Advanced organic
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
1
OHO
OH
HO2-deoxy-D-ribose
Me Me
MeOH
(R)-sulcatol
1
23
4
5
1
2
34
5
• In this example, one stereogenic centre is retained • All others are destroyed
OHO
OH
HO
Me Me
MeOH Ph3P Me
Me
1. MeOH, H2. MsCl
OMsO
OMe
MsO
1. KI2. Raney Ni OMe OMe
H2O
OMe OH
Me CHO
OH
Advanced organic
OHO
HOOH
OH
OH
D-mannose
N
HOH
HO
HO
swainsonine
51
23
4
12
34
56
6
‘Chiral pool’ II
• In this example three stereogenic centres are retained• One stereogenic centre undergoes multiple inversion -- but overall it is retained
2
Pd / CH2
OBnO
OO
MeMe
HN
H
H
1. H2, Pd / C, H2. TFAA
OBnO
N3
OO
MeMe
CHO
1. TBAF2. PCC3. Ph3P=CHCHO
OBnO
N3
OTBDPS
OO
MeMe
NaN3
OBnO
O
OTBDPS
OO
MeMe
PCC
OBnO
OTf
OTBDPS
OO
MeMe
1. NaBH42. Tf2O
OBnO
OH
OTBDPS
3 steps OO
MeMe remove
stereogenic centre
stereoselective reduction
two step reversal of stereogenic centre
overall retention of stereochemistry
addition of protecting groups
reduction of alkene &
azide followed by reductive amination
hydrogenolysis of benzyl (Bn) group & reductive amination of resultant
aldehyde
Advanced organic
BHMe
H
H
HBH2
HMeMe Me
1. TMEDA2. BF3•OEt2
Me
1. TMEDA2. BF3•OEt2
Me
(+)-IpcBH2
H
BHMe
HH Me
B
HMeMe Me
H
H
Me
Me MeH
BH3
BH3
(–)-Ipc2BH
Me
MeMeMe
(+)-α-pinene
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 reactionsSubstrate control
3
Advanced organic
Hydroboration: reagent control
• 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
4
Me
Me
1. (–)-Ipc2BH2. H2O2 / NaOH
MeMe
OHHH
H 98.4% ee
BHMe
HH Me
(–)-Ipc2BH
Me
H
1. (+)-IpcBH22. H2O2 / NaOH
H
HOH
Me
66% eeH
BH2
HMeMe Me
(+)-IpcBH2
Advanced organic
O
O PAr2
PAr2
H
H
MeMe
Ar = 2-MeOC6H4
L =
Hydroboration: catalyst control
• 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)
5
+O
BO
H
catecholborane
1. RhL22. H2O2 / NaOH
Cl
H
H HH
HOH
82% ee
O
O PAr2
PAr2
H
H
MeMe
Ar = 2-MeOC6H4
L = HO2CCO2H
OH
OH(2R,3R)-tartaric acid
Advanced organic
1. LiCHCl22. NaClO2[oxidation] Me
Me
H CO2H
88%; 97% ee
Me
1. [Rh(COD)2] .BF4(R)-BINAP / catechol-borane
2.
HO OH
MeMe
MeMe Me
Me
H B OO
Me
Me
MeMe
99%; 97% ee
Hydroboration: catalyst control II
• This second example utilises BINAP and again gives very impressive ee’s
6
Rh
[Rh(COD)2]
PPh2PPh2
(R)-BINAP
• The second part of the reaction gives an example of an alternative stereospecific...transformation of the boron species
Advanced organic
Homogeneous hydrogenation: substrate control
• 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
7
Me
Me OH H2(g)[(Cy3P)Ir(COD)py] PF6
Me OH
H
Me
Me
MeO
i-Pr
H2(g)[(Cy3P)Ir(COD)py] PF6
MeO
i-PrH
Me
IrPCy3N
[(Cy3P)Ir(COD)py]
Advanced organic
Substrate control in acyclic systems
• 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
8
anti 93:7
Me X
OOH
Me
H2(g)[Rh(nbd)(diphos-4)] BF4
Me X
OOH
MeH Me
syn 91:9
Me X
OOH
MeMe
H2(g)[Rh(nbd)(diphos-4)] BF4
Me X
OOH
MeMe H
P
Ph
[Rh(nbd)(diphos-4)]
RhP
Ph
Ph
Ph
Advanced organic
Mechanism of directed hydrogenation
• 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...
