Umpolung Reactivity of Functional Groups :
The Stetter and The Benzoin Reactions
Pierre-André Fournier
Collins Group
1
What’s an Umpolung?
Any process by which the normal nucleophile and
electrophile are interchanged.
Classical example : the use of dithianes
O
R'
O
+
H
X
R
R
R'
Protection
Deprotection
X
S
R'
S
H
Base
S
S
R
R'
S
R'
S
R
Additional protection/deprotection steps.
Stoichiometric amount of reagents.
Highly basic conditions.
2
Benzoin and Stetter Reactions.
Can we functionalize the aldehyde in one step?
O
R
O
H
EWD
O
Stetter reaction
R'
O
EWD
R
R''
Precatalyst, base
R'
Benzoin reaction
R''
O
Precatalyst, base
R
R'
R''
1,4 addition
X
R
R''
R'
OH
1,2 addition
Catalyst : cyanide, phosphite or heterocyclic carbene.
Benzoin reaction : Addition of an acyl anion equivalent to a carbonyl.
Stetter reaction : Addition of an acyl anion equivalent to an activated olefin.
3
Benzoin and Stetter Reactions : New Synthetic Tools?
Total synthesis of (±)-Hirsutic Acid C (Trost, 1979)
OH
H
HO2 C
O
H
(±)-Hirsutic Acid C
CN
OH
N
S
MeO
O
O
CN
I
(2.3 eq.)
Et3N (50 eq.),
2-propanol,
82°C, 5h
H
8 steps
O
MeO2C
O
MeO2C
H
67%
Rough conditions (50 eq. of Et3N)
Low yields
Very specific
Trost, B.M.; Shuey, C.D.; DiNinno, F.Jr.; MeElvain, S.S.. J. Am. Chem. Soc.. 1979, 101,1284-1285.
4
The Cross Benzoin Reaction.
O
H
H
MeO
CN-
H
H
O
O
MeO
OH
O
H
DBU (70 mol%)
1 (20 mol%)
t-BuOH, 40°C, 1h
O
O
MeO
Thermodynamic Product
O
H
OH
Not Observed
O
OH
OH
OH
50%
N
Br
S
(1)
Not Observed
No control of the chemioselectivity.
Suzuki, K.; Bode, J.W.; Hachisu, Y. Adv. Synth Catal. 2004, 346,1097-1100.
5
Mechanism of the Benzoin Reaction.
DBU (70 mol%)
Catalyst 1 (20 mol%)
t-BuOH, 40°C, 1h
O
H
O
OH
OH
N
Br
S
(1)
50%
X
R
R'
N
O
Ph
Ph
OH
R'
R
R''
Elimination
O
R'
R
S
OH
Ph
Base
N
N
O
R''
S
Ph
H
R''
S
Nu attack
R'
Ph
R
N
R''
O
S
Proton transf er
Ph
H
R'
R
N
HO
R''
Proton transf er
S
O
Ph
1,2 Addition
Ph
Ph
OH R
N
R'
Breslow Intermediate
S
O
Ph
R''
6
Asymmetric Benzoin Condensation.
Meerwein's reagent
O
O
OMe
Me3OBF4
NH
O
quant.
PhHN
PhNHNH2
N
t -Bu
NEt 3
t -Bu
O
Ar
H
Ph
HC(OEt)3
HBF4, MeOH,
12h, 80°C
N
O
77%
NH
N N
O
65%
t -Bu
KOt -Bu (10 mol%)
Catalyst 2 (10 mol%)
THF, 16h, 18°C
BF4
N
(2)
t -Bu
O
Ar
Ar
OH
O
Ph
Cl
O
Br
O
Ph
OH
OH
F
83%, 90 ee%
Me
OH
16%, 93 ee%
MeO
OH
Cl
81%, 83 ee%
O
Me
F
O
82%, 64 ee%
OMe
O
OH
8%, 95 ee%
O
O
OH
Br
80%, 53 ee%
O
O
OH
100%, 64 ee%
0°C, 45 min
O
O
OH
41%, 88 ee%
-78°C
Enders, D.; Kallfass, U. Angew. Chem. Int. Ed.. 2002, 41, 1743-1745.
