Post on 03-Feb-2022
MacMillan Group Meeting!5-20-09!
by!
Anthony Casarez!
H !
Me
H
!Me
Kurt Alder!
!" Born: Königshütte, Upper Silesia in southern Poland, on the 10th of July 1902.!
!" Education: Began chemistry at the University of Berlin in 1922 then finished his PhD in 1926 at the University of Kiel for work supervised by Otto Diels.!
!" Notable Award: Nobel Prize in Chemistry (1950) with Otto Diels for the 4 + 2 cycloaddition (Diels-
Alder) discovered in 1928. !
A Pericyclic Reaction!
Alder, K.; Pascher, F.; Schmitz, A. Ber. Dtsch. Chem. Ges. 1943, 76, 27.!
!" Direct translated quote: !
!“It is concluded that the addition occurs at the carbon atom adjacent to the double bond (ene). During the course of the reaction a hydrogen atom is detached and transposed to the region of the
maleic acid anhydride (enophile).”!
O
O
O
!O
O
O
H
!" Dr. Alder was unaware that his discovery was mechanistically very similar to the Diels-Alder which
would later win him the Nobel Prize.!
Mechanistic Comparison!
!" Diels-Alder! !" Alder-Ene!
HOMO
LUMO
O
O
O
O
O
O
!
HOMO
LUMO
H
O
O
O
H!
O
O
O
!" Normally, both transformations occur with the HOMO of the diene/ene and the LUMO of the
dienophile/enophile. Lewis acids also work to catalyze the Alder-ene reaction.!
In the Beginning!
!" Thermal Alder-ene!
Huntsman et al. J. Org. Chem., 1962, 27, 1983.!
Me
Me457 °C
35%
Me
Me457 °C
35%
MeMe
In the Beginning!
Huntsman et al. J. Org. Chem., 1962, 27, 1983.!
Me
490 °C
25%
Me Me
Me
400 °C
82%
CO2Me CO2Me
!" Thermal Alder-ene!
The Metallo-Ene!
!" Type I!
Cl
MeMe
Mg, THF, 80 °C
PhNCO, 86%
NHPh
O
!" Type II!
Felkin et al. Tetrahedron Lett., 1972, 22, 2285.!
MgBr Me
ether, reflux
67%
Oppolzer et al. J. Am. Chem. Soc., 1982, 104, 6476.!
The Metallo-Ene!
!" Type I!
Cl
MeMe
Mg, THF, 80 °C
PhNCO, 86%
NHPh
O
!" Type II!
Felkin et al. Tetrahedron Lett., 1972, 22, 2285.!
Mg
Me
Mg
Me
PhNCO
MgBr Me
ether, reflux
67%
The Metallo-Ene: M = Mg, Li, Zn!
Type I!
Ring formation: 5 > 6 >> 7!
Selectivity: syn ring juncture!
Heterocycles: problematic!
Type II!
Ring formation: 6 > 5 # 7 >> 8!
Selectivity: syn ring juncture!
Heterocycles: when M = Zn!
X
Me
XMe
Me
Me
"M" "M"
Total Synthesis of Khusimone!
Oppolzer et al. J. Am. Chem. Soc., 1982, 104, 6478.!
O
Me
Me
CO2Et
LDA, THF, -78 °C
then allyl-Br, -40 °C, 50%
O
CO2Et
Me
HOOH
1. TsOH,
2. NaOEt, EtOH, 74%
97%CO2Et
Me Me
H
O
O1. LAH, ether, 92%
2. MsCl, pyr, then LiCl (aq) 51%
Me Me
H
O
O
Cl
Mg0, THF, 60 °C
then CO2, -10 °C, 82%
OO
H
H Me
Me
CO2H
!" Can the diastereoselectivity be accounted for?!
Transition State Analysis!
Oppolzer et al. J. Am. Chem. Soc., 1982, 104, 6478.!
!" Chair conformation
experiences the least
steric interaction!
