Transcript Umpolung reactivity - Test Page for Apache Installation

Umpolung reactivity
Special Topic 27/02/09
Anne Fournier
1
The synthetic problem
Heteroatoms impose an alternating acceptor and donor reactivity pattern
d0 X
X = halogen, O, N
d = donor (-)
a1
3
a
d2
5
d4
a
a = acceptor (+)
An odd number of carbons between functional groups
a1
a1
X
X
X
X
a3
a1
d4
d2
d2
1,3-disubstitution
a1
a3
d2
d2
d4
An even number of carbons between functional groups
X
X
X
4
d
a1
a1
a3
d4
a3
d2
a3
d2
a1
a1
d4
d2
d2
1,2-disubstitution
a3
d4
X
X
X
X
4
d
a
d4
3
a
d2
1
a1
a3
2
a3
d
a1
a1
a3
d2
d2
X
1,4-disubstitution
2
Definition
Umpolung is any process by which donor and acceptor
reactivity of an atom are interchanged (reversal in polarity).
d0 X
a0 X
Umpolung
1
a
a3
2
d
4
d
a5
d1
a2
d3
d5
a4
« usual » reactivity:
Umpolung reactivity:
C2n= donor, C2n+1= acceptor
C2n= acceptor, C2n+1= donor
Reactivity enables us to construct new bonds which are difficult to construct or cannot be
achieved by « usual » reactivity, particulary the construction of 1,2 or 1,4-difunctionality.
Seebach ACIEE 1979, 239
3
Carbonyl Umpolung
Patterns of Carbonyl Reactivity
O
O
_
+
+
R
_
R
_
umpolung reaction polarity
O
O
acyl bonding
Nu
acyl transfer reaction
Friedel-Craft reaction
R
O
E
O
E
alpha bonding
R
enolate anion alkylation
aldol and Claisen reactions
Nu
R
R'
O
R
+
+
"usual" reaction polarity
R
R'
_
R'
R'
O
R'
Nu
beta bonding
conjugate additions
Michael reactions
R
R'
E
4
Carbonyl Umpolung
Carbonyl Umpolung intermediates
O
Application Strategy
_
carbonyls vs. acyl anions
enolates vs. a-electrophiles
Michael acceptors vs. homoenolates
R'
_
R
+
+
umpolung reaction polarity
O
O
R
R
E
..
_
acyl anion
d1 synthon
O
O
Nu
R
R'
O
-electrophile
+
R
a2 synthon
O
R'
_
.. homoenolate
R
E
R
d3 synthon
5
Carbonyl Umpolung
Masked Acyl Anion Equivalents

1a. Benzoin Condensation: Cyanide ion Catalyzed Addition
O
..
_
Ar
H
OH
O
CN
_
Ar
Nucleophilic attack
of cyanide
CN
H
Deprotonation
(umpolung)
a1
O
Ar
• Must use aromatic or heteroaromatic aldehydes; aliphatic
aldehydes tend to undergo an aldol condensation
d1
Ar
OH
Ar
• Cannot selectivity cross couple of two different aldehydes
OH
Ar
R
Ar
Ar
Ar
Ar
Benzoin
NC
Proton transfer
OH
NC
O
..
OH
Regeneration
of catalyst
_
_ CN
H
Addition of aldehyde
O
O
1,2-substitution
CN
Acyl anion equivalent
cyanohydrin
O
Ar
..
Lapworth JACS 1903, 995.
6
Carbonyl Umpolung
Masked Acyl Anion Equivalents

1b. Cyanide ion Catalyzed Cross Silyl-Benzoin Reaction
O
O
O
O
R1
SiR3
R2
H
R1
R1
18-Crown-6
OSiR3
Only product
OH
Not observed
OSiR3
O
R3Si
R1
R2
M-CN
[1,2]-Brook
CN
Rearrangement
R1
.._
CN
R1
Acyl anion equivalent
Kinetic control, regiosepecific, (but need to make acyl silane), lower yields often result
from aliphatic aldehydes (improvement with La(CN)3 catalyst)
Johnson JACS 2005, 1833
7
Carbonyl Umpolung
Masked Acyl Anion Equivalents

