olefin cross metathesis christopher kendall march 20, 2006

Olefin Cross MetathesisOlefin Cross Metathesis

Christopher KendallChristopher KendallMarch 20, 2006March 20, 2006

The metathesis review: Handbook of Metathesis Grubbs, R. H., ed.; Wiley-VCH: Weinheim, 2003Metathesis in total synthesis: Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 4490

The nobel prize in chemistry, 2005The nobel prize in chemistry, 2005

“Considering the short time during which Grubbs’ and Schrock’s catalysts have been available, the breadth of applications, is truly remarkable.”

Prof. Per AhlbergNobel Committee for Chemistry

"for the development of the metathesis method in organic synthesis"

Yves Chauvin Robert H. Grubbs Richard R. Schrock

Commercial MetathesisCommercial Metathesis

cat. [Ru]=CHR

cat. PPh3

n n

x

polyDCPDhighly crosslinkedpolymer network

DCPDbp 170 °Cmp 33 °C

N

OS

OOBr

HN

O

OMe

O

ON

OS

OOBr

HN

O

OMe

O

O

NH N

HO

O

O

O

3-3.5 mol% H-Grubbs (~500 g)

[0.01 M] degassed toluene (2400 L),80 °C, 4-9 h

20.2 kg83% yield

~90% purity (dimerization)"produced almost 400 kg"

• Nicola, T.; Brenner, M.; Donsbach, K.; Kreye, P. Org. Proc. Res. Dev. 2005, 9, 513 (Boehring Ingelheim Pharma GmbH & Co. KG, Germany)• "We are confident that, soon, it will be even possible to use the RCM for market supply of pharmaceutical compounds on a multiton scale"• see also Faucher, A.-M. et al. Org. Lett. 2004, 6, 2901 and WO Patent 00/59929 (Boehringer Ingelheim Canada)

US Patent 6,525,125 (Materia Inc.):• 2000 g DCPD, 2.5 g Grubbs I (0.000002 mol%), 4 g PPh3, 60 g Ethanox 702 (antioxidant), 640 g glass microspheres• 9 h at 40 °C then 1 h at 140 °C• "an aluminum-faced sandwich panel utilizing this material as a core did not dent from the impact of a baseball fired from a cannon with ball velocities up to 180 mph"

19951996

19971998

19992000

20012002

20032004

2005

0

20

40

60

80

100

120

140

160

Articles cited on Web of Science,topic = “cross metathesis”

Olefin Cross Metathesis (CM)Olefin Cross Metathesis (CM)review in Handbook of Metathesis by Chatterjee, A. K. (chapter 2.8, Vol. 2 pp. 246-295)

review covering 1998-2002: Connon, S. J.; Blechert, S. Angew. Chem. Int. Ed. 2003, 42, 1900

Cross-metathesis methodologies have recently been shown to be highly effective in the synthesis of insect pheromones, polymer additives, and fine chemicals, i.e., valuable synthetic intermediates such as novel ,-unsaturated carbonyl systems.

Pederson, R. L. in Handbook of Metathesis Vol. 2 p 491

+

:

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 (%)

The mechanismThe mechanism

[Ru]=CHAr

R[Ru]

[Ru]

H

H

[Ru]

H H[Ru]

H

R

+

+

[Ru] CH2

Initiation

ProductiveCatalytic Cycle

• high catalyst loading means large amount of ArCH=CH2

• release of ethylene gas drives reaction• typical conditions: CH2Cl2, reflux

The CatalystsThe Catalysts

N

Mo

OO

CH3

F3C 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. Soc. 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.;Ziller, J. W.; Grubbs, R. H.

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

C43H72Cl2P2RuMol. 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. Lett. 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

RuCl

ClMesN NMes

H-Grubbs

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

C31H38Cl2N2ORuMol. Wt.: 626.62

Aldrich: 2 g / $899

O

aqua-Grubbs

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

RuCl

ClMesN NMes

O

(OCH2CH2)nOCH3

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:

The functionalization of terminal olefinsThe functionalization of terminal olefins

RCl

10 mol% Grubbs II,CH2Cl2, reflux

R Cl RTMS


R TMS

3 equiv

Liu, B.; Das, S. K.; Roy, R. Org. Lett. 2002, 4, 2723 Thibaudeau, S.; Gouverneur, V. Org. Lett. 2003, 5, 4891


Demchuk, O. M.; Pietrusiewicz, K. M.; Michrowska, A.; Grela, K.Org. Lett. 2003, 5, 3217

P

O

R1R2

R3

P

O

R1R2

R3

2.5 equiv

R1 mol% Grubbs II, rt

Chatterjee, A. K.; Sanders, D. P.; Grubbs, R. H.Org. Lett. 2002, 4, 1939

R

bp 35-38 °C

CO2R2

2-5 mol% Grubbs II,benzene, rt

Smith, C. M.; O'Doherty, G. A. Org. Lett. 2003, 5, 1959

R1

OH

R1

OH

CO2R2R


Morrill, C.; Grubbs, R. H. J. Org. Chem. 2003, 68, 6031Morrill, C.; Funk, T. W.; Grubbs, R. H.

