1 umpolung reactivity of functional groups : the stetter and the benzoin reactions pierre-andré...
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Umpolung Reactivity of Functional Groups : Umpolung Reactivity of Functional Groups : The Stetter and The Benzoin ReactionsThe Stetter and The Benzoin Reactions
Pierre-André Fournier Collins Group
22
What’s an Umpolung?
Any process by which the normal nucleophile and electrophile are interchanged.
Classical example : the use of dithianes
Additional protection/deprotection steps.
Stoichiometric amount of reagents.
Highly basic conditions.
XRR' H
O+
R'
O
R
Protection
R' H
SSBase
XR
R'
SS
R'R
SS
Deprotection
33
Benzoin and Stetter Reactions.
R H
O
R X
O
Can we functionalize the aldehyde in one step?
R' R''
O
Precatalyst, base
R
O
OH
R'R''
R' R''
Precatalyst, base
EWD
R
O
R''R'
EWD
Benzoin reactionStetter reaction
1,2 addition1,4 addition
Benzoin reaction : Addition of an acyl anion equivalent to a carbonyl.Stetter reaction : Addition of an acyl anion equivalent to an activated olefin.
Catalyst : cyanide, phosphite or heterocyclic carbene.
44
Benzoin and Stetter Reactions : New Synthetic Tools?
Total synthesis of (±)-Hirsutic Acid C (Trost, 1979)
CN
OO
MeO Et3N (50 eq.), 2-propanol,
82°C, 5h
S
NOH I
(2.3 eq.)
CN
O
MeO2C
67%
OH
HMeO2C
8 steps
Rough conditions (50 eq. of Et3N)Low yieldsVery specific
Trost, B.M.; Shuey, C.D.; DiNinno, F.Jr.; MeElvain, S.S.. J. Am. Chem. Soc.. 1979, 101,1284-1285.
OHH
HHO2C O
(±)-Hirsutic Acid C
55
The Cross Benzoin Reaction.
Suzuki, K.; Bode, J.W.; Hachisu, Y. Adv. Synth Catal. 2004, 346,1097-1100.
No control of the chemioselectivity.
O
MeO O
H
H HCN-
O
MeOOH
H
Thermodynamic Product
OH
MeOO
H
Not Observed
O
H
O
OH
OO DBU (70 mol%)1 (20 mol%)
t-BuOH, 40°C, 1h
OH
50% Not Observed
S
NOH Br
(1)
66
Mechanism of the Benzoin Reaction.
S
NOH Br
(1)
Ph
O
H
Nu attack
N
S
R
Base
R'
R''
N
S
RR'
R''
X
Ph
O
H
S
NR
R'
R''
Proton transfer
Ph
OH
S
N
R
R'
R''
Breslow Intermediate
PhO
1,2 AdditionPh
HO S
NR
R'
R''
Ph
O
Proton transfer
Ph
O S
NR
R'
R''
Ph
OHElimination
Ph
O
Ph
OH
DBU (70 mol%)Catalyst 1 (20 mol%)
t-BuOH, 40°C, 1h
O
OH
50%
O
H
77
Asymmetric Benzoin Condensation.
Enders, D.; Kallfass, U. Angew. Chem. Int. Ed.. 2002, 41, 1743-1745.
O NH
OMe3OBF4
O N
OMe
t -Bu t -Bu
Meerwein's reagent
O NH
N HC(OEt)3HBF4, MeOH,
12h, 80°C O N
t -Bu t -Bu
quant.
PhNHNH2
NEt3
77% 65%
PhHNNN
Ph
BF4
(2)
Ar
O
H Ar
O
Ar
OH
KOt-Bu (10 mol%)Catalyst 2 (10 mol%)
THF, 16h, 18°C
Ph
O
Ph
OH
83%, 90 ee%
O
OHF
F
81%, 83 ee%
O
OHCl
Cl
82%, 64 ee%
O
OHBr
Br
80%, 53 ee%
O
OHMe
Me
16%, 93 ee%
O
OHMeO
OMe
8%, 95 ee%
O
OH
100%, 64 ee%0°C, 45 min
O
O O
OH
41%, 88 ee%-78°C
O
O
88
Jeffrey S. Johnson
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)
Intermolecular Benzoin Reaction
99
Controlling the Reaction : The Use of Acylsilanes.
