

TMS Cp*RuCl(cod)

dioxane 100 ºC

N TMS

F3CCO2Me

PG

TsN

Cp*RuCl(cod)

dioxane 100 ºC

N2CO2Et

TsN

CO2Et

TsNTsN

TsN

CO2Et

N2CO2EtEthylene

N2, 10 h 75 ºC75 ºC, 10 min

Grubbs I

then

EtO2C

EtO2C EtO2C

EtO2C

Dixneuf, P. H., et al. Org. Lett. 2005, 7, 3741-3743

31

CM - Allylic Alcohol Isomerization

Snapper, M. L., et al. Org. Lett. 2006, 8, 2603-2606

R

OH

RRu

OHH

Ph

R

OH

Ph

Ru

H

R

OH

H

R H

O

Grubbs I

Grubbs I

Cy3P

RuH

PhPCy3

Cl

Cl

Quayle, P., et al. Synlett 2005, 572-576

Werner, H., et al. Organometallics 2003, 22, 1558-1560

32



O

N

O

O

OH OH

N

O

N

O

OOO

OO

RR

O

R

O

R

X X

Ocat 1 or 2

17-44 h, 70 ºC

X = CHO or CH2OHR = H, Me

RuPh

PCy3Cl

ClN N

RuCl

ClMesN NMes

O

1

2

Ketones prevent over reduction

32

33



ROHOH

R

O

Ru

Cl

ClMesN NMes

O

200 ºC, 7 h

+

34

Metathesis - Oxidation


Plietker, B., J. Org. Chem. 2003, 68, 7123-7125

R2R1

R1

O

R2

OHRuCl3Oxone, NaHCO3-

R2R1

Ru

O

OOO

R1

R2O

ORu

O

O

R1

R2O

ORu

O

OO

R1

R2O

ORu

O

OO

R2

O-H

R1ORu

O+

O O

O

OS

-OO

O H

HSO5-

HSO4-

HSO5-

SO5-

HSO4-

R1

O

R2

OH

+

35



R2R1

R1

OH

R2

OHRuCl3CeCl3, NaIO4

R1

R2O

ORu

O+

OO

LA

H2O

Ru

O

OOO

+R1

R2HO

HO

Mes

RuPh

PCy3Cl

ClN MesN

OHO

HO OH

oxone, NaHCO3

CeCl2, NaIO4

Plietker, B., et al. J. Org. Chem. 2005, 70, 2402-2405

36



Mes

RuPh

PCy3Cl

ClN MesN

OHO O OH

+oxone, NaHCO3

R R R R

EtOAc/MeCN/H2ODCM

37


R1

R2

R1R2 R1

R2

OH

O

R1R2

O

OH

++oxone, NaHCO3

EtOAc/MeCN/H2O

Mes

RuPh

PCy3Cl

ClN MesN

DCM


38



Mes

RuPh

PCy3Cl

ClN MesN

OHHO

CeCl3, NaIO4

R R R

EtOAc/MeCN/H2ODCM

39



R1

R2

R1R2 R1

R2

OH

OH

+oxone, NaHCO3

EtOAc/MeCN/H2O

Mes

RuPh

PCy3Cl

ClN MesN

DCM

40

CM - Wittig Olefination


R O R

1) RhCl(PPh3) iPrOH, DPPBE2) TMSCHN2

3) TBAF

O

O N

CO2Et

N CO2Et

Ru(PPh)3, PPh3

N2CHCO2Et, DCM

N2CHCO2Et, PPh3 DCM

Lebel, H., et al. J. Am. Chem. Soc. 2004, 126, 320-328

Fujimura, O., et al. Tetrahedron 1998, 39, 625

41

CM - Wittig Olefination


R2 R1

O R2

R1

OR2

R1

OR

O

Mes

Ru

PCy3Cl

ClN MesN

PPh3

N2CHCO2R+

42

ConclusionsAdvantages of tandem reactions are obvious

Economics

Environment

Time

Though individual reactions may not be interesting, finding methodology of combining them is

Still much work to be done on the development on tandem chemistry............. Nature’s still way ahead of us

Documents

Olefin Metathesis and Use in Tandem Reactions - The Work of Marc L. Snapper James Mousseau Literature Meeting 6 May 2008 1