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1
Asymmetric synthesis
• There are a number of different strategies for enantioselective or
•
•
diastereoselective synthesis
I will try to cover examples of all, but in the context of specific transformations
Such an approach does not include use of the ‘chiral pool’ so here are two examples
4
HO
O
OH
1
5
OH
Me
2
5
Me
2
HO 3
2-deoxy-D-ribose
4
3
1
Me
(R)-sulcatol
• In this example, one stereogenic centre is retained
• All others are destroyed
O
HO
OH
1. MeOH, H
2. MsCl
HO
O
MsO
OMe
1. KI
2. Raney Ni
Me
O
MsO
H2O
Me
OH
Me
OMe
Me
Ph3P
Me
OH
Me
Me
Me
O
OH
CHO
Advanced organic
2
‘Chiral pool’ II
Me
OH
HO
HO
2
4
3
3 steps
OH
6
O 5
D-mannose
1
Me
O
Me
O
O
N3
BnO
O
1. TBAF
Me
2. PCC
3. Ph3P=CHCHO
CHO
OTBDPS
O
O
O
O
BnO
O
overall retention of
stereochemistry
OTBDPS
1. NaBH4
2. Tf2O
Me
stereoselective
reduction
Me
Me
O
O
BnO
Me
reduction
of alkene &
azide
followed by
reductive
amination
PCC
NaN3
N3
OTBDPS
O
O
O
BnO
OTf
O
OTBDPS
hydrogenolysis of benzyl (Bn) group &
reductive amination of resultant
aldehyde
Pd / C
H2
Me
OH
OH
addition of
protecting groups
Me
Me
O
BnO
remove
stereogenic
centre
Me
HO
O
O
H H
N
1. H2, Pd / C, H
2. TFAA
2
3
HO
4
1
two step reversal of
stereogenic centre
N
H
BnO
O
6
H
HO 5
swainsonine
• In this example three stereogenic centres are retained
• One stereogenic centre undergoes multiple inversion -- but overall it is retained
Advanced organic
3
Stereoselective reactions of alkenes
• Alkenes are versatile functional groups that, as we shall see, present plenty of scope
•
for the introduction of stereochemistry
Hydroboration permits the selective introduction of boron (surprise), which itself
can undergo a wide-range of stereospecific reactions
Substrate control
Me
Me
BH3
H
H
B
H
1. TMEDA
2. BF3•OEt2
Me
Me
H
H
B
H
Me
(+)-α-pinene
Me
Me
Me
Me
(+)-IpcBH2
(–)-Ipc2BH
BH3
Me
H
Me
H
B
H
H
1. TMEDA
2. BF3•OEt2
Me
Me
Me
H
Me
BH2
H
Me
Me
H
Me
Advanced organic
4
Hydroboration: reagent control
Me
H
1. (–)-Ipc2BH
2. H2O2 / NaOH
H OH
Me
H
H
B
H
Me
Me
Me
Me
98.4% ee
H
(–)-Ipc2BH
• The two compounds formed previously, mono- & diisopinocampheylborane are
•
•
common reagents for the stereoselective hydroboration of alkenes
Ipc2BH is very effective for cis-alkenes but less effective for trans
IpcBH2 gives higher enantiomeric excess with trans and trisubstituted alkenes
Me
H
1. (+)-IpcBH2
2. H2O2 / NaOH
H
HO
Me
H
66% ee
Me
Me
H
Me
BH2
H
(+)-IpcBH2
Advanced organic
5
Hydroboration: catalyst control
O
H
+
B H
1. RhL2 Cl
2. H2O2 / NaOH
H
OH
O
H
H
H
82% ee
catecholborane
H
L=
Me
Me
O
O
OH
PAr2
PAr2
H
Ar = 2-MeOC6H4
HO2C
CO2H
OH
(2R,3R)-tartaric acid
• Hydroboration can be catalysed using certain rhodium complexes
• Good enantiomeric excesses can be achieved
• The example above utilises an initially complicated diphosphine
• But the central core of the ligand (and the stereogenic centres) is derived from the
natural compound tartaric acid (cheap and readily available as both enantiomers)
Advanced organic
6
Hydroboration: catalyst control II
Me Me
1. [Rh(COD)2] .BF4
(R)-BINAP / catecholborane
Me
2.