9
LM
S
L S+
OH
coordination of the alkene L
ML O
H
HM
L OH
H
L
H2
oxidative addition
HM
L S
O
L
HH
insertion of M–H into C=C
reductive elimination (loss of M–H & formation of
C–H)LM
S
L S+
OH
HH
L = ligandS = solvent
Advanced organic
Explanation of diastereoselectivity
• Once again, allylic strain is responsible for the diastereoselectivity• One diastereoisomeric complex suffers less steric congestion & is favoured
10
R MeMe
OH
anti
R
HH
OH
Me H
RhLL
R
HH
OH
H Me
RhLL
R Me
OH
steric interaction
R MeMe
OH
syn
R MeMe
OHMe
HR
OH
Me H
RhLL
MeHR
OH
H Me
RhLL
steric interaction
Advanced organic
P P
OMe
MeO
RhO
Me NH
CO2H
ArP P
OMe
MeO
Rh O
MeNH
HO2C
Ar
Catalytic enantioselective hydrogenation
• 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...
11
HCO2H
NHAc
MeO
AcO
H2(g)[((S)-DIPAMP)RhL2]
L=solvent MeO
AcO
CO2H
H NHAc
H H
95% ee(S,S)-DIPAMP
P P
OMe
MeO
P P
OMe
MeOO
MeNH
HO2C
Ar
RhL L
Advanced organic
ArPHPh
Rh
H
PAr Ph
O
MeNH
HO2C
Ar
Mechanism for catalytic hydrogenation
12
L
PhPP
Ar
Ph Ar
Rh O
MeNH
HO2C
ArH
H
ArP P
Ph
ArPh
Rh O
MeNH
HO2C
Ar
H2slow
L
ArP P
Ph
ArPh
RhO
Me NH
CO2H
ArH
H
ArP H
Ph
Rh
H
PArPh
O
Me NH
CO2H
Ar
ArP P
Ph
ArPh
RhO
Me NH
CO2H
Ar
H2fast
O
MeNH
HO2C
ArHHH
minor enantiomer
O
Me NH
CO2H
ArHHH
major enantiomer
O
MeNH
HO2C
Ar
+ [DIPAMPRhL2]
oxidative addition fastcomplex more
reactive
oxidative addition
insertion
reductive elimination
One complex more reactive
Advanced organic
N
Ar
H
N
t-BuBn
O Me
HMe
N NH
ArMe
H
PhMe
OH
Me MeMe
NMe
i-PrE
EH
H
Hδ–
δ+
N
Ar Me
H
N
t-BuBn
O Me
Me
H
O
NC
NH2
N
Bnt-Bu
OMe
Cl3CO2
NH
MeO2C
Me i-Pr
CO2MeH H
H
O
NC
H Me
89%; 96% ee
catalyst 10%hydrogen source 1eq
Organocatalytic hydrogenation
• 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)
13
Advanced organic
Me
Me
MeOH
Me
OH
(–)-DET, Ti(Oi-Pr)4, TBHPMe
Me
MeOH
O
>90% ee
(+)-DIPT, Ti(Oi-Pr)4, TBHP Me
OHO
92% ee
Me
Me
MeOH
Me
OH
Sharpless Asymmetric Epoxidation (SAE)
• 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
14
EtO2CCO2Et
OH
OH(–)-DET
i-PrO2CCO2i-Pr
OH
OH(+)-DIPT
Me O
MeMe
OH
TBHP
• Compounds must be allylic alcohols• Second example shows that this limitation allows highly selective reactions
must be allylic alcohol
Advanced organic
OTi
Ot-BuLL
OO
Ot-Bu
OTi
LL
O
t-BuO
OTi
LL
OTi
OLL
Ot-BuTiL4
TBHP+
+
HO
Sharpless Asymmetric Epoxidation II
• 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
15
if you want “O” on top its on your kNuckles so you
use Negative (–)-DET
if you want “O” on top its on your Palm so you use
Positive (+)-DET
using your left hand, the index finger is
the alkene and your thumb the alcohol
R1
R2 R3
OHO
Ti(Oi-Pr)4TBHP
R1
R2 R3
OHO
Ti(Oi-Pr)4TBHP
R3
R1
R2
OH
D-(–)-DET unnatural isomer
“O”
“O”D-(+)-DET
natural isomer
place alkene vertical and
alcohol in bottom right corner
activation of peroxide
Advanced organic
E
OO
O
TiO
O O
O
O
TiO
O
CO2Et
CO2Et
i-Pr
i-Pr
EtOt-Bu
R
HO
RO E
OO
O
TiO
O O
O
O
TiO
O
CO2Et
CO2Et
i-Pr
i-Pr
EtOt-Bu
R
HO
R
t-BuO2H CO2Et
OO
O
TiO
O O
O
O
TiO
O
CO2Et
CO2Et
i-Pri-Pr
i-Pr
EtOt-Bu
OO
O