Tetrahedron Lett. 2004, 45, 7733

BO

O

BO

O

R

R5 mol% Grubbs II,

CH2Cl2, reflux

Chatterjee, A. K.; Toste, F. D.; Choi, T.-L.; Grubbs, R. H.Adv. Synth. Catal. 2002, 344, 634

PhPh

R5 mol% Grubbs II,

CH2Cl2, reflux

Vasbinder, M. M.; Miller, S. J. J. Org. Chem. 2002, 67, 6240

R R

CO2Me

CO2Me

NHBoc NHBoc

G

G

G = Me:G = H:

The functionalization of terminal olefinsThe functionalization of terminal olefins

RSiCl3

0.5 - 5 mol% Grubbs II,CH2Cl2, reflux

RSiCl3

Pietraszuk, C.; Fischer, H.; Rogalski, S.; Marciniec, B.J. Organomet.Chem. 2005, 690, 5912

HO(CH2)nCN

4 mol% Grubbs III,20 mol% Ti(Oi-Pr)4,

CH2Cl2, reflux

HO(CH2)n

CN

Bai, C.-X.; Lu, X.-B.; He, R.; Zhang, W.-Z.; Feng, X.-J.Org. Biomol.Chem. 2005, 4139

2 equiv

E/Z = 1:2 - 1:4

5 mol% H-Grubbs,CH2Cl2, reflux

BouzBouz, S.; Simmons, R.; Cossy, J. Org. Lett. 2004, 6, 3465

R

R

OTBDPSOTBDPS

R1

3 equiv

R2

10 mol% Grubbs III,benzene, 70 °C

Z/E = 3:1 to >25:1

R1 R2

Kang, B.; Lee, J. M.; Kwak, J.; Lee, Y. S.; Chang, S.J. Org. Chem. 2004, 69, 7661


Silva, F. A.; Gouverneur, V. Tetrahedron Lett. 2005, 46, 8705

R

Ar

OH O

Ar

OH O

R

R5 mol% Grubbs II,

CH2Cl2, reflux

R

Hoveyda, H. R.; Vezina, M. Org. Lett. 2005, 7, 2113

2 equivCN

CN

cm in natural product synthesiscm in natural product synthesisWang, Y.; Romo, D. Org. Lett. 2002, 4, 3231

Cl

CO2EtHO

4 steps CHOTIPSO

SPy

OTIPSTBDPSO

ZnCl2, CH2Cl2(68%)

TIPSO OO

TBDPSO

dr = 5:1

TMS

4 equiv

2.5 mol% Grubbs II,CH2Cl2, reflux

(80%)

TIPSO OO

TBDPSO

TMS

E/Z ~ 3:1

TiCl4

CH2Cl2, -78 °C(90%)

CO2H

TBDPSOH

H

TIPSO

3 steps CHO

TBDPSOH

H

TIPSO

2 equiv

2.5 mol% Grubbs II,CH2Cl2, reflux

(86%)

Me

O

O

P

O

EtOEtO

CHOO

OTBDPSO

H

H

TIPSO

Me

PO

EtOEtO

E/Z = 4:1

4 stepsO

OHO

H

H

HO

Me

(+)-brefeldin

NS

SPy

cm in natural product synthesiscm in natural product synthesisBouzbouz, S.; Cossy, J. Org. Lett. 2001, 3, 1451

O

HO

HO OH

HO

O

HO

Me

HO

OH

OH

HH

OHOHOH

OHHOOHOHOH

Me

OH

H

H

HOOH

OH

OH

510 14 20

30

40

50

60

65

amphidinol 3

CHO3 equiv

5 mol% H-Grubbs,CH2Cl2(70%)

OH

CHO

E/Z > 30:1

OHC

OR CHO3 equiv


OAc

CHO

E/Z > 30:1

R = H R = OAc

OHOH

PMPO

CHO3 equiv

5 mol% H-Grubbs,CH2Cl2

OHOH

PMPO CHO OHCCHO

31% 43%

O

OO2N

CO2Et

5 mol% Grubbs,CH2Cl2, reflux

no reaction

Grubbs I: 55% SM rec'dGrubbs II: 62% SM rec'd

RuR2

O

R1

O

RRu

R2

O

R1

O- or - DEAD?

Personal Experience:

cm in natural product synthesiscm in natural product synthesisBouzbouz, S.; Cossy, J. Org. Lett. 2001, 3, 1451

O

HO

HO OH

HO

O

HO

Me

HO

OH

OH

HH

OHOHOH

OHHOOHOHOH

Me

OH

H

H

HOOH

OH

OH

510 14 20

30

40

50

60

65

amphidinol 3

PMBO

OH CHO3 equiv

2.5 mol% H-Grubbs,CH2Cl2(79%)

PMBO

OH

CHO

E/Z > 50:1

1. allyl-Ti*, Et2O, -78 °C

2. Ac2O, pyridine(82%)

PMBO

OAc OAc

dr = 19:1

CHO3 equiv


PMBO

OAc OAc

CHO

E/Z > 50:1

1. allyl-Ti*, Et2O, -78 °C

2. Ac2O, pyridine(74%)

PMBO

OAc OAc OAc

dr > 20:1

CO2Et3 equiv


PMBO

OAc OAc OAc

CO2Et5

10 14

7 steps, 18% overall

cm in natural product synthesiscm in natural product synthesisKitamura, T.; Sato, Y.; Mori, M. Tetrahedron 2004, 60, 9649