Need to prepare the acylsilanes…
O
MeO O
H
SiEt3 H
O
MeOOSiEt3
HKCN (30 mol%)
18-crown-6 (30 mol%)Et2O, 25°C
85%
O
MeO O
H
H Et3Si
Et3SiO
MeOO
HKCN (30 mol%)
18-crown-6 (30 mol%)Et2O, 25°C
79%
Linghu, X.;Johnson, J.S. Angew. Chem. Int. Ed. 2003, 42, 2534-2536.
Ar Cl
O
Ar SiX3
O
10-80%
Me3SiSiMe3 +
PdCl
ClPd
(5 mol%)
P(OEt)3 (10 mol%)
Alk N
O
O
LiSiX3 Alk SiX3
O
60-85%
Alkyl Aryl
1010
Silyl Cross Benzoin Reaction : Mechanism.
Linghu, X.;Johnson, J.S. Angew. Chem. Int. Ed. 2003, 42, 2534-2536.
O
MeO O
H
H Et3Si
Et3SiO
MeOO
HKCN (30 mol%)
18-crown-6 (30 mol%)Et2O, 25°C
79%
Ph
O
SiEt3
Cyanation
O
SiEt3
CN
[1,2]-BrookRearrangement
OSiEt3
C
PMPO
1,2 AdditionPh
Et3SiO
PMP
O
Ph
O CN
PMP
OSiEt3
retro-cyanation
CN
N
CN
1,4-silylmigration
PMP
Et3SiO
Ph
O
1111
Silyl Benzoin Reaction : Scope and Limitations.
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.
Limitation : R1 and R2 must be aryls to prevent aldol reaction.
R1
O
TES H
O
R2+
R1
O
OTES
R2
O
OTES
O
OTES
O
OTES
O
OTES
O
OTES
O
TESO
O
OTES
n-Hex
82% 86% 75%79% 85%
85% 51%MeO
Cl
Cl
OMe
MeO
O
KCN (30 mol%)18-crown-6 (30 mol%)
Et2O, 25°C, 2h
R1
O
TES
1. La(CN)3 (10 mol%)THF, 23°C, <5min.
2. aq. HCL, MeOH aaH
O
R2
+
R1
O
OR
R2
O
OH
Cl
70%15 min.
O
OH
64%15 min.
O
OH
48%15 min.
PhPh
87%* 83% 81%* 84% 88%
1212
Other Synthetic Methods to Make -Hydroxy Ketones.
Needs to form the enolate.Lack of stereocontrol.
OO
N
OO
O
Mo
OP
Me2N
NMe2
NMe2
O O
HO
OO
HO
(MoOPh)
O O
HO
1. LDA, TMSCl2. m-CPBA3. TBAF
1. LDA2. MoOPh
NO
SO2Ph
Ph1. NaHMDS2. Davie's Reagent
Davie's Reagent
N
OSOO
100$ / g
O O
HO
1. LDA2. O23. P(OEt)3
1313
Chiral Metallophosphites for Enantioselective Silyl Benzoin Reaction.
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.
R1
O
TES
Catalyst 3 (5-20 mol%)n-BuLi (20-40 mol%)
THF, 30 min.,0°C to 25°C
H
O
R2
+R1
O
OTES
R2
O
OTES
O
OTES
O
OTES
O
OTES
O
OTES
O
OTES
O
OTES
84%, 82 ee%
OO
OTESMeO
OMeCl
Cl75%, 82 ee%
83%, 88 ee%
82%, 87 ee% 87%, 91 ee%
65%, 85 ee% 78%, 73 ee% 88%, 41 ee%
OP
O
PhPh
Ph Ph
O
O
Me
Me H
O
(3)
1414
Jeffrey W. Bode
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)
Intramolecular Benzoin Reaction – Catalytic Homoenolate Generation
1515
Aldehyde-Ketone Benzoin Cyclization.
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.
