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Advanced organic
Stereoselective reactions of alkenes
• Earlier, we saw that stereospecific reactions can produce single diastereoisomers• If there is a pre-existing stereogenic centre reactions can be stereoselective• In other words, the faces of the alkene are diastereotopic
• Following two examples show highly diastereoselective iodolactonisations
1
OOHMe
I2I
Me O O
OOH
MeI2
O
IMe
O82% de
O
Me
OH
I2
OI
Me
O88% de
• These cyclisations are probably under thermodynamic control • This means the reactions are reversible and equilibrate• Therefore the product is the most stable compound
• If the reactions are under kinetic control we have to look at other factors and need to...look at conformation again...
Advanced organic
Stereoselective reactions of alkenes II
• Two diastereoisomers formed as a result of attack from the two diastereotopic faces• Look at possible conformations...• Arguably the lowest energy conformations have greatest separation of substituents
2
Me SiMe2Ph
Me
Me SiMe2Ph
MeO
Me SiMe2Ph
MeO
m-CPBA +
>95% <5%
• The control of conformation by the interaction of methyl group and stereocentre is...called allylic strain or A(1,3) strain
Me
MeH
if no cis substituent then only small
energy difference
HH H
MeMe
H
HH H
HMe
Melowest energy: H
eclipses plane of alkeneslightly higher energy: Me eclipses plane of alkene
rotate bond
Me
MeMeH
cis substituent present then only
ONE conformation
MeH H
MeMe
HMeH H
HMe
Melowest energy: H
eclipses plane of alkenehigh energy: Me–Me
interaction disfavours conformation
HH H
HMe
Me
HH H
MeMe
H
H HMe
HH
Me
MeMe
HMe
Me
HX
Advanced organic
Stereoselective reactions of alkenes III• Apply this knowledge to the real system...
3
m-CPBA
>95%Me
Me
H SiMe2Ph
O
MeH H
HSi
Me
MeMe
Ph
OMeH H
HSi
Me
MeMe
Ph
Me
Me m-CPBA
H SiMe2Ph
m-CPBAX
lowest energy conformation
silyl group blocks approach
X
m-CPBA approaches from unhindered face
<5%Me
Me
H SiMe2Ph
O
HMe
HMe
H
Si MePh Me
m-CPBA
formation of minor diastereoisomer results
from m-CPBA approaching alkene in above conformation or
approaching passed the silyl group
Advanced organic
m-CPBA
m-CPBA
HMe H
MeH
SiPh
MeMe
O
39%
Me
H SiMe2Ph
OMe
HMe H
HSi
Me
MePh Me
O61%
Me
H SiMe2Ph
OMe
Me
H SiMe2Ph
Me
HMe H
HSi
Me
MePh Me
HMe H
MeH
SiPh
MeMe
Importance of A(1,3) strain
• The importance of a cis-substituent is made clear by the reduced stereoselectivity• This is explained as follows...
4
Me m-CPBA+
61% 39%
H SiMe2Ph
Me
H SiMe2Ph
OMe
H SiMe2Ph
OMe Me Me
X
m-CPBA attacks form least hindered
face
X
lowest energy conformation
gives major product HMe H
HSi
Me
MePh Me
HMe H
MeH
SiPh
MeMe
both conformations low energy -- so mixture of
products
Advanced organic
H2B HH2B
H CH2OBnMeH
Me
OH CH2OBn
MeHMe
O
H
H2O2NaOH
OBn
H Me
O
H Me
OH74% de
Me
OBn
H Me
O
BH3
OBn
H Me
O
H Me
H2B
Other reactions...• Epoxidation is not the only stereoselective reaction of alkenes• Below is an example of hydroboration, a useful reaction that you should be familiar
with...