TiO
O O
O
O
TiO
O
CO2Et
CO2Et
i-Pri-Pr
i-Pr
i-Pr
OEt
EtO
Ti(Oi-Pr)4 +(+)-DET
Mechanism of SAE
16
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
must deliver “O” from lower face
Advanced organic
• SAE works for a wide range of allylic alcohols
• Only cis di-substituted alkenes appear to be problematic
17
R2 OHR2 OH
R1good substrates
high yields and ee's >90%
OHR1
R3
R2 OHR1
R3normally good
ee's >90%few examples
OH
R3 problematicslow reactionsmoderate ee's,
especially with bulky R3
OHO
O
MeMe
OHO
O
MeMe
OHO
O
MeMe
O O
conditions
t-BuO2H, VO(acac)2t-BuO2H, Ti(Oi-Pr)4, (+)-DETt-BuO2H, Ti(Oi-Pr)4, (–)-DET
+
2.3199
:::
1221
• 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
Advanced organic
MeNH2
Ph NHMe
OH1. NaH2. ArCl
Red-Al[NaAlH2(OCH2CH2OMe)2]
Ph OHH
OHSAE(+)-DIPT
Ph OHO
Ph OH
Ph NHMe
O
CF3
fluoxetine
Use of SAE in synthesis
• 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
18
MsCl
Ph OMs
OH
Advanced organic
R2 OHR1
R3 RO
R
R3
R1
R2
OHH
H
R3
R1
R2
OHR
R2 OHR1
R3 R
(–)-DET, Ti(Oi-Pr)4, TBHP
Kinetic resolution
• 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
19
R2 OHR1
R3 R
if allylic alcohol is desired use 0.6eq TBHPif epoxy alcohol is desired use 0.45eq TBHP
slowsteric hindrance fast
racemic mixture
if reaction goes to 100% completion you
get a 1:1 mixture of diastereoisomers
Advanced organic
H
OH
Kinetic resolution II
• 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)
20
Me3Si
C5H11
OH
(+)-DIPT, Ti(Oi-Pr)4, TBHP
Me3Si
C5H11
OH
Me3Si
C5H11
OH+O
>95% ee (R) >95% ee(R/S)
rate of epoxidation (S) : (R) ~700 : 1
OH
O
OH(–)-DIPT
FAST
FASTslow
slow
OH
O wanted
OH
O Omesoreadily
removed
OHH
H
OH
O
slow
OHH
O
FASTslowFAST
Advanced organic
Desymmetrisation in synthesis
• Desymmetrisation has been used in many elegant syntheses
21
OH
OBnOBn
(–)-DIPT, Ti(Oi-Pr)4, TBHP
OH
OBnOBnO
O
OBnOBnO
O
NHPhPhNCO
pyr
BF3•OEt2
HOOBn
OO
O
OBn
O
OH
OHOH
OH
HO2C
HO
KDO
Advanced organic
Jacobsen-Katsuki epoxidation• SAE is a marvelous reaction but suffers certain limitations
substrate must be an allylic alcoholcis-disubstituted alkenes are poor substrates
• (salen)Mn catalysts with bleach (NaOCl) are good for these substrates
22
NNMn
OOt-Bu
t-Bu t-Bu
t-Bu
HHCl
(S,S)-Mn(salen)
H
H
NN
O OMn
O
manganese(IV) oxo species active oxidant
L S
L = larger groupS = smaller group
(S,S)-cat (2-15%) NaOCl, pH 11 L S
O
O
OO
Ph CO2Me
O
O CNMe
MeO
94% ee ≥95% ee 97% ee
Advanced organic
Jacobsen-Katsuki oxidation in synthesis
• This example demonstrates the industrial potential of such catalytic systems
23
N
NN
HN
OH CHBn
CONHt-Bu
OH
O
Indinavir(Merck / HIV treatment)
(salen)Mn catNaOCl, R3N+–O–
O2000kg scale
H2SO4MeCN OH
OH
N CMe
N
O
Me
OH
NH2
H2O
MeCN
Advanced organic
Organocatalytic epoxidations
• 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
24
PhMe
cat.oxone, K2CO3
DME / H2O, –15°CPh
MeO
100%; 86% ee
O
F
F
cat.F
F
OO
RH
H
OO
RR
H
HO
R
Advanced organic
Sharpless Asymmetric Dihydroxylations (SAD)
• 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...
