-Hydroxylation of carbonyl compounds
8
The problem:
O
O
R'
R
?
Important
R'
R
in
natural
product
synthesis
OH
Strategy:
O
O
R'
R
R'
R
+
OH
i.e. Umpolung of O.
+
OH
Using the Vedejs reagent MoO5.py.HMPT:
O
- +
LDA
O Li
MoO5.py.HMPT
O
-23°C
THF, -70°C
Camphor
OH
Disadvantage: Low yields with methyl ketones due to selfcondensation/overoxidation
to diketone.
Using 2-sulphonyloxaziridine:
OH
1 KN(SiMe3)2
Ph
CO2Et
Ph
THF, -78°C
2 PhSO2
N
CO2Et
+
PhSO2
N
O
Ph
83%
35
Difficult to separate
Ph
High steric requirements:
Ar
Ar
O
OH
do
O
O
O
H
H
Only product
91%
Using peroxide:
O
O
Si
Si
O
1 LDA
2 TMSCl
Isophorone
O
MCPBA
Hexane
Si
O
O
90%
NEt3
HF
CH2Cl 2
O
HO
70%
Synthesis of 1,2-diols
Syn-1,2-diols can be synthesized by Sharpless asymmetric dihydroxylation (AD) of
(E)-olefins. The anti-diols are more difficult to obtain, mainly because the (Z)-olefins
are less accessible and show reduced enantioselectivity in the AD.
36
Using the proline-catalyzed direct asymmetric aldol reaction:
O
O
+
30 mol% L-Pro
DMSO
RT, 2d
60 %
H
OH
38-95%
See:
9
O
OH
OH
regioselectivity:
> 20:1
diastereoselectivity: > 20:1
enantioselectivity: >100:1
W Notz, B List, J Amer Chem Soc, 2000, 122, 7386-7387.
Combinatorial chemistry
Simultaneous preparation of a potentially large number of products by combining a
set/s of chemical building blocks in a few synthetic steps. Separation is usually
assisted by making use of a solid support (resin).
See:
Guiles:
J Org Chem, 1996, 61, 5169.
Brown:
J Amer Chem Soc, 1996, 118, 6331.
37
38
39
B Modern enolate chemistry
1
Enolates of weak carbon acids
O
O
O
LiNH2, NH3
O
-
O
CH2
O
-
CH2
[1,1 C-C]
O
OH
O
O
Later: LiNR2 - more hydrophobic -> organic solvents: ether, THF
- less nucleophilic: NB
“LDA era”:
->
O
O
+
EtO
Li
N
Et2O
EtO
25°C, 15 min
-
+
Li
LDA
nBuLi +
+
OEt
NH
O
EtO
40
O
O
...
Weaker bases:
Si
N
Li
Si
Hydrophobic, strong bases -> stoichiometric formation of enolates from normal
ketones.
O
OLi
OLi
LDA, DME
-78°C
+
99 : 1
H
O
H
OLi
OLi
LDA, DME
-78°C
+
H
H
H
98 : 2
-> Kinetic product!
LDA solution structure
S
Li
iPr N
N iPr
iPr
Li
iPr
S = tBuOMe
THF
HMPA
DMPU:
S
N
N
41
O
Transition state
H
R
O
R N
H
Li THF
R
R
THF
With HMPA:
H
H
-
OR
HMPA
2 HMPA
+
iPr N Li N iPr
iPr
Li
iPr
CO2R
solvent
HMPA
O
iPr N
iPr
+
Li
N
iPr
iPr
-
OR
H
iPr N
iPr
O
+
Li
N
Li(HMPA)4
Li(HMPA)4
iPr
iPr
Sun & Collum, J Amer Chem Soc, 2000, 122, 2452-2458.
LTMP:
Highly hindered N atom, therefore useful for regioselective
deprotonation of ketones with two acidic protons in different steric
N
Li
environments.
See:
Rathke, J Org Chem, 1987, 52, 448-450.
42
Hall, J Amer Chem Soc, 1991, 113, 9575.