Me
Me
Me
Me
HO
OH
Me
Me
O
H B O
1. LiCHCl2
2. NaClO2
[oxidation]
Me
H CO2H
Me
Me
Me
99%; 97% ee
Rh
[Rh(COD)2]
88%; 97% ee
PPh2
PPh2
(R)-BINAP
• This second example utilises BINAP and again gives very impressive ee’s
• The second part of the reaction gives an example of an alternative stereospecific
...transformation of the boron species
Advanced organic
7
Homogeneous hydrogenation: substrate control
Me OH
H2(g)
[(Cy3P)Ir(COD)py]
Me OH
PF6
H
Me
Me
Ir
PCy3
N
H2(g)
[(Cy3P)Ir(COD)py]
MeO
i-Pr
Me
MeO
PF6
i-Pr
[(Cy3P)Ir(COD)py]
H
Me
• Cationic iridium or rhodium complexes are very effective catalysts for substrate
•
•
•
directed hydrogenations
Whilst the hydroxyl group gives a very diastereoselective reaction; it is probably not
via hydrogen bonding
The methoxy group also directs hydrogenation
Presumably, coordination of oxygen lone pair and cationic complex causes selectivity
Advanced organic
8
Substrate control in acyclic systems
OH
O
Me
H2(g)
[Rh(nbd)(diphos-4)]
OH
BF4
X
Me
Me
anti 93:7
O
H2(g)
[Rh(nbd)(diphos-4)]
X
Me
Me
X
H Me Me
Me
OH
O
OH
Ph
P
Rh Ph
Ph P
Ph
O
[Rh(nbd)(diphos-4)]
BF4
Me
X
Me H
syn 91:9
Me
• Acyclic systems can undergo highly diastereoselective directed hydrogenations
• Allylic alcohols give the best selectivities
• Importantly - the position of the double bond changes the selectivity
• This allows us to selectively form either the anti or syn diastereoisomers
Advanced organic
9
Mechanism of directed hydrogenation
L
M
S
+
S
L
coordination
of the alkene
OH
H
L
L
H2
M
O
H
oxidative
addition
H
L
M
L
O
H
insertion of
M–H into C=C
reductive
elimination (loss of
M–H & formation of
C–H)
H
L
L
M
S
+ H
S
OH
L = ligand
S = solvent
H
H
L
O
H
M
L
S
• This is a simplified mechanism for alkene reduction by homogeneous hydrogenation
• Replace M–O bond with M–S if the reaction is not directed
• This is the mechanism for dihydride reductants, monohydride reductants also exist
• Note -
the ligands remain attached to the metal, therefore if alkene is prochiral and
the ligands are chiral we can get enantioselective catalysis
• But first, what about the selectivity in these reactions...
Advanced organic
10
Explanation of diastereoselectivity
L
L Rh OH
H
OH
R
H Me
R
H
OH
R
Me
H
H
Me
anti
Me
H
L Rh OH
Me
R
steric
interaction
L
• Once again, allylic strain is responsible for the diastereoselectivity
• One diastereoisomeric complex suffers less steric congestion & is favoured
L
L Rh OH
R
OH
R
H Me
Me
H
Me
Me
OH
R
H
H
R
L Rh OH
L
Me
Me
Me
Me
syn
steric
interaction
Advanced organic
11
Catalytic enantioselective hydrogenation
H
MeO
CO2H
H2(g)
[((S)-DIPAMP)RhL2]
L=solvent
H H
MeO
CO2H
P
P
H NHAc
NHAc
AcO
MeO
AcO
OMe
95% ee
(S,S)-DIPAMP
• One of the most important industrial reactions; above example produces amino acids
• Variety of diphosphines can be used
• It is essential that there is a second coordinating group (here the amide)
• On coordination, two diastereoisomeric complexes are formed
• The stability / ratio of each of these is unimportant
• It is their reactivity we are concerned with...
