rh-catalyzed asymmetric additions: the rise of chiral dienes
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1
Rh-Catalyzed Asymmetric Additions: The Rise of Chiral
Dienes
Daniela SustacFebruary 16, 2010
Tamio Hayashi Erick Carreira
2
Outline
Chiral Diene
O
R
O
NR
O
O
NR
O
O
R
Ar1
Ar2 O
H Ar1 H
O
PhMe2Si CO2MeAr
PhMe2Si CO2Me
Ar1 H
NTs
Ar1 Ar2
NHTs
EE
R
R
E
E
RR
Ar1 CO2Me
CN Ar1 CO2Me
CN
Ar2
R
HEE
OHCHO
REE
TsNR
R
TsNR
R
3
Transition Metal – Olefin Complexes• Alkenes not very basic, backbonding necessary to stabilize M-olefin
bond;• Olefins considered labile, easily displaced from M center.
M M
backbonding increases
lenghten C-C bond
shorten M-C bond
C becomes more sp3
"metallacyclopropane"
Crabtree, H.R. The Organometallic Chemistry of Transition Metals. Wiley: New Jersey, 2005.
4
Transition Metal – Strained Alkene Complexes
H
H
sp2, 120
M
H
HM
more sp3, 109relieves strainvery strained
• Strained alkenes (cyclopropene, norbornene) bind very strongly to metals;
• Rehybridization on binding relieves ring strain.
Crabtree, H.R. The Organometallic Chemistry of Transition Metals. Wiley: New Jersey, 2005.
5
Examples of Olefins in Complexes and Catalysis
• Prepared by Zeise in 1827;• Structure elucidated in the 1950’s;
Pt ClCl
Cl
HHH H
H3C OH PtCl4KCl
Zeise's Salt
InBuI
CO2MePd(OAc)2 (10 mol %) K2CO3, DMF, RT
(1 equiv)
nBu
nBuCO2Me
93%
• Norbornene in the Catellani reaction: “a sort of scaffold to be removed after the building of the molecule is complete; behaves as catalyst, excess necessary to push the reaction”
Wunderlich, A.J.; Mellor, D.P. Acta Crystallogr. 1955, 8, 57.
Catellani, M; Frignani, F.; Rangoni, A. Angew. Chem. Int. Ed. 2007, 36, 119.
6
Who Binds the Strongest?
Ni(P(o-tol)3)3 olefinKeq
Ni
(o-tol)3P
(o-tol)3P
R
P(o-tol)3
O OO > CN > Ph nBu> MenPr
>
4.0x106 4.0x104 10 0.5 2.3x10-3
> > > >
4.4 6.2x10-2 2.6x10-2 2.3x10-2 3.5x10-4
• Electron deficient alkenes bind tighter;
• Stronger binding with strained alkenes.
Tolman, A.C. Organometallics 1983, 2, 614.
7
Rh-Catalyzed 1,4-Addition (before chiral dienes)
O
PhB(OH)2[Rh(acac)(S-binap)] (3 mol %)
dioxane/H2O (10/1) 100 C, 5 h
O
Ph
93%97% ee
Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am. Chem. Soc. 2002, 124, 5052.
Consequently, the reaction can be done using directly [Rh(OH)(S-binap)]2 at 35 ºC.
O
O[Rh]
PhB(OH)2
acac-H[Rh]-Ph
[Rh]-OH
O
Ph
[Rh]
O
path B
path A
H2O
O
Ph
acac-H
H2O
PhB(OH)2
H2O
transmetalationphenylrhodation
hydrolysis
8
Chiral Dienes: First ContactO
RB(OH)2 or (RBO)3
Rh/chiral diene complex (3 mol %)
KOH, dioxane/water, 20-50 C
O
R
Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am. Chem. Soc. 2003, 125, 11508.
Hydrosylilation: Uozumi, Y.; Lee, S.-Y.; Hayashi, T. Tetrahedron Lett. 1992, 33, 7185.