5
R
R1
HS
LL R1
RS H
S = smaller groupL = larger group
R
R1
SL
HR
R1
LH
S
favoured destabilised by repulsion between C-1 & C-3 substituents or A(1,3) strain
13
13
preferred approach Selectivity in addition to cis alkenes
Attack from the least sterically demanding face of the alkene as it resides in the most favoured conformation. Followed by stereospecific oxidation
Advanced organic
Directed epoxidation
• A hydroxyl group can reverse normal selectivity and direct epoxidation• Epoxidation with a peracid, such as m-CPBA, is directed by hydrogen bonding and
favours attack from the same face as hydroxyl group• The reaction with a vanadyl reagent results in higher stereoselectivity as it bonds /
chelates to the oxygen
6
OHreagent
OH
O
reagent:m-CPBAt-BuO2H, VO(acac)2
OH
O+
syn9298
t::
anti82
H
OO
HO
OH
Ar hydrogen bond O
VO OO O MeMe
Me Mevanadyl acetylacetonate
O
H
OV
t-BuO O
Advanced organic
MeMe H
HO
Me
HOO
OH
Ar
Me Me
Me OHHm-CPBA Me Me
Me OHH
OMe Me
Me OHH
O+
95 5
Directed epoxidation in acyclic systems
• Hydroxyl group can direct epoxidation in acyclic compounds as well• Once again, major product formed from the most stable conformation• Thus the cis methyl group is very important
7
• The minor product is formed either via non-directed attack or via the less favoured...conformation
hydrogen bond
favoured conformation
O
MeMe H H
OH
HO
O
Me
Ardisfavoured
conformation
MeMe H
HOH
Me
O
Advanced organic
Directed epoxidation: effect of C-2 substituent
• The presence of a substituent in the C-2 position (Me) facilitates a highly diastereoselective reaction
• The preferred conformation minimises the interaction between the two Me (& Me) groups
8
• With C-2 substituent (H) there is little energy difference between conformations• Therefore, get low selectivity
H O Me
H
O
OV
t-Bu
H Me
LL
MeMe
OHH
t-BuO2HVO(acac)2 Me
MeMe
Me
O OOH OH19 1
+
:
disfavoured conformation as Me & Me eclipse
steric interaction
favoured conformation as
only Me & H eclipse
H O H
Me
O
OV
t-Bu
H Me
LL
Me Me
H OH
t-BuO2HVO(acac)2 Me Me
O OOH OH
2.5 1
+
:
Me Me H O H
Me
O
OV
t-Bu
H H
LL
H too small to differentiate
conformations
Advanced organic
Directed reactions
• It is possible to form the desired allylic epoxide in a highly selective manner by utilising a temporary blocking group
• The silyl group causes one conformation to predominate & can be removed at end• As silyl group bigger than methyl reaction more selective
• Other diastereoselective reactions of alkenes can be controlled by a directing group• Below is an example of cyclopropanation by the Simmons-Smith reagent
9
Me Me
H OH
t-BuO2HVO(acac)2 Me
Me
OO
OHOH
25:1
MeMe
SiMe3 SiMe3TBAF
Zn
carbenoid
+
OH OZn
CH2
I
H
CI
OZnH
HOH
>98% de
CH2I2
ZnI
H2C
I
Advanced organic
Stereoselective reactions of enolates
• The stereoselectivity of reactions of enolates is dependent on:• Presence of stereogenic centres on R1, R2 or E (obviously!)• Frequently on the geometry of the enolate (but not always)
10
R1
OR2
H HR1
OR2
H
M
R1
OR2
H E
E
• Use terms cis and trans with relation to O–M to avoid confusion
R1
OH
R2
M
(E)-enolate(trans)
R2
HMO
R1
αα
C-α re face
C-α si face
R1
OR2
H
M
(Z)-enolate(cis)
H
R2MO
R1
αα
C-α re face
C-α si face
Advanced organic
R1 O
H
H R2≡
H
R2O
R1
H
R1
R2O
H
H
Enolate formation and geometry• Enolate normally formed by deprotonation • This is favoured when the C–H bond is perpendicular to C=O bond as this allows σ
orbital to overlap π orbital• σ C–H orbital ultimately becomes p orbital at C-α of the enolate p bond
11
C=O π orbital
C–H σ orbital
enolate π orbital
R1
R2O
H
base + H base
• Two possible conformations which allow this• First is given below and results in the formation of cis enolate • Initial conformation (Newman projection) similar to transition state• Little steric interaction between R1 and R2
transition state
base base
H
R2O
R1
Hbase
H
R2O
R1
baseH
(Z)-enolate(cis)
Advanced organic
Enolate formation and geometry II
• Second conformation that places C–H perpendicular to C=O gives trans-enolate• Only differs by relative position of R1 and R2
• The steric interaction of R1 and R2 results in the cis-enolate normally predominating• As results below demonstrate stereoselectivity is influenced by the size of R1
12
R1 O
H
R2 H≡
R2
HO
R1
H
base base
R2
HO
R1
Hbase
R2
HO
R1
baseH
(E)-enolate(trans)
RMe
OLDATHF
–78°C R
OLi
MeR
OLi
Me+
R = Eti-Prt-BuOMeNEt2
3060
>985
>97
cis:::::
7040<295<3
trans
Advanced organic
Enolate formation and geometry III• Previous table shows that stereoselectivity of enolate formation not always obvious• In ketones trans-enolate favoured if R1 is small but cis-enolate if R1 is large • Can explain this with transition state (again...)