25
C5H11CO2Et
K2OsO2(OH)4, K3Fe(CN)6, K2CO3, MeSO2NH2, t-BuOH,
H2O, 0°C, (DHQD)2-PHALC5H11
CO2EtOH
OH99% ee
• 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
N
HO
N
MeO
EtN
HO
N
OMe
EtNN
(DHQD)2-PHAL
N
HO
N
OMe
N
HO
N
MeO
N NEt Et
(DHQ)2-PHAL
Advanced organic
Sharpless Asymmetric Dihydroxylation II
• Reaction works on virtually all alkenes• Exact mechanism not known but...• It is relatively predictable (but not as predictable as the SAE)
26
PhPh
PhPh
OH
OHPh
PhOH
OH98.8% ee >99.5% ee
K2OsO2(OH)4, K3Fe(CN)6, K2CO3, MeSO2NH2, t-BuOH,
H2O, 0°C, (DHQ)2-PHAL
K2OsO2(OH)4, K3Fe(CN)6, K2CO3, MeSO2NH2, t-BuOH,
H2O, 0°C, (DHQD)2-PHAL
small steric barrier
large steric barrier
attractive area - attracts flat, aromatic substituents or large, hydrophobic aliphatic
groups
H
MS
L
OsO4
(DHQD)2PHAL
OsO4(DHQ)2PHAL
Advanced organic
SAD & Sharpless aminohydroxylation reaction
• 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
27
Me
OO
Me OsO4, K3Fe(CN)6, K2CO3, MeSO2NH2, t-BuOH, H2O,
0°C, (DHQD)2-PHAL Me
OO
Me
HO
OH
95% ee
TsOH
O
O
Me
Me
exo-Brevicomin
Ph Oi-Pr
O
Ph Oi-Pr
OAcNH
OHregioselectivity >20:1
94% ee
Ph Oi-Pr
OHCl.NH2
OH
HCl, H2O
AcNHBr, LiOH, K2OsO2(OH)4, (DHQ)2-PHAL
ONH
Ph
O OPh
OH
Me
OBz
Me
Me
AcO OHMe
H OAcO
O
HOtaxol
Advanced organic
Me Me
NHSO
O
HO Me
O Et
LiOH
Me Me
NS O
OO
Et
MeH
90% de
Me Me
NSO O
OMg
HMe
MgEt
ClEt
Cl
Me Me
NSO O
OMg
MgEt
ClEt
Cl
HMe
EtMgCl
Me Me
NS O
Me
OO
Me Me
NHS
OO
Oppolzer's camphor sultam
Diastereoselective conjugate additions
• 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
28
trans conformation disfavoured
cis conformation
favouredchelation restricts rotation
Advanced organic
Me Me
NHSO
O
HO Me
O Bu
Me
+
Me Me
NS O
OO
Bu
MeH
95% de
MeH
Me Me
NSO O
OMg LL
Bu
MeH
MeI
Me Me
NS O
Me
OO
1. BuMgCl2. MeI
Chiral auxiliary to control two stereocentres
• 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)
29
addition as slide 28
electrophile approaches from
bottom face
LiOH
Advanced organic
O
N
Ph
OMe
R1
LiR2
H
O
N
Ph
OMe
R1
LiHR2
O
N
Ph
OMe
R1R2
H
H2O
R2–Li1. LDA2. R1CHO3. CF3CO2H
O
N
Ph
OMe
R1
H
O
N
PhMe
OMe
Alternative chiral auxiliaries I
• 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
30
aldol-like reaction & acid catalysed elimination
hydrolysis
R1CO2H
R2HPh
OH
OMeNH2
H3O
95-99% ee
Advanced organic
Raney Ni
O
O
H
Ar
O
OS
O
MeO H
Ar
O
O
MgBr
ZnBr2
O
O
SOZn
MeO
L L
O
OS
O
MeO
Alternative chiral auxiliaries II
• 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
31
nuc
O
O
H
O
O
OOMe
MeO
MeO
(–)-podorhizon95% ee
Ar2COCl
Advanced organic
Enantioselective catalytic conjugate addition
• 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
32
O
75%10% ee
O
Et
Et2Zn, Cu(OTf)2 (2%), lig. (4%), tol, 3h, –30°C
O Et2Zn, Cu(OTf)2 (2%), lig. (4%), tol, 3h, –30°C
O
Et94%
>98% ee
OO
P NMe
Ph
MePh
lig.