PhPh
PPh2
MeO
(R)-MeO-Mop
1. HSiCl3 cat. Pd/(R)-MeO-mop
2. H2O2, KHF2
1. Swern
2. HOCH2CH2OH
OO
O
1. LDA, PyNTf2, 87%
2. PhCH2MgBr cat. Pd, 97%
O
O
Ph
1. HCl, 94%2. LDA, PyNTf2, 70%
3. PhCH2MgBr cat. Pd, 45%
PhPh
HH
HOOH
24.7 mg(R,R)-Bn-nbd
Rh Rh
Cl
ClPh
Ph
9
The (Only) One with A Lot of ScopeO
RB(OH)2 or (RBO)3
Rh/chiral diene complex (3 mol %)
KOH, dioxane/water, 20-30 C
O
R
O
94%96% ee
O
OMe
O
OMe
92%97% ee
89%95% ee
O
Me
88%96% ee
O
Cl
92%93% ee
O
CF3
90%99% ee
O O
F
91%97% ee
96%96% ee
O O O
O
O
88%88% ee
81%90% ee
81%97% ee
73%92% ee
PhPh
Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am. Chem. Soc. 2003, 125, 11508.
10
Explaining StereochemistryPh
Ph
Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am. Chem. Soc. 2003, 125, 11508.
11
Chiral Dienes: First Contact
1. HSiCl3 cat. Pd/(R)-MeO-mop
2. H2O2, KHF2
1. Swern
2. HOCH2CH2OH
OO
O
1. LDA, PyNTf2, 87%
2. PhCH2MgBr cat. Pd, 97%
O
O
Ph
1. HCl, 94%2. LDA, PyNTf2, 70%
3. PhCH2MgBr cat. Pd, 45%
PhPh
HH
HOOH
24.7 mg
Advantages
• Highest catalytic activity of all rhodium catalysts used for 1,4-addition;
• Among the highest enantioselectivities (most over 90% ee);
Disadvantages
• Long synthesis of chiral diene;
• Bistriflate intermediate hard to isolate.
TfO
OTf
Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am. Chem. Soc. 2003, 125, 11508.
12
New Route to Chiral Dienes
TfO
OTf BnMgCl, cat.
THF Bn
Bn
Ph
Ph
1 2
entry T ( C) t (min) 1/2 yield (%)cat. (mol %)
1
2
3
4
NiCl2(dppe), 1
PdCl2(dppf), 1
Co(acac)3, 5
Fe(acac)3, 5
40
40
0
0
60
60
15
15
0.7
0.6
0.6
13
44
45
28
98
O
O KHMDS
PyNTf2-78 C
TfO
OTf unstable (prone to decomposition in presence of acid)must be stored over anhydrous K2CO3
(R,R) (R,R) 85%10 mmol scale
Berthon-Gelloz, G.; Hayashi, T. J. Org. Chem. 2006, 71, 8957.
Vandyck, K.; Matthys, B.; Willen, M.; Robeyns, K.; Van Meervelt, L.; Van der Eycken, J. Org. Lett. 2006, 8, 363.
13
One Unstable Chiral Diene, One Stable Rh Complex
Ph
Ph
TfO
OTf
(R,R)
Fe(acac)3, PhMgBrTHF/NMP, 0 C, 5 min
unstable, inseparable from biphenyl
(R,R)-Ph-nbd
[RhCl(C2H4)2]2 (0.5 equiv.)toluene, RT, 2 h
Ph
RhCl
2Ph
stable!
Berthon-Gelloz, G.; Hayashi, T. J. Org. Chem. 2006, 71, 8957.
O
Ph
89%97% ee
14
One More Carbon
• Optical resolution by recrystallization inefficient route;• Alternatively, can do racemic synthesis and separate by chiral HPLC,
either intermediate or final product.
O
O 1. RNHNH2
2. recryst. N
NNH
O
O
HN Ph
MeHN
O
O
NH
Ph
Me
1. aq H2SO4
2. recryst. O
O
rac
(R,R)
4.5%
1. LDA, PyNTf2
2. BnMgBr, cat. Pd Bn
Bn
41%(R,R)-Bn-bod
stable
Otomaru, Y.; Okamoto, K.; Shintani, R.; Hayashi, T. J. Org. Chem. 2005, 70, 2503.
15
To Be Stable or Not to Be Stable
PhPh
stable
Ph
Phunstable
Ph
Ph
"indefinitely" stableFree Diene
Rh complexPh
Ph Ph
Ph> Ph
Ph
Bn-nbd Ph-nbd Ph-bod
16
The One with iMean ArylationNTs
H (ArBO)3[RhCl(C2H4)2]2/L* (3 mol %)
KOH/H2Odioxane, 60 °C, 6 h Cl
NHTs
Cl
PPh2PPh2
(R)-Binap
O
O
O
O
PPh2PPh2
(R)-SegPhos
28%, 31% ee
30%, 70% ee
Ph
Ph(R,R)-Ph-bod*
PhPh
(R,R)-Bn-bod*
PhPh
(R,R)-Bn-nbd*
96%, 98% ee
98%, 94% ee
98%, 92% ee
Tokunaga, N.; Otomaru, Y.; Okamoto, K.; Ueyama, K.; Shintani, R.; Hayashi, T. J. Am. Chem. Soc. 2004, 126, 13584.