Ar
MeO
HO2C
P
L
OMe
Rh
P
L
N
H
O
MeO
Me
P
Ar
P
Rh O
HO2C
N
OMe H
Me
MeO
P O Ar
Rh
Me
OMe N
H
P
CO2H
Advanced organic
12
Mechanism for catalytic hydrogenation
Ph
Ar
Ar
Ar
Ar
P
Rh O
Ph
P
HO2C
N
H
Me
HO2C
Me
Me
oxidative addition fast
complex more
reactive
Ph
Ar
P
Rh O
Ar
N
P
Ar H
N
H
Ar
P
Ph
CO2H
H2
fast
oxidative
addition
H
H
N
H
P O Ar
Rh
Ar
+ [DIPAMPRhL2]
H2
slow
insertion
HO2C
Ph
O
H
Ph
One complex more reactive
Me
P O Ar
Rh
Ar
Me
Ph
Ph
H
N
CO2H
P
H
Ar
reductive
elimination
Ph H
P
Ar
L
Ar
Ar
O P
Rh
Ph
HO2C
N
H
H
Me
H
H
H
HO2C
Ar
N
H
O
O
Me
minor enantiomer
Me
Ar
N
H
H
H
H
CO2H
major enantiomer
L
Ar
P O
Rh
Ar
Ph
Me
N
H
H
H Ar
P
Ph
CO2H
Advanced organic
13
Organocatalytic hydrogenation
Me
O
Me
N
t-Bu
O
Bn
H
H Me O
N
H2 Cl3CO2
H
H H
MeO2C
NC
CO2Me
NC
89%; 96% ee
i-Pr
N
H
catalyst 10%
hydrogen source 1eq
Me
HE
O
Me
N
Bn
H
t-Bu
N
H
Ar
δ–
HE
Ar
Me
O
Me
N
H N
Ph
Me
Me
Me
H
O
Me δ+
N H
i-Pr
Me
N
Bn
t-Bu
N
Me
H
Ar
H
Me
• A recent development is the use of small organic molecules to achieve hydrogenation
• Inspire by nature
• Based on the formation of a highly reactive iminium ion (this is the basis of many
organocatalytic reactions)
Advanced organic
14
Sharpless Asymmetric Epoxidation (SAE)
Me
Me
(+)-DIPT, Ti(Oi-Pr)4, TBHP
O
OH
must be
allylic alcohol
OH
92% ee
Me
Me
(–)-DET, Ti(Oi-Pr)4, TBHP
Me
Me
Me
Me
OH
Me
O
Me
>90% ee
OH
Me
O
TBHP
OH
i-PrO2C
OH
OH
CO2i-Pr
OH
(+)-DIPT
EtO2C
CO2Et
OH
(–)-DET
• Sharpless asymmetric epoxidation was the first general asymmetric catalyst
• There are a large number of practical considerations that we will not discuss
• Suffice to say it works for a wide range of compounds in a very predictable manner
• Compounds must be allylic alcohols
• Second example shows that this limitation allows highly selective reactions
Advanced organic
15
Sharpless Asymmetric Epoxidation II
D-(–)-DET
unnatural isomer
“O”
Ti(Oi-Pr)4
TBHP
R2
R3
O
R1
R2
OH
“O”
D-(+)-DET
natural isomer
OH
place alkene
vertical and
alcohol in bottom
right corner
R3
R1
if you want “O” on top its
on your kNuckles so you
use Negative (–)-DET
Ti(Oi-Pr)4
TBHP
R2
R3
O
R1
using your left hand,
the index finger is
the alkene and your
thumb the alcohol
if you want “O” on top its
on your Palm so you use
Positive (+)-DET
OH
• SAE is highly predictable -- the mnemonic above is accurate for most allylic alcohols
• To understand where this comes from we must look at the mechanism
• A simplified version of the basic epoxidation is given below
TiL4
+
TBHP
+
t-Bu
O
Ot-Bu
L
L Ti
O
O
L
L
Ti
O
O
L
L
Ot-Bu
Ti
O
O
L
L Ti
Ot-Bu
O O
HO
activation of
peroxide
Advanced organic
16
Mechanism of SAE
i-Pr
Ti(Oi-Pr)4 +
(+)-DET
O
O
i-Pr
CO2Et
i-Pr
O
O
Ti
O
O
CO2Et Ti
OEt
O
O
O
i-Pr
t-BuO2H
O
Ti
O
i-Pr
O
O
O
i-Pr
CO2Et
i-Pr
O
O
CO2Et Ti
CO2Et
O
O
O
O
t-Bu
EtO
Active species thought to be 2 x Ti
bridged by 2 x tartrate
Reagents normally left to ‘age’
before addition of substrate thus
allowing clean formation of dimer
i-Pr
HO
i-Pr
R
O
O
CO2Et Ti
E
O
O
R
i-Pr
O
Ti
O
HO
CO2Et
O
O
O
EtO
O
O
i-Pr
O
Ti
O
O
CO2Et Ti
E
O
O
t-Bu
EtO
O
O
R
CO2Et
O
O
O
t-Bu
R
EtO
must deliver “O” from lower face
Advanced organic
17
R2
R2
OH
OH
R1
R3
R3
R2
OH
R1
OH
good substrates
high yields and ee's >90%
• SAE works for a wide range of