7
Jeffrey S. Johnson
Intermolecular Benzoin Reaction
B.Sc. : University of Kansas (1994)
Ph.D. : Harvard University (1999) (David A. Evans)
PDF : University of California (1999-2001) (Robert Bergman)
Assistant Professor : University of North Carolina (2001 – present)
8
Controlling the Reaction : The Use of Acylsilanes.
O
H
SiEt3
H
MeO
KCN (30 mol%)
18-crown-6 (30 mol%)
Et 2O, 25°C
O
H
O
OSiEt3
MeO
85%
O
H
H
Et3Si
MeO
KCN (30 mol%)
18-crown-6 (30 mol%)
Et 2O, 25°C
O
H
Et3 SiO
O
MeO
79%
Need to prepare the acylsilanes…
Aryl
Alkyl
O
Alk
LiSiX3
N
O
O
Alk
SiX3
60-85%
Me 3SiSiMe3 +
Ar
Cl
Pd
Cl
(5 mol%)
Pd
O
Cl
O
Ar
P(OEt) 3 (10 mol%)
Linghu, X.;Johnson, J.S. Angew. Chem. Int. Ed. 2003, 42, 2534-2536.
SiX3
10-80%
9
Silyl Cross Benzoin Reaction : Mechanism.
O
H
H
Et3Si
MeO
KCN (30 mol%)
18-crown-6 (30 mol%)
Et 2O, 25°C
O
H
Et 3 SiO
O
MeO
79%
O
Ph
Et3SiO
PMP
O
CN
O
retrocyanation
CN
Ph
PMP
OSiEt3
Ph
SiEt3
Cyanation
O CN
1,4-silyl
migration
Et3SiO
SiEt3
[1,2]-Brook
Rearrangement
CN
Ph
PMP
O
1,2 Addition
OSiEt3
C
O
N
PMP
Linghu, X.;Johnson, J.S. Angew. Chem. Int. Ed. 2003, 42, 2534-2536.
10
Silyl Benzoin Reaction : Scope and Limitations.
O
R1
O
+
TES
R2
H
KCN (30 mol%)
18-crown-6 (30 mol%)
Et2O, 25°C, 2h
O
R2
R1
OTES
O
R1
O
+
TES
H
R2
1. La(CN)3 (10 mol%)
THF, 23°C, <5min.
2. aq. HCL, MeOH aa
O
R2
R1
OR
Cl
O
OTES
O
OTES
Cl
82%
87%*
OTES
O
85%
MeO
OTES
51%
75%
88%
85%
84%
Cl
O
O
Ph
OH
64%
15 min.
O
OTES
OTES
MeO
O
n-Hex
TESO
O
O
79%
81%*
86%
83%
O
OMe
O
Ph
OH
70%
15 min.
OH
48%
15 min.
Limitation : R1 and R2 must be aryls to prevent aldol reaction.
Linghu, X.;Johnson, J.S. Angew. Chem. Int. Ed. 2003, 42, 2534-2536.
Linghu, X.; Bausch, C.C.; Johnson, J.S. J. Am. Chem. Soc. 2005, 127, 1833-1840.
11
Other Synthetic Methods to Make a-Hydroxy Ketones.
O
1. LDA
2. O 2
3. P(OEt)3
1. LDA, TMSCl
2. m-CPBA
3. TBAF
HO
O
O
HO
O
O
O
1. LDA
2. MoOPh
O
O
O
HO
Mo
O
N
O
1. NaHMDS
2. Davie's Reagent HO
O
O
NMe2
P
NMe 2
Me2 N
(MoOPh)
O
Ph
O
N
N
SO2 Ph
Davie's Reagent
S
O
O
O
100$ / g
Needs to form the enolate.
Lack of stereocontrol.
12
Chiral Metallophosphites for Enantioselective
Silyl Benzoin Reaction.