2
Formation of regiodefined enolates
Bulky amides remove protons from the less-substituted position - the kinetic enolate
(as opposed to thermodynamic):
MeI
LICA,
THF
LiO
-78°C
O
kinetic
H
H
O
tBuOK,
tBuOH
heat
AcOH
O
KO
thermodynamic
LICA:
Li
N
OLi
OLi
O
LDA
0°C, DME
Z
7%
84%
+
+
E
9%
43
OLi
OLi
O
LiCPh3
DME, 25°C
OLi
+
thermodynamic
Add ketone to excess base:
Add base to excess ketone:
28
94
kinetic
:
:
72
6
General observations
Kinetic enolate is favoured by:
Thermodynamic enolate is
favoured by:
Very strong base
LDA, LiCPh3
Aprotic solvent
Alkoxide base
THF, DMF, DME
tBuOK
Protic solvent
tBuOH
Low temperature
-78°C
Higher temperature
No excess ketone
Small counter-ion
Excess ketone
Li+
Larger counter-ion
The classical solutions:
1
0°-25°C
Activation of the  position.
44
K+
+
O
O
Na
O
H
-
O
O
+
HCO2Et
NaOEt
H
Blocking
i.e.
O
O
nBuSH,
pTsOH, benzene
H
O
O
O
SBu 1 tBuOK, tBuOH
2 MeI
KOH,
H2O, reflux
2
SBu
Reversible blocking of the  position.
1,3-Dicarbonyl compounds can stabilize a second anion. The anion formed last will
react first:
O
CO2Et
O
-
O
CO2Et
O
CO2Et
Et CO Et
2
EtBr
NaOEt
O
Activation
(see below)
-
EtO
O
Et
45
O
OM
O
O
O
R'X
Base
R
R
R
Base
OM
R'
OM
OM
R'X
R
R
Examples:
O
O
O
1 KNH2, NH3
2 BnCl
3 NH4Cl, H2O
O
O
Ph
O
1 NaNH2, NH3
2 nBuBr
3 HCl, H2O
Use KNH2/NaNH2/BuLi
:
O
R'
R
O
O
O
O
1
NaH
2
BuLi
Differently-substituted 1,3-diketones:
46
O
R'
O
O
O
O
O
1 NaNH2, NH3
2 MeI
+
89
O
O
O
O
:
11
O
O
1 NaNH2, NH3
2 MeI
O
+
99
:
1
 -Aminoketones

They behave kinetically like the C analogues.

Thermodynamic enolization with Et3N-Et3SiCl is often in the direction of N:
Ph
MeO2C
O
Ph
N
MeO2C
OSiEt3
N
Ph
OSiEt3
+ MeO C N
2
1 Add ketone to LDA/THF at -78°C
1
2 Add ketone to LHMDA at -78°C, then eq. at 0°C 1
3 Heat ketone, reagents, DMF 48h at 80°C
1
:
:
:
4,5
49
9
E:Z::1:4
Z>98
E:Z::3:1
Compare the following:
O
CO2Me
N
Ph
O
O
O
N
N
N
CO2Et
See:
3
Garst: J Org Chem, 1980, 45, 2307.
Stereochemistry of enolate formation
47
Ireland: Stereochemistry is related to the polarity of the medium:
OR
O
OR
LDA
THF
LDA
THF/HMPT
OLi
OLi
OR
How?
48
R
R
O
O
H C Me
Li
Li
H
N
C H
Me
H
N
OLi
OLi
R
R
"E enolate"
"Z enolate"
R
R
O
O
HLi+
+ -
(Me2N)3P O
MeLi+
Me
+ -
H
(Me2N)3P O
N
H
N
Other important effects:
% HMPT
Substituent (R) size
[BuLi] <--> % hexane
[LiCl] or [LiBr]
Other bases
49
H
Some examples:
O
OLi
R
R
R
Base
Solvent
Z:E
-OMe
LDA
THF(hexane)
5:95
LDA
THF-23%HMPT
84:16
LDA
THF(hexane)
6:94
LHMDS
THF-23%HMPT
>95:5
-OBn
LDA
THF
20:80
-OtBu
LDA
THF-23%HMPT
77:23
-Et
LDA
THF(hexane)
30:70
[(PhCH2)2N]3SiLi
THF(hexane)
>97:3
-OEt
Preparation of (E) or (Z) enolborinates
OTf
B
O
B
O
B
+
O
(iPr)2NEt
97% (Z)
3% (E)
(iPr)2NEt
O
B
O
BOTf
B
2
2
+
2
86% (E)
50
14% (Z)
Masamune, Tetrah Lett, 1979, 24, 2229.
O
OBnBu2
nBu2BOTf
iPr2NEt
OBnBu2
+
3% (E)
97% (Z)
Evans, J Amer Chem Soc, 1981, 103, 3099.
51