10 mol% H-Grubbs,CH2Cl2, rt

(60%)

SMe

NH2HO2CNCbz

MeO2C

CH2=CH2

5 mol% Grubbs I,CH2Cl2, rt

(76%)

NCbz

MeO2C N

HN

O

O

HMe

BnO

CO2Et

N

HN

O

O

HMe

BnO

CO2Et

RhCl3·3H2O

EtOH, 110 °C(50%)

N

HN

O

O

HMe

BnO

CO2Et

N

HN

OH

O

HMe

OH

NH2

O

(+)-anthramycin (antitumor)

cm in natural product synthesiscm in natural product synthesisRandl, S.; Blechert, S. J. Org. Chem. 2003, 68, 8879

Ghosh, A. K.; Liu, C. J. Am. Chem. Soc. 2003, 125, 2374

OMe

OSESMe

O

ON

O

Bn


(96%)

Me

O

ON

O

Bn

OMe

OSES

E/Z = 1:1

O

O

H

Me

MeC3H7

OH

O

OH

Me

amphidinolide T1S

SiMe3O

O

OOSES

!!• first cycle: 60% yield + dimers• separate dimers and re-subject• second cycle: 36% yield

2 equiv

NHCbz

O

C4H9

O


(89%)

O

C4H9

O

NHCbzH2 (1 atm)

10% Pd-C, MeOH(75%)

N

H

Me C4H9

1 equiv

cm in natural product synthesiscm in natural product synthesisSpessard, S. J.; Stoltz, B. M. Org. Lett. 2002, 4, 1943

O

O

O 1. toluene, 140 °C

2. CH2N2, Et2O(62%)

O

O

OMe

1. CH3CH=C(CH3)2, 10 mol% Grubbs II, 40 °C (58%)

2. NaOH, H2O, 90 °C (87%)

O

O

OH

O

OR

OH

OH

garsubellin A(R = COi-Pr)

NH

OBn

OTBS

O

5


no reaction

NCbz

OBn

OTBS

O

5


(58%)

NCbz

OBn

OTBS

O

5

1. H2 (1 atm), 10% Pd-C, 2% HCl/MeOH (60%)

2. TBAF, THF (90%) NH

OH

OH

O

9

(-)-prosophylline

Cossy, J.; Willis, C.; Bellosta, V.; Bouzbouz, S. J. Org. Chem. 2002, 67, 1982

cm in natural product synthesiscm in natural product synthesisFerré-Filmon, K.; Delaude, L.; Demonceau, A.; Noels, A. F. Eur. J. Org. Chem. 2005, 3319

Velder, J.; Ritter, S.; Lex, J.; Schmalz, H.-G. Synthesis 2006, 273

5 mol% Grubbs II

OR

RO OR

toluene, reflux

OR

OROR

RO OR

RO OR

RO OR

1 1 (83%) 18 63 19

1 10 94% precipitatedR = Me

R = H1 1 (87%) 17 60 23

1 10 89%resveratrol

1.5 1 76%CH2Cl2, reflux

B

A

A

A

A

A

B

Atom economy of cm vs. altenate reactionsAtom economy of cm vs. altenate reactions

MeO

OMe

OMe

1.5 equiv

MeO

OMe

OMe

270.3

1.5x164.2 + 134.2= 54.0%0.76 x

270.3

164.2 + 134.0= 90.6%


(76%)

Velder, J.; Ritter, S.; Lex, J.; Schmalz, H.-G. Synthesis, 2006, 273

MeO

OMe

P(OMe)2

O

OHC

OMe

1.1 equiv

KOH

18-crown-6, CH2Cl2(94%)

MeO

OMe

OMe

E/Z > 95:5

Kim, S.; Ko, H.; Park, J. E.; Jung, S.; Lee, S. K.; Chun, Y.-L. J. Med. Chem. 2002, 45, 160

Atom Economywith yield and stoichiometry

[theoretical maximum]

270.3

260.2 + 1.1x136.2= 62.0%

MeO

OMe

B

OMe

1.3 equiv

MeO

OMe

OMeBr

F HO

HO5 mol% PdCl2(PPh3)2,

10 mol% PPh3,TBAF, THF, reflux

(86%)

0.94 x

F

288.3

261.1 + 1.3x152.0= 54.1%0.86 x

270.3

260.2 + 136.2= 68.2%

270.3

243.1 + 152.0= 68.4%

Eddarir, S.; Abdehadi, Z.; Ronaldo, C. Tetrahedron Lett. 2001, 42, 9127

MeO

OMeI

OMe

1.5 equiv

MeO

OMe

OMe

270.3

1.5x164.2 + 234.0= 43.3%0.77 x

270.3

164.2 + 234.0= 67.9%

Botella, L.; Najera, C. Tetrahedron 2004, 60, 5563

0.1 mol% catalyst,Cy2NMe, TBAB,

DMA/H2O (4:1), 120 °C(77%)

