methodsanddesigninorganicsynthesis

2018-19Master Course

PereRomea

inOrganicChemistry

4.2.Single&DoubleBonds

Rubik’scube

NonfunctionalgroupR R disconnection

Carbon-dR

Carbon-aR

¿"?

Alkyl%d Alkyl%a

Potentialprecursors Li

MgBr

Alkyllithium

Alkylmagnesiumhalide

XAlkylhalide,X:Cl,Br,I

RSO3Alkylsulfonates

M + Y

M:Li,MgX M:halide,sulfonate

ThereactionisplaguedbymanysidereactionsduetohighpKaofAlkyl-d(pKa45–50)

?Polyfibrospongia

(–) Hennoxazole A antiviral

Smith,T.E.JOC2008,73,142

O N

O

OH

MeO H

OMe

N

O

O N

O

OH

MeO H

OMe

N

O

O N

O

OPG

MeO H

OMe

N

OTBS

O N

O

OPG

MeO H

OMe

N

OTBS

BrLi

FGA ?¿

Oxazolealkylationstudies

Ph N

O

twopotentialreactingsites

Oxazolealkylationstudies

Ph N

O

Ph N

O Li

Ph N

OLibase

–78 °C

Ph N

O Me

Ph N

OMe

MeI

1 2

MeIratio1:2

BuLiLDALiNEt2

(14:86) (99:1)(37:63)

ThisreversalofregioselectivityisthoughttoarisefromtheabilityofEt2NHtomediatethelow-temperatureequilibrationofakineticmixtureofotherwisenoninterconvertinglithiatedintermediates

However,suchasituationwasdramaticallymodifiedinamodelclosetotheTGTstructure

TAKE-HOMEMESSAGE:themodelshouldbeassimilaraspossibletotherealsystem

Oxazolealkylationstudies

Theseresultssuggestthatdeprotonationattheheterocycleisthermodynamicallyaswellaskineticallyfavored

N

ON

OH

OMeMeO

threepotentialreactingsites

N

ON

OH

OMeMeO Li

Chelationcouldbethereason

N

ON

OH

OMeMeOTBS

1) base, –78 °C

2) 2 equiv MeI N

ON

OH

OMeMeOTBS Me

N

ON

OH

OMeMeOTBS Me

Me

+

(60:12:28)

ratiomono:di:SM

BuLiLDALiNEt2(88:5:7)(43:8:48)

SOLUTION:BLOCKINGTHATPOSITION?

base:BuLi,LDA,LiNEt2

base–78 °C N

ON

OH

OMeMeOLi

singleproduct

Alkylationoftherealsystem

(–) Hennoxazole A

O

OTBS

MeO HO

N

N

O

TBSOMe

O

OTBS

MeO HO

N

N

O

TBSOMe

O

OH

MeO HO

N

N

O

TBSOMe

TBAF, THF, rt 99%

Br1) LiNEt2, THF, –78 °C 2)

77%

Alkynyl&d Alkyl&a

FGA

Alternative(I):TerminalAlkynes

pKa ca 25 pKa 50

HR + EtH+ EtMgBr MgBrRTHF, 0 °C

HR + n-BuH+ n-BuLi LiRTHF, –78 °C

?LarvaofMexicanbeanbeetle

Epilachnadiene defense agains ants

ONH

O

Rao,B.V.TL1995,36,147

ONH

O

OH

OH

OH

OHFGI

Br

OH

OH

Alkyl%a

Alkynyl%d

OPGOHBr

Alkyl%a Alkynyl%d

O

Alkyl%a Alkynyl%d

Rao,B.V.TL1995,36,147

Alternative(II):Organocuprates

ORGANOCOPPERREAGENTS,easilypreparedbytransmetallation,areveryselective

2 RLi + CuX R2CuLi + LiX

RLi + CuX RCu + LiX

RLi + CuCN RCu(CN)Li

Monoorganocopper

Homocuprates or Gilman’s reagents

Heterocuprates

90%

I

Me

I

Me75%81%

Br

Me

Me2CuLiEt2O, 0 °C to rt

RI

RMe

90%

Cecropiamoth

?(±) Cecropia Juvenile Hormone Hormone involved in the development of larvae

Corey,E.J.JACS1968,90,5618

OMeO

OAclassicalsynthesis

1) TsCl, pyrOH

OTHP2)OTHP

OH

I1) H3O+

2) LiAlH4, then i2

OH

Li2CuEt2

Br

TMS

PBr3TMS

H

OH

1) BuLi2) CH2O

OH

Me1) LiAlH4, I2

2) Li2CuMe2

OMe

O

OMe

O

O

Bacillusspecies

?Iedomycin D

Maulide,N.OL2015,17,4486

HO

OHO

HO

OHO OHCO2H

O

OH

H OH

4π#Electrocyclic#transform

Strainedbicycle

IOTIPS OTIPS

CO2H

O

OH

H

Activated ZnThen CuCN, LiCl

98%

1) H2SO4, MeOH2) LiOH, MeOH

OHCO2H

HO

OHOΔ

63% over three steps

Reactants

TRANSMETALATION

PdL2

R1PdX

L2R1

PdR2

L2

R2 MM X

R1 X

R1 R2

Pd(0)

Pd(II)Pd(II)

Oxidative addition

Reductive elimination

R2:alkyl,alkenyl,alkynyl,aryl

R1:betternoß-HX:I,Br,(Cl),OTf

Fürstner,A.ACIE2005,44,674

GENERALMECHANISM

Alternative(III):Pd-MediatedCross-CouplingReactions

R1 X R2 M R1 R2 M X+ +cat Pd(0)

Pd-Mediated Cross-Coupling Reactions

Reactants

TRANSMETALATIONTransferofanorganicgroupfromonemetalcentertoanother.Theprocessinvolvesnoformalchangeinoxidationstateforeithermetal.