O
R1
O
+
TES
O
H
R2
Catalyst 3 (5-20 mol%)
n-BuLi (20-40 mol%)
THF, 30 min.,
0°C to 25°C
OTES
84%, 82 ee%
O
MeO
Cl
O
OTES
75%, 82 ee%
O
OTES
83%, 88 ee%
O
OTES
65%, 85 ee%
Ph Ph
O
R2
R1
OTES
O
Me O
O
O
P
O H
Me O
Ph Ph
OMe
O
OTES
Cl
82%, 87 ee%
O
(3)
OTES
87%, 91 ee%
O
OTES
OTES
78%, 73 ee%
88%, 41 ee%
Limitation : R1 and R2 must be aryls to prevent aldol reaction.
Linghu, X.; Potnick, J.R.; Johnson, J.S. J. Am. Chem. Soc. 2004, 126, 3070-3071.
13
Jeffrey W. Bode
Intramolecular Benzoin Reaction – Catalytic Homoenolate Generation
B.Sc. : Trinity University (San Antonio) (1996)
Ph.D. : ETH Zürich (2001) (Erick M. Carreira)
PDF : Tokyo Institute of Technology (2001-2003) (Keisuke Suzuki)
Assistant Professor : University of California (2003 – present)
14
Aldehyde-Ketone Benzoin Cyclization.
O
Catalyst 4 (20 mol%)
DBU (20 mol%)
THF, r.t.,
24 h, 44%, 96 ee%
O
O
N
O
(4)
OH
Cl
N
N
Ph
OH
O
OH
O
7h, 70%, 96 ee%
O
OH
O
0.5h, 69%, 60 ee% 15h, 73%, 39 ee%
OMe N
O
O
Et
OH
18h, 47%, 90 ee%
N
O
O
O
i-Pr
OH
19h, 74%, 85 ee%
O
Ph
OH
6h, 91%, 98 ee%
O
OH
19h, 73%, 99 ee%
Suzuki, K.; Bode, J.W.; Hachisu, Y. Adv. Synth Catal. 2004, 346,1097-1100.
Takikawa, H.; Hachisu, Y.; Bode, J.W.; Suzuki, K. Angew. Chem. Int. Ed. 2006, 45, 3492-3494.
15
Catalytic Homoenolate Generation : Synthesis of g-Butyrolactones.
O
Catalyst 5 (8 mol%)
DBU (7 mol%)
10:1 THF:t-BuOH
r.t., 15h
Br
O
H
H
+
O
Mes N
O
Cl
Br
N Mes
(5)
84%, 7:1 dr
Mes N
N Mes
Cl
1-Naph
Base
Ar
O
O
1-Naph
O
N
N
4-MeOC 6 H4
Mes
Ph
p-CO2 Me-C6 H4
Nu attack
76%, 4:1 dr
Mes
Ph
N
4-MeOC6 H4
Ph
N
Proton Transf er
87%, 5:1 dr
65%, 4:1 dr
Mes
OH
1-Naph
Mes
O
H
1-Naph
N
1-Naph
O
Mes
79%, 4:1 dr
O
O
O
4-BrC 6 H4
Elimination
O O
H
O
Mes
4-BrC 6H 4
Ar
O
O
O
N
O
O
O
Mes
N
O 1-Naph
MeO2 C
Mes
N
O
Breslow Intermidiate
O
TIPS
Addition
1-Naph
Ar
O
O
Mes
N
1-Naph5:1 dr
67%,
Mes
OH
TIPS
1-Naph
Nu addition
83%, 5:1 dr
N
Mes
N
Mes
N
TIPS
Homoenolate
41%,
3:1 dr
O
H
Ar
Sohn, S.S.; Rosen, E.L.; Bode, J.W. J. Am. Chem. Soc. 2004, 126, 14370-14371.
16
Catalytic Homoenolates Generation : Synthesis of g-lactames.