NOH

Me

Pd

Cl

HO2

catalyst

CM in pharmaceutical synthesisCM in pharmaceutical synthesisPederson, R. L.; Fellows, I. M.; Ung, T. A.; Ishihara, H.; Hajela, S. P. Adv. Synth. Catal. 2002, 344, 728

F

CHO

5 equiv

2.5 mol% H-Grubbs,CH2Cl2, reflux

(73%)

F

CHO

F

O

O

O

paroxetine (5-HT inhibitor)

PaxilTM

BzOCHO

31 equiv

5 mol% H-Grubbs,toluene, rt

(68%)

BzO CHO

BzOOH

NH NO

Ph

CO2H

(-)-ketorolac (NSAID)

AcularTM and ToradolTM

CM in pharmaceutical synthesisCM in pharmaceutical synthesisHsu, M. C.; Junia, A. J.; Haight, A. R.; Zhang, W. J. Org. Chem. 2004, 69, 3907

Grubbs I,CH2Cl2, reflux

O

O

O

O

O

O

NMe2

OHO

N

HN

OO

ABT-773

O

O

O

OH

O

O

NMe2

OBzOHN

OO

2 equivolefin

O

O

O

OH

O

O

NMe2

OBzOHN

OO

R

olefin mol% Grubbs I yield E/Z

N 10 71% > 95:5

25 75%

Ph 10 ?? > 95:5

> 95:5

C3H7 10 87% 1.8:1

• Grubbs II inferior to Grubbs I:

"Instead, its higher reactivity promoted homodimerization of the substrates"

OMeO2C

OO

OO 1.5 equiv

C10H21

5 mol% Grubbs I,CH2Cl2, 30 °C

(57%)OO

OO

C10H21

E/Z = 3.5:1

OO C13H27

CO2HMe

(-)-roccellaric acid

OO

CHO4 equiv

C8H17

5 mol% Grubbs I,CH2Cl2, reflux

(53%)27% SM rec'd

OO

CHO

C8H17

E/Z = 7:1

OO C11H23

CO2HMe

(-)-nephrosteranic acid

OO

CHO1.3 equiv(CH2)11CO2Me

2.5 mol% Grubbs I,CH2Cl2, reflux

(38%)56% SM rec'd

OO

CHO

(CH2)11CO2Me

E/Z = 7:1

OO C14H28CO2H

CO2H

(-)-protopraesorediosic acid

cm in natural product synthesiscm in natural product synthesisChlor, R. B.; Nosse, B.; Sörgel, S.; Böhm, C.; Seitz, M.; Reiser, O. Chem. Eur. J. 2003, 9, 260

Cm in library synthesisCm in library synthesisPlettenburg, O.; Mui, C.; Bodmer-Narkevitchy, V.; Wong, C.-H. Adv. Synth. Catal. 2002, 344, 622

7 mol% Grubbs I,CH2Cl2, reflux

(62-80%)

O

OAcAcO

AcOAcO O

4 equivR

O

OAcAcO

AcOAcO O R

hydrolysisand/or

hydrogenation

R = C6H13, C8H17, C10H21, C12H25, C14H29, C16H33,

CH2Ph, (CH2)2Ph, CH2OPh, CH2OBn

Centrone, C. A.; Lowary, T. J. Org. Chem. 2002, 67, 8862

OP

O

OOBn

BnO

BnO OBn

ORRO


(51-66%)

OP

O

OOBn

BnO

BnO OBn

OR

R = C7H15, C8H17, C9H19,

C10H21, C12H25, C16H33

OP

O

OO

HO

HO OH

OR

Rai, A. N.; Basu, A. J. Org. Chem. 2005, 70, 8228

O

PivOOPiv

PivOPivO

O

NHFmoc

OPMB

10 equivR


O

PivOOPiv

PivOPivO

O

NHFmoc

OPMB

R

R = C5H11, C7H15, C13H27, C15H31

Comin, M. J.; Parrish, D. A.; Deschamps, J. R.; Marquez, V. E. Org. Lett. 2006, 8, 705


2-5 equiv

RO

OEt

OOH O

OEt

OOH

R

CH2OBn 90%

Si(OEt)3 98% CO2Me 95%

CH2P(OEt)2 88%

O

1. TBS-Cl, imidazole, CH2Cl2

2. TsN3, Et3N, MeCN

O

OEt

OTBSO

R

N2

CuSO4

cyclohexane, 80 °C R

CO2Et

H

O

TBSO

CH2OBn 75% (2:1)

Si(OEt)3 62% (4:1) CO2Me 18% (1:1)

CH2P(OEt)2 95% (3.5:1)

O

OMeO2C

O

OO

O

AcO OAc

OAc

OAcR

10 mol% Grubbs II,toluene, 100 °C O

MeO2C

O

OO

O

AcO OAc

OAc

OAc

R

R = C3H7, C4H9, C6H13, C(CH3)3

O

OHC

MeO2C

O O

HO OH

OH

OH

secologanin 1

Galan, M. C.; O’Conner, S. E. Tetrahedron Lett. 2006, 47, 1563

Cm in library synthesisCm in library synthesis

cm in natural product synthesiscm in natural product synthesisStatsuk, A. V.; Liu, D.; Kozmin, S. A. J. Am. Chem. Soc. 2004, 126, 9546

