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Home , Alkyne metathesis, Enyne metathesis, Grubbs catalyst, Metallacycle, Olefin metathesis

in Organic Synthesis

Wendy Jen MacMillan Group Meeting January 17, 2001

I. Well-defined metathesis catalysts II. Applications of Olefin Metathesis A. Ring closing metathesis B. Cross metathesis C. Ring opening metathesis

Recent Reviews: Furstner, A. Angew. Chem. Int. Ed. 2000, 39, 3013. Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. Furstner, A. Topics in Organometallic 1998, 1, 1. Schuster, M.; Blechert, S. Angew. Chem. Int. Ed. 1997, 36, 2036

Olefin Metathesis: Introduction

1 2 1 2 R R catalyst R R

R1 R2 R1 R2

! Chauvin-type mechanism: model proceeds through a metallacyclobutane intermediate

R2 R2 R2 R2 R2 R2

[M] [M] [M] R1 R1 R1

! Catalyst systems

WCl6/ EtAlCl2/ EtOH i-Pr i-Pr ArO Re O / Al O / SnMe PCy3 2 7 2 3 4 Cl ArO Ta Ru N Cl (F3C)2MeCO ArO WCl6/ Me4Sn Ph Mo Ph PCy3 (F3C)2MeCO Ill-defined catalyst systems Well-defined catalyst systems Background: Metal

X ! Definition: Transition metal complex possessing a formal metal to carbon double bond ! LnM C X, Y = alkyl, aryl, H, or heteroatom (O, N, S, Halogen) Y ! Two types of metal carbenes: Fischer-type and Schrock-type

OMe Me CH Fischer-type (OC)5W C Ta 2 Schrock-type Ph

! low oxidation state middle to late TM ! high oxidation state early TM

! Substituents (X & Y): at least one electronegative atom ! Substituents (X & Y) are H or alkyl

! are generally good ! acceptors ! Ligands are generally good " or ! donors

! Electrophilic carbenes: attacks at Ccarbene ! Nucleophilic carbenes: electrophile attacks at Ccarbene

! Ccarbene is L-type : Metal oxidation state unchanged ! Ccarbene is X2-type ligand: metal oxidation state changed by +2

Metal (sp2) Metal carbene (sp)

Schrock's Metathesis Catalyst

! Commercially available, as is synthetic precursor Mo(CHt-Bu)(NAr)(OTf)2(dme)

! Must be handled under Ar or N2 using dry solvents and substrates i-Pr i-Pr ! Relatively intolerant of protons on heteroatoms (RCOOH, RSH, ROH, etc.) and N Me some functionalities (eg. RCHO) (F3C)2MeCO Mo Ph (F C) MeCO Me ! Tolerant of S, P and functional groups 3 2

! High reactivity

Structural Features

Ar Ar ! Electon deficient Mo(VI), 14 electron species N H2 N C H2 RO M CH2 RO C ! Pseudo-tetrahedral coordination sphere C M CH2 H2 RO C OR H2 ! NAr ligand, OR ligands, and initial alkylidene need to be bulky to allow for isolation. Trigonal bipyramidal Square planar ! Electron withdrawing increase electrophilicity of metal center, hence increasing reactivity. Schrock's Catalyst: Influence of Ligand Set on Reactivity

! Two possible rotamers

Ar Ar N N ka/s RO RO anti M M 1 syn H R C RO C RO ks/a R1 H

Generally, syn isomer is more stable and anti isomer is more reactive

! Rate of interconversion between two rotamers is dependant on metal ligands and substrate

L L NAr NAr -L ka/s -L RO M anti syn RO M H R k +L s/a +L OR R OR H anti CNO adduct syn CNO adduct

Ar Ar Ar N N N o o H 90 H 90 R C C R R H

electron withdrawing substituents and bulky aryl groups decrease ks.a

Schrock, R.R. Tetrahedron 1999, 55, 8141.

