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Advanced organic
The Diels-Alder reaction
• Diels-Alder (DA) reaction is incredibly valuable method for the synthesis of 6-rings• It is not within the remit of this course to go into detail about this reaction • We are interested in the stereochemical outcome but need a bit of revision...• Normally DA is highly regioselective (as seen above)• It is controlled by the ‘relative sizes’ of the p orbitals in the LUMO & HOMO involved• More accurately referred to as the orbital coefficients • In the presence of a Lewis acid dienophile is polarised giving higher regioselectivity
and a faster reaction
1
NMe2
+CO2Me
NMe2CO2Me
NMe2CO2Me
HOMO LUMO
Me
+CO2Me
Δ +
MeCO2Me
Me
CO2Memajor minor
Me+
CHOΔ
Me
CHO+
Me CHO
toluene, 120°C, no catalystbenzene, 25°C, SnCl4
5996
::
414 Lewis acid
improves selectivity
regioselectivity often follows simple electronic argument (consider which C is δ+ve or δ–ve)
Advanced organic
B
A
D
C B
AH
HDHC
H AC
DB
≡exo
exo
B
AH
DHCH
H AC
DB
≡
endo
B
A
D
Cendo
B
AC
D
Endo vs. exo selectivity
• Endo transition state & adduct is more sterically congested thus thermodynamically less stable
• But it is normally the predominant product• The reason is endo transition state is stabilised by π orbital overlap of the group on
C or D with the diene HOMO; an effect called ‘secondary orbital overlap’
• The reaction is suprafacial and we observe that the geometry of the diene & dienophile is preserved
2
favoured
secondary orbital overlap
Advanced organic
Diels-Alder reaction
• The ‘cube’ method is a nice way to visualise the relative stereochemistry
• Finally, remember that the dienophile invariably reacts from the less hindered face• If you are a little rusty on the Diels-Alder reaction either re-read your lecture notes or
any standard organic text book
3
draw a cube
add the diene
add dienophile (endo product has
substituents directly under diene)
remember other substituents
present
do reaction (make new
bonds)
A
B CD B
A
CD B
AH
H
HH C
D
A
B
should be able to see relative stereochemistry
CD
A
B
H
HH
H CD
HH
HHB
A
≡
OMe
NO2
+
HMeO
H
O2N NO2
H
HMeO
Advanced organic
+ O N O
O
MeMe
single(ish) diastereoisomer
Et2AlClR
R = H 86% deR = Me 90% de>98% endo
achiral diene
ON
O
MeMe
O
R
chiral dienophile
Cl
O
OHN
O
MeMe
(S)-valine derivative
R
1 : 1 mixture of enantiomers
O OBn
+
O OBnCl
O BnOH
OBn
O
achiral diene
+
achiral dienophile +
Chiral auxiliaries on the dienophile
• One diastereoisomer is formed - the endo product• But mixture of enantiomers • If we add a chiral auxiliary then there are two possible endo diastereoisomers• But one predominates - thus we can prepare a single enantiomer
4
O OBn
BnOH
single enantiomer
R
Advanced organic
ON
O
MeMe
OAl
Et Et
NO
Et2Al O
OH
MeMe
Et2AlCl2
ON
O
MeMe
O
NO
Et2Al O
OH
MeMe
NO
Et2Al O
OH
MeMe
Explanation of diastereoselectivity
• Coordination to the Lewis acid activates dienophile• The rigid chelate governs reactive conformation (s-cis) as s-trans disfavoured• iso-Propyl group blocks bottom face• Diene’s approach maximises secondary orbital overlap and favours endo product
5
lower face blocked
s-cis favoured
s-trans disfavoured
Advanced organic
Me Me
NS O
R
O O TiLn
Me Me
NS
OO
O
R +TiCl4–78°C
RH
NOO2S
MeMeR = H 99% deR = Me >97% de>98% endo
Camphor-derived auxiliary
• A range of auxiliaries can be utilised• Most give good diastereoselectivities
6
Me Me
NSO2 O
R
Advanced organic
Me
O
O MeMe
BnO
CO2R
H
BnO
≡Me
O
O MeMe
HH
OBn ≡
BnOMe
O
O MeMe
AlCl3+
Chiral auxiliaries II
• It is possible to attach the chiral auxiliary to the diene as well
7
O
O OH
O
OOMe
H Ph +B(OAc)3
O
O
OHO
O
H
H
MeO
H Ph
>95% deendo
phenyl group blocks lower face
diene approaches from the top
Advanced organic
Chiral catalysis and the Diels-Alder reaction
• The fact the Diels-Alder reaction is mediated or catalysed by Lewis acids means enantioselective variants are readily carried out
• The aluminium catalyst above has been utilised in enolate chemistry (aldol) reaction and is very effective in this Diels-Alder reaction
8
MeON
O
O
Me
Br+cat.