N

O

O

OBn

Me

1. 1.5 equiv cyclopropene, 10 mol% Grubbs II, benzene, 60 °C

2. 1M H2SO4, MeCN(63%)

NR2

OBn

Me

O

E/Z = 2:3

BnO

Me

OBn0.5 equiv

10 mol% Grubbs II,CH2Cl2, 35 °C

(68%)

BnO

Me

OBn

NR2

OBn

Me

OH2 (80 psi)

Pd(OH)2-C,EtOAc/MeOH (1:1)

(56%)

O

ON

O

O

Me

OHMe

NH

HN O Me

O

O O

H H

MeMe

OH

bistramide A

O

O

MeH

Me Me

Me

OHH

O O

cyclopropene

cm in natural product synthesiscm in natural product synthesisAlbert, B. A.; Sivaramakrishnan, A.; Naka, T.; Koide, K. J. Am. Chem. Soc. 2006, 128, 2792

OMe

Me

H

NH

OAcO Me

20 equivMe

CHO


(57%)

OMe

Me

H

NH

OAcO Me

CHO

Me

Ph3PCH3Br

t-BuOK,THF, 0 °C

(86%)

OMe

Me

H

NH

OAcO Me

Me

O OHMe

HOO

10 mol% H-Grubbs,ClCH2CH2Cl2, rt

(40%)

OMe

Me

H

NH

OAcO Me

Me

O OHMe

HOO

H

H

FR 901464

cm in natural product synthesiscm in natural product synthesisGhosh, A. K.; Gong, G. J. Org. Chem. 2006, 71, 1085


(82%)

O

OMe

O

MeOMOM

Me

Me

Me

CO2H

HO

Me

O

Me

OMOM

Me

Me

Me

cat. DMAP,CH2Cl2(77%)

DCC

O

Me

Me

OMOMO

O

Me

Me

AcO

Me

Me

OMOM

Me

Me CO2EtOTIPS


(86%)

O

O

2 equiv

Me

Me

OR

O

O AcO

OMOM

Me

Me CO2Et

E/Z = 11:1

CO2HHO

Me

O

MeOMOM

Me

Me

Me

2,4,6-Cl3C6H2COCl,i-Pr2NEt then

DMAP, benzene

O

OMe

O

MeOMOM

Me

Me

Me

(2S) 35%(2R) 12%

2S

O

OMe

O

MeOH

Me

Me

Me

2S

6R

amphidinolide W

cm in natural product synthesiscm in natural product synthesisWu, B.; Liu, Q.; Sulikowski, G. A. Angew. Chem. Int. Ed. 2004, 43, 6673

(d) TES-OTf, 2,6-lutidine, CH2Cl2, 0 °C 81%

(e) 24, isopropenyl pinacol boronic ester (18 equiv), CH2Cl2, reflux 30% (plus 30% rec'd 23)

(f) Pd(PPh3)4, TlOEt, THF/H2O (3:1) 60%

(g) HF-pyridine, THF, -5 °C 61%

cm in natural product synthesiscm in natural product synthesisYoshimura, T.; Fakushiji, F.; Kondo, S.; Wu, X.; Shindo, M.; Shishido, K. Org. Lett. 2006, 8, 475

10 steps

cm in natural product synthesiscm in natural product synthesisCrimmins, M. T.; Caussanel, F. J. Am. Chem. Soc. 2006, 128, 3128

8 steps

(a) Grubbs II, CH2Cl2, reflux: 68% + 10% Z isomer

cm in complex molecule synthesiscm in complex molecule synthesisLera, M.; Hayes, C. J. Org. Lett. 2001, 3, 2765

O NHO

HO

NH

OMe

O

5 steps

4 steps

O N

TBDPSO

NH

OMe

O

O NTBSO

O

NH

OMe

O

PO

MeO

20 mol% Grubbs II,CH2Cl2, 35 °C

(58%)

1.0 equiv

1.3 equiv

O N

TBDPSO

NH

OMe

O

O NTBSO

O

NH

OMe

O

PO

MeO

• also formed

O N

OTBDPS

NH

OMe

O

ON

TBDPSO

HN

OMe

O

(10%)

O N

TBDPSO

NH

OMe

O

Ph

(20%)

• 5 mol% Grubbs II: sluggish reaction of low conversion• excess metathesis partner: impractical

cm in complex molecule synthesiscm in complex molecule synthesisChen, G.; Schmieg, J.; Tsuji, M.; Franck, R. W. Org. Lett. 2004, 6, 4077

O

AcO

AcOAcO

OAc2.5 equiv


(61%)

O O

C14H29

NHBoc

O

AcO

AcOAcO

OAc

E/Z = 3:1

O

AcO

AcOAcO

OAc2.5 equiv

10 mol% Grubbs II,CH2Cl2, reflux,

CH2=CH2

(72%)

O O

C14H29

NHBoc

OAcO

AcOAcO

OAc

O O

C14H29

NHBoc

(no CH2=CH2: 27% yield)

O

HO

HOHO

OH

O

HN

OH

C14H29

OH

C25H51

O

KRN7000 (immunostimulant)

cm in complex molecule synthesiscm in complex molecule synthesisCho, Y. S.; Wan, Q.; Danishefsky, S. J. Bioorg. Med. Chem. 2005, 13, 5259