R1Li,R1MgY

R1B(OR)2

R1CuLn

R1ZnY

R1SnR3

Kumada

SUZUKI

SONOGASHIRA

Negishi

STILLE

Mignani,G.CR2006,106,2651Magano,J.;Dunetz,J.R.CR2011,111,2177

Forpalladium-mediatedcross-couplingreactions

R1 X + Pd R1 Pd X

Suzuki Cross-Coupling Reaction

Reactants

R1 R2

R1 X

+

R2 B

Pd(0) Base

Csp2

XX X:I>Br>OTf>>Cl

Csp2 R2 BOH

OHR2 B

O

OR2 B

O

OR2:alkenyl,aryl

Csp3 R2:alkylBR2 9-BBNR2

Pd(0):Pd(PPh3)4

Pd(II):Pd(OAc)2/PR3orAsR3 FeP

PPdCl2

PhPh

PhPh

dppf

forCsp3–Csp2

Suzuki Cross-Coupling Reactions

Reactants

NO2I NO2BOH

OH+

0.2 mol% Pd(OAc)2K2CO3

Acetone / H2O, 65 °C

97%

Br OTHP

B O

O

B O

O

3 mol% Pd(PPh3)4, NaOEt PhMe, 85°C

OTHP

OTHP 73%

85%

OHB OH

2 mol% Pd(PPh3)4NaOEt

PhMe, 65 °C

98%

I+

Suzuki Cross-Coupling Reactions

Reactants

Regioselective Hydroboration

Csp3–Csp2 Coupling

Epothilone A

Danishefsky,S.ACIE1996,35,2801

OTBS

OTBDPS

OMe

OMe

B

OAc

SN

OTBS

OTBDPS

OMe

OMe

OTBS

OTBDPS

OMe

OMe

BH

THF, rtI

OAc

SN

PdCl2(dppf), AsPh3Cs2CO3

DMF, H2O71%

O

SN

O OH O

OH

O

OMe

OTBSOEtO

O

H H

OMe

OHOHO

O

H H

O

IOEtO

O

H H

OMe

OTBS

BHO

HO

5 mol % Pd(PPh3)4,Tl2CO3, THF/H2O, rt

91%

(+) Herboxidiene GEX 1A

RomeaP.;Urpí,F.OL2011,13,5350;OBC2017,15,1842

Csp2–Csp2 Coupling

Sonogashira Cross-Coupling Reaction

Reactants

R1 X

+

Pd(0)

R2XCu

R2R1

Csp2

XX X: I > Br ≈ OTf >> Cl

pKa 12

H R2 + CuX H R2

CuXR3N

XCu R2 + R3NH

pKa 25

The acidity of Csp–H is enhanced via π-complexation

Pd(0): Pd(PPh3)4

Pd(II): PdCl2(PPh3)2

Doucet,H.;Hierso,J.-C.ACIE2007,46,834

Sonogashira Cross-Coupling Reactions

Reactants

OHTBSO I

MeO O

NCO2Me

OHTBSO

MeO O

NCO2Me

5 mol% PdCl2(PPh3)2CuI, Et3N

CH3CN, –20 °C to rt+

85%

Meyers,A.I.JOC2001,66,6037

5 mol% PdCl2(PPh3)2CuI, Et3N

CH3CN, –20 °C to rt

74%

O

O

I

S

N

CO2Et

TBSO

TBSO

O OO

O

S

N

CO2Et

TBSO

TBSO

O O

Kirschning,A.ACIE2008,47,9134

Stille Cross-Coupling Reaction

Reactants

R1 X

+

Pd(0)

R1 R2

R2 SnR3

Csp2

XX X:I>Br>OTf>>Cl

R2:alkynyl>alkenyl>aryl>benzyl≈allyl>alkyl

Pd(0):Pd(PPh3)4,Pd2(dba)3/PR3orAsR3

Pd(II):Pd(OAc)2/PR3orAsR3

Stille Cross-Coupling Reactions

Reactants

Bu3Sn OTIPS

OO

OH

I

O

OH

OTIPS

OO

OH

O

OH

20 mol% Pd2(dba)3, AsPh3CuTC

NMP, 35 °C

50%

Williams,D.R.JACS2001,123,765

O

OH

OMe

O

I O H OMe

OH

O

NH

O

OH OH

O

I

OMe

O

OH

OMe

O

O H OMe

OH

O

NH

O

OH OH

O

OMe

SnBu3

Bu3Sn20 mol% PdCl2(MeCN)2, i-Pr2NEt

DMF / THF, rt

27%

Nicolaou,K.C.JACS1993,115,4419

ExtraordinaryFunctionalGroupTolerance

Stille Cross-Coupling Reactions

Reactants

Paterson,I.ACIE2017,56,645

AtotalsynthesisofChivosazoleFshowsthetremendouspotentialoftheStillecoupling

MeO

OH

O OH OHO

N

OHO

Chivosazole F

Stille Cross-Coupling Reactions

Reactants

Paterson,I.ACIE2017,56,645

AtotalsynthesisofChivosazoleFshowsthetremendouspotentialoftheStillecoupling

MeO

OH

O OH OHO

N

OHO

Stillecoupling

Stillecoupling

Stillecoupling

Still-Gennariolefination

MeO Br

OTBSO

N

I

Me3Sn

O OOSi

t-Bu t-Bu

O

PO

(OCH2CF3)2

Bu3Sn OH

OTES

Bu3Sn H

O

1Stillecoupling

2Stillecoupling

3SGolefination

TheStillecouplingwerecarriedoutusingPd(PPh3)4andCuTC[copperthiophene-2-carboxylate]