2. N-Heterocyclic Carbenes Catalyzed Acyloin Formation
O
R2
R2
N
Base
H
-H
S
R3
R
H
N
O
S
R
R2
OH
N
umpolung
S
R3
R2
N
OH
S
R
..
N
..
R2
R1
R1
R1
R1
..
R1
R3
S
R3
R
R3
Breslow intermediate
ylides or nucleophilic carbenes
thiazolium salts
Acyl anion equivalent
R1
O
R2
R1
R2
O
N
R4
OH
N
R
R
OH
acyloin
R3
R4
OH
O
R
S
R3
S
R4
O
R4
Effective for aliphatic and (hetero)aromatic aldehydes
Applicable to acylsilanes
H
(a) Breslow JACS 1958,3719.
(b) Enders Acc. Chem. Res. 2004, 534.
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Carbonyl Umpolung
Masked Acyl Anion Equivalents

3. Recent Progress in Asymmetric Benzoin Reactions
O
O
cat. (10mol%)
KOtBu (10mol%)
Ar
Ar
Ar
H
8-83%
OH
ee = 80-95%
Ph
N
O
cat.
N
N
tBu
Ar = Ph, m-Me-Ph,
p-Me-Ph, p-MeO-Ph,
m-Cl-Ph, p-F-Ph,
p-Cl-Ph, p-Br-Ph,
o-Furyl, o-Naphtyl
Triazolium salt
Enders ACIEE, 2002, 1743
9
Carbonyl Umpolung
Masked Acyl Anion Equivalents

4. Stetter Reaction: Generation of 1,4-dicarbonyls
General reaction
O
R4
O
R3
R1
R5
Nuc. cat.
R5
R2
1,4-disubstitution
R1
polar solvent
X
R4
R2
O
R3
O
X = H or SiR3
Nuc. cat. = CN- or NHCs
R4
O
d1
R1
R2
R5
a
3
R3
Scope includes unsaturated esters, nitriles, ketones and aldehydes
O
(a) Stetter ACIEE 1976, 639.
(b) Scheidt JACS 2004, 126, 2314
10
Carbonyl Umpolung
Masked Acyl Anion Equivalents

5a. Recent Advancements in Asymmetric Stetter Reactions
Aromatic substrates
O
O
OMe
5
CO2R2
1
R
7
63-95%
CO2R2
X
6
cat. (20mol%), KHMDS (20mol%)
xylenes, rt, 24h.
H
R1
N
N
BF4
X
8
N
O
ee = 82-97%
cat.
R1 = 6-Me, 8-Me, 8-MeO
R2 = Me, Et
X = O, S, NMe, CH2
Aliphatic substrates
O
O
CO2Et
cat. (20mol%), KHMDS (20mol%)
xylenes, 25°C, 24h.
CO2Et
N
N
Bn
cat.
81%
N
BF4
Ph
ee = 95%
Enantioselective intramolecular Stetter reaction
Rovis JACS, 2002, 10298
11
Carbonyl Umpolung
Masked Acyl Anion Equivalents

5b. Quaternary Stereocenters via Asymmetric Stetter
Aromatic substrates
O
O
EWG
cat. (20mol%), Et3N (2eq.)
PhMe, 25°C, 24h.
X
R
R
55-96%
EWG
X
ee = 89-99%
X = O, S, CH2
R = Et, Me, Ph
F
F
N N
Opposite
stereochemistry
Aliphatic substrates
F
F
N
F
BF4
O
O
O
cat.
cat. (20mol%), KHMDS
R
PhMe, 25°C, 24h.
EWG
R
EWG
63-90%
ee = 84-99%
R = Me, n-Bu
Rovis JACS, 2004, 8876
12
Carbonyl Umpolung
Masked Acyl Anion Equivalents

6. Metallophosphites as Umpolung Catalyst: The Enantioselective
Cross Silyl Benzoin Reaction
Ar
Me
Ar
O
O
O
P
Me
H
O
O
O
O
O
Ar
R1
SiEt3
H
Ar = 2-FPh
R2
(5-20mol%)
Ar
n-BuLi (5-20mol%)
THF, 0.5h.
65-88%
R2
R1
OSiEt3
41-91% ee
Johnson JACS 2004, 3070
13
Carbonyl Umpolung
Masked Acyl Anion Equivalents

