robert g. bergman justine degruyter - the scripps … · justine degruyter baran group meeting...

Justine deGruyterBaran Group Meeting

02/07/2015Robert G. Bergman

• Born:Chicago,IL.1942Educa&on• B.A.:CarletonCollege,1963• Ph.D.:UniversityofWisconsin,Mad.,1966

NIHFellow,JeromeA.Berson• Post‐doc:ColumbiaUniversity,1967

NATOFellow,RonaldBreslow

IndependentCareer• CaliforniaInsRtuteofTechnology

‐1967:NoyesResearchInstructor‐1969:AssistantProfessor‐1971:AssociateProfessor‐1973:ProfessorofChemistry

• UniversityofCalifornia,Berkeley‐1977:ProfessorofChemistry‐2002:G.E.K.BranchDisRnguishedProfessorLawrenceBerkeleyNaRonalLaboratory

HonorsandAwards• 1969:AlfredP.SloanFellowship• 1984:NaRonalAcademyofSciences• 1984:AmericanAcademyofArtsandSciences• 1986:ACSAwardinOrganometallicChemistry• 1987:ACSArthurC.CopeAward(1996)• 1994:DOEE.O.LawrenceAwardinChemistry• 2003:ACSJamesFlackAwardinPhys.Org.Chemistry• 2007:NASAwardinChemicalSciences

Commi6eeMemberships• EditorialBoards(JOC,Organomet.,ChemRev.,IJCK,JACS,OL.• ACSExecuRveCommi^ees(Org,Inorg.,Organometallic)• DepartmentReviewCommi^ees(Caltech;UN,Reno;UM,AnnArbor;Harvard;Rutgers;NCState;UCSB

ResearchInterestsbyDecade• 1960s:ReacRvityofmethylnorbornylderivaRvesandcyclopropyl‐carbinylcaRons• 1970s:mechanismsoforganicreacRons;“unusuallyreacRve”molecules(e.g.1,3‐diradicalsandvinylcaRons);BergmancyclizaRon;organometallicchemistry• 1980s:synthesisandchemistryoforgano‐TMs,migratoryinserRonandoxidaRveaddiRonreacRons,chemistryofdinuclearcomplexes,organo‐TMenolates,• 1990s‐present:C−HacRvaRon,GreenChemistry

‐>577paperspublishedtodate ‐Mentoredover200undergraduates,graduatestudentsand

postdocs‐Numerousteachingawards

PublicOutreachEfforts• Outspokenadvocatefortheadvancementofethicsinscience• CreatedtheCommunityintheClassroom(CIC)ProgramatUCB

TopCitedPapers1.“Rhodium‐CatalyzedC‐CBondFormaRonviaHeteroatom‐

DirectedC‐HBondAcRvaRon.”Chem.Rev.2010,110,624.2.“SelecRveIntermolecularCarbon‐HydrogenBondAcRvaRonbySyntheRcMetalComplexesinHomogeneousSoluRon.”Acc.Chem.Res.1995,28,154.3.“ReacRve1,4‐dehydroaromaRcs.”Acc.Chem.Res.1973,6,25.4.“C‐HAcRvaRoninCompletelySaturated‐Hydrocarbons‐DirectObservaRonofM+R‐HM(R)(H).”JACS.1982,104,352.5.“ParaBenzyne‐GeneraRonasanIntermediateinaThermalIsomerizaRonReacRonandTrappingEvidencefor1,4‐BenzenediylStructure.”JACS.1972,94,660.



S S SR'

O OR

H

HO

NHAc

HS R 2

O

HO

NHAc

S OR

O

HO

NHAc

S OR

O

HO

NHAc

S OR

Calicheamycin

Bergman Cyclization

O2

Enediyne drugs: "smart bombs"- delivery system- warhead- safety catch

H

H

cd. 4.12Å

vs.

cd. ca. 2.98-3.02Å

dsDNA

cleavedDNA

Reac1ve1,4‐Dehydroaroma1cs

EnediyneDrugsImineMetathesis

ZrTHF

NtBu

NR2

HR1

NR4

HR3

NR4

HR1

NR2

HR1

N[Zr]

N

R1

R

H

R

N[Zr]

N

R

R1

H

R

[Zr] NR

[Zr] NR1

NR1R

H

NR1R1

H

NRR1

H

NRR

H

Me

MeMe

MeMe

MetalEnolates

Rh ClOC

PMe3

PMe3

R

CHO

tBuMe

OK

PhMe, —40°C tBu

O

Me

ORh

R

Me3P

PMe3OC

R= H, Me

TMSClPhH, rt

tBu

O

Me

OTMS

R

Ph

ORh

Me3P

PMe3

CO

PhMe

OTMS DMSO

Ph

ORh

Me3P

PMe3

CO

Me Ph

OTMS

89:11 syn:anti

R1

R2

OTMSPhCHO

1

1 (1-4%)