SeeFürstner,A.ChemCommun.2008,2873

Heck Reaction

Reactants

PdL2

R1

PdX

L L

PdR1

R2H

HH

XLPd

H

R2H

R1H

XL

HPdX

LR2

R1

R1 X

R2

L

R1

PdX

LR2

PdX

H L

R1

R2

HXL Oxidative additionReductive elimination

β-Hydride elimination Olefin insertion

E olefin

R1:noß-HX:I,Br,(Cl),OTf

Pd(0):Pd(PPh3)4,Pd(dba)2+PR3

Pd(II):Pd(OAc)2,PdCl2(PR3)2,

PdCl2(CH3CN)2

Base:R3N,R2NHAcO–,CO32–

R1 X HB X+ +cat Pd(0)

R2 Base R2R1

Heck Reaction

Reactants

TheregioselectivityoftheHeckreactionisnotcompletelydefined.Twopathwaysareavailablefortheolefininsertion...

versus

ParticularlyimportantwhenR2:EDG

R1

Pd LXR2

R1

Pd LX

R2

PdR1

LXR2

PdR1

LX

R2

R1

Pd LX

PdR1

LX

R2 R2

HH

HH

R1

R2

R1

R2

– H

– H

ortheβ-hydrideelimination...

Heck Reactions

Reactants

Br

I

Br

OMe

O

OMe

O

CH3CN, Δ

68%

2 mol% Pd(OAc)2 Et3N

CH3CN, Δ

63%

1 mol% Pd(OAc)2 P(o-Tol)3, Et3N

OMe

O

TBSO O I

OMe

HH+ OMe

OTBSO O

OMe

HHOMe

ODMF, Δ

69%

10 mol% Pd(PPh3)4 Et3N

I+ OMe

O DMF, rt

90%

0.02 mol% Pd(OAc)2 Bu4NCl, K2CO3

OMe

O

Reactants

Alternative(IV):C=CBondFormingReactions

FGA

FGA

?

E-Alkene

Z-Alkene

Wittig(stabilizedylides)HWEJulia-KocienskiMetathesis

Wittig(non-stabilizedylides)Still-Gennari,Ando

PetersonolefinationTebbeolefinationTakaiolefination

Reactants

©GarethRowlands

C=C Forming Reactions: Carbanions and Carbonyls

Reactants

Regioselectivityisnotaproblem...Theonlyconcernisstereoselectivity!

C N O

Si P S

X:Si,PetersonReaction

X:P,WittigReactionandvariants

R3P+,WittigReactionR2P=O,Horner-Wittig(RO)2P=O,Horner-Wadsworth-Emmons(HWE)

X:S,Julia-KocienskiReaction

S

NSO

O NN

N

NSO

OPh

GeorgWittigNobelPrizeinChemistry1979

…forthedevelopmentoftheuseofphosphorus-containingcompounds

intoimportantreagentsinorganicsynthesis

+ +R1R3

R4

R2

R1R4

R3

R2

R1 R2

O

R3 R4

X

Wittig Reaction: Concept

Wittigreaction:additionofaphosphorusylidetoacarbonyl

Phosphorus Ylide Phosphine Oxide

R1 H

O

R1 R2R1

R2

R3P R2

H

+ +

ZEThermodynamically favored

Non-stabilized ylidesSemi-stabilized ylides

Stabilized ylides

R2: alkylR2: aryl

R2: CO2R, CN

minor MAJOR mixtures (E > Z)

MAJOR minor

Maryanoff,B.E.CR1989,89,863Nicolaou,K.C.LiebigsAnn.1997,7,1283

R1

R2O

R3

R4R3P

R1

R2

R3

R4+ + O=PR3

Wittig Reaction: Mechanism

ThemechanismoftheWittigreactionhasbeenthesubjectofmuchdebate.Initially,Wittigdescribedthisreactionasanadditiontoacarbonyl...

Betaine OxaphosphetaneYlide

The thermodynamic force of the reaction relies on the P=O bond

R H

O OPPh3R

O PPh3

R

O PPh3

R

PPh3

PPh3

H H

HH

...buttheacceptedpictureintheabsenceoflithiumsaltsisratherdifferentnowadays

Formal [2,2] Cycloaddition Pseudorotation

O P

RPhPh

Ph

R H

O PPh3

HH+ O P

R

PhPhPh

O PPh3

R

Wittig Reaction: Mechanism

Wittigreactionscarriedoutintheabsenceoflithiumsalts(salt-freeWittigreactions)aredescribedaskinetically–controlledtransformations...