OOH
7h, 70%, 96 ee% 0.5h, 69%, 60 ee%
O
OH
15h, 73%, 39 ee%
OOH
18h, 47%, 90 ee%
O
EtOH
19h, 73%, 99 ee%
N
OOH
6h, 91%, 98 ee%
O
PhOH
19h, 74%, 85 ee%
O
i-PrOH
OMe N O OOO
O
O Catalyst 4 (20 mol%)DBU (20 mol%)
THF, r.t.,
(4)O
OH24 h, 44%, 96 ee%
NN
NPh
O
Cl
1616
Catalytic Homoenolate Generation : Synthesis of -Butyrolactones.
Sohn, S.S.; Rosen, E.L.; Bode, J.W. J. Am. Chem. Soc. 2004, 126, 14370-14371.
N N Mes
Cl (5)
Catalyst 5 (8 mol%)DBU (7 mol%)
10:1 THF:t-BuOHr.t., 15h
84%, 7:1 dr
O
H Mes
Br
O
H+ O
O
Br
O
Ph
OO
4-BrC6H4
4-MeOC6H4
OO
p-CO2Me-C6H4
Ph
OO
Ph
4-MeOC6H4
O
79%, 4:1 dr 76%, 4:1 dr 87%, 5:1 dr 65%, 4:1 dr
O OO OO
1-Naph
O1-Naph
TIPS
TIPSMeO2C
TIPS
4-BrC6H4
67%, 5:1 dr 83%, 5:1 dr 41%, 3:1 dr
Nu attackN
N
Mes
Base
N NMes
Cl
Breslow Intermidiate
Elimination
Mes
O
N
N
Mes
Mes
H
1-Naph
OH
N
N
Mes
Mes
1-Naph
OH
N
N
Mes
Mes
1-Naph Homoenolate
O
ArH
O
N
N
Mes
Mes
1-Naph
OAr
O
N
N
Mes
Mes
Addition
OH
1-Naph
Proton Transfer
Nu addition
O
1-Naph
Ar
OAr
1-Naph
O
Mes
1717
Catalytic Homoenolates Generation : Synthesis of -lactames.
He, M.; Bode, J.W. Org. Lett. 2005, 7, 3131-3134.
N
Ph
ON
Ph
ON
Ph
ON
Ph
O
70%, 4:1 dr 69%, 3:1 dr 73%, 1.7:1 dr 61%,8:1 dr
Np-Tol
ON
p-Tol
ON
p-Tol
O
TIPS
p-Tol
70%, 3:2 dr 65%, 3.5:1 dr 51%, 10:1 dr
N
Ph
O
62%, 5:1 dr
ArO2S ArO2S ArO2S ArO2S ArO2S
MeOO Ph Ph
Me
ArO2SNp-Tol
O
70%, 3.5:1 dr
ArO2SArO2SArO2S
CF3 F3C O
Average yields, but low diastereoselectivities.
Catalyst 5 (8 mol%)DBU (7 mol%)
10:1 THF:t-BuOHr.t., 15h
N N Mes
Cl (5)
96%, >10:1 dr
N
HMes
Me
O
H
1-Naph+
N
1-Naph
O
Me
SO
O
Ar
S OO
Ar
Ar : p-MeOC6H4
1818
Intermolecular Stetter Reaction in Total Synthesis.
Tius’ synthesis of the macrocyclic core of Roseophilin.
Harrington, P.E.; Tius, M.A. Org. Lett. 1999, 1, 649-651.
ONH
ClOMe
N
Roseophilin
O
N
O
1.Li
•
2. AcOH3. BzCl, Et3N
O
BzO 6-Heptenal, Et3N, 6
S
NOH
Bn
Cl
(6)
O
BzO
O
Grubbs' I
O
BzO
OH2 Pd/C, THF
49% (2 steps)60%
90%
92%
O
BzO
O(NH4)2CO3,
propionic acid140°C, 10h
HN
O
52%
MeO
1919
Intermolecular Stetter Reaction.
Lack of selectivity.