R1 Ph

OTMS

R2

O- TONmax= 100- syn:anti ratios dependent on reaction conditions

I

Me

O

OAc

OTs

AgNO2

H2O

AgOAc

HOAc

AgOTs

MeCN

1‐CyclopropylvinylCarboca1ons

JACS.1971,93,1925.JACS.1969,91,2115.

JACS.1998,120,11828.

JACS.1989,111,938. Acc.Chem.Res.1973,6,25.(andreferencestherein)

“ControllingtheReacRvityofBergmanandMyers‐SaitoCyclizaRons.”D.A.Ryan,UIUC(2002).

Cl

Cl

CH2OH

RH

CCl4

MeOH

150-200°C

PhH, CHD

Bergman Cycloaromatization

*

H H

H

H

H

H

HH

H

H

H

H

*

*= +, —, •

- H2O

H

H

O OO400°C slow



C−HAc1va1on:The“HolyGrail”

Iridium(I)

Cp*(L)IrH2

[Ir]Me

XMe

H

(L)

Cp*X= NH2

X= OH

[Ir]Me

NH2

MeCl

(L)

Cp*

[Ir]Me

OHMe

Cl

(L)

Cp*

IrN

H H

Me

MeL

Cp*

IrX

Me

MeL

Cp* X= NHX= OH

Ir X

N

tBu

Cp*

L

MeMe

IrO

X

O

Me Me

Cp*

L

IrN

Me

MeL

Cp*

HO O

IrN

Me

MeL

Cp*

N O

H

tBu

h!

tBuX CHCl3

CHCl3 (TMS)2NK

tBuNCCO2

(X=O)CO2

(X=NH)tBuNCO(X=NH)

(TMS)2NK

Cp*(PMe3)Ir(CH3)(OTf)

[Ir]

TfO+ 13CH4

+ CH4

[Ir]13CH3

OTf[Ir]

TfO

Me

Me

H2C

Me

[Ir]

OTfMe

Me

[Ir]

OTf

C2H6

[Ir]

H

H2CCH2 OTf

Me4C

no reaction

Iridium(III)

LnM L + Ln-1M

R

H

Ln-1MR

Ln-1M

H

M—R1 + R

2—H M

R1

H

R2

M—R2

R1—H+

R—H

ox. add'n

!-bond

metathesis

(1)

(2)

Me

Me [Ir]

PMe2

H

HMe

Me

[Ir]

PMe2

Ph

XMe

Me

[Ir]

PMe2

X

PhMe

Me

[Ir]

PMe2

C6H11

HMe

Me

[Ir]

PMe2

H

C6H11Me

Me

+h!

h!

h!

150°C

X

X

1a (X=H)

2a (X=Cl)

1b (X=H)

2b (X=Cl)

150°C

1a + 1b

• Bondstrength:90‐100kcal/mol• Ubiquitous,butdifficulttodifferenRate• MechanisRcinsightallowsforopRmizaRon/scopeexpansion

JACS.1998,120,3253.

JACS.1993,115,10462.

Science.1995,270,1970.

JACS.1988,110,3704.

JACS.1982,104,352.

"We now wish to report the discovery of an organotransition-metal system capable of intermolecular oxidative addition to single C—H bonds in saturated hydrocarbons...in

high yield at room temperature in homogeneous solution."

[(Me5C5)IrCl2]2

Me

MeMe

Me

Me Ir HH

PMe3

[Ir]

[Ir]

H

H

[Ir]

H

h!/C6H12

h!/PhH

h!/Me4C

1. PMe3

2. LiEt3BH

Me

MeMe

Me

Me Ir HR

PMe3

CHBr3

Al2O3

PhH

Me

MeMe

Me

Me Ir RBr

PMe3

Me

MeMe

Me

Me Ir HC6H5

PMe3

+ CH2Br2

+ R—H



Zirconium‐Mediated

RhH2

Me3P

Me

Me

Me

Me

Me

O

O

[Rh]

H

H

H

H O

[Rh]

I

H

H

H

H[Rh]

O

H H

H

H[Rh]

O

H H

I0°C

CHI3

—78°C

25°C

CHI3,—78°C

h!, —50°C

O

[Rh]