allylic alcohols
• Only cis di-substituted alkenes
normally good
ee's >90%
few examples
R1
appear to be problematic
problematic
slow reactions
moderate ee's,
especially with bulky R3
R3
OH
• Example below shows that SAE can over-ride the inherent selectivity of a substrate
• Furthermore, it demonstrates the concept of matched & mismatched
• When the catalyst & substrate reinforce each other spectacular (or matched) results
are achieved
Me
Me
Me
conditions
O
O
Me
Me
Me
O
+
O
OH
OH
O
O
OH
O
t-BuO2H, VO(acac)2
t-BuO2H, Ti(Oi-Pr)4, (+)-DET
t-BuO2H, Ti(Oi-Pr)4, (–)-DET
2.3
1
99
O
:
:
:
1
22
1
Advanced organic
18
Use of SAE in synthesis
SAE
(+)-DIPT
Ph
OH
Red-Al
[NaAlH2(OCH2CH2OMe)2]
O
Ph
OH
Ph
OH
OH
H
MsCl
CF3
O
Ph
1. NaH
2. ArCl
OH
Ph
OH
MeNH2
NHMe
Ph
OMs
NHMe
fluoxetine
• Fluoxetine is a commercial anti-depressant (better known as Sarafem® or Prozac®)
• Can be synthesized in a number of methods
• One involves the use of the SAE reaction
Advanced organic
19
Kinetic resolution
R3
R
R2
racemic mixture
OH
R1
slow
steric hindrance
fast
(–)-DET, Ti(Oi-Pr)4,
TBHP
R2
R2
R3
R
R1
R3
H
R1
OH
OH
H
R
if reaction goes to
100% completion you
get a 1:1 mixture of
diastereoisomers
if allylic alcohol is desired use 0.6eq TBHP
if epoxy alcohol is desired use 0.45eq TBHP
R3
R3
R
R2
OH
R1
O
R2
R
OH
R1
• Both enantiomers should be epoxidised from same face
• But rate of epoxidation is different
• If sufficient rate difference then stop the reaction at 50% conversion
Advanced organic
20
Kinetic resolution II
Me3Si
OH
C5H11
(R/S)
(+)-DIPT, Ti(Oi-Pr)4,
TBHP
Me3Si
Me3Si
O
OH
rate of epoxidation
(S) : (R) ~700 : 1
C5H11
>95% ee
+
OH
C5H11
(R) >95% ee
• Kinetic resolution normally works efficiently
• The problem with kinetic resolution is that is can only give a maximum yield of 50%
• Desymmetrisation of a meso compound allows 100% yield
• Effectively, the same as two kinetic resolutions, first desymmetrises compound
•
second removes unwanted enantiomer
ee of desired product increases with time (84% ee 3hrs ➔ >97% 140hrs)
OH
FAST
slow
FAST
O
slow
wanted
OH
OH
O
(–)-DIPT
O
slow
FAST
OH
O
meso
readily
removed
O
H
OH
H
O
Advanced organic
21
Desymmetrisation in synthesis
NHPh
OH
OBn
OH
(–)-DIPT, Ti(Oi-Pr)4,
TBHP
OBn
PhNCO
pyr
O
OBn
O
OBn
O
O
OBn
OBn
BF3•OEt2
HO
HO2C
OH
O
O
OH
O
O
OH
OH
KDO
OBn
HO
OBn
• Desymmetrisation has been used in many elegant syntheses
Advanced organic
22
Jacobsen-Katsuki epoxidation
• SAE is a marvelous reaction but suffers certain limitations
•
substrate must be an allylic alcohol
cis-disubstituted alkenes are poor substrates
(salen)Mn catalysts with bleach (NaOCl) are good for these substrates
L
(S,S)-cat (2-15%)
NaOCl, pH 11
S
L
S
Ph
CO2Me
O
O
L = larger group
S = smaller group
O
t-Bu
CN
O
97% ee
≥95% ee
O
H
O
Me
O
O
94% ee
Me
H
H
N Cl N
Mn
O
O
t-Bu
t-Bu
(S,S)-Mn(salen)
N
t-Bu
Mn
O
H
N
O
manganese(IV) oxo
species active oxidant
Advanced organic
23
Jacobsen-Katsuki oxidation in synthesis
N
N
OH
CHBn
N
CONHt-Bu
H
N
OH
O
Indinavir
(Merck / HIV treatment)
(salen)Mn cat
NaOCl, R3N+–O–
H2SO4
MeCN
OH
O
2000kg scale
MeCN
OH
NH2
H2O
OH
O
N
Me
N C
Me
• This example demonstrates the industrial potential of such catalytic systems
Advanced organic
24
Organocatalytic epoxidations
cat.