H
MgCl
Me
Me
OO
H
OO
H
H
MgCl
ClMg
Me
MeHH
OO
OO
H
H
MgCl
X
Total Synthesis of Khusimone!
Oppolzer et al. J. Am. Chem. Soc., 1982, 104, 6478.!
O
Me
Me
CO2Et
LDA, THF, -78 °C
then allyl-Br, -40 °C, 50%
O
CO2Et
Me
HOOH
1. TsOH,
2. NaOEt, EtOH, 74%
97%CO2Et
Me Me
H
O
O1. LAH, ether, 92%
2. MsCl, pyr, then LiCl (aq) 51%
Me Me
H
O
O
Cl
Mg0, THF, 60 °C
then CO2, -10 °C, 82%
OO
H
H Me
Me
1. LAH, THF, 92%
2. MsCl, TEA, CH2Cl2, then1 N HCl (aq)/ether, 93%
H
H Me
Me
O
CO2HOMs
t-BuOK, t-BuOH/PhH
98%H Me
Me
O
(+)-Khusimone9-steps, 11% overall yield
The Catalytic Metallo-Ene: M = Zn!
Marek et al. J. Org. Chem., 1995, 360, 863.!
TBAF
KF
Me
OH
Me
OSithexMe2
OSthexMe2
SiMe3
nBuLi, THF, -70 °C
ZnBr2, warmed to 20 °C then HCl, 80%
Me
OSithexMe2
SiMe3
H •
SiMe3
ZnBr
RO OSithexMe2
SiMe3
ZnBr
!" Product can be differentially desilated.!
The Catalytic Metallo-Ene: M = Zn!
Marek et al. J. Org. Chem., 1995, 360, 863.!
TBAF
KF
Me
OH
Me
OSithexMe2
OSthexMe2
SiMe3
nBuLi, THF, -70 °C
ZnBr2, warmed to 20 °C then HCl, 80%
Me
OSithexMe2
SiMe3
R
SiMe3
nBuLi, THF, -70 °C
ZnBr2, warmed to 20 °C R
SiMe3
ZnBr
I2
HCl
R
Me
R
R = CH2t-Bu
I
R = Me
!" Product can be differentially desilated.!
!" Alkyl-Zn can be hydrolyzed or trapped with electrophiles.!
!" Can also be used directly in cross-coupling reactions.!
Tandem Zn Promoted 1,2-Brook Rearrangement Metallo-Ene!
Marek et al. Org. Lett., 2009, ASAP.!
t-But-Bu
OH
N
OH
L =
H •
R
ZnBr
Me3SiO OSiMe3
R
ZnBr
Me3SiO
ZnEt
(CH2)3CH=CH2
R
O
SiMe3
1. ZnEt2, 20 mol% L* Tol, rt, 12 h
2. THF, 40 °C, 24 h3. HCl, TBAF
Me
OH
RHR R = Ph, 92%, >99:1 dr, 81:19 erR = Hex, 91%, >99:1 dr, 77:23 er
Tandem Zn Promoted 1,2-Brook Rearrangement Metallo-Ene!
Marek et al. Org. Lett., 2009, ASAP.!
t-But-Bu
OH
N
OH
L =
O
SiMe3
1. ZnEt2, 20 mol% L* Tol, rt, 12 h
2. THF, 40 °C, 24 h3. HCl, TBAF
Me
OH
RHR R = Ph, 92%, >99:1 dr, 81:19 erR = Hex, 91%, >99:1 dr, 77:23 er
O
SiMe3
1. ZnEt2, 20 mol% L* Tol, rt, 12 h
2. THF, 40 °C, 24 h3. HCl, TBAF
OH
RHPh
SiMe3
Me3Si
79%, 77:23 er
The Catalytic Metallo-Ene: M = Ni!
Oppolzer et al. Tetrahedron Lett., 1988, 29, 6433.!
36 h
58%
!" The same trends are observed for Pd.!
