Stereoselective reactions of enolates - Massey Universitygjrowlan/stereo2/lecture7.pdf · 123.702...
Transcript of Stereoselective reactions of enolates - Massey Universitygjrowlan/stereo2/lecture7.pdf · 123.702...
123.702 Organic Chemistry
C-α re faceC-α si face
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)
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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 si face
R1
OR2
H
M
(Z)-enolate(cis)
H
R2MO
R1
αα
C-α re face
123.702 Organic Chemistry
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
2
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)
123.702 Organic Chemistry
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 R
3
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
123.702 Organic Chemistry
if R is small, 1,3-diaxial interaction is important as it
destabilises this TS‡ and trans predominates
MeO
OLi
Metrans
MeOMe
OLi
cis
MeOMe
O
O
H
NLiH
Me
i-Pr
i-Pr
OMe
O
H
NLiMe
H
i-Pr
i-Pr
OMe
LDA
R
OLi
Metrans
O
H
NLiH
Me
i-Pr
i-Pr
R
RMe
O
O
H
NLiH
Me
i-Pr
i-Pr
R
O
H
NLiMe
H
i-Pr
i-Pr
R
LDA
Enolate formation and geometry III• The selectivity observed can be explained via chair-like transition state• In ketones cis-enolate favoured if R is large but trans-enolate favoured if R is small
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if R is large, this TS‡ is destabilised by R–Me
interaction and cis predominates
R = small
RMe
OLi
cis
O
H
NLiMe
H
i-Pr
i-Pr
R
R = large
• With esters the R vs OMe interaction is alleviated and 1,3-diaxial interaction controls...geometry - hence trans-enolate predominates
predominates
X
123.702 Organic Chemistry
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
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
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predominates
EtOMe
O 1. LDA2. TBSCl
EtOMe
OTBS+ EtO
OTBS
Me
THFTHF / HMPA
cis682
trans9418
123.702 Organic Chemistry
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
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X = leaving group
σ* orbital (LUMO electrophile)
π orbital (HOMO nucleophile)
123.702 Organic Chemistry
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
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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...
123.702 Organic Chemistry
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
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MeOOEtMe
HMe
R Li
H
OOEt
HMe
R
H
≡R OEt
Me O
MeLDA R OEt
Me O
H Me
preferred approach
preferred approach
123.702 Organic Chemistry
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
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O
R1 R3
R2
OHO OM
R1
R2R3
Zimmerman–Traxler
R1
OM
R2
+O
R3
• Interestingly, enolate geometry effects diastereoselectivityonly possible
enolate
123.702 Organic Chemistry
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‡
• You must learn to draw chair-like conformation of 6-membered rings
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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
123.702 Organic Chemistry
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
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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
123.702 Organic Chemistry
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
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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
123.702 Organic Chemistry
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
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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
123.702 Organic Chemistry
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
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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
123.702 Organic Chemistry
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
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PhMe
O+
Et3N H Ph
O
Ph Ph
O
Me
OH
syn aldol (96% de)
BTfO
Ph
O
cis-enolate
B
Me
123.702 Organic Chemistry
H
OMg O
H
H
MeL R1
R
Me
OR1
HH
OMg
MeMe
O
Me
OH
O
Me
Me
Me
83%93% d.e.
MeMgBrCH2Cl2
C13
C10
C9
H
O
Me
O
O
Me
Me
Me
OBnMe
O
MeMe
OH93%
97% d.e.
C13
C10C9
OO
B
H Cy
H
CyMe R
H Me
BnO
OO
B
HCy
H
Cy MeR
HMeBnO
re-face favoured
disfavouredlone-pair interaction?
versus
MeCHOC9
OBnMe
OBCy2
MeOBn
Me
O
Me Cy2BCl Et3N
C13
C10
Substrate control in total synthesis I
16
C13
OHMe
O
OO
Me
OR
ORMe
O
Me
Me
Me
C1
Oleandomycin aglycon(R=H but should be a sugar)
C9
C7
trans-enolate gives anti-aldol product
123.702 Organic Chemistry
OSnO
Me
H
H
R
TfO
BnO MeH
O SnO
Me
H
H
R
OTf
OBnHMe
re-face attackfavouredversus
CHO
MeC7 C5
O
Me
MeOBn
SnOTf
OBnMe
O
Me Sn(OTf)2Et3N
C1
C4
Substrate control in total synthesis II
• Seen oleandomycin earlier• Here see the opportunities offered
by the aldol reaction• It creates 1 C–C bond and 2
stereogenic centres per reaction• Ian Paterson, Roger D. Norcross,
Richard A. Ward, Pedro Romea and M. Anne Lister, J. Am. Chem. Soc., 1994,116, 11287
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C13OHMe
O
OO
Me
OR
ORMe
O
Me
Me
Me
C1
C9
C7
stereogenic centres setup by
aldol reaction
C–C bonds formed by aldol
reaction
OBnMe
OH
Me
O
Me
90%93% d.e.
C7 C1
C4C5
cis-enolate gives syn-aldol product