oxone, K2CO3
DME / H2O, –15°C
Me
Ph
Me
Ph
O
100%; 86% ee
F
F
O
O
O
F
F
cat.
O
R
O
R
H
R
O
H
R
H
H
• As with most chemical reactions, epoxidation has seen a move towards ‘greener’
chemistry and the use of catalytic systems that do not involve transition metals
• A number of systems exist, notably the catalysts of Shi & Armstrong
• Most are based on the in situ conversion of ketones to the active, dioxirane
species, that actually performs the epoxidation
• Non of these have yet to match the utility of their metal counter-parts Advanced organic
25
Sharpless Asymmetric Dihydroxylations (SAD)
K2OsO2(OH)4, K3Fe(CN)6,
K2CO3, MeSO2NH2, t-BuOH,
H2O, 0°C, (DHQD)2-PHAL
CO2Et
C5H11
OH
C5H11
CO2Et
OH
99% ee
• Looks complicated but isn’t too bad...
• The active, catalytic, oxidant is K2OsO2(OH)4 - OsO4 is too volatile & toxic
• K3Fe(CN)6 is the stoichiometric oxidant
• K2CO3 & MeSO2NH2 accelerate the reaction
• Normally use a biphasic solvent system
• And the two ligands are...
Et
N
Et
Et
N
N N
O
H
Et
O
N
H
MeO
N
N
(DHQD)2-PHAL
O
H
OMe
N
N N
O
H
MeO
OMe
N
N
(DHQ)2-PHAL
• Ligands are pseudo-enantiomers (only blue centres are inverted; red are not)
• They act if they were enantiomers (see slide 26)
• Coordinate to the metal via the green nitrogen
Advanced organic
26
Sharpless Asymmetric Dihydroxylation II
OH
Ph
Ph
K2OsO2(OH)4, K3Fe(CN)6,
K2CO3, MeSO2NH2, t-BuOH,
H2O, 0°C, (DHQD)2-PHAL
Ph
Ph
K2OsO2(OH)4, K3Fe(CN)6,
K2CO3, MeSO2NH2, t-BuOH,
H2O, 0°C, (DHQ)2-PHAL
OH
Ph
Ph
OH
98.8% ee
OH
>99.5% ee
• Reaction works on virtually all alkenes
• Exact mechanism not known but...