AcO
TsN Ni(COD)2, dppb (10 mol%) rt, 6 h, 88%
TsN
H
H
NTs
NiIITHF
AcO
TsN Ni(COD)2, dppb (10 mol%)
TsN
H
H
NTs
NiII
THFX
The Catalytic Metallo-Ene: M = Pd!
Oppolzer et al. Tetrahedron Lett., 1988, 29, 4705.!
AcO
E E
AcO
E E
AcO
Cl
SN2
!-ally-Pd
Pd(PPh3)4, AcOH
70 °C, 72%
E E
Pd(PPh3)4, AcOH
70 °C, 80%
E E
H
H
H
H
The Catalytic Metallo-Ene: M = Pd!
Oppolzer et al. Tetrahedron Lett., 1988, 29, 4705.!
AcO
E E
AcO
E E
AcO
Cl
SN2
!-ally-Pd
!" Also works to form cis or trans decalin systems:!
Pd(PPh3)4, AcOH
70 °C, 72%
E E
Pd(PPh3)4, AcOH
70 °C, 80%
E E
H
H
H
H
H
H
E EH
H
E E
or
Stereochemistry of Pd-Catalzed Metallo-Ene!
Oppolzer, W. Pure & Appl. Chem. 1990, 62, 1941.!
!" Terminal olefin results in loss of stereochemical integrity.!
!" E-alkene allows for transfer of stereochemistry.!
BocN
OAc
Pd(PPh3)4
AcOH, 70 °C
BocN
Pd
BocN
Pd
64%
BocN
(S)
racemic
BocN
Me
OAc
Pd(PPh3)4
AcOH, 70 °C
BocN
Me
Pd
BocN
Me Pd
H
64%
BocN
Me
H(S)(S)
> 99% ee
Stereochemistry of Pd-Catalzed Metallo-Ene!
Oppolzer, W. Pure & Appl. Chem. 1990, 62, 1941.!
!" Alkene geometry impacts expected outcome.!
76%
BocN
Me
H(R)
97% ee
BocN
OAc
Pd(PPh3)4
AcOH, 70 °C
BocN
Pd
BocN
Pd
(S)
Me
MeMeH
anti-!-allyl
BocN
Pd
MeH
BocN
Me
Pd
syn-!-allyl
Doing More in One Step!
Oppolzer et al. Tetrahedron Lett. 1989, 30, 5883.!
TsN
I
Ni(COD)2/dppb (25 mol%)
THF/MeOH 4:1CO (1 atm), rt
TsN
H
NiIILn
H
80%
TsN
H H
ONiIILn
TsN
H H
O
MeO2C
!" CO-insertion happens at both alkyl-Ni stages!
Doing More in One Step!
Oppolzer et al. Tetrahedron Lett. 1989, 30, 5883.!
TsN
I
Ni(COD)2/dppb (25 mol%)
THF/MeOH 4:1CO (1 atm), rt
TsN
H
NiIILn
TsN
H
ONiIILn
87%
TsN
H
O
MeO2C
TsN
I
Ni(CO)3/PPh3 (25 mol%)
THF/MeOH 4:1CO (1 atm), rt
TsN
NiIILn
TsN
MeO2C
69%
!" Changing the ligand allows for control of CO-insertion.!
Doing More in One Step!
Oppolzer et al. Tetrahedron Lett. 1989, 30, 5883.!
TFAN
AcO
Pd(dba)2/PPh3 (10 mol%)
AcOH, CO (1 atm)45 °C
TFAN
H
PdIILn
H
TFAN
H
CO2H
H
H2O
CH2N2, CH2Cl2
TFAN
H
CO2Me
H
70%
!" Pd-affords the trans-ring juncture.!
Models for Diastereoselectivity!
Oppolzer et al. Tetrahedron Lett. 1990, 31, 1265.!
NiII
H
H
TsN
L
L
PdII
H
H
L
LTFAN
!" Endo! !" Exo!
TFAN
H
CO2Me
H
TsN
H H
O
MeO2C
The Catalytic Metallo-Ene: M = Rh!