O
O
N
H
+
1-Naph
S
Ar
1-Naph
Catalyst 5 (8 mol%)
DBU (7 mol%)
10:1 THF:t-BuOH
r.t., 15h
O
H
Me
Me
O
N
O
ArO2 S
ArO 2S
N
MeO
Ph
69%, 3:1 dr
ArO2 S
N
p-Tol
O
CF3
70%, 3:2 dr
N Mes
(5)
Cl
ArO2 S
N
p-Tol
70%, 3.5:1 dr
ArO2 S
N
p-Tol
O
Ph
Me
Ph
73%, 1.7:1 dr
F3 C
ArO 2S
N
Ph
Ph
O
O
N
O
Ph
ArO 2S
O
N
p-Tol
70%, 4:1 dr
Mes N
96%, >10:1 dr
Ar : p-MeOC6 H4
ArO2 S
O
N
O
O S
Ar
61%,8:1 dr
O
62%, 5:1 dr
ArO2 S
N
p-Tol
O
TIPS
O
65%, 3.5:1 dr
Ph
51%, 10:1 dr
Average yields, but low diastereoselectivities.
He, M.; Bode, J.W. Org. Lett. 2005, 7, 3131-3134.
17
Intermolecular Stetter Reaction in Total Synthesis.
Tius’ synthesis of the macrocyclic core of Roseophilin.
OMe
Cl
N
O
NH
Roseophilin
MeO
O
1.
O
•
Li
N
O
O
6-Heptenal, Et 3N, 6
BzO
2. AcOH
3. BzCl, Et3N
BzO
O
OH
O
H2 Pd/C, THF
92%
Grubbs' I
BzO
90%
49% (2 steps)
O
O
BzO
O
Bn
N
Cl
S
(6)
(NH4)2CO3,
propionic acid
140°C, 10h
52%
Harrington, P.E.; Tius, M.A. Org. Lett. 1999, 1, 649-651.
60%
HN
O
18
Intermolecular Stetter Reaction.
EWD
O
Precatalyst, Base
+
R'
R''
R
O
EWD
R'
R''
R
H
Lack of selectivity.
Scheidt’s Methodology : Modification of the substrate.
EWD
R'
R''
R
EWD
R''
ONa
R
O
O
EWD
R'
R''
R
SiEt 3
O
+
R'
Precatalyst,
Base, Alcool
O
+
Precatalyst,
Base, Alcool
O
EWD
R'
R''
R
19
Karl A. Scheidt
Intermolecular Stetter Reaction – Acylsilanes Chemistry
B.S. : University of Notre-Dame (1994)
Ph.D. : Indiana University / University of Michigan (1999) (William
R. Roush)
PDF : Harvard University (1999-2002) (David A. Evans)
Assistant Professor : Northwestern University (2002 – present)
20
Biomimetic Conjugate Addition of Acyl Anion.
Nature‘s approach to acyl anions.
O
O
Pyruvate
OH Dehydrogenase
-CO2
RS SR
O
O
S
R
acetylCoA
Biomimetic approach to acyl anions.
O
R'
O
ONa +
R'
O
N
R
N
Catalyst 6 (20 mol%)
pH 7.2 buffer
MeOH, 70°C
O
O
N
R
N
OH
Bn
N
Cl
S
(6)
Myers, M.C.; Bharadwaj, A.R.; Milgram, B.C.; Scheidt, K.A. J. Am. Chem. Soc. 2005, 127, 14675-14680.
21
Pyruvate as a Source of Acyl Anion Equivalent : Mecanism.
O
R'
O
ONa +
R'
Catalyst 6 (20 mol%)
N
Conditions
R
O
O
N
R
N
O
OH
N
Bn
N
Cl
S
(6)
O
O
R'
O
Bn
N
O
HO C O
S
R'
N
Bn
Addition
S
HO
O
IM
O
OH
Elimination
CO2
R
R'
Loss of
CO2
O
IM
OH
R
OH
S
R'
Bn
Addition
N
Bn
O
HO
OH
S
R'
N
Breslow Intermidiate
IM
R
O
O
R
N
+
N
NaOEt, EtOH
E: Z > 95:5
O
N
R
N
22
Pyruvate as a Source of Acyl Anion Equivalent.
Organic conditions:
O
O
OH +
Me
N
Ph
O
N
R'
Catalyst 6 (20 mol%)
THF, DBU, 70°C
85%
O
O
N
R
OH
N
Bn
N
Cl
S
(6)
Aqueous conditions:
ONa +
Ph
Me
N
Me
O
Me
O
O
IM
Me
MeO
Me
O
O
IM
O
OMe
O
87%
Me
O
IM
O
IM
Cl
Me
O
IM
87%
O
N
Me
O
IM
87%
O
N
Me
O
O
R
pH form 5 to 12
91-94%
N
O
R'
Catalyst 6 (20 mol%)
buffer, MeOH, 70°C
O
O
O
S
87%
O
Me
IM
Me
O
O
IM
CF3
76%
80%
90%
35%
Organic Conditions
23
Pyruvate as a Source of Acyl Anion Equivalent.