H

Y

X

X

O Y

X

X

[Rh]

[Rh]X

O

X

Y

O

X

[Rh]X

X

O

Y

[Rh]X

Possible Mechanistic Pathways

1,2-[Rh] Migration

1,2-H Migration

Rhodium‐Mediated

Me

MeMe

Me

Me Ir MeClCH2Cl

PMe3

B(Arf)4[Ir]

ClH2CCl

[Ir]ClCH2Cl

13CH3

[Ir]H

[Ir]H

Me

CH2Cl2 CH2Cl2

[Cp2Zr=NR]

NZr

N

ZrCp

CpCp

Cp

R

R

NZr

Cp

Cp

R

R2

R1

R1

RHN H

R2

R1R2

O

ZrN

R

O

Cp

Cp

Cp2Zr(NHR)2

ZrNHR

Me

Cp

Cp

Cp2Zr(CH3)(X)

ZrNHR

Ph

Cp

Cp

R1C CR2

H2O/Silica Gel

H2O

THF

RNH2

- CH4

1,3-enamine dianion synthons

LiquidNobleGases

[Cp2Zr=NtBu]

X X

X

X[Zr]

NHtBu

[Zr]NtBu

THF

[Zr] NHtBu

ZrNHtBu

CpZrBuHtN

Cp

Fe

[Zr]

NHtBu

Re(CO)3

[Zr]

BuHtN

Re(CO)3

[Zr]

BuHtN

[Zr]

NHtBu

Mn(CO)3

[Zr]

BuHtN

75°C 75°C

THF -THF

Cp2Fe, cy. CpRe(CO)3, cy. CpMn(CO)3, cy.

75°C

JACS.1989,111,7628.

JACS.1995,117,5877.JACS.1988,110,8729.

JACS.1989,111,6841.

Me

MeMe

Me

Me Ir HH

PMe3

[Ir]H

Me

[Ir]H

[Ir]H

[Ir]

H

[Ir]OH

Me MeH

OH

Me

[Ir]H

OMe[Ir]

H

[Ir]O Me

H

[Ir]H

CH4

[Ir]H

tBuOHiPrOH

MeOH

EtOH

- Interaction energy between M and Kr or Xe ! 5-10 kcal/mol- Interaction energy between M and liquid alkanes ! 8-12 kcal/mol

Science.1995,270,1970.



Bergman‐Arnold

Me

Ph

Ph

H

Me

H

N

N

Me

Me

Nb

ArCO

CO

NtBu

Ar

1 atm CO (12 equiv)1 equiv. H2

20% molar 1

PhH

1

Z-!-methylstyrene75%

N

N

Me

Me

Nb

Ar

Ar

NtBu

Me

Ph

Niobium(III)ImidoComplexes

N

N

Me

Me

Nb

ArMe

Me

NtBu

Ar

N

N

Me

Me

Nb

ArF

F

Ar

F

NtBu

RCF3

R

neat

1 atm H2

12 h, rt

- 2 CH4

JACS.2013,135,8145.

JACS.2011,133,14904.

N

N

Me

Me

Nb

Ar

N

Ar

Ar

NtBu

N

N

Me

Me

Nb

Ar

N

tBu

Ar

NAr

NbN

Me

Me

Ar NtBu

NAr

L

+

ArN3

!

- THF, - N2

JACS.2014,136,2994.

TantalumComplexes

Ta

N

N

N

N

Me

N

O

R

R=H, CH3

Ta

N

N

N

N

O

Me NR Me

+

N

N= Me

NH2

NH2

TMS

TMS

Organometallics.1999,18,4465.

DaltonTrans.2006,203.

ForfurtherreadingonrecentRGBcollaboraRonssee:BurnsGroupMeeRngs−Ma^Landry(Stanford)

TaNCMe3

3 PhCH2MgCl

Cl3(py)2

TaNCMe3

Ph

Ph

Ph

Ph3CB(C6F5)4-

TaNCMe3

PhPh

B(C6F5)4

Ph

Ph

Ph

Ph

Ph

Ta

B(C6F5)4

PhPh H2NPh1 (5 mol%)

C6D5Cl, 135°CPh

Ph

NPh

Ph

PhHN

Ph

+ +

1 2

H2N

2 (5 mol%)

135°C, C6D5Cl

HN

Ph

H2N

+

•

NH2

Me Me

2 (5 mol%)

135°CN

Me MeMe

Me

H

HNH2

2 (5 mol%)

135°C

N

Me

Me

R1

R2

H2NPh

[Ta] (5 mol%)

135°C, C6D5ClR1

N

R2

Ph

R1

N

R2

Ph

Markovnikov anti-Markovnikov

+

Ta

N

N

N

N

Me

MeI

Ta

N

N

N

N

Me

Me

IRCN

R=Tol, MeTa

N

N

N

N

N

Me

R

CN

Me

Me

Ta

N

N

N

N

Me

N

Me

Me

Ta

N

N

N

N

Me

SS

Me

Me

-

Org.Le6.2004,6,2519.Org.Le6.2006,8,2445.