Oppolzer, W.; Furstner, A. Helv. Chim. Acta 1993, 76, 2329.!
X! n! Yield (%)!
NTs! 1! 80!
NTFA! 1! 83!
NCbz! 1! 63!
C(CO2Me)2! 1! 75!
C(SO2Ph)2! 1! 88!
NTs! 2! 65!
C(SO2Ph)2! 2! 55!
X
AcO
RhH(PPh3)4/P[Ph(OMe)3]3 2 mol% 4 mol%
AcOH, 80 °C
X
n n
PdII-Catalyzed Formal Alder-Ene!
Trost, B. M.; Lautens, M. J. Am. Chem. Soc. 1985, 107, 1781.!
EE
E
C6D6, 60 °C, 85%
Pd(OAc)2(PPh3)3 (5 mol%) EE
E
H
H
!" PdII is necessary for catalysis. !
!" Can be performed in one pot.!
OAcE
12 h, Then PdII, reflux 1.5 h, 68%
Pd(PPh3)4, NaH, THF, reflux EE
E
H
HE
E
PdII-Catalyzed Formal Alder-Ene!
Trost, B. M.; Lautens, M. J. Am. Chem. Soc. 1985, 107, 1781.!
!" 1,4-Diene observed with no allylic substitution outside of pendant ring.!
!" A trans-relationship results when allylic substitution exists inside the pendant ring.!
C6D6, 60 °C, 68%
Pd(OAc)2(PPh3)3 (5 mol%)E
E
E
E
MeMe
H
(CH2)8CH(OMe)2 C6D6, 60 °C, 71%
Pd(OAc)2(PPh3)3 (5 mol%)E
E
E
E
(CH2)8CH(OMe)2
Mechanistic Proposal!
Trost, B. M.; Lautens, M. J. Am. Chem. Soc. 1985, 107, 1781.!
E
E R'
R
PdII PdIV
E
E
RR'
HH
!"H elim.
!"H elim.
E
E
R R'
PdIV
H
E
E
R R'
PdIV
H
E
E
R R'
E
E
R R'
red.
elim.
red.
elim.
H
H
PdII
PdII
PdII-Catalyzed Formal Alder-Ene!
Trost, B. M.; Lautens, M. J. Am. Chem. Soc. 1985, 107, 1781.!
!" 1,3-Diene observed with allylic substitution outside of pendant ring.!
C6D6, 66 °C, 64%
Pd(OAc)2(PPh3)3 (5 mol%)
E
EE
E
C6D6, 66 °C, 71%
Pd(OAc)2(PPh3)3 (5 mol%)
E
EE
EO
O
O
O
C6D6, 66 °C, 80%
Pd(OAc)2(PPh3)3 (5 mol%)
E
EE
E R
Me
Me
R
Mechanistic Support for Palladacycle Pathway!
R
E
E
Pd
CO2Me
CO2MeMeO2C
MeO2C
PPh3, C6H6, 60 °C
E
E
E
E
R
R = Me, 59%, 2 : 3R = H, 54%
E
E
E
E
CO2Me
CO2Me
E
E
CO2Me
CO2Me
not
Pd
CO2Me
CO2MeMeO2C
MeO2C
P(o-OTol)3, 60 °C
CO2MeMeO2C
, DCE
Me
Me
Pd
CO2Me
CO2MeMeO2C
MeO2C
P(o-OTol)3, 60 °C, 83% Me
Me
CO2MeMeO2C
CO2Me
CO2Me Crossover expmt withCO2EtEtO2C
shows only acetylene incorporation.
, DCE
Trost, B. M.; Tanoury, G. J. J. Am. Chem. Soc. 1987, 109, 4753.!
Mechanistic Support for Palladacycle Pathway: Remote Binding!
Trost et al J. Am. Chem. Soc. 1994, 116, 4255.!
Cat!n = 1!
A:B!Yield!
n = 2!
A:B!Yield!
Pd(OAc)2! 21:1! 76! 1.1:1! 75!