N
O
O
Me
Br
H
H
MeO
>97% ee
NAl
N
Me
SO2CF3F3CO2S
Me
Me Me
Me
Advanced organic
Chiral catalysis and the Diels-Alder reaction II
• The oxazolidinone substituent on the dienophile is important• Good selectivities are only achieved when there are two binding points on the
dienophile• The two carbonyl groups allow a rigid chelate to be formed & maximise the
commincation of chirality
9
N NCl
Cl Cl
Cl+
N O
O O lig. (10%)Cu(OTf)2 (9%) H
O N O
O
92% ee
OH O
O
+
OMe
BH3 / HOAc
O
OOHH
H
OMe>98% ee
OH
Ph
OH
Ph
Advanced organic
OMeN
N
Et
ArO Me
N
NMeO
OMeEt
96% eeendo / exo >200 : 1
cat. (20%)HClO4
OMe
+Et
O COEt
OMe
Organocatalysis and the Diels-Alder reaction
• Organic secondary amines can catalyse certain Diels-Alder reactions• The reaction proceeds via the formation of an iminium species• This charged species lowers the energy of the LUMO thus catalysing the reaction• In addition one face of dienophile is blocked thus allowing the high selectivity
10
NH
NMe
Ph
O
O Me
Advanced organic
TFA
OPh
OO
O
TBS
Me
OH
O
HPh
H
N N
PhPh
TfTf
TBSO
MeO
TBSO
OMe O
HO
Ph+1. cat. (10%)2. TFA
O
OPh
O87% ee
Organocatalysis and the Diels-Alder reaction II
• This is an example of a hetero-Diels-Alder reaction• The aldehyde is the dienophile• We have to use a very electron rich diene• The amine catalyst acts as a Lewis acid via two hydrogen bonds
11
OPh
OO
O
TBS
MeH
NH H
N
Ph Ph
Tf Tf
Advanced organic
O
Ph
NMeMe
TBSOO
HO H O H O
H
Ph
HO
TBSO
NO
H Ph
MeMe
+1. cat. (10%)2. AcCl
O
PhO
>98% ee
Organocatalysis III
• Another hetero-Diels-Alder reaction• It looks very similar to the previous reaction but...• It is believed that only one hydrogen bond activates the aldehyde• The other is used to form a rigid chiral environment for the reaction
12
AcClOHOHO
O
Ph Ph
Ph Ph
MeMe
Advanced organic
bX
c
HR2
dR
a
bX
c
HR2
dR
aX
R
R2
da b
c
heatX
R2
R3R1
X
R1 R3
R2
[3,3]-Sigmatropic rearrangements
• A class of pericyclic reactions whose stereochemical outcome is governed by the geometric requirements of the cyclic transition state
• Reactions generally proceed via a chair-like transition state in which 1,3-diaxial interactions are minimised
• General relationship is outlined below...• Indicates that geometry of double bonds important to controlling relative
stereochemistry
13
X
R1 R3
R2
X
R2
R
dcb
a
Advanced organic
H
Me
MePh
H Me
PhMe
91%
H
Ph
MeMe
Me H
MePh
9%
Me
Me
Ph
Cope rearrangement
• A very simple example of a substrate controlled [3,3]-sigmatropic rearrangement is the Cope rearrangement
• To minimise 1,3-diaxial interactions phenyl group is pseudo-equatorial • Note: the original stereocentre is destroyed as the new centre is formed• This process is often called ‘chirality transfer’
14
1,3-diaxial interactions disfavoured
Advanced organic
Claisen rearrangements
• One of the most useful sigmatropic rearrangements is the Claisen rearrangement and all it’s variants
15
Claisen rearrangement
Johnson-Claisen rearrangement
Eschenmoser-Claisen rearrangement
Ireland-Claisen rearrangement
OH +OEt Hg+ O O
H
heat
OH +Me OMe
MeO OMe H+ O
OMe
O
OMe
heat
OH +Me NMe2
MeO OMe H+ O
NMe2
O
NMe2
heat
OH +Me O Me
O O Et3N
Me
O
O
O
OSiR3
O
OSiR3
heatR3SiClbase
Advanced organic
Me
Me
OMe
NMe2
Me NMe2
MeO OMe
Me
Me
OH MeH2
Lindlar cat.
