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.
Justine deGruyterBaran Group Meeting
02/07/2015Robert G. Bergman
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
Justine deGruyterBaran Group Meeting
02/07/2015Robert G. Bergman
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
Justine deGruyterBaran Group Meeting
02/07/2015Robert G. Bergman
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.
Justine deGruyterBaran Group Meeting
02/07/2015Robert G. Bergman
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.
Justine deGruyterBaran Group Meeting
02/07/2015Robert G. Bergman
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.
Justine deGruyterBaran Group Meeting
02/07/2015Robert G. Bergman
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.
Justine deGruyterBaran Group Meeting
02/07/2015Robert G. Bergman
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