O
O
ONa +
R
N
Ph
O
R'
Catalyst 6 (20 mol%)
pH 7.2 buffer
MeOH, 70°C
O
N
H 2P
N
O
O
N
Ph
O
Ph
OH
IM
O
Ph
92%
O
O
IM
Ph
90%
O
O
IM
Cl
S
(6)
O
Ph
72%
Bn
N
IM
95%
N
O
O
Ph
O
S
O
IM
Ph
96%
O
N
O
IM
Ph
76%
F3 C
O
IM
91%
O
O
Ph
IM
No Reaction
Imidazole easily transformed to an amide or an ester .
R
O
MeOTf
O
N
Ph
N
R
O
O
MeOH, DABCO
N
Ph
N
R
Ph
O
O
OMe
78% (2 steps)
24
Addition of Acylsilanes.
O
O
R
+
TMS
R1
R2
R
catalyst 1 (30 mol%)
DBU, i-PrOH,
THF, 70°C
O
O
R1
OH
R2
N
Br
S
(1)
O
R
TMS
Et
OTMS
N
Addition
[1,2] Brook
S
S
R
HO
O
Et
N
OH
2
R
O
i-PrOH
Elimination
R1
Desilylation
R
O
R2
OH
R1
HO
S
R
Et
TMSOi-Pr
OH
Addition
S
R
N
Et
O
N
OH
Breslow Intermidiate
R2
R1
Lots of solvents, bases and catalysts screened.
Mattson, A.E.; Bharadwaj, A.R.; Zuhl, A.M.; Scheidt, K.A. J. org. Chem. 2006, 71, 5715-5724.
25
Addition of Acylsilanes.
Ph
TMS
+
Ph
Ph
catalyst 1 (30 mol%)
DBU, i -PrOH,
THF, 70°C
O
O
Ph
O
O
Ph
OH
Ph
77%
Ph
O
Ph
O
Ph
O
O
Ph
Ph
O
1-Naph
Cl
Ph
O
O
O
Ph
80%
Br
S
(1)
Ph
O
O
Ph
OMe
82%
N
Ph
MeO
OMe
72%
75%
77%
Effective preparation of 1,4-diketone.
O
HN
O
O
O
AcO
OH
Salviadione
3-acetoxy-19-hydroxyspongia13(16),14-dien-2-one
26
Synthesis of Pyrroles and Furanes by Sila-Stetter/Paal-Knorr Sequence.
Furans:
O
O
R
+
TMS
R1
R2
1. catalyst 1 (20 mol%)
DBU, i -PrOH, THF, 70°C
2. AcOH
O
R
R2
OH
R1
O
Ph
Ph
O
Et
Ph
Ph
Ph
81%
Et
O
Ph
3,4-ClPh
82%
O
Et
Ph
O
Me
4-BrPh
84%
Br
S
(1)
O
Me
Ph
Ph
p-Tol
Ph
81%
N
74%
83%
Pyrroles:
Ph
O
O
R
TMS
+
R1
R2
1. catalyst 1 (20 mol%)
DBU, i -PrOH, THF, 70°C
2. PhNH2 TsOH, 4A sieves
N
Ph
Ph
OH
Ph
N
Br
S
(1)
66%
Ph
Ph
H
N
Ph
Ph
Cy
N
Ph
62%
Ph
Ph
4-ClPh
N
4-OMePh
69%
Ph
Ph
N
Ph
69%
Ph
n-Pr
Ph
Ph
Me
N
Ph
N
Ph
Ph
Ph
82%
Ph
4-NH2 Ph
54%
70%
Good yields for a one-pot synthesis of this type of molecule.
Bharadwaj, A.R.; Scheidt, K.A. Org. Lett. 2004, 6, 2465-2468.