17
Stereochemistry is Explained
Tokunaga, N.; Otomaru, Y.; Okamoto, K.; Ueyama, K.; Shintani, R.; Hayashi, T. J. Am. Chem. Soc. 2004, 126, 13584.
18
The One with (a Bit) of ScopeNTs
H (ArBO)3[RhCl(C2H4)2]2/L* (3 mol%)
KOH/H2Odioxane, 60 °C, 6 h Cl
NHTs
X
X
NHTs
X Yield ee
Cl
CF3
OMe
NMe2
o-OMe
Np
96% 98%
97% 95%
96% 99%
94% 98%
98% 99%
95% 98%
ONHTs
99%99% ee
X
NHTs
X Yield ee
Cl
OMe
o-Me
99% 99%
97% 96%
96% 99%
Tokunaga, N.; Otomaru, Y.; Okamoto, K.; Ueyama, K.; Shintani, R.; Hayashi, T. J. Am. Chem. Soc. 2004, 126, 13584.
19
The One where They Do It Better?
Ar
N
H
PO
PhPh
Me2Zn
Cu(OTf)2 (5 mol %)(R,R)-BozPhos (5 mol %)
3 equiv.toluene, RT, 48 h Ar
HN
Me
PO
PhPh
Ar Yield(%) ee (%)
Ph 87 97
3-MeC6H4
2-furyl
80 92
90 89
P
PO
(R,R)-BozPhos
3 entries
Boezio, A.A; Pytkowicz, J.; Cote, A.; Charette, A.B. J. Am. Chem. Soc. 2003, 125, 14260.
Ar H
NTsMe2Zn
1.5 equiv
[RhCl(C2H4)2]2 (3 mol %) (R,R)-Ph-bod (6 mol %)
dioxane, 50 C, 3-6 h Ar Me
NHTs
Ar Yield(%) ee (%)
Ph 82 97
3-MeC6H4
4-CF3C6H4
82 98
83 94
10 entries Ph
Ph
(R,R)-Ph-bod
Nishimura, T; Yasuhara, Y.; Hayashi, T. Org. Lett. 2006, 8, 979.
20
The One with the iMean Mechanism
Nishimura, T; Yasuhara, Y.; Hayashi, T. Org. Lett. 2006, 8, 979.
[RhMe(diene)]Ar H
NTs Rh Me
Ar H
NTs
[Rh]
Me
Ar H
NTs
Me2Zn
NZnMe
Ts H
ArMe
H2O HN
Ts H
ArMe
-bond methathesis
methyl transfer
[RhCl(diene)]
21
More Stereochemistry Explained
Nishimura, T; Yasuhara, Y.; Hayashi, T. Org. Lett. 2006, 8, 979.
22
Is Nine the Lucky Number?O
O
PhLi/CeCl3
THF, -78 C, 6 h Ph
PhOHHO
POCl3, pyr
reflux, 12 h Ph
Ph
chiral HPLC
resolution
95% (2 steps)
Ph
Ph
(R,R)-Ph-bnd
Ph
Ph
(S,S)-Ph-bnd
[RhCl(C2H4)2]2(R,R)-Ph-bnd
benzene, 50 C, 12 h [RhCl(R,R)-Ph-bnd]287%
Ar1 H
NNs
(Ar2BO)3[RhCl(R,R)-Ph-bnd]2
KOH/H2O, dioxane, 60 C, 6 h Ar1 Ar2
HNNs
12 examples 94-99% 95-99% ee
Otomaru, Y.; Tokunaga, N.; Shintani, R.; Hayashi, T. Org. Lett. 2005, 7, 307.
23
The One with the Deprotection
Ar Me
HNP
O Ph
Ph HCl, MeOH
RT, 4h Ar Me
NH2
99% ee99% ee quant.
Ar Me
HNTs Li, NH3
-78 C, 15 min
79%99% eeAr Me
NH2
99% ee
Boezio, A.A; Pytkowicz, J.; Cote, A.; Charette, A.B. J. Am. Chem. Soc. 2003, 125, 14260.