R1 H H R2

O PPh3

O PPh3

R1 R2H H

O PPh3

R1 HH R2

P

R2

PhPhPh

O R1HH

R1 R2R1R2

+P

R2

PhPhPh O

R1H

H

O PPh3+

O PPh3+

cis-oxaphosphetane trans-oxaphosphetane

Z alkene E alkeneVedejs,E.JACS1989,111,5861

Aggarwal,V.K.&Harvey,J.N.JACS2006,128,2394Gilheany,D.G.JACS2012,134,9225

Forareview,Gilheany,D.G.CSR2013,42,6670

R2: alkyl R2: CO2R

rds

rds

Wittig Reaction in Synthesis

O

O

OO

H

H H

OH

H

O

O

O

H

HH H

O O

O O

H HH

HH

H

HO

H

CHO

O

O

O

H

H H

OH

H

O

O

O

H

HH H

O

O OH

HH

H

TBSO

H

OTBDPS

RO SS

Et

Et

O

O

O

H

H H

OH

H

O

O

O

H

HH H

OTMS

PPh3

H

I

O

O

O

H

H H H

OTBS

HOTBDPS

EtSEtSH

O

1) BuLi, THF-HMPA, –78 °C

R : TMS

R : HPPTS

Z olefin

75% over two steps

2)

Brevetoxin B

Through Non-stabilized ylide

Nicolaou,K.C.JACS1995,117,10252

Wittig Variants: Concept

Horner-Wadsworth-Emmons

Still-Gennari

Ando

(AlkylO)2POCH2CO2R2

(CF3CH2O)2POCH2CO2R2

(ArylO)2POCH2CO2R2

Phosphonate

Wittigvariants:additionofphosphonatecarbanionstocarbonyls

Phosphonate Carbanion Phosphate salt

R1 R2

O

+R1EWG

R3

R2

ROP EWG

R3

O

RO+RO

PO

O

RO

HWE, Still-Gennari & Ando Reactions: Stereoselectivity

R1 H

O

R1 CO2R2R1

CO2R2

+ +(RO)2P OR2

OO

ZEThermodynamically favored

Horner-Wadsworth-Emmons

Still-Gennari

Ando

(AlkylO)2POCH2CO2R2

(CF3CH2O)2POCH2CO2R2

(ArylO)2POCH2CO2R2

MAJOR

minor

minor

minor

MAJOR

MAJOR

Phosphonate

Still-Gennari Reaction: Stereoselectivity

Still-GennarireactionprovidesareliableentrytoZolefines...

PO

OMe(CF3CH2O)2

O

2) RCHO

1) KHMDS, 18-crown-6, THF RCO2Me

CHOCHO

CHOCHO

12:1 90% 4:1 74% > 50:1 87% > 50:1 95%

PO

OMe(CF3CH2O)2

O

2) RCHO

1) KHMDS, 18-crown-6, THF RCO2Me

CHOCHO

CHOCHO

46:1 88% 50:1 80% > 50:1 79% 30:1 95%

Still,W.C.&Gennari,C.TL1983,23,4405

Ando Reaction: Stereoselectivity

AndoreactionalsogivesZolefins...

Ando,K.JOC.1997,62,1934;JOC.1998,63,8411

CHOCHO

CHOCHO

90:10 100% 91:9 98% 89:11 97% 93:7 98%

PO

OEt(PhO)2

O

2) RCHO

1) NaH or R4NOH, THF, –78 to –10 °C RCO2Et

PO

OEt(PhO)2

O

Bu

H

O

+NaH, THF, –78 °C

CO2Et

Bu

Z / E 95:5 85%

HWE & Variants: Mechanism

ItisgenerallyacceptedthatthestereoselectivityoftheHWEreactionisaresultofbothkineticandthermodynamiccontroluponthereversibleformationoftheerythroandthreoadducts

followedbytheoxaphosphetaneformation,pseudorotation,anddecompositiontoolefins.

Brandt,P.&Rein,T.JOC1998,63,1280Ando,K.JOC.1999,64,6817

R H (RO)2P

O O

OR

O+R P (OR)2

OH

H CO2R

O

R P (OR)2

OH

RO2C H

O

threo erythro

O PO

(OR)2

R CO2R

O PO

(OR)2

R CO2R

R OR

O

OR

OR

E Z

Wittig, HWE & Variants in Synthesis

Yadav,J.S.JOC2012,77,9628

OH

O O O

t-Bu

O

O

O O

t-Bu

O

OP

O

(CF3CH2O)2

O

KHMDS, 18-c-6

THF, –78 °C

Z / E 20:1 80%

OO

OH

N

O

O HTirandamycin C

Still-Gennari

OO O

O O

OO

O

H

P O

O O

(EtO)2

O

THF, 0 °C to rt

NaH

E only 93% HWE

OO

O

HOO CO2Et

Ph3PO

OEt

PhMe, 110 °C

E / Z 10:1 87%

WittigStabilized ylide

Wittig, HWE & Variants in Synthesis

Menche,D.OL2019,21,271Archazolid F

EtOO

O

HEtO

OPh3PCH2Br, BuLi

THF, –78 °C H

O OTBS

89%

OTBS

MeO O

P(OCH2CF3)2

OO

MeO

KHMDS, 18-c-6, THF, –78 °C

OTBS

H O

Wittig

Still-Genari

Z/E > 20:1 90%

P(OCH2CF3)2

OO

MeO

KHMDS, 18-c-6THF, –78 °C

OTBS

O

EtO

OTBS

O

H

Still-Genari

Z/E > 20:1 96%

MeO

HO

O

O

OH

NS

R

P(OMe)2

OO

MeO

BuLi, DMPU, THF, 0 °C

O

MeO

OTBS

ON

O

HR:

HWE

E/Z > 20:1 98%

Julia-Kocienski Reaction: Concept

Het-SH SHet R SHet R

OO[O]

RX (SN2)

or ROH, DEAD, Ph3P (Mitsunobu) Sulphone

S

NSO2R

BT

NN

N

NSO2R

PhNN

N

NSO2R

t-Bu

SO2RN

PT TBT PYR

Julia, 1991 Kocienski, 1998 Kocienski, 2000 Julia, 1993

Julia-Kocienskireaction:additionofsulfonecarbanionstoaldehydes

Blakemore,P.R.JCSPerkinTrans12002,2563;Aïssa,C.EJOC2009,1831

R1

H

OHetSO2 R2+ + SO2 + HetOR1

R2

Julia-Kocienski Reaction: Mechanism

SN

S

OO

R1

SN

S

OOR1

H R2

O

R1 R2

OSS

N

R1 R2

OSSN

OO

OO

R1 R2

OSS

NOO

R1 R2RCHO, Base

B

SO2

OS

N

Sulfoneacidity

SPh

OOR

R

pKa

H

29.0

Me

31.0

t-Bu

31.2

Ph

23.4

ForacomputationalanalysisoftheJuliaKocienskireaction,seeLegnani,L.;Vidari,G.JOC2015,80,3092

Julia-Kocienski Reaction: Stereoselectivity

O

HSN

S

OO

+MN(SiMe3)3

–78 °C to rt E

More E

PhMe

50 : 5054 : 4654 : 46

Et2O

50 : 5050 : 5050 : 50

THF

66 : 3462 : 3854 : 46

DME

70 : 3075 : 2576 : 24

M

LiNaK

O

H +MN(SiMe3)3

–78 °C to rt E

SNN

N N

OO

Ph

More E

PhMe

51 : 4965 : 3577 : 23

Et2O

61 : 3965 : 3589 : 11

THF

69 : 3173 : 2797 : 3

DME

72 : 2889 : 1199 : 1

M

LiNaK

More EKocienski,P.J.Synthesis1998,26

Julia-Kocienski Reaction: Stereoselectivity

Hong,R.ACIE2018,57,16200

E/Z > 20:1 83%

TBSOO

OTMSTBSO

S

N NN

NOO Ph

OO

TBSOO

OTMSTBSO

CHO

OO

KHMDS, THF, –78 °C

SS

N NN

NOOOO

S

N

Ph

O

OTBS

H

O

O

OBL2TBSOO

OTMSTBSO

OO

OR

OTBS

LiHMDS, THF, –75 °C, then HCl

E/Z 12:1 65%

O

OOH

O

OHO

O

HOH

HO

HO

O

R:

Lasonolide A

Stereoselectivity of Wittig, HWE & Variants

Z olefin E olefin

Z olefin E olefin

H EWG

X

H Alkyl

X

Regioselectivity Stereoselectivity(ZversusE)?

Wittig

Still-Gennari & Ando

Julia-Kocienski

Wittig & HWE

+ +R1

R2R1

R2R1 H

O

H R2

X

Synthesis of Natural Products

LHMDS, 5:1 THF-HMPA –78 °C to rt

E / Z 12:1 67%

O

O

O

H

t-Bu

O

O

OS OTBDPS

OON

NN N

Ph O

O

O

t-Bu

O

O

OTBDPS O

O

O

t-Bu

O

O

S

S

NOO

O

O

TBSOH

HI

H(CF3CH2O)2

P CO2MeO

O

TBSOH

HI

MeO2C

KHMDS,18-crown-6THF, –78 °C

E / Z 1:15 85%

O

TBSOH

HI

O

O

OH

HI

O

O

O

t-Bu

O

OTBS

E / Z 20:1 70%LDA, THF, –78 °C

O

O

OR1OO

R1OH

HO

O

OR2

OR1

O

OR1OO

R1OH

HO

PPh3OR2

OR1

O

KHMDS,THF, –78 °C to rt

Z 60%

I

R1: TBSR2:R1: TBSR1: H

Lasonolide ALee,E.JACS2002,124,384

Other C=C Bond Forming Reactions: Peterson Olefination

CHOOPMBTBSO

OTBS

PMBO OPMBTBSO

OTBS

PMBO

Br SiMe3CrCl2, THF, 15 °C

1)