Grubbs' Metathesis Catalyst

! Commercially available

PCy3 Cl ! Reasonably stable toward H2O, O2, and minor impurities ease of handling Ru Cl Ph PCy3 ! Lower reactivity vs. imido alkylidene catalyst ! High tolerance

Mechanism: olefin binds cis to carbene and trans to Cl; formation of believed to be rate determining

PCy + Cy3P Cy3P H 3 - PCy3 PCy3 R Cl Cl Cl Ru Cl Ru Cl Ru products Cl Ru R + PCy Cl R R PCy3 3 R - Cl R R R

Ligand Effect on Catalyst Activity:

Halides: Catalyst activity increases from I < Br < Cl Trans influence I > Br > Cl olefin is bound tightest for Cl complex Cl is smallest large halogens disfavor olefin binding due to steric crowding

Phosphines: Catalyst activity increases as cone angle and eletron donating ablilty increase As cone angle increases, dissociation of more facile for steric reasons More electon donating ligand labilizes trans ligand and stabilizes vacant orbital in 14 e- intermediate

Dias, E. L.; Nguyen, S.T.; Grubbs, R.H. J. Am. Chem. Soc. 1997, 119, 3887. R R Catalysts Containing N-Heterocyclic N N

Carbene (NHC) Ligands Arduengo et. al. JACS 1991, 113, 361

! Sought to find more basic and sterically demanding ligand than PCy3; ! "Stable" imidazol-2-ylidene ligands (NHC) are such phoshine mimics

Herrmann et al. Angew. Chem. Int. Ed. 1999, 38, 2416.

PCy3 PCy3 Cl Ph PCy3 Cl Ph Grubbs et al. Org. Lett. 1999, 1, 953. Ru Cl Ru Cl Cl Ru Nolan et al. J. Am Chem. Soc. 1999, 121, 2674. R R Cl Ph R R N N R R N N N N Activity is significantly higher than parent Ru complex

Orgin of increased reactivity:

k1 k2

PCy Cy3P k3 Cy3P H 3 - PCy PCy3 + olefin 3 Cl Cl Cl Ru Cl Ru Cl Ru Cl Ru R + PCy3 Cl - olefin R R PCy3 R k Cl R -3 R k-1 k-2

High activity of NHC complex is due to improved selectivity for binding !-acidic olefinic substrates

in the presence of "-donating free phosphine (decreasing k-1/k2).

Sanford, M.S.; Ulman, M.; Grubbs, R.H. J. Am. Chem. Soc. 2001, ASAP

Other Metathesis Catalyst Systems

Hansen, S. M.; Rominger, F.; Metz, M.; Hofmann, P. Angew Me Me P Ru Cl OTf Chem. Int. Ed. 1999, 38, Al P Solv Ti 1273. Me Cl Me Tebbe, F. N.; Parshall, G.W.; Reddy, G.S. J. Am. Chem. Soc. 1978, 100, 3611 Me Ti CH2 Me Demonceau, A.; Noels, A. F.; Saive, E.; Hubert, Cl A. J. J. Mol. Catal. Ru 1992, 76, 123. Cy3P Cl

R 87% R 2[Cp2Ti{P(OEt)3}2], Mg R SPh - [Cp2Ti(SPh)2 TiCp2 SPh

Fujiwara, T.; Takeda, T. Synlett 1999, 354. Fundamental Olefin Metathesis Reactions

RCM Ring Closing Metathesis (RCM)

R2 Cross Metathesis (CM) CM R1 R2 R1

ROMP Ring Opening Metathesis (ROMP) n

ADMET Acyclic Metathesis Polymerization (ADMET)

n

Ring Closing Metathesis (RCM)

! Intramolecular metathesis of a diene to form a cyclic olefin

- ADMET H2C CH2 n M

RCM M CH2 M

n

M

! Reaction pathway of diene depends on catalyst, dilution, ring size, and substrate (functional groups and sterics)