13
O
H
NLiH
Me
i-Pr
i-Pr
R
O
H
NLiMe
H
i-Pr
i-Pr
R
RMe
OLDA
if R is small, 1,3-diaxial interaction is important as it destabilises this
TS‡ and trans predominates
if R is large, this TS‡ is destabilised by R–Me interaction
and cis predominates R
OLi
Metrans
R = small
RMe
OLi
cis
R = large
• With esters the R vs OMe interaction is alleviated and 1,3-diaxial interaction controls...geometry - hence trans-enolate predominates
MeOMe
O
O
H
NLiH
Me
i-Pr
i-Pr
O
O
H
NLiMe
H
i-Pr
i-Pr
OMeO
MeOLi
MeO
OLi
Metrans
cis
Me
Me
LDA
predominates
Advanced organic
Enolate formation and geometry IV
• Amides invariably give the cis-enolate; remember restricted rotation of C–N bond
• The previous arguments are good generalisations, many factors effect geometry• Use of the additive HMPA (hexamethylphosphoric triamide) reduces coordination and
favours the thermodynamically more stable enolate
14
Et2NMe
O
O
H
NLiH
Me
i-Pr
i-Pr
N
O
H
NLiMe
H
i-Pr
i-Pr
REt2N
MeOLi
Et2N
OLi
Metrans
cis
Et
Et
LDA
predominates
EtOMe
O 1. LDA2. TBSCl
EtOMe
OTBS+ EtO
OTBS
Me
THFTHF / HMPA
cis682
trans9418
Advanced organic
H
R2O
R1
H RH
H
R2O
R1
X
H HR
≡H
R2O
R1
X
H HR
Addition of an electrophile to an enolate
• Finally, need to know the trajectory of approach of the enolate and electrophile• Reaction is the overlap of the enolate HOMO and electrophile LUMO • Therefore, new bond is formed more or less perpendicular to carbonyl group• Above is simple SN2 with X = leaving group
15
X = leaving group
σ* orbital (LUMO electrophile)
π orbital (HOMO nucleophile)
Advanced organic
Enolate alkylation
• Simple alkylation of a chiral enolate can be very diastereoselective• As we have a cis-enolate diastereoselectivity can be explained in an analogous
fashion to simple alkenes via A(1,3) strain• Larger the substituent, R, greater the selectivity
16
R OEt
Me O
LDA[Li–N(i-Pr)2]
R OEt
Me OLi
Me I R OEt
Me O
R OEt
Me O
+
Me Me
syn778395
anti23275
::::
RR = PhR = BuR = SiMe2Ph
HOOEt
HMe
R
Me
≡ R OEt
Me O
MeMeI
OOEtH
HMe
R Li
most stable conformation; C–H
parallel to C=C
alkylation on face opposite to R
• Note: minor diastereoisomer probably arises from electrophile passing by R group• Therefore, size does matter...
Advanced organic
EL OEt
OS H
E H
OEt
OLi
HS
LOLi
OEt
HS
L
≡ ≡
L OEt
OS H LDA
L OLi
OEtS H
L OEt
OLiS H
(E)-enolatetrans
(Z)-enolatecis
Enolate alkylation II
• In this example enolate geometry is not important - both are cis-alkenes• Therefore, selectivity the same in both cases• If we want to reverse selectivity, change the electrophile to H • This route far less selective as H is small so less interaction with substituents
17
MeOOEtMe
HMe
R Li
H
OOEt
HMe
R
H
≡R OEt
Me O
MeLDA R OEt
Me O
H Me
preferred approach
preferred approach
Advanced organic
Nomenclature (again!!)