Pd(OAc)2[P(o-Tol)3]2! >20:1! nd! 1:1.6! 74!
Pd(OAc)2(PPh3)2! 2.7:1! nd! 1:4.6! 81!
Pd(OAc)2(PPh3)3! 1:2.3! 24!
E
E
E
ECat
n
n
BA
E
E
n
PdIV
HaHb
Hb
PPh3
PdII-Catalyzed Formal Alder-Ene!
!" No reaction observed w/o AcOH!
Trost et al J. Am. Chem. Soc. 1994, 116, 4268.!
AcOH (5 mol%), rt, TOTP (5 mol%)
Pd2dba3CHCl3 (2.5 mol%), C6D6
Me
MeTBSO
Me
TBSO
Me
TBSO
88%, 7.5 : 1
PdII-Catalyzed Formal Alder-Ene!
!" No reaction observed w/o AcOH!
Trost et al J. Am. Chem. Soc. 1994, 116, 4268.!
AcOH (5 mol%), rt, TOTP (5 mol%)
Pd2dba3CHCl3 (2.5 mol%), C6D6
Me
MeTBSO
Me
TBSO
Me
TBSO
88%, 7.5 : 1
AcOH (5 mol%), rt, TOTP (5 mol%)
Pd2dba3CHCl3 (2.5 mol%), C6D6
R
R
E
E
E
E
95% 75%
c-Hex
E
E
86%
E
E
OMeMeO
E
E
OAcAcO
!" Sensitive functional groups also tolerated!
Mechanistic Proposal!
Trost et al J. Am. Chem. Soc. 1994, 116, 4268.!
E
E
R'R
PdII
H
OAc
E
E R'
R
E
E
R'R
PdIIOAc
E
E
R R'
PdII
H
H
E
E
R R'
Pd0 + AcOH
H-PdII-OAc
Predominent Product
Mechanistic Proposal!
E
E
R'R
PdII
H
OAc
E
E R'
R
E
E
R'R
PdIIOAc
E
E
R R'
PdII
H
H
E
E
R R'
Pd0 + AcOH
H-PdII-OAc
Predominent Product
Trost et al J. Am. Chem. Soc. 1994, 116, 4268.!
Mechanistic Proposal!
E
E
R'R
PdII
H
OAc
E
E R'
R
E
E
R'R
PdIIOAc
E
E
R R'
PdII
H
H
E
E
R R'
Pd0 + AcOH
H-PdII-OAc
Predominent Product
Trost et al J. Am. Chem. Soc. 1994, 116, 4268.!
Mechanistic Proposal!
E
E
R'R
PdII
H
OAc
E
E R'
R
E
E
R'R
PdIIOAc
E
E
R R'
PdII
H
H
E
E
R R'
Pd0 + AcOH
H-PdII-OAc
Predominent Product
Trost et al J. Am. Chem. Soc. 1994, 116, 4268.!
Mechanistic Proposal!
E
E
R'R
PdII
H
OAc
E
E R'
R
E
E
R'R
PdIIOAc
E
E
R R'
PdII
H
H
E
E
R R'
Pd0 + AcOH
H-PdII-OAc
Predominent Product
Trost et al J. Am. Chem. Soc. 1994, 116, 4268.!
Mechanistic Support for Hydro-Palladation Pathway!
Trost et al J. Am. Chem. Soc. 1987, 109, 3161.!
E
E
R R'
PdII
H
H
AcOH (1 eq), rt, TOTP (5 mol%), PMHS
Pd2dba3CHCl3 (2.5 mol%), C6H6
R
R
E
E
E
E
96% 75%
c-Hex
E
E
E
E
OAcAcO
AcOH (5 mol%), rt, AsPh3 (5 mol%)
OPd2dba3CHCl3 (2.5 mol%), CH2Cl2O
Ph
Ph
Ph
20%
Ph
Mechanistic Support for Hydro-Palladation Pathway!
Trost et al J. Am. Chem. Soc. 1987, 109, 3161.!
