Stereoselective reactions of enolates

13 Pages·2006·0.55 MB·English

1
Stereoselective reactions of enolates
• Chiral auxiliaries are frequently used to allow diastereoselective enolate reactions
• Possibly the most extensively studied are the Evan’s oxazolidinones
• These are readily prepared from amino acids
O
O
(EtO) C=O
2
reduction Ph OH K CO
2 3 HN O
Ph OH
NH
2
NH
2
Ph
(S)-phenylalanine oxazolidinone
chiral auxiliary
• Enolate formation gives the cis-enolate (remember enolisation of amides)
• Two possible conformations exist - but chelation results in one being preferred
Li
O O O O
Me
Me
N O LDA N O
Me
O Me
Me
Me
1. n-BuLi
HN O 2. EtCOCl
Me Me Me
O O
Me
valine Li
O N O LDA O N O
derivative
Me Me
Advanced organic
Me Me
2
Diastereoselective alkylation of Evan’s enolate
Li
O O O O
Me
Me
PhCH I N O
N O 2
Ph
Me
Me
Me
Me
I
Ph
Li O Bn O
O O O O
N H N H
Me Me
H
Me Me
Me Me
iso-propyl group
blocks bottom face
• Clearly (I hope) one face of the enolate is blocked
• Chelation results in a rigid structure that provides maximum steric hindrance
• The electrophile can only approach from one face
Advanced organic
3
Diastereoselective functionalisation
Li
O O O O
Br
Me
LDA Me
N O
N O
H
Ph
Ph
96% de
H O
Na
O O O O N O O
Me NaN(SiMe ) Ph SO Ph Me
3 2 Me 2
N O N O
N O
HO H
Ph Ph
Ph i-Pr i-Pr
>90% de
K
O O SO N O O
KN(SiMe ) 2 3
3 2
Me
KHMDS Me i-Pr
N O
N O
N H
3
Ph
Ph
>90% de
• A range of electrophiles can be used with predictable selectivity
Advanced organic
4
Removal of the auxiliary
O
LiOOH Me
OH
Ph
O O O
O
Me
N O LiOBn Me Bn HN O
O +
Ph
Me Me
Ph
Me Me
H H
LiAlH Me
4
OH
Ph
• For an auxiliary to be of any use in synthesis it must be readily removed
• Oxazolidinones are easily converted to carboxylic acids, esters and alcohols
Advanced organic
5
α-Substitution of prochiral aldehydes & ketones
H H
N N
NH2 OMe OMe NH2
SAMP RAMP
• A simple auxiliary for the reaction of the enolates of ketones & aldehydes is Ender’s
hydrazones, SAMP & RAMP
• A rigid enolate-like structure allows highly diastereoselective reactions
• Hydrolysis is not always possible & the auxiliary must be removed via ozonolysis
OMe
OMe
O H N Li
LDA N Ni-Pr
+ N 2
N
Me Me N
Me H
NH2 OMe Me Me
Me
Pr–Br
H O+ OMe
3 OMe
O or
N N Li
O
Me Pr 3 N N Br
Me Pr Me Pr
Me
Me Me
Advanced organic
6
Chiral auxiliaries & the aldol reaction
Bu Bu
O O O PhBu Bu
B
O O B Me Me
Me Bu2BOTf H O O
N O i-PrNEt2 Me Ph H
N O Me
N
Me
O
Me
Me
O
Me
Bu Bu
OH O O Me Me
O O O O
B B
Ph Ph
Ph N O
H Bu Me H Bu Me
Me
H N H N
Me O O
Me Me
Me
O O
500:1
(opposite syn isomer) Bu
Me
disfavoured
O O
B
Ph
Me Bu H
N H
O
Me
O
• Initially, boron-enolate formation gives the chelate
• This must be broken for the boron to chelate the aldehyde, a requirement of the aldol
• The auxiliary then rotates to minimise steric and electronic repulsions
• Aldehyde approaches from the opposite face to auxiliary
Advanced organic
7
Reversal of diastereoselectivity
Bu Bu
Bu Bu
B OH O O
B O
O O O
RCHO R
Me Et2AlCl Me R N O
N O
N O
Me
O H
H
Me
H
Me Me
Me
Me Et2AlCl Me
• The reaction can be made to favour anti diastereoisomer by forcing it to proceed via
an ‘open’ transition state
• The aluminium Lewis acid preferentially coordinates to the aldehyde instead of the
boron
Advanced organic
8
Chiral reagents in the aldol reaction
OH O
(–)-Ipc BOTf
2 Ipc B
O i-Pr2NEt 2 O RCHO Me
Me Me R
Me Me
Me
(cid:15495) (cid:15495)
Me Me
Me Me
Me Me
Me H
B
O
H O
Me B Me H
Me O OH
H
Me O Me R
2 R Me
Me
Me
• Hopefully it is becoming clear that the use of chiral reagents is more efficient
• In this reaction, the standard pinene derivative is being utilised
• The transition state is analogous to that of Brown allylation
• Interaction between the enolate and the methyl group of the Ipc moiety is minimised
Advanced organic
9
Chiral reagents in the aldol reaction II
R* BBr O
2
i-Pr NEt OH O
2
O OBR*
CH Cl 2 Ph H
2 2
Me Me Ph SPh
SPh SPh
Me
97% ee
96% de
Ph Ph
F C O O CF
3 3
N N
S S
R* BBr = B
2
O O
Br
F C CF
3 3
• Once again, the geometry of the enolate is important - it controls relative
stereochemistry
• Use of the thio-ester results in the cis-enolate and thus the syn aldol
• Alternatively, use of the ester & a change of solvent gives the trans-enolate & anti
product
O
R* BBr
2
OBR* OH O
Et N 2
O 3
Tol / hex Ph H
Me Ot-Bu Ph Ot-Bu
Ot-Bu
Me Me
94% ee
96% de
Advanced organic
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Chiral catalysis and the aldol reaction
O
SiMe
3 O O OH
O cat. (20%) O
+ N
N B
R1 H R2 R1 R2 H Ts
86-93% ee Bu
Lewis acid derived
from tryptophan
• The Mukaiyama aldol reaction is the reaction of silyl enol ethers with aldehydes
• The reaction can be catalysed by chiral Lewis acids
• The above example shows the use of a boron derivative of tryptophan
• The example below utilises a bis(oxazoline) ligand; these amino acid derived
ligands are extremely versatile ligands for enantioselective synthesis (note they are
symmetric but chiral)
• The regioselectivity probably results from attack at the least hindered carbonyl
Me Me
SiMe O O
O 3 O O Me OH
Et cat. (10%) Et N N
+
Me t-BuS Cu
t-BuS
t-Bu L L t-Bu
O Me O
Me
regioselectivity 98:2 L = CF SO
3 2
97% ee
amino acid / alcohol
86% de
derivative
Advanced organic