2) KOH, MeOH/H2O

81%

NovartisapproachtoDiscodermolide.OPRD2004,8,92,101,107,113&122

Nozaki-Hiyama-Kishi-typecoupling

R1 H

O+

H R2

SiMe3HO

SiMe3

R1

R2HO

SiMe3

R1

R2

+

R1R2R1

R2

acid acid

baseRemembereliminationreactionstounderstandthemechanism

Other C=C Bond Forming Reactions: Tebbe Olefination

TiClCl

+ AlMe3 TiCl

AlMe2PhCH3, rt+ HCl

R R

OTiClAlMe2+

PhCH3 R R

CH2

Fromamechanisticpointofview,itlookslikeametathesis

TiClAlMe2 Ti Ti

O

O

CH2

Other C=C Bond Forming Reactions: Tebbe Olefination

Ti CH2R H

CH2

R R

CH2O

R H

O

R R

R OR

CH2

O

R OR

R NR2

CH2

O

R NR2

O

R Cl

R OTiCp2Cl

CH2

Olefin Olefin

Vinylether Enamine

Titanium(IV)enolate

Aldehyde Ketone

AmideEster

Acidchloride

O

R X

CH2

R X

Cp2TiMe2

TheTebbe-PetasisvariantutilizesCp2TiMe2

Other C=C Bond Forming Reactions: Tebbe Olefination

TheTebbereagentisanon-basicreagent

Highlyreactiveinfrontofstericallyhinderedcarbonylgroups

Ø

ØO

O

Ph

Ph

OPh

Ph

Wittig Tebbe

89%

4%

38%

97%

77%

63%Pine,S.H.Synthesis1991,165

TheTebbereagentisgeneratedandreactsatlowtemperatureØTheTebbereagentisaLewisacidsensitivetomoistandoxygenØTheTebbereagentislimitedtomethylenationØ

Other C=C Bond Forming Reactions: Takai Olefination

I

IIH

Cr(II)Cr(III)

IIH

Cr(II)Cr(III)

Cr(III)IH

R H

O

Cr(III)

H

R H

I

OCr(III)R

I

IodoolefinsareveryusefulintermediatesforPd-mediatedcouplings

Occasionally,itcanbeappliedtobromoandchloroderivatives

CHOCl OH

Cl

Cl

ClCl

Cl OH

Cl

Cl

ClCl

ClCHCl3, CrCl2THF, 65 °C

47%

Carreira,E.M.Nature2009,457,573

Foraninsightfulanalysisofthemechanism,seeAnwander,R.JACS2018,140,14334

Metathesisakeyreactionbeyondionicanalysis

Olefin Metathesis: A New Reaction?

RobertH.Grubbs.TheDevelopmentofOlefinMetathesisCatalysts:AnOrganometallicSuccessStory,inACR2001,34,18–29

OlefinMetathesis:thereactionofthe90s?

TheNobelPrizeinChemistry2005…forthedevelopmentofthemetathesismethodinorganicsynthesis

YvesCHAUVIN RobertH.GRUBBS RichardR.GRUBBS

Alkenemetathesisinallitsvariousguiseshasarguablyinfluencedandshapedthelandscapeofsyntheticorganicchemistry

morethananyothersingleprocessoverthelast15yearsNicolaou,K.C.ACIE2005,44,4490

Olefin Metathesis: Concept

Metathesis = Meta (change) & thesis (position)

AB + CD AC + BD

Olefinmetathesiscanbeformallydescribedasthe

intermolecularmutualexchangeof

alkylidenefragmentsbetweentwoolefins

promotedbymetal-carbenecomplexes

Nicolaou,K.C.ClassicsinTotalSynthesisII.p.162

R1 R2 R1

R2+

[M]+

GrelaK.OlefinMetathesis.TheoryandPractice.WileyForananalysis,seeACIE2015,54,3856

Olefin Metathesis: Features & Mechanism

Olefinmetathesisisa

reversible,

catalyticprocess(1–5mol%),

withhighlevelsofchemo-,regio-,andstereoselectivity

Exceptforthesynthesisofsmallcycles,

thereversiblecharacterofolefinmetathesisusually

resultsintheformation

ofthethermodynamicallymostfavorableEproduct. M

R1 R2

M

R1

M

M

R1

R1R2

R1

R2

CURRENTCHALLENGE:KINETICSTEREOCONTROL

Fürstner,A,Science2013,341,1357Fischmeister,C.ChemCatChem2013,5,3436

Grubbs,R.H.Chem.Sci.2014,5,501Cycloaddition

Cycloaddition

R1R2+ +R1

R2M

Olefin Metathesis: Catalysts

Rutheniumcarbenes,[M]=,themostcommoncatalystsusedinolefinmethathesissofar

MesN NMes

Ru CHPh

PCy3

Cl

Cl

PCy3

Ru CHPh

PCy3

Cl

ClMoN

(F3C)2MeCO(F3C)2MeCO

i-Pr i-PrPhTi

Cp

CpW(CO)5

R

Ph

Grubbs I 1995 Grubbs II 1999Schrock 1990Katz 1976 Tebbe 1978

MesN NMes

Ru

O

Cl

Cl

Hoveyda 2000

MesN NMes

Ru

O

Cl

Cl

Grela 2002

NO2

Nicolaou,K.C.ClassicsinTotalSynthesisII.p.162Foranaccountofdifferentrutheniumcatalysts,Grela,K.ASC2013,355,1997

ForaperspectiveonOlefinMetathesis,Hoveyda,A.H.JOC2014,79,4763

R1 R2 R1

R2+

[M]+

N N

Ru

OOO

NO

R

RR MorecomplexrutheniumbasedcomplexesarebeingdevelopedtoachievehighZstereoselectivity

Olefin Metathesis: A Powerful Synthetic Tool

Nicolaou,K.C.ClassicsinTotalSynthesisII.p.162Blechert,S.ACIE2003,42,1900;Nicolaou,K.C.2005,44,4490

Schrodi,Y.&Pederson,R.L.AldrichimicaActa2007,40,45Hoveyda,A.H.Nature2007,450,243;Mori,M.ASC2007,349,121