E
E
R R'
PdII
H
H
AcOH (1 eq), rt, TOTP (5 mol%), PMHS
Pd2dba3CHCl3 (2.5 mol%), C6H6
R
R
E
E
E
E
96% 75%
c-Hex
E
E
E
E
OAcAcO
rt, AsPh3 (5 mol%)
OPdOAc2(AsPh3)2 (5 mol%), CH2Cl2O
Ph
Ph
Ph
96%
Ph
Mechanistic Support for Hydro-Palladation Pathway!
Trost et al J. Am. Chem. Soc. 1987, 109, 3161.!
E
E
PdIIOAc
E
E
R R'
PdII
H
H
AcOH (1 eq), rt, TOTP (5 mol%), DSiEt3
Pd2dba3CHCl3 (2.5 mol%), C6H6
R
E
E
E
E D
AcOD (1 eq), rt, TOTP (5 mol%), PMHS
Pd2dba3CHCl3 (2.5 mol%), C6H6
R
E
E
E
E
D
A Much Cheaper Alternative: Fe!
Furstner et al. J. Am. Chem. Soc. 2008, 130, 1992.!
XCH2R2
R3
Fe0 Li O
O
Toluene, 90 °C
(5 mol%) 1
XR1
R1
H
R3
R2
Me
H
EE
97%, 6:1 trans/cis
Me
H
EE
93%, 5.8:1 trans/cis5 mol% 2
TsN
n-Pr
H
90%, 7.9:1 trans/cis
EE
80%
TsN
79%
Me
H
EE
97%, 6.3:1 trans/cis5 mol% 2
p-OMe-Ph
nn
On-Pr
H
82%, 20:1 trans/cis20 mol% 2
Ph
EE
79%, 15 mol% 1
A Much Cheaper Alternative: Fe!
Furstner et al. J. Am. Chem. Soc. 2008, 130, 1992.!
Fe0 Li N
N
Toluene, 90 °C
X
H
H
R
m
n
XH
R
m n
H
H
p-OMe-Ph
EE
50%, 10 mol% 2
(5 mol%) 2
H
HPh
EE
93%
TsN
H
HPh
60%, 10 mol% 2
Ph
E EH
H
68% 2.5:1 cis/trans10 mol% 2
Ph
EEH
H
63
Ph
EEH
H
95%
Me
EEH
H
93%
EEH
H
93%
Divergent Pathways to Observed Sterochemistry!
Furstner et al. J. Am. Chem. Soc. 2008, 130, 1992.!
!" Pseudo-axial approach affords cis-diastereomer!
!" Pseudo-equatorial approach affords trans-diastereomer!
trans!
cis!
H
Fe
E
E
R H
HR
EE
E E
R
H
Fe
H
R
E
E
R
EEH
H
R
E E H
HFe
E
E
Fe
H
H
R
R
E
E
Expectation of D-Labeling Study!
Furstner et al. J. Am. Chem. Soc. 2008, 130, 1992.!
Ph
E E
D
syn to D
anti to D
Ph
E E
HFe
D
Ph
EE
DFe
Ph
EE
D
Ph
E E
DFe
H Ph
E E
DFe
H
Ph
EE
HFeD
FePh
DH
EE
H
Ph
EE
DFeH
H
Ph
EE
HD
Ph
EE
DH
Ph
E E
HFe
D
H
Expectation of D-Labeling Study!
Furstner et al. J. Am. Chem. Soc. 2008, 130, 1992.!
Scrambling!
Ph
E E
D
syn to D
anti to D
Ph
E E
HFe
D
Ph
EE
DFe
Ph
EE
D
Ph
E E
DFe
H Ph
E E
DFe
H
Ph
EE
HFeD
FePh
DH
EE
H
Ph
EE
DFeH
H
Ph
EE
HD
Ph
EE
DH
Ph
E E
HFe
D
H
Expectation of D-Labeling Study!
Furstner et al. J. Am. Chem. Soc. 2008, 130, 1992.!
Scrambling!
D-Transfer!