MeNMe2
Me
Me O
≡
MeMe
Me
NMe2
O HMe
Me
O
Me
NMe2
Me NMe2
MeO OMeNaNH3 Me
Me
OH
MeMe
Me
Me
OH
Me
Me
Me
OH
‘Enantioconvergent’ synthesis
• Both enantiomers of initial alcohol can be converted into the same enantiomer of product
• This process (Eschenmoser-Claisen) shows the importance of alkene geometry
16
SET reduction gives most stable alkene
heterogeneous hydrogenation leads to syn addition of H2
O
H NMe2
i-Pr
Me
O
H NMe2
i-Pr
Me
HH
Me2N
O
H Me
Hi-PrMe2N
O
H Me
Hi-Pr
same configuration
MeH
Me
NMe2
O Me
≡
Advanced organic
O
H
H
OSiR3MeMe O
H
H
OSiR3MeMe
O
OSiR3Me
Me
1. LDA, THF/HMPA2. R3SiCl
O
MeMe
OSiR3
O
H
Me
OSiR3Me
H
O
OSiR3Me
MeO
H
Me
OSiR3Me
H
1. LDA, THF2. R3SiCl
O
MeOSiR3
Me
O
MeMe
O
Ireland-Claisen reaction
• Enolate geometry controls relative stereochemistry• Therefore, the enolisation step controls the stereochemistry of the final product
17
Advanced organic
Substrate control in Ireland-Claisen rearrangement
• In a similar fashion to the Cope rearrangement we saw earlier, the Ireland-Claisen rearrangement occurs with ‘chirality transfer’
• Initial stereogenic centre governs the conformation of the chair-like transition state• Largest substituent will adopt the pseudo-equatorial position
• Once again, the relative stereochemistry is governed by the geometry of the enolate
18
O
Me Me
OHO
91% ee
1. LHMDS2. TMSCl
H
O
OTMS
H
Me
OTMS
Me
H
O
OTMS
H
Me
OTMS
Me
HO2CMe
OTMS
Me98% syn91% ee
methyl group is pseudo-equatorial
Advanced organic
O
NAr*
Me
MeN
O
Me
Me
Li Ar*N
O
Me
Me
Li Ar*
O
NAr*
Me
Me
anti / syn 98:294% de for anti
Me
Me
O
NHAr*
LDA
Auxiliary control in the Ireland-Claisen rearrangement
• Use of chiral auxiliaries allows the control of absolute stereochemistry• Good news is that it is hard to predict and so will not be examined...
19
OMeNH2
Ar*NH2 =
Advanced organic
O
OHMe
Me96% ee
warmO
O
Me
R*2B
MeEt3NTol / hexane
–78°C
O
OHMe
Me>97% ee
warmO
OMe
Me
R*2Bi-Pr2NEtCH2Cl2–78°C
O
OMe
Me
+ NBN
Ph Ph
ArO2S SO2Ar
Br
Chiral reagent control in the Ireland-Claisen rearrangement
• Funnily enough, it is possible to carry the reaction out under “reagent” control • Although, it could be argued that this is just a form of temporary auxiliary control!• Enolate formation (enolate geometry) governs relative stereochemistry
20
Advanced organic
Chiral catalyst control in the Ireland-Claisen rearrangement
• It is also possible to perform the reactions under chiral catalyst control• Presumably, the Lewis acid coordinates to the oxygen & influences the reactive
conformation thus controlling enantioselectivity
21
O
Ph
SiMe
MeMe
HO
SiMe3
Ph
O
Ph
SiMe3
MeAl(OR*)2
OO
Al Me
SiMe2t-Bu
SiMe2t-Bu
MeAl(OR*)2 =
Advanced organic
The Heck reaction
• The Heck reaction is a versatile method for the coupling sp2 hybridised centres• Again it is not the purpose of this course to teach organometallics etc
22
R1 X + R2cat. PdX2
R3N[R3
3P]
R2 R1
R1 = Ar, ArCH2,X = Br, I, OTf
Br
PdL
LBr
oxidative addition
PdL
Br
syn addition
R3N
R3NH Br
Pd(0)(14e)
L Pd L
L Pd BrH
L
Pd
H
PdLH
Br
LBr
–L
+L Pd(II)(16e)
Pd(II)(16e)
Pd(II)(16e)
β-hydride elimination
Advanced organic
O
Ph
PdI
L
H
O
Ph
Pd(I)Ln
H
hydro-palladation
β-hydride elimination
O
PhPd
IL
HO
Pd IL
δ+ δ–
syn addition
O
Pd(I)LnH
HH
Alkene isomerisation
• β-Hydride elimination is reversible• This alkenes can ‘walk’ or migrate to give the most stable alkene• Only restriction is every step must be syn
23
O+
I
O
0.01% Pd(OAc)2R3N
100°C
O
Ph
Pd(I)LnH
O
Ph
PdHI
LO
Advanced organic
Enantioselective Heck reaction
• With the use of chiral ligands the Heck reaction can be enantioselective• Remember that we often see alkene migration
24
OTf
CO2Et+
O
Pd[(R)-BINAP]2proton sponge
O
EtO2C62%
>96% ee
NMe2 NMe2
proton sponge
PPh2PPh2
(R)-BINAP
O TfO+