Catalyst: O Re O /Al O -SnBu Si 2 7 2 3 4 Si ADMET Si Si + oligomers O dilute 14% 86% Schrock's catalyst 95% 5% concentrated

Dilution: Intermolecular ADMET can generally be prevented by applying dilution principle

Finkel'shstein et al. J. Mol. Cat. 1992, 76, 133. Forbes et al. J. Am. Chem. Soc. 1992, 114, 10978. RCM of Small Rings: Olefin Substitution ! Synthesis of 5-7 membered rings fairly facile; proper selection of catalyst depends on functional groups and steric demands of the substrate ! Typically ruthenium catalysts are preferred over molybdenum catalysts from a synthetic standpoint due to ease

of handling and high function group tolerance of Ru catalyst. ! Choice of catalyst depends on olefin substitution of product

Yield (%) using substrate product time 1 2 3 i-Pr i-Pr N Me (F3C)2MeCO Mo Ph (F3C)2MeCO Me 1

PCy3 Cl Ru Cl R PCy3 2

PCy Cl 3 Ph Ru Cl Mes Mes N N

3

Molybdenum and Ruthenium NHC catalysts are more effective for highly substitued olefins

Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R.H Org. Lett 1999, 1, 953.

PCy3 Cl Ph PCy3 Cl Ru 1 Ru Cl 2 RCM of Small Rings: Cl Mes Mes R PCy3 N N

! Free alcohols: highly compatible with Ru based catalysts; Mo catalysts have low tolerance for ROH

Exception: Me Me Me Me OH 2% Schrock's Me

OH catalyst Me

Schrock, R. R. Top. Organomet. Chem. 1998, 1, 1. ! Allylic Alcohols: compatible with Ru catalysts

O O OH O O OH 1% 1 O N O N CH2Cl2 97% Bn Bn Crimmins, M.T.; King, B. W. J. Org. Chem. 1996, 61, 4192.

Potential for isomerization of olefin if catalyst is not reactive enough

OH OH OH O

O 2 O 1 O O

O O O O

OH OH OH OH

Ackermann, L.; Tom, D. E.; Furstner, A. Tetrahedron, 2000, 56, 2195. RCM of Small Rings: Ethers

! Allyl ethers and : Both Mo and Ru catalysts tolerate these functionalities

Me Ph Ph Ph O Grubbs' Schrock's catalyst Me Me O catalyst O O O Ph O (87%) 93% Me Me

Fu, G.C.; Nguyen, S.T.; Grubbs, R.H. JACS 1993, 115, 9856. Fu, G.C.; Grubbs, R.H. JACS 1992, 114, 5426.

[M] OR Caveat: allylic ethers have potential for decomposition R O R [M]

! Vinyl ethers: Mo catalyst used for the reaction/ formation of enol ethers; Ru is incompatible because resulting Ru carbene is unreactive

OBn

BnO O O 12% Schrock's O O O OBn catalyst (85%) OBn O

Fujimura, O.; Fu, G.C.; Grubbs, R.H. J. Org. Chem. 1994, 59, 4029.

RCM of Small Rings: Vinyl Ethers

! Tebbe reagent: carbonyl ester olefination and metathesis to form cyclic enol ether

BnO Me Me BnO H O Ti Al H O Me Cl Me O O H 50% yield O H O 4 equiv H THF, reflux O H

Nicolaou et al. J. Am. Chem. Soc. 1996, 118, 10335.