Ph
E E
D
syn to D
anti to D
Ph
E E
HFe
D
Ph
EE
DFe
Ph
EE
D
Ph
E E
DFe
H Ph
E E
DFe
H
Ph
EE
HFeD
FePh
DH
EE
H
Ph
EE
DFeH
H
Ph
EE
HD
Ph
EE
DH
Ph
E E
HFe
D
H
!" If the metallacycle is the pathway for the
trans-ring juncture then deuterium should
be transferred.!
Expectation of D-Labeling Study!
Furstner et al. J. Am. Chem. Soc. 2008, 130, 1992.!
E E
Ph
D
H
Fe
H
D
EE
Ph
Ph
EE
HFe
D
Ph
EE
H
D
!" If the metallacycle is the pathway for the cis-ring juncture then hydrogen should be transferred.!
The Dramatic Conclusion!
Furstner et al. J. Am. Chem. Soc. 2008, 130, 1992.!
!" Deuterium labeling study supports a metallacyle intermediate.!
Ph
E E
D
Fe0 Li N
N
Toluene, 90 °C, 90%
(10 mol%) 2
HPh
EE
DH
E E
R
D
H
Fe0 Li N
N
Toluene, 90 °C, 82%
(10 mol%) 2
R
EE
H
D
Intermolecular Rh-Catalyzed Alder-Ene!
Brummond et al J. Am. Chem. Soc. 2002, 124, 15186.!
!" First report of high yield and selectivity to form cross-conjugated trienes.!
TsN
•
R2
Rh(CO)2Cl2 (2 mol%)
Toluene, rt
TsN
R2
TsN
C5H11
90%, 6:1 E/Z
TsN
93%
R1
R1
TsN
85%, 5:1 E/Z
C5H11
TMS
Intermolecular Rh-Catalyzed Alder-Ene!
Brummond et al J. Am. Chem. Soc. 2002, 124, 15186.!
!" Will This work with ene-allenes?!
Rh(CO)2Cl2 (5 mol%)
Toluene, rt
TsN
•
C6H13
TsNMe
C5H11
TsN
C7H15
or
TsNRhIII
C6H13
Intermolecular Rh-Catalyzed Cycloisomerization!
Brummond, K. M.; Chen, H.; Mitasev, B.; Casarez, A. D. Org. Lett. 2004, 6, 2161.!
!" Tetrahydroazepines are formed instead.!
Rh(CO)2Cl2 (5 mol%)
Toluene, rt
TsN
•
C6H13
TsN
C6H13
!" Product possessed interesting unsaturation for further functionalization.!
Intermolecular Rh-Catalyzed Cycloisomerization!
!" Selected azepine products!
Brummond, K. M.; Chen, H.; Mitasev, B.; Casarez, A. D. Org. Lett. 2004, 6, 2161.!Brummond, K. M.; Casarez, A. D. unpublished work.!
TsN
R3
R1
Rh(CO)2Cl2 (5-10 mol%)TsN
•
R3
R1
TsN
t-Bu
Me
Solvent, reflux
95%, DCE
TsN
t-Bu
SiMe2Bn
97%, DCE
TsN
t-Bu
Ph
95%, 1,4-Dioxane
TsN
Si(i-Pr)3
73%, 5.8:1 E/Z, 1,4-Dioxane
TsN
Me
85%, 1,4-Dioxane
Me TsN
t-Bu
86%, 1,4-Dioxane
Me
R2
R2
TsN
t-Bu
78%, 1,4-Dioxane
TsN
Si(i-Pr)3
69%, 1,4-Dioxane
Me
Two Plausible Mechanisms!
Me
N•
t-Bu
MeD
D
Ts
N •t-Bu
D
Ts
Rh-D
MeN
t-Bu
MeD
Rh-D
Ts
Rh(I) TsN
t-Bu
D
D
Me
N
Rh
Ts
H
H t-Bu
D
D
N
t-Bu
MeD
Rh-D
Ts
path A
path B
89%
Brummond, K. M.; Chen, H.; Mitasev, B.; Casarez, A. D. Org. Lett. 2004, 6, 2161.!