• It is relatively predictable (but not as predictable as the SAE)
(DHQD)2PHAL
OsO4
small steric
barrier
attractive area attracts flat, aromatic
substituents or large,
hydrophobic aliphatic
groups
S
M
L
H
large steric
barrier
OsO4
(DHQ)2PHAL
Advanced organic
27
SAD & Sharpless aminohydroxylation reaction
Me
OsO4, K3Fe(CN)6, K2CO3,
MeSO2NH2, t-BuOH, H2O,
0°C, (DHQD)2-PHAL
Me
O
OH
Me
Me
Me
HO
O
O
O
TsOH
O
Me
O
95% ee
exo-Brevicomin
• The simple example above shows the power of the SAD reaction in synthesis
• A variant has now been developed that permits aminohydrodroxylation
• Used in the semi-synthesis of Taxol
O
Ph
Oi-Pr
AcNHBr, LiOH,
K2OsO2(OH)4,
(DHQ)2-PHAL
AcNH
O
Oi-Pr
Ph
HCl, H2O
O
Ph
OH
O
Me
O
Oi-Pr
Ph
OH
regioselectivity >20:1
94% ee
AcO
HCl.NH2 O
Me
OH
Me
Ph
N
H
O
Me
OH
HO
taxol
OBz
H
AcO
O
Advanced organic
28
Diastereoselective conjugate additions
Me
Me
Me
Me
Me
NH
Me
Me
EtMgCl
N
N
S O O
O
S O
O
Oppolzer's
camphor sultam
S
trans conformation
disfavoured
Me
Me
HO
Me
NH
S O
O
O
LiOH
Et
Me
Me
H
N
S O O
O
90% de
Et
Et
O Mg Cl
Mg Cl
O O
Et
cis
conformation
favoured
chelation
restricts rotation
Me
Me H
Me
Me
Me
N
S
H
Et
O Mg Cl
Mg Cl
O O
Et
• Possible to use chiral auxiliary to control 1,4-nucleophilic addition
• Chelation of amide and sultam oxygens to Mg restricts rotation and favours cis
conformation
• Addition occurs from most sterically accessible side
• Chiral auxiliary readily cleaved (& reused) to give enantiomerically pure compound
via diastereoselective reaction
Advanced organic
29
Chiral auxiliary to control two stereocentres
addition
as slide 28
Me
Me
Me
Me
N
1. BuMgCl
2. MeI
Me
Me
H
N
S
S O O
O
Me
Bu
Me
H
Me
H
N
O
Mg L
O O
L
electrophile
approaches from
bottom face
Me
Bu
S O O
O
95% de
Me
I
LiOH
Me
Me
Me
NH
S O
O
+
HO
Me
O
Bu
• It possible to utilise 1,4-addition to introduce two stereogenic centres
• The first addition (BuMgBr) occurs as before to generate an enolate
• The enolate can then be trapped by an appropriate electrophile
• Once again the sultam chiral auxiliary controls the face of addition (of Me)
Advanced organic
30
Alternative chiral auxiliaries I
aldol-like reaction & acid
catalysed elimination
O
Ph
Ph
O
1. LDA
Me
N
OH
Ph
R1
R1
N
H
3. CF3CO2H
R1
OMe
NH2
R2–Li
2. R1CHO
OMe
H
OMe
O
CO2H
Ph
O
Ph
N
Li
OMe
O
Ph
H2O
H3O
R1
H R2
95-99% ee
R2
H
R2
R1
N
OMe
H
R2
N
Li
OMe
hydrolysis
• A second chiral auxiliary is the oxazoline (5-membered ring) of Meyers’
• It can be prepared from carboxylic acids (normally in 3 steps) or from condensation
•
of the amino alcohol and a nitrile
As can be seen excellent enantiomeric excesses can be achieved via a highly
diastereoselective reaction
Advanced organic
31
Alternative chiral auxiliaries II
L L
Zn
O
O
O
O
S
ZnBr2
O
O
MeO
MgBr
S
MeO
O
O
S
O
O
H
MeO
Ar
O
Raney Ni
nuc
O
MeO
O
O
O
Ar2COCl
H
MeO
OMe
O
H
O
Ar
(–)-podorhizon
95% ee
O
• Sulfoxide is a good chiral auxiliary; not only does it introduce a stereocentre but it
•
•
•
•
activates the alkene by addition of an extra electron-withdrawing group
Lewis acid tethers groups together to give a rigid cyclic chelate
Nucleophile attacks from opposite face to bulky aryl group
Sulfoxide is readily removed under reductive conditions
Simple substrate control of enolate chemistry instals aryl group on opposite face to
substituent
Advanced organic
32
Enantioselective catalytic conjugate addition
O
Et2Zn, Cu(OTf)2 (2%),
lig. (4%), tol, 3h, –30°C
O
Ph
O
O
Et
Me
P N
Me
Ph
94%
>98% ee
lig.