CM in Natural product modificationCM in Natural product modificationKarama, U.; Höfle, G. Eur. J. Org. Chem. 2003, 1042

O

O OH O

OH

O

HS

N

epothilone A

O3

O

O OH O

OH

O

H

O

O

O OH O

OH

O

H

O

O OH O

OHH

S

N

epothilone C

C2H4 (1 atm)


(76%)

O

O OH O

OH

S

NTBS-OTf

2,6-lutidine,CH2Cl2(80%)

HO2C

TBSO O

OTBS

S

N

OH

DCC, cat. DMAP, CH2Cl2(91%)

O

O OTBS O

OTBS

S

N1. 5 mol% Grubbs I, CH2Cl2, rt

2. TFA, CH2Cl2, 0 °C

O

O OH O

OH

O

H

S

N

16,17-alkyne epothilone A analogue

O

O OH O

OHH

S

N

O

O OH

H

S

NO

OH

(22%) (22%)

DMDO

CH2Cl2/acetone,-20 °C(32%)

NMe Me2,6-lutidine

CM in Natural product modificationCM in Natural product modificationSmith III, A. B.; Rucker, P. V.; Brouard, I.; Freeze, S. B.; Xia, S.; Horwitz, S. B. Org. Lett. 2005, 7, 5199

CM in Natural productCM in Natural productstructure determinationstructure determination

Tanaka, K.; Nakanishi, K.; Berova, N. J. Am. Chem. Soc. 2003, 125, 10802

O

(CH2)6CO2EtH

H

C5H11

OH

PGA1 ethyl ester

10 equiv

Ph


O

(CH2)6CO2EtH

PhH

C5H11

OH

Ph

85% 89%

• absolute configuration of allylic alcohols commonly determined by circular dichroism of corresponding benzoate• can be complicated by other chromophores

• PGA1 enone MAX 231 nm, allylic benzoate MAX ~ 230 nm• reaction "easily" run on 0.1 mg scale

Ene-yne cmEne-yne cmreview: Diver, S. T.; Giessert, A. J. Synthesis 2003, 466

OAc

SiMe3OAc

3 equiv


(71%)

AcO

SiMe3 OAc5 mol% Grubbs II,CH2Cl2, reflux

(74%)

OBz

CH3

4 equiv

OBz

CH3

Kulkarni, A. A.; Diver, S. T. J. Am. Chem. Soc. 2004, 126, 8110 Kim, M.; Park, S.; Maifeld, S. V.; Lee, D.J. Am. Chem. Soc. 2004, 126, 10242

R3

OR2

R1

C2H4 (60 psi)

20 mol% Grubbs II,CH2Cl2, rt

Smulik, J. A.; Diver, S. T. Org. Lett. 2000, 2, 2271

R1

10 equiv

R2R3R2O

R110 mol% Grubbs II,

CH2Cl2, rt,CH2=CH2 (1 atm)

R1 R2

Lee, H.-Y.; Kim, B. G.; Snapper, M. L. Org. Lett. 2003, 5, 1855

Ene-yne cmEne-yne cmRoyer, F.; Vilain, C.; Elkaïm, L.; Grimaud, L. Org. Lett. 2003, 5, 2007

Desired: RCEYM (ring closing ene-yne metathesis)

OTBS

O CO2Et

[Ru]

O

TBSO CO2Me

Result: Failure

Modification: RCEY-CM (tandem ring closing ene-yne / cross metathesis)

OTBS

X

3 equivR

10 mol% H-Grubbs,CH2Cl2, reflux X

TBSO R

RX = CH2

yieldX = Oyield

CO2Me 88% 67%

COMe 73% 68%

CHO 61% 65%

Ene-yne cm in natural product synthesisEne-yne cm in natural product synthesisKummer, D. A.; Brenneman, J. B.; Martin, S. F. Org. Lett. 2005, 7, 4621


(83%)

OH

H O

O

(+)-8-epi-xanthatin

10 equivO

OH

H OMeO2C

OH

stepwise: Evans, M. A.; Morken, J. P. Org. Lett. 2005, 7, 3371

tandem cm reactionstandem cm reactionsO 5 mol% Grubbs II

40 °C, 12 h(89%)

O

neat 3 equiv 1 equiv

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

B

O

O

O

O

3 equiv

2 mol% Grubbs II,CH2Cl2, 40 °Cthen PhCHO, rt

(69%)

Ph

OH

O O

dr > 20:1

Goldberg, S. D.; Grubbs, R. H. Angew. Chem. Int. Ed. 2002, 41, 807

OH OH

O

3 equiv

5 mol% H-Grubbs,1 atm H2, 5 mol% PtO2,

CH2Cl2, rt, 15 h(50%)

O

O

PhPh

Cossy, J.; Bargiggia, F.; Bouzbouz, S. Org. Lett. 2003, 5, 459

One-pot cm/intramolecular cycloadditionOne-pot cm/intramolecular cycloadditionHodgson, D. M.; Angrish, D.; Labande, A. H. Chem. Commun. 2006, 627