Intermolecular Ru-Catalyzed Alder-Ene!
Trost, B. M.; Toste, F. D. Tetrahedron Lett. 1999, 40, 7739.!Trost et al J. Am. Chem. Soc. 2002, 124, 10396.!
RuCp(MeCN)3PF6 (10 mol%)
DMF, 84%
MeO2C
7 Ph
NHBoc
MeO2CPh
NHBoc
7
!" Selectivity for the branched diene can be high depending on substrate!
!" Selectivity for the branched diene can be high depending on substrate!
OTroc
RuCp(MeCN)3PF6 (5 mol%)
Actone, 85%
OTBS
Me
MeO
OTroc
Callipeltoside ATBSO
OMe
Me 22 longest linear46 overall steps
The Catalytic Cycle!
Trost et al J. Am. Chem. Soc. 2002, 124, 10396.!
RuI
NNN
TBSO
OMe
Me
OTroc
RuI
OTroc
TBSO
MeO
Me
S
RuIII OTroc
TBSO
OMe
Me
H
RuIII
TBSO
OMe
Me
OTroc
H
S
OTBS
Me
MeO
OTroc
H
S
The Catalytic Cycle!
Trost et al J. Am. Chem. Soc. 2002, 124, 10396.!
RuI
NNN
TBSO
OMe
Me
OTroc
RuI
OTroc
TBSO
MeO
Me
S
RuIII OTroc
TBSO
OMe
Me
H
RuIII
TBSO
OMe
Me
OTroc
H
S
OTBS
Me
MeO
OTroc
H
S
Intermolecular Co-Catalyzed Alder-Ene!
Hilt, G.; Treutwein, J. Angew. Chem. Int. Ed. 2007, 46, 8500.!
Etn-Pr
Ph
89%, 8:1 E/Z
MeSiMe3
EtO2C
99%, 99:1 E/Z
Me
EtO2C
95%, 8:1 E/Z
OMe
OMe
n-Pr
99%, 99:1 E/Z
OMe
MeO
EtOTMS
Ph
95%, E only
Et
Ph
80%, 4:1 E/Z
B(pin)
Co(dppp)Br2 (10 mol%)R2 R2
R1
R3 Zn, ZnI2 (20 mol%), CH2Cl2
R1
R3
Intermolecular Co-Catalyzed Alder-Ene!
Hilt, G.; Treutwein, J. Angew. Chem. Int. Ed. 2007, 46, 8500.!
Etn-Pr
Ph
89%, 8:1 E/Z
MeSiMe3
EtO2C
99%, 99:1 E/Z
Me
EtO2C
95%, 8:1 E/Z
OMe
OMe
n-Pr
99%, 99:1 E/Z
OMe
MeO
EtOTMS
Ph
95%, E only
Et
Ph
80%, 4:1 E/Z
B(pin)
Co(dppp)Br2 (10 mol%)R2 R2
R1
R3 Zn, ZnI2 (20 mol%), CH2Cl2
R1
R3
Other Ene Reactions!
!" The Carbonyl-ene!
Okachi, T.; Onaka, M. J. Am. Chem. Soc. 2004, 126, 2306.!
!" The Imino-ene!
Nakagawa et al. Org. Lett., 2000, 2, 159.!
Ph
Me O
HH
NaY zeolite, cyclohexane
Ph OH20 °C, 94%
Ph
Me NTol
PhH
Yb(OTf)3, TMSCl (5 mol% ea)
Ph NHTolCH2Cl2, rt, 94%
Ph
Other Ene Reactions!
!" The Acetal-ene!
Ghosez et al., Synthesis, 2004, 1375.!
!" The Arynyl-ene!
Ph OMe
OMe FeCl3, CH2Cl2, rt, 95%
Ph
OMe
SiMe3
KF, 18 crown 6
n-Burt, 69%
• n-PrOTf
n-PrHSiMe3
OTf
F-