! Schrock's molybdenum and catalyst can also mediate olefin metathesis/ carbonyl olefination

O 1.0 equiv Schrock's

O(CH2)3Ph Mo catalyst O(CH2)3Ph 86% yield

O R R [Mo] [Mo] O

catalyst metathesizes olefins faster than it olefinates ketones

Fu, G.C.; Grubbs, R.H. JACS 1993, 115, 3800. RCM of Small Rings: Amines

! Primary and secondary amines: incompatible with Schrock and Grubbs' Catalysts

! Tertiary amines: typically tolerated by Mo and Ru catalysts, but they can be problematic

Bn 2 N No Reaction i-Pr i-Pr N Me Bn H 1. 4% 2 Cl - (F3C)2MeCO N Bn N Mo 2. NaOH Ph (F3C)2MeCO Me 1 Me Me Bn 4% 1 N PCy3 N Bn Cl Ru Cl R PCy3 Fu, G.C.; Grubbs, R.H. JACS 1992, 114, 5426. 2 Fu, G.C.; Nguyen, S.T.; Grubbs, R.H. JACS 1993, 115, 9856.

However newer ruthenium NHC initiatiors are not as tolerant of amine salts PCy3 Cl Ph Ru 5 mole% 3 - Cl H H Cl Cl - H Mes Mes N N N N o CH2Cl2, 40 H 24hours <20% conversion 3 A. Furstner et al. J. Org. Chem. 2000, 65, 2204.

RCM of Small Rings: Carbonyls

! Ketones: inert to ruthenium catalysts; typically tolerated by molybdenum catalysts, but olefination can occur

! Carboxylic acids and aldehydes: tolerated by Grubbs' catalyst, but not by Schrock's catalyst

! Esters: compatible with both ruthenium and molybdenum catalysts

OR RO Exception: !, " and ", # unsaturated esters form stable O chelates with Schrock's catalyst and inhibits reaction O [M] [M] R.R. Schrock et al. Organometallics, 1989, 8, 2260

Synthesis of !, " unsaturated lactones from acrylate esters: Ruthenium NHC catalyst

O 24 hours O 2 hours! PCy3 79% yield Cl Ph 92% yield Me Ru O O Cl O O Mes Mes N N Me R Me R O O 2 hours 40 hours Me 5 mol% 93% yield Me R 63% yield

A. Furstner et al. J. Org. Chem. 2000, 65, 2204. RCM of Small Rings: Amides

O O Schrock cat. N N N N 15 min, 89%yield O O

Fu, G.C.; Grubbs, R.H. JACS 1992, 114, 7325.

O O Bn catalyst However chelative effect is also an issue with amides N Bn N R NR2 R2N O O [M] R = H Schrock cat.! 0% [M] R = Et Schrock cat. 80% R = H Grubbs cat. 93% ! Ruthenium catalysts are more general for amides

O O 10% Grubbs 5 mol% N N Ph cat. (82% yield) O N PCy3 O N Cl Ph H H Ph OTr Ru OTr Cl 82% Mes Mes N N N-H amides can be used only if sterically protected

Rutjes, F.P.J.T.; Schoemaker, H. E. Tet. Lett. 1997, 38, 677. A. Furstner et al. J. Org. Chem. 2000, 65, 2204.

RCM of Small Rings: Sulfur and Phosphorus

! Sulfides and : incompatible with ruthenium catalysts; use molybdenum catalyst

3.5% Schrock S S catalyst

Bn 3.5% Schrock P P Bn catalyst (95% yield)

J. M. Basset et al. J. Chem. Soc. Chem. Comm. 1995, 857.

! Newer Ruthenium NHC catalysts are compatible with phosphinic acids

PCy3 Cl Ph Ru HO O 5 mol% 1 OH Cl Mes Mes P P N N quantitative yield O 1

Briot, A.; Bujard, M.; Gouverneur, V.; Nolan, S. P.; Mioskowski, C. Org. Lett. 2000, 2, 1517. RCM of Small Rings:

R1

R2 Eyne metathesis: alkylidene enyne 1 R migration reaction from the metathesis alkene to part to carbon R2 R R