Nishimura, T; Yasuhara, Y.; Hayashi, T. Org. Lett. 2006, 8, 979.
Ar Ar
NHNs
PhSH, K2CO3
DMF, rt, 4 h Ar Ar
NH2
98% ee 96% 98% ee
Otomaru, Y.; Tokunaga, N.; Shintani, R.; Hayashi, T. Org. Lett. 2005, 7, 307.
By far the mildest approach!
24
The One with the Cyclization of Alkynals
BnO
BnO CHO
Me [RhCl(C2H4)2]2 (7 mol %) ligand (7.5 mol %)
KOH, dioxane/H2O, 60 C, 4h
BnO
BnO
Me
Ph
OH
PhB(OH)2
Entry Ligand Yield (%)
1 (S)-binap 24
2 Dppp 23
3 Dppb 20
4 Dppf 27
5 PPh3 20
6 Cod 73
7* Cod 76
*[Rh(OH)(cod)]2 used directly
BnO
BnO
Et
Ph
OH
93%
Me
Ph
OH
76%
Me
PhMeO2C
MeO2C
OH
75%
TsN
OH
Et
Ph
64%
Shintani, R.; Okamoto, K.; Otomaru, Y; Ueyama, K.; Hayashi, T. J. Am. Chem. Soc. 2005, 127, 54.
25
The One with the Mechanism
Shintani, R.; Okamoto, K.; Otomaru, Y; Ueyama, K.; Hayashi, T. J. Am. Chem. Soc. 2005, 127, 54.
BnO
BnO CHO
Me
[Rh]-OH
BnO
BnO
MePh
[Rh]
O
BnO
BnO
Me
Ph
OH
BnO
BnO
Me
Ph
O [Rh][Rh]-Ph
PhB(OH)2
H2O transmetalation
alkyne insertion
hydrolysis
CO insertion
26
The One with the Cyclization of Alkynals
BnO
BnO CHO
Me [RhCl(C2H4)2]2 (7 mol %) ligand (7.5 mol %)
KOH, dioxane/H2O, 60 C, 4h
BnO
BnO
Me
Ph
OH
ArB(OH)2
PPh2PPh2
Bn
Bn
(S)-binap
(S,S)-Bn-bod
Bn
Bn(R,R)-Bn-nbd
24%76% ee
76%94% ee
78%95% ee
Entry Ar Yield (%)
ee (%)
1* Ph 89 94
2 4-MeOPh 71 93
3 4-FPh 77 93
4 3-ClPh 71 96
5 2-naphtyl 78 96
*Et instead of Me.
Shintani, R.; Okamoto, K.; Otomaru, Y; Ueyama, K.; Hayashi, T. J. Am. Chem. Soc. 2005, 127, 54.
27
Let’s Do Some CycloadditionsMeO2CMeO2C
Ph[RhCl(ligand)2]2 (2 mol %) AgSbF4 (4 mol %)
DCM, RTMeO2CMeO2C
PhMe
Shintani, R.; Sannohe, Y.; Tsuji, T.; Hayashi, T. Angew. Chem. Int. Ed. 2007, 46, 7277.
28
[4+2]MeO2CMeO2C
Ph[RhCl(diene)2]2 (5 mol %) AgSbF4 (10 mol %)
DCM, RT
MeO2CMeO2C
PhMe
Ph
Ph
Ph
PhPh
Ph
(S,S)-Ph-bod 87% 94% ee
(S,S)-Bn-bod 86% 5% ee
(S,S)-Ph-bnd 58% 35% ee
Shintani, R.; Sannohe, Y.; Tsuji, T.; Hayashi, T. Angew. Chem. Int. Ed. 2007, 46, 7277.
MeO2CMeO2C
R
R1
[RhCl(diene)2]2 (5 mol %) AgSbF4 (10 mol %)
DCM, RT
MeO2CMeO2C
RR1
8 examples 87-95%83-99% ee
HR2
R2
R = Ph, PhBr, Me, iPr R1 = Me, Ph R2 = H, Ph
29
Cycloaddition Mechanism
Shintani, R.; Sannohe, Y.; Tsuji, T.; Hayashi, T. Angew. Chem. Int. Ed. 2007, 46, 7277.