27
Tomislav Rovis.
Intramolecular Asymmetric Stetter Reaction – NHC Design
B.Sc. : University of Toronto (1990)
Ph.D. : University of Toronto (1993-1998) (Mark Lautens)
PDF : Harvard University (1998-2000) (David A. Evans)
Assistant Professor : Colorado State University (2000 – present)28
Asymmetric Intramolecular Stetter Reaction : First Screening.
Catalyst Screening .
O
O
R
1
N
R
O
2
N
X
N Ph
O
CO2 Et
(20 mol%)
KHMDS (20 mol%)
CO2 Et
xylenes, 25°C, 24h
O
R1/R2
X
Yield (%)
ee (%)
H/Bn
BF4
85
90
H/t-Bu
BF4
0
-
H/i-Pr
Cl
27
79
H/Ph
Cl
48
80
Indanyl
BF4
58
95
Effect of the Electronic Properties of the Catalyst.
O
N
N
N
BF4
O
X
O
(20 mol%)
O
CO2 Et KHMDS
(20 mol%)
xylenes, 25°C, 24h
O
CO2 Et
X
Yield (%)
ee (%)
H
58
95
Cl
60
91
OMe
94
94
Possible EWG : Ketones, Esters, Nitriles.
Kerr, M.S.; de Alaniz, J.R.; Rovis, T. J. Am. Chem. Soc. 2002, 124, 10298-10299.
29
Asymmetric Intramolecular Stetter Reaction : a-Substituted
Cycloketones.
O
O
CO2 Et
O
Catalyst 7 (20 mol%)
O
O
CO2 Et
KHMDS (20 mol%)
xylenes, 25°C, 24h
O
CO2 Et
N
CO2 Et
N
N
BF4
OMe
O
(7)
94%, 94ee%
O
CO2 Et
O
CO2 Me
Me
O
O
O
Me
80%, 97ee%
O
CO2 Me
N
Me
64%, 82ee%
S
OMe
90%, 84ee%
O
95%, 87ee%
CO2 Me
O
63%, 96ee%
CO2 Et
O
CO2 Et
N
N
Bn
CO 2Me
72%, 84ee%
35%, 94ee%
(8)
N
BF4
N Ph
90%, 92ee%
With catalyst 8
Epimerization observed only in rare cases.
O
H
Catalyst 8 (20 mol%)
O
O
O
CO2 Me
KHMDS (20 mol%)
xylenes, 25°C, 24h
CO2 Me
O
90%,<5ee%
O
Catalyst 8 (20 mol%)
CO2 Me KHMDS (20 mol%)
xylenes, 25°C, 24h
CO2 Me
81%,95ee%
30
Formation of Quaternary Stereocenters via Stetter Reaction.
O
O
O
Catalyst 9 (20 mol%)
Me
CO2 Me
O
Et3N (2 eq.)
PhMe, 25°C, 24h
O
Me
CO2 Me
(9)
F
Ph
O
92%, 89ee%
O
Et
CO2 Me
S
95%, 99ee%
O
O
Me O
Me
4-NO 2Ph
85%, 96ee%
Et
CO2 Me
95%, 92ee%
Me O
81%, 95ee%
F
O
O
Br
Me
CO2 Me
F
F
BF 4
96%, 97ee%
O
O
N
F
N
N
O
O
Me
55%, 99ee%
O
n-Bu
O
CO 2Me
CO2 Me
Ph
71%, 98ee%
N
Bn
86%, 90ee%
With catalyst 8
(8)
N
BF4
N Ph
Highly selective methods for the formation of quaternary centers.
O
O
Me
O
Ph
O
Catalyst 9 (20 mol%)
Me
KHMDS (20 mol%)
O
CO2 Me
PhMe, 25°C, 24h
From E olef in : 85%, 96ee%
From Z olef in : 50%, 56ee%
Kerr, M.S.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 8876-8877.
31
Formation of Contiguous Stereocenters via Stetter Reaction.