Bergman‐Toste‐Raymond

O

Me

Me

Me OHMe

Me

Me

OHMe

Me

OH

Me

Me

Me

OHMe

Me

Me

OHMe

Me

MeOH

Me

O

O

MeMe

Me

Me

Me

H+

+ H2O

- H+

+ 1 - H2O

- 1 + H2O

trans preference

cis preference

Path A

Path B

JACS.2013,135,18802.JACS.2012,134,17873.

Bergman‐Toste

JACS.2008,130,3777. Org.Le6.2009,11,3698.

X

NCo

N

O

O

Me

MeMe

Me XR

O

X

R OH

O

HO

H

H2N

H2N

O

HO

H

NCo

N

O

O

Me

MeMe

Me

OLiAlH

125°C, µwaveOH

Me

MeMe

Me

NCo

N

O

OMe

MeMe

Me

NCo

N

O

OE

E+, Sc(OTf)3, LHMDS

5:1 THF:HMPA, rt

E+= Michael acceptor

X

NCo

N

O

O

Me

MeMe

Me XR

O

X

R OH

NitrosoCobaltComplexes

PolymersN

Ms

Me

DMF, 45°CN

Ms

Bn

Me

N

Ms

H23

Mn= 3300, PDI=1.04

N

Bn

Ms1 equiv. N

Ms

Me

DMF, 45°C

4 equiv.

N

Ms

Bn

Me

N

Ms

H107

Mn=14,700, PDI=1.01

O X

O

OH

X

O

NMe2m n

m

O

O

O

O

Me

MeO

H O

O

NMe2n

Me

MeO

1

neat, 25-75°C

1

PhMe, 75°C

1/2 [Al(NMe2)3]2 +

NH

TMS

NH

TMS

PhMe

100°C, 60 min

- HNMe2

N

TMS

N

TMS

AlNMe2

NHMe2

1

JACS.2005,127,17616.

Organometallics.2011,30,3217.

Me MeMe OH

Me Mea= E,Eb= Z,Zc= Z,E

7% Ga-host

1:1 D2O:[D6]DMSO45°C, pD= 8.0

MeMe

Me Me

MeHN OO

Me

Me

Me

Me

NH

O

O

a or b

7% Ga-host

Unbuffered D2O

rt

a

b

c

kcat (s-1) kuncat (s

-1) kcat/kuncat

2.9(4) x 10-2

1.6(1) x 10-2

5.7(1) x 10-2

4.0(3) x 10-8

7.7(8) x 10-9

3.3(1) x 10-8

(730,000)

2,100,000

1,700,000

Chem.Eur.J.2014,20,3966.

R1 R3

R4R2

1, NO

0°C

N

CoN

O

O

Cp R1

R2R4

R3LiAlH H2N R1

R2

R3H2NR4

NCo

NCo

O

O

CpCp1=

JACS.1980,102,5676.Organometallics.1983,2,787.



N

HN

N

HN

[RhCl(coe)2]2 (5 mol%)PCy3 (7.5 mol%)

MgBr2 (5 mol%)150°C, THF

N

HN

RS

NR

O

NR

N

SMe

Me R

N

N

NH

NR

R

R=

NH

NO

O

NH

N

OOiBu

N

SMe

MeO

OtBu

N

SMe

Me

CN

BnN R1

X

R3

R2

X= CH2, O, NRn= 0,1

X

O R1R2

R3

X

O R1R2

R3or

1. (PPh3)3RhCl125 or 150°C, PhMe

2. I N HCl (aq.)n n

n

O Me O Me

O

O MeMe

N

O MeMe

R

R=Me, Ac, SO2Ph

O

O HMe

N

N

N

N

[RhCl(coe)2]2 (5 mol%)PCy3 (7.5 mol%)

THF, 160°C

N

N

N

N

N

N

N

N

N

N

X

N

R2

R1 I

R3 X

N

R2

R1

R3

n

n

[RhCl(coe)2]2 (5 mol%)PCy3 (40 mol%)

EtN3 (4 equiv)THF, 150°C

NH

NPh

O

NPh

N

N Ph

O

NPh

JACS.2001,123,2685.