R' R''
Precatalyst, BaseEWD
R
O
R''R'
EWD
R H
O+
R' R''
Precatalyst,Base, Alcool
EWD
R
O
R''R'
EWD
R SiEt3
O+
R' R''
Precatalyst,Base, Alcool
EWD
R
O
R''R'
EWD
R
O+
ONa
O
Scheidt’s Methodology : Modification of the substrate.
2020
Karl A. Scheidt
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)
Intermolecular Stetter Reaction – Acylsilanes Chemistry
2121
Biomimetic Conjugate Addition of Acyl Anion.
O
O
OH
PyruvateDehydrogenase
-CO2
O RS SR O
SR
acetylCoA
Nature‘s approach to acyl anions.
Biomimetic approach to acyl anions.
Myers, M.C.; Bharadwaj, A.R.; Milgram, B.C.; Scheidt, K.A. J. Am. Chem. Soc. 2005, 127, 14675-14680.
R'
O
O
ONa +
N
N
O
RCatalyst 6 (20 mol%)
pH 7.2 bufferMeOH, 70°C N
N
O
R
R' O
S
NOH
Bn
Cl
(6)
2222
Pyruvate as a Source of Acyl Anion Equivalent : Mecanism.
R'
O
O
ONa +
N
N
O
RCatalyst 6 (20 mol%)
ConditionsN
N
O
R
R' O
S
NOH
Bn
Cl
(6)
AdditionN
S
Bn
Breslow Intermidiate
Elimination
R'
C
N
S
R'
OH
N
S
BnO
IM
Loss ofCO2
Addition
R'
O
O
O
HO
O
Bn
O
CO2
R
R'
OH
N
S
Bn
R
O
IM
O
IM
R
R'
O
HOOH
OH
HO
R
O+
N
N
ONaOEt, EtOH
N
N
O
RE:Z > 95:5
2323
Pyruvate as a Source of Acyl Anion Equivalent.
IM
OMe O
Me
IM
OMe O
MeO
IM
OMe O
Cl
IM
OMe O
CF3
IM
OMe O
IM
OMe O
OMe
O IM
OMe O
S
87% 87% 87% 87%
76% 80% 90%
IM
OMe O
Me
35%Organic Conditions
S
NOH
Bn
Cl
(6)Me
O
O
OH +
Catalyst 6 (20 mol%)THF, DBU, 70°C
N
N
O
R
R' O
85%Ph
O
N
N
Organic conditions:
Aqueous conditions:
Me
O
O
ONa +
Catalyst 6 (20 mol%)buffer, MeOH, 70°C
N
N
O
R
R' O
pH form 5 to 1291-94%
Ph
O
N
N
2424
Pyruvate as a Source of Acyl Anion Equivalent.
Imidazole easily transformed to an amide or an ester .
Ph
OOR
N
N
MeOTf
Ph
OOR
N
NMeOH, DABCO
Ph OMe
OOR
78% (2 steps)
Ph Ph Ph
Ph Ph Ph
92% 90% 72% 95%
96% 76% 91%
R
O+
Catalyst 6 (20 mol%)pH 7.2 bufferMeOH, 70°C
N
N
O
H2P
R' O
S
NOH
Bn
Cl
(6)Ph
O
N
N
Ph
No Reaction
PhIM
OO
IM
OOPh
IM
OO
IM
OO
IM
OO
OO
IM
SO
IM
OO
IM
OOF3C
N
N
ONa
O
2525
Addition of Acylsilanes.
Mattson, A.E.; Bharadwaj, A.R.; Zuhl, A.M.; Scheidt, K.A. J. org. Chem. 2006, 71, 5715-5724.
Lots of solvents, bases and catalysts screened.
Addition[1,2] Brook
N
S
Et
Breslow Intermidiate
Elimination
RN
S
R
OH
N
S
EtO
R2
Desilylation
Addition
OTMS
Et
TMSO i-Pr
R1
R
OH
N
S
Et
R1
O
R2
O
R2
R1
R
O
R
O
TMS+
catalyst 1 (30 mol%)DBU, i-PrOH,
THF, 70°CR1 R2
O
R1 R2
R OO
S
NOH Br
(1)
R
O
TMS
OH
OH
HO
HO
i-PrOH
2626
Addition of Acylsilanes.