OO

t-BuO O

N2

R


O

t-BuO O

O

R

OO

t-BuO O

N2

R2 mol%

Rh2(OAc)4

rt O

R

t-BuO2C O

R = CO2Me, Cy, Ar43-80%

E/Z = 85:15 to >95:5

Tandem ene-yne cm/[4Tandem ene-yne cm/[4++2]cycloaddition2]cycloadditionMix, S.; Blechert, S. Org. Lett. 2005, 7, 2015

5 mol% H-Grubbs,benzene, 80 °C

(90%)

Ph

OTBS

CN

Ph

CN

H

OTBS

Tandem cm in natural product synthesisTandem cm in natural product synthesisQuinn, K. J.; Isaacs, A. K.; Arvary, R. A. Org. Lett. 2004, 6, 4143

Michaelis, S.; Blechert, S. Org. Lett. 2005, 7, 5513

C10H21


(65%)

OBn

O

O

OBn

C10H21

OO

H2 (? atm)

Pd-C, EtOH(82%)

OH

C10H21

OO

(-)-muricatacin


(73%)

OTr

OH

O

H3C

OTBSOTr

OH

O

H3C

OTBS

OH

O

O

H3C

OTBS

O

5 mol% H-Grubbs

ClCH2CH2Cl, 80 °C(68%)

OH

O

O

H3C

OTBS

O OO

O

O

O

CH3

OH

H

(+)-phomopsolide C

Rom/cmRom/cmMihovilovic, M. D.; Grötzl, B.; Kandioller, W.; Snajdrova, R.; Muskotál, A.; Bianchi, D. A.; Stanetty, P.

Adv. Synth. Catal. 2006, 348, 463

1 mol% Grubbs I,CH2Cl2

X

O

X = CH2, O

R

X

O

RH H

R Yield E/Z Yield E/Z

X = CH2 X = O

CH2=CH2 4350 - -

CH3 40 3.5:1 40 3.5:1

C2H5 65 6:1 42 8.5:1

C4H9 50 7.5:1

Ph 61 > 95:5

50 1:2Ph

Weeresakare, G. M.; Liu, Z.; Rainer, J. D. Org. Lett. 2004, 6, 1625

10 mol% Grubbs II,CHCl3, 55 °C

BocN

Ts

5-15 equiv

R

NBoc

R

Ts

HN O

CO2H

Br

BnNC

furfural,BnNH2,

MeOH, rt(73%)

O NBnBnHN

OH

O

H

HN O

Br

Br

CsOH,THF, 0 °C

(79%)

O NBnBnHN

OH

O

H

N O

Br

Ph10 equiv


(81%)

O

BnN

N

Ph

BnHN

O

O

HH

HO

Br

BnHN O

CO2H Br NC

furfural, BnNH2,MeOH, rt

(45%)

O NBnNH

OH

O

H

BnHN O

Br

Br

CsOH,THF, 0 °C

(77%)

O NBnN

OH

O

H

BnHN O

Br

Ph10 equiv


(65%)

BnNN

O

HO

Br

H

Ph

O

NHBn

Rom/cm/rcmRom/cm/rcmOikawa, M.; Ikoma, M.; Sasaki, M. Tetrahedron Lett. 2005, 46, 5863

cm in natural product synthesis: ROM/CM/RCMcm in natural product synthesis: ROM/CM/RCMHart, A. C.; Phillips, A. J. J. Am. Chem. Soc. 2006, 128, 1094

ON

O O

Bn

TIPSO


(59%)

ON

O O

Bn

TIPSO HTIPSO

O

OO

O

3 equiv


(59%)

O H

H

OTIPS

OO

OE/Z = 2:1

14 steps

HN

O

MeH

H

cylindramide A

NH

OH

O

O

HO

H

My favourite example: rom/cm/rcmMy favourite example: rom/cm/rcmTakao, K.; Yasui, H.; Yamamoto, S.; Sasaki, D.; Kawasaki, S.; Watanabe, G.; Tadano, K. J. Org. Chem. 2004, 69, 8789

OOH

OTBDPS

5 steps OMe

OTBDPS

HOHO

3 steps Me

OTBDPSO

3 mol% Grubbs II

benzene, reflux(86%)

Me

OTBDPSO3 steps Me

OHO

Me

OO O

AcOH

H

(+)-mycoepoxydiene12 steps

OOH

OTBDPS

2 steps OMe

OTBDPS

2 equiv

2 mol% Grubbs I,benzene, rt then

10 mol% Grubbs II,benzene, reflux

Me

OTBDPSO

+ by-products

TBAF

THF(23%)

Me

OHO

4 steps

Alkyne cross metathesisAlkyne cross metathesisFürstner, A.; Grela, K.; Mathes, C.; Lehmann, C. W. J. Am. Chem. Soc. 2000, 122, 11799

Fürstner, A.; Mathes, C. Org. Lett. 2002, 3, 221review: Fürstner, A.; Davies, P. W. Chem. Commun. 2005, 2307