Grela,K.CR2009,109,3708;Fürstner,A.CC2011,47,6505;Fürstner,A.ACIE2013,52,2Sarabia,F.Synthesis2018,50,3749

Metathesisiswidelyconsideredasoneofthemostpowerfulsynthetictoolsinorganicsynthesis

C1 C2C3 C4

C1C3

C2C4

+Cat

CrossMetathesis

C1 C2C3 C4

C1C3

Cat C2C4

+ Ring-ClosingMetathesis(RCM)

C1C3

C2C4

+Cat C1 C2

C3 C4Ring-OpeningMetathesis

C1 C2C3 C4

Cat C1C3

C2C4

EnyneMetathesis

C1C3

C2C4

C1 C2C3 C4

Cat+ AlkyneMetathesis

Cross Metathesis

R1

R1

R2

R2+R1R1

R2R2

CrossMetathesishastofacenon-selectivecouplings...

R1

R1

EWG

R1R1 EWG

EWG+ EWG

ThegeometryoftheresultantolefinturnstobeE,thethermodynamicallymoststableisomer

Cross Metathesis

O

O

H

O

O

N O

Bn

O

O

O

N O

Bn

O

OSiMe3

O OSiMe3 SiMe3

Ph3PMe Br

THF, 0 °C

84%

MesN NMes

Ru CHPh

PCy3

Cl

Cl5 mol%

CH2Cl2, 40 °C, 36 h

BuLi

2 equivalentsWittig

Ghosh,A.K.JACS2003,125,2374

O

OSiMe3

O

OMe3Si

O

N O

Bn

O

O

NO

O

Bn

O

OSiMe3

MesN NMes

Ru CHPh

PCy3

Cl

Cl

5 mol%

CH2Cl240 °C, 36 h

69% + 25%

Cross Metathesis

TBSO

TBSO

O

MesN NMes

Ru

O

Cl

ClNO2

(1–2.5 mol %)EWG+CH2Cl2, rt, 30 min–16 h

TBSO EWG

TBSO OMe

O

TBSO SO2Ph E only 90%

E/Z 95:5 95%

E/Z 99:1 82%Grela,K.ACIE2002,41,4038

Romea,P.&Urpí,F.OL2011,13,5350;OBC2017,15,1842

OH

OMeOOH HHO

O

(+) Herboxidiene /GEX 1 A

OH OH

OBn

OH

EtO2C

OBnHO

MesN NMes

Ru

O

Cl

Cl5 mol %

CH2Cl2, rt, 24 h

E/Z > 97:3 90%

CO2Et

Ring-Closing Metathesis

HN

O

ONH2

OHHO

O

HN

O

ONHCbz

OAcAcO

O

HN

O

ONHCbz

OAcAcO

O

PhH, rt, 4 h

92%

MoN

(F3C)2MeCO

(F3C)2MeCO

i-Pr i-PrPh

Sch38516Hoveyda,A.H.JACS1997,119,10302

MesN NMes

Ru CHPh

PCy3

Cl

Cl

EtO2CEtO2CEtO2C

EtO2C

1 mol%

CH2Cl2, rt, 1.5 h

99%

1 mol%

CH2Cl2, rt, 1.5 h

99%

TsNTsN

MesN NMes

Ru

O

Cl

ClNO2

2.5 mol%

CH2Cl2, rt, 4 h

99%

O OR

O OR

OPhPh

1 mol%

CH2Cl2, rt, 2 h

99%

O

Ring-Closing Metathesis

O O OBn

OH

TIPSO

HOO O OBn

OH

TIPSO

HO

MesN NMes

Ru

O

Cl

Cl

10 mol%

PhMe, 100 °C

80%

O OOH

O

O

Kozmin,S.JACS2011,133,12172

Streptolic acid

O

O

PCy3

Ru CHPh

PCy3

Cl

Cl

H2C=CH2

2 mol%

CH2Cl2, rt

98%

O

O

O

PMBO

HOPMB

O

HO

O

MesN NMes

Ru

O

Cl

Cl

25 mol%

PhMe, Δ

76%

ROM & RCM

HOHO

HOOH

O

H

Wood,J.L.JACS2004,126,16300

Ingenol

Ring-Closing Metathesis

Foraninsightfuloverviewoftheimpactof

RCMinthesynthesisofpharmaceuticalcompoundssee

YuM.;Lou,S.;Gonzalez-Bobes,F.OPRD2018,22,918

HWE & Enyne & Cross Metathesis

TOTALSYNTHESISofDIHYDROXANTHAIN:synthesisofC=Cinaction

OMeTBSOO

OPMe OMe

OMe , BuLi

THF, –78 °CTBSO

O OP

OMeOMe

, Et3N, LiBrH

O

THF, 0 °C to rtTBSO

O

75% over two steps

HWE

TBSOO O

H

H

OO

H

H

O

MesN NMes

Ru CHPh

PCy3

Cl

Cl

CH2Cl2, rt

70%

5 mol% Enyne metathesis

OH

H

OO

H

H

O

MesN NMes

Ru CHPh

PCy3

Cl

Cl

CH2Cl2, rt

66%

5 mol%

O

OH

H

OO1) LDA, THF, –78 °C

2) MeI

dr 20:1 90%

Cross-Metathesis

Morken,J.P.OL2005,7,3371

Cross Metathesis: E/Z Diastereoselectivity

German Edition: DOI: 10.1002/ange.201411588Olefin Cross MetathesisInternational Edition: DOI: 10.1002/anie.201411588