Advanced organic
OCuR
LL
XZnR
Potential mechanism
33
copper(II) (with 2 P ligands) reduced to
copper(I) by zinc reagent
transmetallation of alkyl group (R) to copper
alkyl transfer occurs after enone and copper bind
zinc probably activates enone
L2CuR + RZnX
ZnR2
OO
XZn
R
L2CuX2
L2CuX+
RZnX
ZnR2
Advanced organic
Li
OAl
O O
OO
O O
RO OR
H
Li
OAl
O O
OO
Li
OAl
O O
O
Bifunctional catalysis
• 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
34
O(R)-ALB (0.3%)t-BuOK (0.27%)
MS 4Å, THF, rt, 120hO
MeO
O
OMe
O
CO2Me
CO2Me
94%99% ee
+
OOAl
OO
Li
(R)-ALB
Advanced organic
N
N CO2H
Me
Me
H
CO2Bn
CO2Bn
N
N CO2H
Me
Me
H
CO2Bn
BnOOH
Ph Me
O
BnO OBn
O O
N
NH
CO2HBn
Me
cat. (10%), neat, rt, 165h Ph
Me
CO2BnBnO2C
O
86%99% ee
+
Organocatalysis
• 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
35
Advanced organic
N
N
MeO
Me
MeMe
H
X ArH
N
N
MeO
Me
MeMe
H
X
N
N
MeO
Me
MeMe
H
X
NR2
H
X O
H
NR2
N
NH•HCl
Bn
MeO
Me
MeMe
R2N
O
HX
68-90%84-92% ee
+
Organocatalysts II
• 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
36
steric hindrance results in predominantly one
conformation
Advanced organic
Organocatalysts III
• 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)
37
OTMSO Me R O
HO
HR
OO
Me
N
NH•HCl
Bn
MeO
Me
MeMe
cat. (20%)DCM / H2O
–20 to –70°C, 11–30h77%
syn:anti = 1-31:184-99% ee
+
MeH
O
O CO2Et O
O
CO2EtMe
cat. (20%)KHMDS (20%)
25°C, 24h
80%97% ee
NN
NO
OMe
HBF4
Advanced organic
Mechanism of Stetter reaction
38
NN
NO
Ar
NN
N
Ar
Ar2
OHH
NN
N
Ar
HO
OMe
H base
OEt
O
base
O
CO2EtMe
O HN
N
N
Ar
NN
N
Ar
OH
O
Me
O
OEt
MeH
O
O CO2Et
base
O
O
CO2EtMe
• The Stetter reaction is analogous to the activity of thiamine (vitamin B1) in our bodies and the reaction is thus biomimetic
Advanced organic
N N
S
F3C
CF3
NH HO O
N
Ph
H
CO2Et
CO2EtH
MeMe
N N
S
F3C
CF3
H HO O
N
Ph
H
N MeMe
HO
O
OEtEtO
H
H
NO2NO2
EtO2C CO2EtNH
NH
S
F3C
CF3
NMeMe
EtO2C CO2Ettoluene, rt, 24h
86%93% ee
+
Organocatalytic bifunctional catalysis
• 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
39