JACS.2001,123,9692.

JACS,2002,124,13964.

Org.Le6.,2004,6,35.

Bergman‐Ellman

HeterocyclicC−HAc&va&on

MeBnN

R

R

MeBnN

Me

MeBnN

SiMe2Ph

MeBnN

Ph

MeBnN

N

MeBnN

MeO

Me

MeBnN

[RhCl(coe)2]2 (5 mol%)

Ligand (15 mol%), PhMe

JACS.2004,126,7192.

JACS.2008,130,2452.

Me

NMe

H

N Me

Me[RhCl(coe)2]2 (5 mol%)

(p-NMe2)PhPEt2

PhMe, 100°C

mechanism?

TMS

R5

R1 R3

NR4

R2

NR4

TMS

R5

R1

R2

R3

NR4

R5

R1

R2

R3

NR5

R1

R2

R3

Bn

R7

R6

NR4

Me Me

Me

H

R

[RhCl(coe)2]2 (2.5 mol%)

4-Me2N-C6H4-PEt (5 mol%)

PhMe, heat

not isolated

(PhO)2PO2H

Me4NBH(OAc)3

(PhO)2PO2H

R6

R7

1. PhSO3H

—78°C

2. Me4NBH(OAc)3

JACS.2013,135,2478.



HO

OH

O O

CO2H

O

CO2H

OH

OH

CHO

OMe

OMe OMe

OMe

CO2Me

CHO

O

OMe

MeO2C

OMe

OMe

O

OMe

CHO CO2Me

OMe

OMeO

OMe

CO2Me

OMe

OMe

CO2H

O

OMe

CO2Me

OMe

OMe

OO

OMe

MeO

CO2Me

1. CBr4, PPh3, 88%

2. i. nBuLi ii. ClCO2Me 93%

isovanillin, Na, MeOH

MeOH: py. (1:1), 120°C59%

1. (R)-(-)-aminoindane PhH, reflux, 99%2. i. [RhCl(coe)2]2, FePCy2

PhMe, 75°C ii. HCl, H2O, 88%

75% ee56%, 99% ee after recryst.

piperidine, py. 100°C, 85%

HO OH

O O

OMe

MeO

CO2Me

OH

EDC, DMAPCHCl3, 80%

N

TMS

neat, 100°Csealed tube

35%

TotalSynthesisof(+)‐LithospermicAcid

JACS.2005,127,13496.

TotalSynthesisofBiologicallyAc&veDihydropyrroloindoles

N

N Cl

Cl

OH

O Cl

OH

Cl

Br

Cl Br

N

N

Cl

N

N NMe2

1. H2SO4, MeOH 85°C, 94%

2. DiBAl-H, CH2Cl2 —78°C, 96%

PBr3

CCl4, 0°C(96:4), 96% (mix)

K2CO3, DMF 0°C to rt

>20:1 regioselectivity, 65%

NH

N

[RhCl(coe)2]2 (5 mol%)2 (15 mol%)

o-Cl2C6H4

1.

CuI (25 mol%)

F3C NH2

O

(2 equiv)

NHMe

NHMe

(50 mol%)

K2CO3, 1,4-dioxane140°C

2. HCl, H2O, 52% brsm

3. KHFe(CO)4, CH2O, 5 bar CO, EtOH, 105°C 58%

TotalSynthesisofVasicoline

PCy

2=

Org.Le6.2006,8,1745.

JOC.2006,71,1969.ClCl

Me3SnOH R= Me

R= H

N

OH

OMe

N

OH

OMe

NOMe

N

Br Br

OO

PG

NOMe

N

Br

O

O

PG

NOMe

HN

NH

O

O1. RNH2, 3 Å ms PhH, rt,

2. i. [RhCl(coe)2]2 (10 mol%) 20% L, PhMe, 90°C ii. 10% AcOH/THF 61%, 90% ee

RhCl(dppp)2 (5 mol%)

xylene, reflux, 86% K2CO3, THF, 85°C75%

1. Pd(OAc)2 (5 mol%) (R)-BINAP (7.5 mol%) Cs2CO3, PhMe, 105°C 62%

2. CH3SO3H, CH2Cl2, 61%

OOMe

OO

CO2Me

OMe

OMe

CO2MeOMe

MeO

OOH

OO

CO2Me

OH

OH

CO2MeOH

HO

robert g. bergman justine degruyter - the scripps … · justine degruyter baran group meeting...

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