RhI
X
Ph
Me
RhI
X RhIII
H
RhIII
X
Ph
Me
H
XPh
X
PhMe
H
coordination
oxidative cyclization
1,3-allylicmigration (supra)
reductiveelimination
30
Stereochemistry Explained
Shintani, R.; Sannohe, Y.; Tsuji, T.; Hayashi, T. Angew. Chem. Int. Ed. 2007, 46, 7277.
31
1,6-Enynes Cycloisomerization
TsN Ph
[{RhCl(P-P)}2] (5 mol %) PPh3 (5 mol %) NaBArF
4 (10 mol %)DCE, 50 C, 24 h
TsN
PhH
dppe
(R)-binap
0%
F
FF
F
R
R
0%
7%
23%
R = H
R = Me
R = pentyl
R = CH2OCH2OCH3
2%
48% (50% ee)
64% (56% ee)
94% (80% ee)
Nishimura, T.; Kawamoto, T.; Nagaosa, M.; Kumamoto, H.; Hayashi, T. Angew. Chem. Int. Ed. 2010, 49, In Press.
O
PhH
PhPh
86%90% ee
O
OPhPh
84%99% ee
Selected Scope
32
Tfb (tetrafluorobenzobarrelene) Diene Synthesis
F
FF
F
F
HF
FF
F
F
FF
F
O
OBuLi
OiPr
OiPr
aq. TFA
chiral HPLCresolution
(S,S) + (R,R)
F
FF
F
O
O
(S,S)
2-PyNTf2KHMDS, THF
F
FF
F
TfO
OTf
(S,S)
78%
40%
RMgBr
PdCl2(dppf), THF
F
FF
F
R
R
(S,S)
R = C5H11 (37%)
rac
Nishimura, T.; Kumamoto, H.; Nagaosa, M.; Hayashi, T. Chem. Commun. 2009, 5713.
• Chiral HPLC to separate enantiomers;
• Low yielding steps.
33
The One with the Catalyst Design
[{RhCl(diene)}2] PPh3
DCM[RhPPh3(diene)]
Nishimura, T.; Kawamoto, T.; Nagaosa, M.; Kumamoto, H.; Hayashi, T. Angew. Chem. Int. Ed. 2010, 49, In Press.
A chiral diene and a phosphine on the same catalyst!
34
“Dig” the Mechanism
Nishimura, T.; Kawamoto, T.; Nagaosa, M.; Kumamoto, H.; Hayashi, T. Angew. Chem. Int. Ed. 2010, 49, In Press.
RhPPh3
RhPPh3
TsN
Ph
A
B
RhPPh3
TsNH
H PhC
TsN Ph
Rh Carbenoid
TsN
PhH
TsNPh
[Rh]
coordination
6-endo-dig
-H shift
35
Stereochemistry Explained
Nishimura, T.; Kawamoto, T.; Nagaosa, M.; Kumamoto, H.; Hayashi, T. Angew. Chem. Int. Ed. 2010, 49, In Press.
36
More Chiral Dienes
Me
Me2AlClCO2Me
H73% Me
CO2Me
(R)-(-)--phellandrene
Me
Me Me
OMe
Me
OMe
$27.35 (5 mL)
98.8% ee
Okamoto, K.; Hayashi, T.; Rawal, H.V. Org. Lett. 2008, 10, 4387.
O [RhCl(C2H4)2]2 (3 mol %) diene (3.3 mol %)
KOH, dioxane/water, 20-50 C
O
R
RB(OH)2
O
R
O
R
> 90%99% ee
> 90%98-99% ee
Me
Me Me
OMeMe
Me Me
OH
Most effective ligands reported so far for Rh-catalyzed asymmetric addition!
37
Last Stereochemistry Picture
Okamoto, K.; Hayashi, T.; Rawal, H.V. Org. Lett. 2008, 10, 4387.
38
Hayashi’s Dienes: SummaryO
PhB(OH)2[RhCl(C2H4)2]2 /ligand
KOH, dioxane/H2O
O
Ph
PhPh
94%96% ee
97%96% ee
Ph
Ph
Ph
Ph
93%83% ee
Ph
Ph
98%90% ee
Me
Me Me
OH
(R,R)-Bn-nbd (R,R)-Ph-bod
(R,R)-Ph-bnd (R,R)-Ph-bdd
90%99% ee
39
Ir-Catalyzed Allylic Displacement
R
OCO2Me [IrCl(alkene)2]2 (1.5 mol %)
PhOH (0.5 equiv.) DCM, RT
R
OPh
R = alkyl, aryl
Alkene
COD (cycloctadiene)
COE (cyclooctene)
100% conversion in 24 h at RT
inactive catalyst
Comments
Norbornadiene partial conversion after 4 days
Ph
Phdoes not form complex with Ir
rac
OMeMe
Ar
equal reactivity to COD
rac
Fischer, C.; Defieber, C.; Suzuki, T.; Carreira, E.M. J. Am. Chem. Soc. 2004, 126, 1628.