7a. Anions of 1,3-Dithianes (Corey-Seebach reaction)
O
O
S
HS
R
H
S
BuLi
SH
Lewis Acid (cat.)
R
H
THF, -30°C
S
S
E+
S
S
Cleavage
R
R
Li
R
E
E
Acyl Anion equivalent
• Usually formed from corresponding aldehydes by thioacetalization
• R = primary, secondary and tertiary alkyl, allyl, benzyl, aryl, and O-containing groups
• Biggest drawback: removal of dithiane
1. HgCl2, H2SO4, H2O 2. NaIO4 or m-CPBA 3. MeX (X = I, OTs,…)
(a) Corey, Seebach ACIEE 1965 1075
(b) Corey, Seebach ACIEE 1965 1077
14
Carbonyl Umpolung
Masked Acyl Anion Equivalents

7b. Anions of 1,3-Dithianes (Corey-Seebach reaction)
15
Carbonyl Umpolung
Unmasked Acyl Anion Equivalents

Zirconium mediated or catalysed Umpolung reactions
O
Cl
[Cp2ZrHCl]
R
ZrCp2
CO
R
R
ZrCp2
Cl
Acyl anion equivalent
(Acyzirconocene chloride)
R''X
R'CHO
Lewis acid
PdCl2(PPh3)2
R''X = phenyl, benzyl, allyl halides,
acid chlorides, allyl acetates
R' = alkyl, alkenyl
O
O
R'
(a) Hanzawa ACIEE 1998, 1696
(a) Hanzawa TL 1998, 6249
(a) Guan Curr. Org. Chem. 2008, 1406
R
R
-ketol
OH
R''
ketone or -diketone
16
Carbonyl Umpolung
Unmasked Acyl Anion Equivalents

Zirconium mediated or catalysed Umpolung reactions
R4
O
R
R1
R3
ZrCp2Cl
O
R2
Pd(OAc)2 (5mol%)
monophosphine (10mol%)
Pd(OAc)2 (10mol%)
BF3.OEt2 (1eq)
toluene
Et2O-THF
R4
R1
R3
O
R4
R1
R
R3
O
OH
(a) Hanzawa TL 1998, 8141
(b) Hanzawa ACIEE, 1999, 2395
(c) Hanzawa T 2002, 8141
R2
1,2-addition
R
O
R2
1,4-addition (generation of 1,4-dicarbonyls)
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Carbonyl Umpolung
Acyl Anion Equivalents

A Summary (Acyl anions are the most sought umpolung reagents)
Masked Acyl Anion Equivalents
 1,3-Dithianes (stoichiometric synthesis, pre-functionalization)
 Cyanohydrin derivatives (stoichiometric synthesis, pre-functionalization)
 Isonitriles, Nitronates anions, t-Butyl hydrazones, Vinyl thioether anions,…
 Metal cyanides (catalytic formation, direct)
 Nucleophilic carbenes (catalytic formation, direct)
 Metallophosphites (catalytic formation, direct)
Unmasked Acyl Anion Equivalents
 Acylzirconocene chloride
18
Carbonyl Umpolung
-Electrophile Equivalents

1. -Halo Carbonyl Substitution
O
-halogenation of ketones
R
O
Nu
+
or
R
R'
R'
X = Cl, Br or I
Hell-Volhardt-Zelinski reaction
X -
Nu
-Electrophile equivalent
O
1. CH3COCH2Cl
2.
2 BrCH(CO2Et)2
NaCH(CO2Et)2
Na2CO3
CO2Et
CO2Et
(EtO2C)2C=C(CO2Et)2
19
Carbonyl Umpolung
-Electrophile Equivalents