Mechanism: R

R1 M

R R M R1 R1 M

R M R1 R

R1

RCM of Small Rings: Enyne Reactions

! Fischer carbenes can be used to initiate enyne metathesis reactions

OMe

1 mol% (OC)5W C Ph

(OC)5W CH2

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

OMe OEt 1.10 mol% (OC)5Cr C Ph N Ts O N 2. aq HCl Ts

! Enyne metathesis can also be initiated by Grubbs and Schrock catalysts

OTBS PCy3 OTBS Cl 1 mol% Ru Cl Ph PCy3 n n

N n = 0, 1, 2 N Ts Ts

Mori et al. Synlett 1994, 1020 RCM of Medium Rings

! Because of enthalpic and entropic influences, medium sized rings are difficult to prepare; hence substrates are more prone to intermolecular acyclic diene metathesis reactions (ADMET)

! Desired cyclization can be facilitated by providing some sort of conformational constraint.

Cyclic Confomational Constraints

H CO2Et CO Et H O Ar 2 O Ar Grubbs N 95% yield 83% yield N N N Catalyst N H N H O O Z Z

OH O CO2Et N Ar 67% yield balanol N H N

O Z Cook et al. Org. Lett. 1999, 1, 615

H Attachment of olefin side chains to !-lactams n =1 95% yield n = 2 95% yield n = 3 40% yield Diedrichs, N.; Westermann, B. Synlett 1999, 1127 O O n H Delgado et al. J. Org. Chem. 1999, 64, 4798

RCM of Medium Rings: Cyclic Conformational Control

OPG OPG OPG OPG

OPG PGO OPG OPG O O taxol B,C ring systems

Model Study: Cyclic protecting group facilitates cyclization

Schrock no cyclization catalyst o PhH, 80 O O (93%) OTES O O OH 1:1 mixture diastereomers

Grubbs or + Schrock catalyst O O O O O O 34% 46% O O O

Prunet et al. Angew. Chem. Int. Ed. 2000, 39, 726. RCM of Medium Rings: Acyclic Conformational Control

! Use of gauche effect of 1,2-dioxygen substituents to facilitate ring closure

catalyst dimers and oligomers O

OAc OAc OAc [(Cy3P)2Cl2Ru=CHPh] RO OAc 94% OAc OAc yield o H CH2Cl2, 40 , 1-2h O O H

Crimmins, M.T.; Choy, A.L. J. Am. Chem. Soc. 1999, 121, 5653

Use of acyclic conformational control: synthesis of laurencin

Bn Bn [(Cy3P)2Cl2Ru=CHPh] N O N O BnO (+)-laurencin BnO o O O CH2Cl2, 40 C H H O O O 94% yield O

Crimmins, M.T.; Emmitte, K.A. Org. Lett. 1999, 1, 2029

RCM: Macrocyclizations

! devoid of any conformational predisposition towards ring closure can be good RCM substrates

! Formation of cis and trans isomers in the formation of large rings

! Experimental Considerations: 1. Rate of oligimerization can be slowed by diluting the reaction or adding the diene slowly 2. Higher temperatures generally required 3. Higher catalyst loadings

! Substrate considerations

1. Presence of a polar functional group (ester, amide, ketone, ether, sulfonamide, urethane)

O O O O 4 mol% O O [(Cy3P)2Cl2Ru=CHPh] M high dilution L 79% L

4 mol%

[(Cy3P)2Cl2Ru=CHPh] oligomers high dilution RCM: Macrocyclizations

2. Site of ring close is a key issue

O M O [(Cy3P)2Cl2Ru=CHPh] O no reaction R N 5 mol% R stable intermediates O O M O [(Cy3P)2Cl2Ru=CHPh] O O N 5 mol% N R R R 84% yield

3. Steric Hinderance close to the double bonds significantly lowers yield

[(Cy P) Cl Ru=CHPh] 3 2 2 R = H (52%)

O O 4 mol% O O R = Me (10%) high dilution

R R

Due to bulky nature of metal ligands, bulky substituents close to olefins to be metathesized will have adverse effect on the cyclization

Furstner, A. Top. Organomet. Chem. 1998, 1, 37.