Z-Selective Cross Metathesis with Ruthenium Catalysts:Synthetic Applications and Mechanistic ImplicationsMyles B. Herbert and Robert H. Grubbs*

cross metathesis · natural products ·olefin metathesis · Z-alkenes

1. Introduction

Olefin cross metathesis (CM) has been widely utilized forthe formation of complex natural and nonnatural products,generally favoring formation of the more thermodynamicallystable E- (or trans) carbon–carbon double bond isomer.[1]

Olefin metathesis reactions proceed through a [2+2] cyclo-addition reaction of an olefin with a metal alkylidene,generating a metallacyclobutane intermediate which can thenundergo cycloreversion to produce a new olefin product(Scheme 1). Research into the structure and stability of

substituted metallacyclobutanes has led to the developmentof catalysts capable of producing Z- (or cis) olefins with highstereoselectivity.[2] This was first realized by the groups of

Schrock and Hoveyda, who synthe-sized monoaryloxide pyrrolide com-plexes of tungsten and molybdenumthat could promote a variety of Z-selective metathesis reactions.[3]

More recently, a series of ruthe-nium catalysts with cyclometalated N-

heterocyclic carbene (NHC) ligands capable of promoting Z-selective olefin metathesis has been reported. Catalysts 1–3are three of the best-studied catalysts and are all derived fromC!H activation of the N-adamantyl substituent contained onthe NHC ligand (Figure 1).[5] Catalyst 1 features an N-mesityl

(Mes) group as the nonchelated NHC substituent and issubstituted with a pivalate X-type ligand. This catalystpromoted the homodimerization of terminal olefins with ca.90% selectivity for the Z-olefin at as low as 1 mol% catalystloading. Catalyst 2 was obtained by substitution of thepivalate ligand with a nitrate ligand, to produce a catalystthat showed a marked improvement in selectivity, exhibitingabout 95% Z-selectivity across a broad range of homodime-rization reactions. When the nonchelating N-aryl NHCsubstituent was changed to a bulkier N-DIPP (2,6-diisopro-pylphenyl) group, a further improvement in Z-selectivity wasobserved, as catalyst 3 exhibited > 98 % Z-selectivity inanalogous homodimerization reactions. Catalysts 2 and 3 also

Olefin cross metathesis is a particularly powerful transformation thathas been exploited extensively for the formation of complex products.Until recently, however, constructing Z-olefins using this methodologywas not possible. With the discovery and development of three familiesof ruthenium-based Z-selective catalysts, the formation of Z-olefinsusing metathesis is now not only possible but becoming increasinglyprevalent in the literature. In particular, ruthenium complexescontaining cyclometalated NHC architectures developed in our grouphave been shown to catalyze various cross metathesis reactions withhigh activity and, in most cases, near perfect selectivity for theZ-isomer. The types of cross metathesis reactions investigated thus farare presented here and explored in depth.

Scheme 1. Mechanism of olefin metathesis.

Figure 1. Cyclometalated ruthenium catalysts for Z-selective olefinmetathesis.

[*] Dr. M. B. Herbert, Prof. Dr. R. H. GrubbsDepartment of Chemistry and Chemical EngineeringCalifornia Institute of TechnologyPasadena, CA, 91125 (USA)E-mail: rhg@caltech.edu

.AngewandteMinireviews R. H. Grubbs and M. B. Herbert

5018 ! 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2015, 54, 5018 – 5024

Grubbs,R.H.ACIE2015,54,5018

Z-Selectiveolefincrossmetathesiscanbeachievedbyusinganewgenerationofrutheniumcatalysts

R2 R RRu-catalysts 1–3

THF, 35 °C+

Cross Metathesis: E/Z Diastereoselectivity

Hoveyda,A.H.Science2016,352,569

Thermodynamicallydisfavouredalkylchlorides

canalsobepreparedthroughcrossmetathesis

Cross Metathesis: E/Z Diastereoselectivity

Grubbs,R.H.ACIE2017,56,11024

CatalystscannowadaysprovidekineticallycontrolledEandZolefinmetathesis

Cross Metathesis: E/Z Diastereoselectivity

O

BocOMgBr

OTBS

H

O

i. CuBr·SMe2, LiCl, THF, –78 °C

ii.O OTBSOH

O OTBS

MsCl, DMAP

CH2Cl2

45%

O OTBS

OH OHHO

Ru

NNAr ArS

S

Cl

Cl

O5 mol%

THF, 40 °C95% > 99:1 Z/E

Xu,C.,Stoltz,B.&Grubbs,R.H.JACS2018,XXX,XXX

O OH

CO2H

1) TPAP·NMO CH3CN

2) HF, CH3CN

89% ∆12-PGJ2

Diels-Alderakeyreactionbeyondionicanalysis

SeeChapter6&7

Ring-Closing Metathesis

Diels-AlderandRing-ClosingMetathesis:twoapproachestocyclohexenes

+

Diels-Alder RCM

+ 2 C–C & – 1 C=C

(Catalytic)process

Interorintramolecularprocess

Reversible

Uptofournewstereocenters

0 C–C & 0 C=C

Catalyticprocess

Intramolecularprocess

Reversible

Nonewstereocenters