Effective preparation of 1,4-diketone.
77%Ph
O
TMS+
catalyst 1 (30 mol%)DBU, i-PrOH,
THF, 70°CPh Ph
O
Ph Ph
Ph OO
S
NOH Br
(1)
Ph
Ph OO
Ph
Ph OO
1-Naph Ph
Ph OO
Cl OMe
82% 80% 72%
Ph
Ph OO
OMe
Ph
Ph OO
MeO
75% 77%
HN
O
O
Salviadione
O
AcO
O
OH
3-acetoxy-19-hydroxyspongia-13(16),14-dien-2-one
2727
Synthesis of Pyrroles and Furanes by Sila-Stetter/Paal-Knorr Sequence.
Good yields for a one-pot synthesis of this type of molecule.
Pyrroles:
Furans:
Bharadwaj, A.R.; Scheidt, K.A. Org. Lett. 2004, 6, 2465-2468.
R
O
TMS+
1. catalyst 1 (20 mol%)DBU, i-PrOH, THF, 70°C
2. AcOHR1 R2
O
S
NOH Br
(1)
81% 82% 84% 74% 83%
OPh
Ph
Ph OEt
Ph
Ph OEt
3,4-ClPh
Ph OEt
4-BrPh
Ph OMe
Ph
Ph OMe
p-Tol
Ph
81%
OR
R1
R2
R
O
TMS+
1. catalyst 1 (20 mol%)DBU, i-PrOH, THF, 70°C
2. PhNH2 TsOH, 4A sievesR1 R2
O
S
NOH Br
(1)
62% 69% 82% 54% 70%
HNPh
Ph
Ph NCy
Ph
Ph N4-ClPh
4-OMePh
Ph NPh
Ph
Ph NPh
Ph
Ph NPh
Ph
Ph
69%
NPh
Ph
Ph
Ph
66%
Ph Ph n-Pr 4-NH2PhPh Me
2828
Tomislav Rovis.
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)
Intramolecular Asymmetric Stetter Reaction – NHC Design
2929
Asymmetric Intramolecular Stetter Reaction : First Screening.
Kerr, M.S.; de Alaniz, J.R.; Rovis, T. J. Am. Chem. Soc. 2002, 124, 10298-10299.
O
O CO2Et
O
N N
N
PhR1
R2
X
(20 mol%)
KHMDS (20 mol%)xylenes, 25°C, 24h
O
O CO2Et
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
X Yield (%) ee (%)
H 58 95
Cl 60 91
OMe 94 94
Catalyst Screening .
Effect of the Electronic Properties of the Catalyst.
Possible EWG : Ketones, Esters, Nitriles.
O
O CO2Et
(20 mol%)
KHMDS (20 mol%)xylenes, 25°C, 24h
O
O CO2Et
NN N
O
X
BF4
3030
Asymmetric Intramolecular Stetter Reaction : -Substituted Cycloketones.
Epimerization observed only in rare cases.
94%, 94ee%
O
O CO2Et
Catalyst 7 (20 mol%)
KHMDS (20 mol%)xylenes, 25°C, 24h
O
O CO2Et
O
O CO2Et
O
O CO2Et
O
O CO2Et
S
O CO2Me
NMe
O CO2Me
N
O CO2Me O CO2Et O CO2Et
80%, 97ee% 90%, 84ee% 95%, 87ee% 63%, 96ee%
64%, 82ee% 72%, 84ee% 35%, 94ee% 90%, 92ee%
Me
Me OMe
CO2Me
With catalyst 8
(7)
NN N
O
OMe
BF4
NN N Ph
BF4
Bn (8)
90%,<5ee%
O
O
Catalyst 8 (20 mol%)
KHMDS (20 mol%)xylenes, 25°C, 24h
CO2Me O
OCO2MeH
81%,95ee%
O
Catalyst 8 (20 mol%)
KHMDS (20 mol%)xylenes, 25°C, 24h
CO2Me
OCO2Me
3131
Formation of Quaternary Stereocenters via Stetter Reaction.