Macrocyclizations using RCM:

! Alkyne Metathesis: viable solution to lack of E/Z control in alkene RCM macrocyclizations

Lindlar cis R1 alkene R1 alkyne + R2 metathesis R2 / trans alkene protonation

Chauvin-type mechanism:

2 2 2 2 R [M] R R R M [M] [M] + + 1 R1 R1 R1 R1 R R2 R1 R1

Katz, J.; McGinnis, J. J. Am. Chem. Soc. 1975, 97, 1592

Cross metathesis

! Allyl silanes: stabilization of !-cation (silicon !-effect) enhances nucleophilicity

2% Schrock catalyst R = Me 72% E/Z = 2.6:1 SiR3 OBn OBn R3Si R = i-Pr 77% E/Z = 7.6:1 DME, 4h

H SiMe N 1.5 equiv 3 H Cbz N 97% ee Cbz SiMe3 92% ee COOMe 10 mol% Schrock cat. COOMe CH2Cl2, 8h, reflux (95%yield)

H H 1.5 equiv SiMe3 O N O N Me3Si 3 3 O 10 mol% Grubbs cat. O OTr CH2Cl2, 4h, reflux (50%yield) OTr

Blechert et al. Chem. Eur. J. 1997, 3, 441 Fleming et al. Org. React. 1989, 37, 57 Schinzer, D. Synthesis 1988, 263.

! Allyl stannanes: compatible with Schrock's catalyst, but not with ruthenium catalysts

OAc OAc

O O 2.0 equiv SnPh3 O O

AcO OAc 10 mol% Schrock cat. AcO OAc SnPh3 CH Cl , (67%yield) OAc 2 2 OAc Blechert et al. Synlett. 1997, 129

Cross metathesis

! Trisubstituted Olefins: Ruthenium NHC catalyst

BzO PCy3 Cl Ph 5 mol% 1 BzO Ru OAc Cl 80% yield Mes Mes N N E/Z 2.8:1 OAc 1 Chatterjee, A. K.; Grubbs, R.H. Org. Lett. 1999, 1, 1751

! Cross Metathesis using ",! unsaturated carbonyl substrates: Ruthenium NHC catalyst

R1 R1 R1 = H (91%) E/Z = 4.5:1 COOMe 5 mol % 1 RO COOMe R1 = Me (62%) E/Z = >20:1 RO 7 7 Grubbs et al. J. Am. Chem. Soc. 2000, 122, 3783

! Enyne cross metathesis

OH OH 5 mol% 1 99% ee 99% ee (60psi) (68% yield) CH2Cl2, rt

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

! Ring opening of strained cyclic olefin to give open chain metal carbene provides driving force for ROM

ROMP

M [M] polymer R

ROM cross products R acylic olefins

! Selection of catalyst decided by functionality in the substrate ! Use of terminal olefin results in exclusive formation of monosubstitued diene; however E/Z ratios are low

1.0 equiv O CN 1.0 equiv OH O CN O CH2OAc O O OH O Schrock's cat. Grubbs' cat. OH O (79%) O (58%) OH Blechert et al. Angew. Chem. Int. Ed. 1997, 36, 257

hex hex OMe hex 10 mol% OMe OMe Grubbs' cat.

Snapper et al. J. Am. Chem. Soc. 1995, 117, 9610 53% 13%

Ring Opening Metathesis

PCy3 Cl Ph ! Cross Metathesis selectivity Ru Cl Mes Mes N N strained olefin 1

M less substituted alkylidene R R more substituted alkylidene M

R R terminal olefin

Tallarico, J. A.; Randall, M. L. Tetrahedron 1997, 48, 16511

! Synthetic application of ring opening metathesis: (+) and (-)-Asteriscanolide

Me O Me H Me Me 1 Cope Me Me

H2C CH2 Me Me Me O O Me O O O Asteriscanolide

Limanto, J.; Snapper, M.L. J. Am. Chem.Soc. 2000, 122, 8071