• Much effort has been expended trying to develop enantioselective catalysts for
•
•
conjugate addition
Whilst many are very successful for certain substrates, few are capable of acting on
a wide range of compounds
The system above gives excellent enantioselectivities for cyclohexenone but...
no selectivity for cyclopentenone
O
Et2Zn, Cu(OTf)2 (2%),
lig. (4%), tol, 3h, –30°C
O
Et
75%
10% ee
Advanced organic
33
Potential mechanism
transmetallation of alkyl
group (R) to copper
ZnR2
L2CuX2 ZnR2
copper(II) (with 2 P
ligands) reduced to
copper(I) by zinc
reagent
XZn
L2CuX
+
RZnX
L2CuR + RZnX
O
O
R
L
L Cu
O
R
XZn
alkyl transfer occurs after
enone and copper bind
R
zinc probably
activates enone
Advanced organic
34
Bifunctional catalysis
O
O
O
+
MeO
O
(R)-ALB (0.3%)
t-BuOK (0.27%)
MS 4Å, THF, rt, 120h
CO2Me
OMe
CO2Me
94%
99% ee
H
O
O
Li
Al
O
Al
O
O
O
O
O
O
(R)-ALB
O
RO
Li
O
OR
• Heterobimetallic catalyst of Shibasaki works remarkably well even at low catalyst
•
•
•
loadings
Aluminium acts as Lewis acid to activate enone
Lithium alkoxide acts as Brønsted base to deprotonate malonate
Lithium alkoxide also positions the enolate
Advanced organic
35
Organocatalysis
Me
N
O
O
Bn
O
+
Ph
Me
BnO
OBn
N
H
CO2H
cat. (10%),
neat, rt, 165h
CO2Bn
BnO2C
Ph
O
Me
86%
99% ee
Me
Me
N
CO2H
N
Me
H
N
N
BnO
H
O
CO2Bn
CO2H
Me
CO2Bn
H CO Bn
2
• New small molecule organic catalysts are now achieving remarkable results
• Enone is activated by formation of the charged iminium species
• The catalyst also blocks one face of the enone allowing selective attack
Advanced organic
36
Organocatalysts II
O
Me
N
X
Bn
NR2
O
Me
X
Me
N
H•HCl Me
+
H
O
H
R2N
O
O
Me
N
Me
H
H
X
X
H
Me
N
Me
Me
Me
N
Me
Me
O
Me
N
N
68-90%
84-92% ee
Me
Me
N
NR2
Me
H
X
Ar
H
steric hindrance results
in predominantly one
conformation
• A range of reactions can be achieved, including enantioselective Friedel-Crafts
• Catalyst ensures that the enone reacts via one conformation
• Must use electron rich aromatic substrates
Advanced organic
37
Organocatalysts III
O
Me
N
Bn
H
+
TMSO
O
Me
R
O
Me
Me
N
H•HCl Me
O
O
cat. (20%)
DCM / H2O
–20 to –70°C, 11–30h
Me
O
R
H
77%
syn:anti = 1-31:1
84-99% ee
• Possible to introduce two stereogenic centres with good diastereoselectivity and
•
enantioselectivity
An interesting reaction is the Stetter reaction - this is the conjugate addition of an
acyl group onto an activated alkene and proceeds via Umpolung chemistry (the
reversal of polarity of the carbonyl group)
OMe
cat. (20%)
KHMDS (20%)
25°C, 24h
O
Me
H
O
CO2Et
O
Me
N N
CO2Et
O
80%
97% ee
N
O
H
BF4
Advanced organic
38
Mechanism of Stetter reaction
O
O
Me
Me
Ar
CO2Et
H
N N
O
O
N
CO2Et
O
N
Me
Ar
N
Ar
N N
base
O H
N
CO2Et
OH
H
N
base
Ar2
O
Ar
N N
N N HO
OEt
N
O
Ar
O
H
N
OEt
OH
O
base
O
Me
Me
• The Stetter reaction is analogous to the activity of thiamine (vitamin B1) in our bodies
and the reaction is thus biomimetic
Advanced organic
39
Organocatalytic bifunctional catalysis
CF3
S
F3C
NO2
+
EtO2C
CO2Et
N
H
N
H
Me
N
EtO2C
CO2Et
Me
NO2
toluene, rt, 24h
86%
93% ee
CF3
CF3
S
F3C
S
H
N H
N Me
H
H
Me
O
O
H O
N
O
H
EtO
Ph
F3C
N
OEt
N
N
H
H
O
O
N
N
H
Ph
Me
Me
H
CO2Et
CO2Et
• The thio(urea) moiety acts as a Lewis acid via two hydrogen bonds
• The amine both activates the nucleophile and positions it to allow good selectivity
Advanced organic