N
O
Bn
Me
O
CO2Et
N
BF 4
N Ar
O
(20 mol%)
H
CO2Et
Me
Base (20 mol%)
PhMe, 25°C, 24h
O
Ar
Base
Yield (%)
ee (%)
dr (%)
Ph
KHMDS
85
90
3:1 to 12:1
Ph
---
88
90
15:1
p-CF3Ph
---
94
95
30:1
HMDS and the carbene can epimerize the stereocentres.
No epimerization observed with a less basic carbene (p-CF3Ph)
32
Formation of Contiguous Stereocenters via Stetter Reaction.
O
O
Me
O
CO2 Et
O
H
Catalyst 8 (20 mol%)
PhMe, 25°C, 24h
CO2Et
O
H
CO2 Et
O
O
O
H
O
O
O
H
Bn
CO2 Et
(8)
O
O
95%, 83ee%,
13:1 dr
O
H
O
80%, 95ee%,
18:1 dr
O
H
Me
H
O
H
H
O
O
N
N 4-CF Ph
3
N
O
80%, 84ee%,
20:1 dr
H
95%, 94ee%,
10:1 dr
Me
Bn
O
53%, 94ee%,
12:1 dr
CO2 Et
81%, 95ee%,
30:1 dr
n-Bu
O
H
94%, 99ee%,
50:1 dr
O
Ph
N
O
H
O
H
O
85%, 55ee%,
10:1 dr
80%, 88ee%,
15:1 dr
33
Source of The Diastereoselectivity.
Reactions with E and Z olefins shows that
bond rotation is slower than protonation.
34
Synthesis of Hydrobenzofuranones via Desymmetrization.
Ar
Yield (%)
ee (%)
O
dr (%)
O
4-MeOPh
90
88
>95:5
Ph
75
80
>95:5
C6F5
92
31
MeO
O
Me
H
Et
O
90%, 92ee%
H
4-BrPh
H
O
O
78%, 85ee%
Me
O
87%, 94ee%
MeO
O
87%, 88ee%
O
86%, >99ee%
O
H
O
Me
O
O
Ph
O
Me
O
H
O
i-Pr
O
MeO
O
H
O
Me
KHMDS (20 mol%)
PhMe, 25°C, <5 min
O
86%, 94ee%
O
O
O
H
(20 mol%)
O
H
O
O
BF4
>95:5
O
N
N Ar
N
OMe
O
O
71%, 99ee%
t-Bu
t-Bu
H
t -Bu
O
O
62%, >99ee%
2h
Liu, Q.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 2552-2553.
35
Stetter and Benzoin Reaction.
Intermolecular Benzoin Reaction:
Acylsilanes are required.
Alkyls are problematic.
Reaction works well with aryls.
Intramolecular Benzoin Reaction:
No substrate modifications required.
Works with alkyl and aryl.
Promising asymmetric version.
Intermolecular Stetter Reaction:
Acylsilanes or pyruvates are required.
Limited to aryls.
Effective synthesis of pyrroles and furanes.
T. Rovis
Intermolecular Stetter Reaction:
No substrate modifications required.
Works with alkyl and aryl.
Synthesis of multiple stereocenters in one step.
J.S. Johnson
J.W. Bode
K.A. Scheidt
36
--.
Bode – Opening of epoxides.
37
--.
Bode - Opening of cyclopropanes.
38
Applications of Ru-Based Chiral Metathesis Catalysts.
Jeff Bode – Cross Stetter, intramolecular benzoin, intramolecular benzoin on ketones
Johnson – Sylil benzoin (racemic and chiral)
Enders - ?
Karl Scheidt – Biomimetic Stetter, « esterification » of aldehydes, Sila-Stetter (+ PaalKnorr one-pot)
Tom Rovis – Asymmetric Stetter
Tius, Trost,
39
Sylil Benzoin Reaction : Scope and Limitations.
O
R1
O
+
R2
H
TES
KCN (30 mol%)
18-crown-6 (30 mol%)
Et 2O, 25°C, 2h
O
R2
R1
OTES
Cl
O
OTES
OTES
OTES
Cl
82%
O
OTES
75%
85%
OTES
85%
O
O
TESO
O
MeO
79%
86%
O
OMe
O
O
MeO
OTES
51%
Limitation : R1 and R2 must be aryls.
40