Potential for the diene to be synthesized asymmetrically from cheap (R) or (S)-carvone.
40
Spin-Off: Carreira’s Diene
R
OCO2Me [IrCl(COE)2]2 (1.5 mol %)
PhOH (0.5 equiv.) DCM, RT
OMeMe
R
OCO2Me
R
OPh
27-46% 80-98% ee 50-71% ee
R = alkyl, aryl
tBu
O
1. NBS, MeOH2. tBuOK, tBuOH
(R)-(-)-carvone
O
OMeMe
+ diastereomer
1. LDA, PhNTf2
2. ArZnCl, cat. Pd
OMeMe
Ar
68% 46%
Fischer, C.; Defieber, C.; Suzuki, T.; Carreira, E.M. J. Am. Chem. Soc. 2004, 126, 1628.
[RhCl(C2H4)2]2 (1.5 mol %) diene (3.3 mol %)
KOH, dioxane/water, RTPhB(OH)2
O
Ph
O
52%71% ee
41
Carreira’s Dienes Generation II“The Long Way Home”
Defieber, C.; Paquin, J.-F.; Serna, S.; Carreira, E.M. Org. Lett. 2004, 6, 3873.
OMeMe OMeMe
Ph
PhOMeMe
Ph
OMeMe
Ph
OMeMe
Ph
O
1. R1MgBr, Et2O
2. PCC, DCMR1O
1. NBS, MeOH
2. KOtBu, THFO
OMeMe
R1
LDA, R2-Br
O
OMeMe
R1
R2 1. LiNEt2, PhNTf2, THF
2. Pd(OAc)2, Ph3P, HCO2H, DMF
OMeMe
R1
R2
52% (iBu) 54%
87% (iBu, allyl) 62%
42
Again with the Enones?
OMeMe
87%95% ee
OMeMe
Ph
Ph
91%88% ee
OMeMe
Ph
91%91% ee
OMeMe
Ph
85%82% ee
OMeMe
Ph
63%93% ee
[RhCl(C2H4)2]2 (1.5 mol %) diene (3.3 mol %)
KOH, dioxane/water, RTRB(OH)2
O
Ph
O
Defieber, C.; Paquin, J.-F.; Serna, S.; Carreira, E.M. Org. Lett. 2004, 6, 3873.
• Additional substrates in the scope (not covered by Hayashi)
O
O
Ph
80%90% ee
O O
43%98% ee
Ph
Ph2N
O
MeO
OPh Ph
98%93% ee
93%98% ee
43
One Ligand, One Day, Two Papers
Ar1
O
H Ar2B(OH)2
diene (3.3 mol %)[RhCl(C2H4)2]2 (1.5 mol %)
KOH, MeOH/H2O 50 C, 1.25 h
Ar1
O
H
Ar2
Me
Ph Me
Me
Me OMe 63-90%89-93% ee
Ar1
O
OtBu Ar2B(OH)2
diene (3.3 mol %)[RhCl(C2H4)2]2 (1.5 mol %)
KOH, MeOH/H2O 50 C, 18 h
Ar1
O
OtBu
Ar2
76-95%89-94% ee
Paquin, J.-F.; Defieber, C.; Stephenson, C.R.J.; Carreira, E.M. J. Am. Chem. Soc. 2005, 127, 10850.
Paquin, J.-F.; Stephenson, C.R.J.; Defieber, C.; Carreira, E.M. Org. Lett. 2005, 7, 3821.
Me
Ph Me
Me
Me OMe
44
The Short Way Home
O
1. NBS, MeOH2. tBuOK, tBuOH
O
OMeMeLDA, PhNTf2
THF, -78 COTf
OMeMe
+ diastereomer
Pd(OAc)2, dppfArB(OH)2, K2CO3
PdCl2(PhCN), dppf RMgBr, Et2O R
OMeMe
81%68%
• Ortho substituted boronic acids a challenge;
• Most accessible route;
• Library of 14 ligands;
• High enantioselectivities (over 90%).