2. Anodic Oxidation of Silyl Enol Ethers
Anodic oxidative cyclization
O
OTBS
H
RVC anode
carbon cathode
0.4 M LiClO4
MeOH/CH2Cl2 (1:4)
2,6-lutidine, RT
15-20mA, 2,2F/mole
TBSO
O
OSiR3
R1
R1
CH2Cl2/CH3OH
0.4M LiClO4
O
MeO
OSiR3
porous C anode
15-20 mA
R2
TBSO
.
R2
TsOH, RT
O
O
very reactive
H
O
OH
TBSO
O
O
Allicacol A
Moller JACS 2003, 36
20
Carbonyl Umpolung
Homoenolate Equivalents

1. The Tautomerism Problem
• Enolates
M
• tautomerism is generally not a problem
because oxyanionic tautomer still acts as
carbon nucleophile
O
O
M
• Homoenolates
O
M
O
M
• tautomerism is a much larger problem
because it is often irreversible and
oxyanioic tautomer rarely acts as a
carbon nucleophile
21
Carbonyl Umpolung
Homoenolate Equivalents
2. The Acetal Approach

M
Br
1. RX
M
O
O
O
R
2. H3O+
O
O
Homoenolate equivalent
Synthesis of enantiopure 4-substituted quinolizidines
Ph
O
Ph
OH
(CH2)3MgBr
O
N
CH3
N
O
O
69%
O
CH3
H2, Pd/C
aq. HCl
66%
N
CH3
H
Bosch JOC 2003, 1919
22
Carbonyl Umpolung
Homoenolate Equivalents
3. Silyl Enol Ethers of Ketones

OM
O
OSiR3
R''X
M
R'
SiR3
M = Li or MgBr
OSiR3
M
R'
R3Si
R'
R'
R''
Homoenolate equivalent
Kuwajima Chem. Comm. 1979, 708
Synthesis of ()-δ-Araneosene
MeOO2C
Br
Br
O
MeOO2C
Li
TBS
THF, -78°C, 2h
82%
O
4 steps
OTBS
TAS-F, THF-DMF
-35°C to 0°C, 3h
90%
Corey Org. Lett. 2002, 2441
23
Carbonyl Umpolung
Homoenolate Equivalents

4a. Cyclopropane Ring Opening : Titanium Homoenolates
Homoaldols Reactions of Titanium Homoenolates
RO
OTMS
RO
OR
OTMS
TiCl4
TiCl3
TiCl4
CH2Cl2
TMSO
Cl
R = Et, Me, iPr
- TMSCl
O
O
O
R'COR''
R'
or/and
O
RO
R''
R'
R''
lactones
TiCl3
RO
OH
-hydroxyesters
Homoenolate equivalent
(a) Nakamura, Kuwajima JACS 1977, 7360
(b) Nakamura, Kuwajima JACS 1986, 3745
24
Carbonyl Umpolung
Homoenolate Equivalents

4b. Zinc Homoenolates: Preparation
• Cyclopropane Ring Opening
O
OR
OTMS
ZnCl2
2
OR
2 TMSCl
Et2O
O
Zn
OEt2
RO
Nakamura, Organometallics, 1985, 641
• Direct Oxidative Addition
O
EtO
I
O
Zn-Cu
Benzene/DMA
60°C, 3-4h
ZnI
EtO
Yoshida, TL, 1985, 5559
25
Carbonyl Umpolung
Homoenolate Equivalents

4b. Zinc Homoenolates: Reactivity
• Copper-Catalyzed Conjugate Additions
O
OR
O
O
OTMS
2 TMSCl
O
OEt2
Zn
RO
Cu(I), HMPA, THF
RO
Kuwajima JACS 1984, 3368
• Catalytic Homo-Reformatsky Reactions
O
OTMS
RCHO
1.2 eq
OEt
cat. ZnX2
CH2Cl2, RT
R
EtO
OTMS
Nakamura, Kuwajima JACS 1987, 8056
26
Carbonyl Umpolung
Homoenolate Equivalents

4b. Zinc Homoenolates: Reactivity
• Palladium Coupling Reactions
OR1
O
0.5 eq
O
O
Zn
5mol% PdCl2(PPh3)2
O
R2
1
R O
Cl
Et2O, RT
R2
R1O
O
Nakamura JOC, 1987, 8056
27
Thank you
for
your attention
28