Highly selective methods for the formation of quaternary centers.
Kerr, M.S.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 8876-8877.
85%, 96ee% 81%, 95ee% 71%, 98ee% 86%, 90ee%With catalyst 8
NN N Ph
BF4
Bn (8)
O O O O
Me Men-Bu
CO2MeCO2Me
4-NO2Ph Me
O O
Ph
O
From E olef in : 85%, 96ee%From Z olef in : 50%, 56ee%
O
O
Catalyst 9 (20 mol%)
KHMDS (20 mol%)PhMe, 25°C, 24h
OMe
O
Me
CO2MeO
Ph
96%, 97ee%
O
O
Catalyst 9 (20 mol%)
Et3N (2 eq.)PhMe, 25°C, 24h
CO2Me OMe
O
O
O
92%, 89ee% 95%, 92ee% 95%, 99ee% 55%, 99ee%
Br
(9)
NN N
O
FBF4
O
Me
CO2Me
O
MeCO2Me S
O
EtCO2Me
O
EtCO2Me
Ph
Me
O
FF
FF
3232
Formation of Contiguous Stereocenters via Stetter Reaction.
HMDS and the carbene can epimerize the stereocentres.
No epimerization observed with a less basic carbene (p-CF3Ph)
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
O
O CO2Et
N NN
Ar
BF4
(20 mol%)
Base (20 mol%)PhMe, 25°C, 24h
O
O CO2EtBn
Me
H
Me
3333
Formation of Contiguous Stereocenters via Stetter Reaction.
81%, 95ee%,30:1 dr
O
O CO2Et
Catalyst 8 (20 mol%)
PhMe, 25°C, 24h O
O CO2Et
Me
H
Me N
N N 4-CF3PhBn (8)
53%, 94ee%,12:1 dr
O
O CO2EtH
n-Bu
80%, 84ee%,20:1 dr
O
O CO2EtH
Bn
95%, 83ee%,13:1 dr
O
O CO2EtH
94%, 99ee%,50:1 dr
95%, 94ee%,10:1 dr
O
OH
80%, 95ee%,18:1 dr
O
OH
85%, 55ee%,10:1 dr
O
OH
Me
80%, 88ee%,15:1 dr
O
H
O
H
O O
H
H
N
OO
O
OO
O
Ph
H
H
3434
Source of The Diastereoselectivity.
Reactions with E and Z olefins shows that bond rotation is slower than protonation.
3535
Synthesis of Hydrobenzofuranones via Desymmetrization.
Ar Yield (%) ee (%) dr (%)
4-MeOPh 90 88 >95:5
Ph 75 80 >95:5
C6F5 92 31 >95:5
(20 mol%)
KHMDS (20 mol%)PhMe, 25°C, <5 min
NN N
O
Ar
BF4
O
O O
MeO OO
MeOO
H
Liu, Q.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 2552-2553.
2h
O
O
MeO
H
90%, 92ee%
O
O
EtO
H
86%, 94ee%
O
O
i-PrO
H
87%, 94ee%
O
O
PhO
H
87%, 88ee%
O
O
4-BrPhO
H
78%, 85ee%
O
O
MeO
H
86%, >99ee%
O
O
MeO
H
71%, 99ee%
O
O
t -BuO
H
62%, >99ee%
Me t-BuMe t-BuOMeMeO
3636
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.
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
T. Rovis
3737
--.
Bode – Opening of epoxides.
3838
--.
Bode - Opening of cyclopropanes.
3939
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 (+ Paal-Knorr one-pot)
Tom Rovis – Asymmetric Stetter
Tius, Trost,
4040
Sylil Benzoin Reaction : Scope and Limitations.
R1
O
TES
KCN (30 mol%)18-crown-6 (30 mol%)
Et2O, 25°C, 2hH
O
R2
+
R1
O
OTES
R2
O
OTES
O
OTES
O
OTES
O
OTES
O
OTES
O
TESO
O
OTES
82% 86%
75%
79% 85%
85% 51%MeO
Cl
Cl
OMe
MeO
O
Limitation : R1 and R2 must be aryls.