N

R1 MeR2

R2

10 mol% Mo[N(t-Bu)(Ar)]3,CH2Cl2/toluene, 80 °C

R1

R2N

N

Mo

Mo[N(t-Bu)(Ar)]3

Cl

OMe

Cl

CO2Me

62% 67%

CN

OMe OMe

OTHP

82% 68%

ClS

55%

C4H9TBSO H

H

Cl

O

46%

C4H9TBSO H

H

CO2Me

O

43%

TBSO H

HO

C5H11

OTES

CO2Me

51%

MeSO2Ph

10 mol% Mo[N(t-Bu)(Ar)]3,CH2Cl2/toluene, 80 °C

(71%)

SO2Ph

Alkyne cross metathesisAlkyne cross metathesisSashuk, V.; Ignatowska, J.; Grela, K. J. Org. Chem. 2004, 69, 7748

Ar Me

2 equiv

5 mol% Mo(CO)6,1 equiv 2-FlC6H4OH,

C6H5Cl, reflux (135 °C)

Ar Et

Ar Yield

Ph 96%

3-CF3C6H4 81%

2-MeOC6H4 70%

speculation Mo(CO)6R R

ArOH

135 °CMo(OAr)3R

Mo(O) Mo(VI)

Asymmetric cmAsymmetric cmVan Veldhuizen, J. J.; Garber, S. B.; Kingsbury, J. S.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 4954

Gillingham, D. G.; Kataoka, O.; Garber, S. B.; Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 12288

O

O

O

R

10 mol% Cat A*,THF, 50 °C

O

H H

O O

RR Yield (%) ee (%)

Ph 71 80

C5H11 57 > 98

c-C6H11 60 > 98

OPh

2 mol% Cat B-I*(68%)

OPhH H

98% ee

OPh

5 mol% Cat B-Cl*(70%) OPh

H H

96% ee

H

OBn

5 equiv

2 equiv OBn

RuX

NMesN

OO

R

Cat A*: R = H, X = ClCat B*: R = Ph

Schrock, R. R.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2003, 42, 4592

Shawn Collins, Literature Meeting, October 4, 2004

Full Story:

Cm improvement: catalyst loadingCm improvement: catalyst loadingForman, G. S.; Tooze, R. P. J. Organomet. Chem. 2005, 690, 5863

Check Forman 2005 Organomet page ??

0.1 mol% Grubbs II,50 °C, 2 h

24% conversionE/Z = 13:1

2 equivMeO2C

C8H17 C8H17MeO2C

0.1 mol% Grubbs II,0.5 equiv p-cresol

50 °C, 2 h100% conversion86% isolated yield

E/Z = 35:1

2 equivMeO2C

C8H17

50 mmol scale

p-cresol

MeHO

Cm improvement: reaction timeCm improvement: reaction timeBargiggia, F. C.; Merray, W. V. J. Org. Chem. 2005, 70, 9636

H-Grubbs,CH2Cl2, microwave

CO2Me

(EtO)2P

OO

(EtO)2P

OO

CO2Et

H-Grubbs(mol%)

Temperature Time Yield NoteMethyl Acrylate(Equivalents)

4 10 100 °C 15 min 79%

1.1 10 100 °C 15 min 65% 1 min: 66% yield

1.1 5 100 °C 15 min 81%

1.1 1 100 °C 15 min 50%

1.1 10 150 °C ~ 45 sec 72% "1 sec" in publication

1.1 10 60 °C 15 min 51% no "mirowave" effect

4 10 reflux 6 h 80% thermal conditions

Catalyst delivery vehicle in CmCatalyst delivery vehicle in CmHansen, E. C.; Lee, D. Org. Lett. 2004, 6, 2035

OAc

PhBnO

OBn


(37%)

OAc

Ph

OBn

E/Z = 1:20

[Ru]BnO +

OAc

Ph

OAc

Ph OBnO

OBn


(63%)

OAc

Ph

OBn

E/Z = 1:4

AcO

Ph O

[Ru]O OAc

Ph[Ru]

R

OAllyl

ROBn

NET

6 steps

OH

O

O

OH

TBSO

H H8

+

O

O

O

TIPSO

Me

HOH H

OH

O

11 steps

1. xs (i-Pr)2SiCl2, imidazole, CH2Cl2 (74%)2. Grubbs (1.8 equiv), ClCH2CH2Cl, reflux (83%)

O

TBSO

H HO

O

O

TIPSO

Me

H HO

SiO

i-Pr i-Pr

1. HF, MeCN, CH2Cl2 (91%)2. TsNHNH2, NaOAc, DME/H2O, reflux (95%)

O

HO

H HO

H HOH HO

O

O

OH

Me

!!

• 50 mg scale• 70 mg catalyst

A temporary silicon-tethered rcmA temporary silicon-tethered rcmEvans, P. A.; Cui, J.; Gharpure, S. J.; Polosukhin, A.; Zhang, H.-R. J. Am. Chem. Soc. 2003, 125, 14702

summarysummary

• Cross Metathesis increasingly used as disconnection late in natural product total synthesis

• Useful tool for library synthesis, especially in biochemical-type applications

• “Ideal” reaction: a catalytic method for a highly efficient (re: atom economy) C-C bond forming reaction

• Improvement still possible in catalyst loading, stoichiometry, reaction time/temperature, selectivity, …

olefin cross metathesis christopher kendall march 20, 2006

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