Carreira
Darses
[RhCl(C2H4)2]2 (1.5 mol %) diene (3.3 mol %)
KOH, dioxane/water, RTPhB(OH)2
O
Ph
O
Carreira's diene: 71% ee Darses' dienes: 39% ee (Bn) >90% ee (rest)
Gendrineau, T.; Chuzel, O.; Eijsberg, H.; Genet, J.-P.; Darses, S. Angew. Chem. Int. Ed. 2008, 47, 7669.
Fischer, C.; Defieber, C.; Suzuki, T.; Carreira, E.M. J. Am. Chem. Soc. 2004, 126, 1628.
O
1. NBS, MeOH2. tBuOK, tBuOH
(R)-(-)-carvone
O
OMeMe
+ diastereomer
1. LDA, PhNTf2
2. ArZnCl, cat. Pd
OMeMe
68% 46%tBu
45
Enantioselective Diene Synthesis
Cl
O
OR
NB O
Ph
H
H Ph
o-tolTf2N-
20 mol %
DCM, -78 C, 15 hClCO2R
R = CH2CF3
1. LiHMDS, THF, -78 C, 0.5 h2. MeLi, THF, -78 C, 0.5 h
OH
90%
99%>98% ee
KH, MeI, 0 C, 1 h
BOMCl, iPr2NEt, DCM, RT, 1h
or OR
R = Me (94%)R = BOM (82%)
[RhCl(C2H4)2]2 (1.5 mol %) diene (3.3 mol %)
KOH, dioxane/water, RTPhB(OH)2
O
Ph
O
OR R = Me (90%, 96% ee)R = BOM (95%, 96% ee)
Brown, K.M.; Corey, E.J. Org. Lett. 2010, 12, 172.
46
Order of Addition Is ImportantOBOM
[RhCl(C2H4)2]2 (1.5 mol %) diene (3.3 mol %)
KOH, dioxane/water, RTPhB(OH)2
O
Ph
O
Order of Addition
1. Stir Rh, diene in dioxane for 30 min2. Add KOH, stir 10 min3. Add PhB(OH)2, stir 10 min4. Add enone
1. Stir Rh, diene in dioxane for 30 min2. Add KOH, stir 10 min3. Add enone4. Add PhB(OH)2
<2% enone conversion >98% enone conversion
• Diene is inhibited
OBOMKOH, dioxane/water, RT
[RhCl(C2H4)2]2, PhB(OH)2 OBOM
Ph
• Less strained system necessary
Brown, K.M.; Corey, E.J. Org. Lett. 2010, 12, 172.
47
Adding One More Carbon
O
OCH2CF3
NB O
Ph
H
H Ph
o-tolTf2N-
10 mol %
NaOMe, MeOH, RT, 15 min
4 C, 15 h
CO2Me 90%99% ee
i. LDA, Et2O, -78 C, 0.5 h
ii. -78 C, 45 min
PhS
Cl
NtBu
CO2Me
60-70%
RLi, CeCl3
THF, -78 C, 15 min OH
R R
R = Me (85%)R = iBu (71%)
Brown, K.M.; Corey, E.J. Org. Lett. 2010, 12, 172.
[RhCl(C2H4)2]2 (0.25 mol %) diene (0.3 mol %)
KOH, dioxane/water, RTPhB(OH)2
O
Ph
O
98%96% eeOH
OH 98%95% ee
Me
iBu
Me
iBu
48
Summary
Reviews:
Defieber, C.; Grutzmacher, H.; Carreira, E.M. Angew. Chem. Int. Ed. 2008, 47, 4482.
Johnson, B.J.; Rovis, T. Angew. Chem. Int. Ed. 2008, 47, 840.
Chiral Diene
O
R
O
NR
O
O
NR
O
O
R
Ar1
Ar2 O
H Ar1 H
O
PhMe2Si CO2MeAr
PhMe2Si CO2Me
Ar1 H
NTs
Ar1 Ar2
NHTs
EE
R
R
E
E
RR
Ar1 CO2Me
CN Ar1 CO2Me
CN
Ar2
R
HEE
OHCHO
REE
TsNR
R
TsNR
R
49
A Bit of Shopping: Chiral Dienes at Aldrich
Ph
Ph
$161.50 (100 mg)
O
O
rac $65.80 (100 mg)
$90.30 (100 mg)
OMeMe
Bn
$211.50 (100 mg)
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