Pd(dba)2 (3%), lig (6%)i-Pr2NEt
O
92%>99% ee
N
O
PPh2
t-Buligamino acid derivative
Advanced organic
Enantioselective Heck reaction II
• Intramolecular variant allows the construction of ring systems• The silver salt accelerates the reaction and prevents alkene isomerisation
25
I
TBSO Pd[(R)-BINAP]Cl2AgPO4, CaCO3
NMe
O H
TBSO
78%82% ee
O
O
N
O
I
Me Pd2(dba)3(R)-BINAP
Ag3PO4N,N-dimethylaniline
O
O
NO
Me
71% ee
PPh2PPh2
(R)-BINAP
Advanced organic
Suzuki-Miyuara reaction
• The Suzuki-Miyuara reaction is (normally) the palladium catalysed coupling of an alkenyl or aryl halide with an alkenyl or aryl boronic acid
• Normally the components should be sp2 hybridised to avoid β-eliminations• Mechanism etc is (surprise surprise) outside the scope of this course but the
wonderful enantioselective examples are not...
26
Pd0L L
Pd0L
–Loxidative addition
transmetallation
reductive elimination
PdL
X
B(OH)2
X
PdL
R1
R2
R1
R2
R2
R1R2
Advanced organic
Enantioselective biaryl formation
• Virtually every (if not every...) reaction we have covered in this course has formed a stereogenic centre (central chirality)
• These two examples form axially chiral compounds• Please note: both ligands are thought to be mono-dentate (in the active species at
least, although they may be bidentate in ‘resting state’) via the phosphine
27
BrP(O)(OMe)2 +
B(OH)2
Me P(O)(OMe)2
Me
95%86% ee
Pd2(dba)3 (0.2%)lig2
PCy2
NMe2
lig2
MeB
O O
+Me
I
(PdClC3H5)2lig1
CsF MeMe
60%85% ee
FePPh2
lig1Me
NMe2H
Advanced organic
Other catalytic enantioselective reactions
• Pd(0) chemitry has been utilised in the enantioselective arylation of enolates• The reaction is related to much of Pd chemistry you have covered• Below is an example of a chiral variant of the Schrock metathesis catalyst• The reaction involves desymmetrisation by selective reaction if one disubstituted
alkene
28
O
NMePh
Me
+
Br Pd2(dba)3 (1%)lig1
NaOt-Bu
O
NPh
Me
Me
80%93% ee
i-Pr2PO
lig1
N
O
Me
Me
N
O
MeMe
L2 (10mol%), PhH, 22°C, 48h
91%98% ee
NMo THF
OOAr
Ar
i-Pri-Pr
Me
Me
Ph
L2
Advanced organic
Enantioselective Negishi reactions
• Last year (2005) saw the first examples of catalytic enantioselective Negishi couplings• The system still has some limitations but is an exciting development• On a practical note, many of the reactions above were run in air!!!
29
BnN
EtO
Ph Br
hex ZnBr+
NiCl2•glyme (10mol%), L1 (13mol%), DMI:THF
(7:1), 0°C BnN
EtO
Ph hex90%
95% ee
Cl
Br
+BrZn O
O
NiBr2•diglyme (10mol%), L1
(13mol%), DMA, 0°C
Cl
OO
82%91% ee
NN
OO
N
i-Pr i-PrL1
Advanced organic
Summary of methods for stereoselective synthesis
30
Method Advantages Disadvantages Examples
resolution both enantiomers available maximum 50% yield synthesis of (–)-propranolol
chiral pool 100% ee guaranteed often only 1 enantiomer available
synthesis of (R)-sulcatol
chiral auxiliary often excellent ee’s; built in resolving agent
extra steps to introduce and remove auxiliary
oxazolidinones
chiral reagent often excellent ee’s; stereoselectivity can be independent of substrate control
only a few reagents are successful and often only for a few substrates
alpine-borane®, Brown allylation reagents
chiral catalyst economical; only small amounts of recyclable material used
only a few reactions are really successful; frequently a lack of substrate generality
asymmetric hydrogenation; Sharpless epoxidation
• Hopefully this course has shown that the area of stereoselective synthesis (or more particularly, methodology for stereoselective synthesis) is a vast & fascinating topic
• There are many reactions we have not covered (there is already far too much material in the course)
• I hope you found the course as interesting as I did...
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