• You may have noticed some annoying changes nomenclature!• With ester enolates the E / Z nomenclature changes depending on the nature of M (if
we use the Cahn-Ingold-Prelog rules)
• As a result we will classify enolates as cis or trans with respect to O–MR1 = cis R2 = trans
18
R
OM
R1
R2
O
R1 R2
X
Y O
R1 R2
X
Y
syn anti
• Syn and anti in the aldol reaction refer to relative stereochemistry of enolate...substituent X and hydroxyl group (or equivalent) Y
Advanced organic
H Ph
O
t-Bu
O
Ph
OH
Mesyn aldol
t-BuMe
O LDA
t-BuMe
OLi
cis-enolate
H Ph
OO
Ph
OH
Hanti aldol
OLDA
OLi
trans-enolate
The aldol reaction
• The aldol reaction is a valuable C–C forming reaction • In addition it can form two new stereogenic centres in a diastereoselective manner• Most aldol reactions take place via a highly order transition state know as the
Zimmerman–Traxler transition state• It will not come as much surprise that this is a 6-membered, chair-like transition state
19
O
R1 R3
R2
OHO OM
R1
R2R3
Zimmerman–Traxler
R1
OM
R2
+O
R3
• Interestingly, enolate geometry effects diastereoselectivityonly possible
enolate
Advanced organic
level
level
The aldol reaction II
• Generally speaking the above guideline sums up aldol chemistry!• To understand why this happens we need to examine Zimmerman-Traxler TS‡
• So need to be able to draw a chair-like TS‡
20
XMe
OLi H R
O
X
O
R
OH
Me
trans-enolate anti aldol
cis-enolate syn aldol
X
OLiH R
O
X
O
R
OH
MeMe
start at one end of 6-ring
draw two parallel lines
bottom should be level with initial
lines
new line parallel to first
tops should all be level
draw final line parallel to first
should have 3 pairs of parallel lines
H
H HH
HH
add axial groups so that they are vertical and alternate up & down. Each carbon should
be tetrahedral
H
H
add equatorial substituents so that they are parallel to
two C–C bonds
HH
add equatorial substituents so that they are parallel to
two C–C bondsadd equatorial substituents so that they are parallel to
two C–C bonds
HH
Advanced organic
X
O
R
OH
Mesyn aldol
OO
MX
H
Me
HR
OO
MXH
Me
HR
XMe
OLi H R
O
cis-enolate
Zimmerman-Traxler transition state
• We only have one choice in the aldol reaction - the orientation of the aldehyde• Enolate substituents are fixed due to the double bond• Aldehyde substituent is pseudo-equatorial to avoid 1,3-diaxial interactions
21
OO
MX
H
Me
HR
cis-enolate
R pseudo-equatorial
OO
MX
R
Me
HH
cis-enolate
R pseudo-axialdisfavoured
1,3-diaxial interaction
OO
MXH
Me
HR
to ‘see’ relative stereochemistry
consider S as plane and see which groups are above and which
belowre face of enolate attacks
si face of aldehyde
Advanced organic
Zimmerman-Traxler transition state II
• Attack via the enantiomeric transition state (re face of aldehyde) gives the enantiomeric aldol product
• This differs only by the absolute stereochemistry - the relative stereochemistry is the same
22
XMe
OLi H R
O
X
O
R
OH
Mecis-enolate syn aldol
X
O
MO
Me
H
RH
si face of enolate attacks re face of aldehyde
X
O
MO
Me
H
RH
X
O
MO
Me
H
RH
visualising relative stereochemistry
Advanced organic
Zimmerman-Traxler transition state III
• The opposite stereochemistry of enolate gives opposite relative stereochemistry• Once again the enolate has no choice where the methyl group is placed
23
trans-enolate anti aldol
X
OLiH R
O
X
O
R
OH
MeMe
X
O
MO
H
H
RMe
re face of enolate attacks re face of aldehyde
X
O
MO
H
H
RMe visualising relative
stereochemistry
X
O
MO
H
H
RMe
Advanced organic
Enolisation and the aldol reaction• Hopefully, all the previous discussion highlights that selective enolisation is essential
for diastereoselective aldol reaction• Each geometry of enolate gives a different relative stereochemistry• With the lithium enolates of ketones the size of the non-enolised substituent, R, is
important
24
RMe
O LDA
RMe
OLi+ R
OLi
MeR = t-BuR = Et
98%30%
2%70%
• With boron enolates we can select the geometry by altering the boron reagent used
Ph
O
Me
B
trans-enolate
PhMe
O+
BCl
Et3N H Ph
O
Ph Ph
O
Me
OH
anti aldol (>90% de)bulky
substituents
forces enolate to adopt trans geometry
Advanced organic
Enolisation and the aldol reaction II
• 9-BBN (9-borabicyclononane) looks bulky• But most of it is ‘tied-back’ behind boron thus allowing formation of the cis-enolate
25
PhMe
O+
Et3N H Ph
O
Ph Ph
O
Me
OH
syn aldol (96% de)
BTfO
Ph
O
cis-enolate
B
Me