stereoselective reactions of enolates
TRANSCRIPT
Advanced organic
LDA ON
O
MeMe
O
Me
Li
LDA ON
O
MeMe
MeO
Li
1. n-BuLi2. EtCOCl
ON
O
MeMe
MeO
ON
O
MeMe
O
Me
OHN
O
MeMe
valine derivative
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
1
Ph OH
O
NH2
(S)-phenylalanine
reduction Ph OHNH2
(EtO)2C=OK2CO3 OHN
O
Phoxazolidinonechiral auxiliary
• Enolate formation gives the cis-enolate (remember enolisation of amides)• Two possible conformations exist - but chelation results in one being preferred
Advanced organic
Me NOO
O
MeMe
HBn
H
I
Ph
Me NOO
OLi
MeMe
H
ON
O
MeMe
MeO
Li
PhCH2I ON
O
MeMe
MeO
Ph
Diastereoselective alkylation of Evan’s enolate
• 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
2
iso-propyl group blocks bottom face
Advanced organic
NaN(SiMe3)2ON
O
Ph
MeO
NaN
O
Ph
H
SO2PhON
O
Ph
MeO
HHO
>90% de
LDAON
O
Ph
MeO
LiBr
ON
O
Ph
MeO
H
96% de
ON
O
Ph
MeO
Diastereoselective functionalisation
• A range of electrophiles can be used with predictable selectivity
3
KN(SiMe3)2KHMDS
ON
O
Ph
MeO
KSO2N3
i-Pr
i-Pr
i-Pr
ON
O
Ph
MeO
HN3
>90% de
Advanced organic
Removal of the auxiliary
• 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
4
ON
O
MeMe
MeO
Ph
OHMe
O
Ph
OMe
O
Ph
Bn
OHMe
Ph
OHN
O
MeMe
+
LiOOH
LiOBn
LiAlH4H H
Advanced organic
LDA
MeNLiOMe
NNi-Pr2
Me
H
Me PrN
N
OMe
Me
MeNLiOMe
NBr
Me
Pr
Pr–Br
+ NNH2
H
OMe Me MeN
N
OMe
Me MeO
α-Substitution of prochiral aldehydes & ketones
• 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
5
NNH2
H
OMeSAMP
NNH2
H
OMeRAMP
H3O+orO3Me Pr
O
Me
Advanced organic
ON
O
MeMe
O
Ph
OH
Me
500:1(opposite syn isomer)
B
Bu
O OMe
NH
Ph
Bu
H
O
OMe
Me
B
Bu
OOMe
N H
Ph
Bu
H
O
OMe
Me
Ph H
O
MeN
OB
OH
Ph
OO
Me MeBuBu
ON
O
MeMe
MeO
B
ON
O
MeMe
MeO
Bu2BOTfi-PrNEt2
Bu Bu
Chiral auxiliaries & the aldol reaction
• 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
6
B
Bu
O OMe
NH
Ph
Bu
H
O
OMe
Me
disfavoured
Advanced organic
Reversal of diastereoselectivity
• 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
7
ON
O
MeMe
MeO
BBu Bu
H
Me
H
N
O
O H
R
Et2AlCl
O
OB
MeMe
Bu Bu
ON
O
MeMe
O
R
OH
Me
RCHOEt2AlCl
Advanced organic
OHO
Me
H
R
H
Me
O B
O
Me
H
H
MeMe
Me
MeMe
MeR
Me
RCHO MeO
R
OH
Me
(–)-Ipc2BOTfi-Pr2NEt
Me MeO
Ipc2B
Me MeO
Chiral reagents in the aldol reaction
• 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
8
Me
Me
B
2
Me
OMe
Me≡ ≡
Advanced organic
MeOt-Bu
OR*2BBr
Et3NTol / hex
MeOt-Bu
OBR*2
Ph H
O
SPh
O
MePh
OH
97% ee96% de
MeSPh
OR*2BBri-Pr2NEtCH2Cl2
SPh
OBR*2Me
Chiral reagents in the aldol reaction II
• 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
9
R*2BBr =N
BNS
Br
S
PhPh
O
O
O
O
F3C
F3C
CF3
CF3
Ph H
O
Ot-Bu
O
MePh
OH
94% ee96% de
Advanced organic
Chiral catalysis and the aldol reaction
• 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
10
R1
OSiMe3
+H R2
O cat. (20%)
R1 R2
O OH
86-93% ee
N BO
NH
O
BuTs
Lewis acid derived from tryptophan
t-BuS
OSiMe3
+ Me
Ocat. (10%)
t-BuS
O
regioselectivity 98:297% ee86% de
Me
Et
O Me
OHMeEt
O
NCu
N
OO
t-Bu t-BuL L
L = CF3SO2amino acid / alcohol
derivative
MeMe
Advanced organic
The catalytic direct aldol reaction
• All the stereoselective aldol reactions we have looked at so far involve the preparation of activated enolate prior to reaction (metal or boron enolate or silyl enol ether)
• This adds additional steps to our methodology• More attractive is the direct aldol reaction of non-activated carbonyl groups• Above shows Trost’s bimetallic zinc catalyst for the reaction of acetone• Shibasaki has also designed a number of bifunctional catalysts for this reaction
11
Me Me
O+ H
MeO
Me
cat.(10%)ZnEt2
4Å MS5°C
MeMe
O
Me
OH
91% ee
Me Me
O NN
PhPh O
Zn Zn PhPhO
O
Me
O H
i-Pr
Me Me
O NN
PhPh O
Zn Zn PhPhO
O
Me
Et H
Me Me
O NN
PhPh O
Zn Zn PhPhOEt
cat Me Me
O NN
PhPh O
Zn Zn PhPhO
O Me
Oi-PrH
acetone coordinates to zinc -- proton transfer gives product and
generates the enolate
Advanced organic
Organocatalysis I
• Secondary amines can be utilised as catalysts in enolate-like chemistry• Initially an enamine is formed that then reacts in a diastereoselective manner• Finally, in situ hydrolysis gives the product and regenerates the catalyst
12
H
O
i-Pr
cat. (10%)+N
NN S
PhH
O
i-Pr
SBn NaBH4
OH
i-Pr
SBn
81%98% ee
PrH
O+ N
SO2PhPhO2S
F
cat. (10%) FH
O
Pr
NaBH4 FOH
Pr95%
96% ee
N
Pr
O
ArAr
SiMeMe
Me
F
NSO2Ph
PhO2S F N
Pr
O
ArAr
SiMeMe
MeNH OTMS
F3C
CF3CF3
CF3
Advanced organic
H
MeH
OHH
O
Me
Me
N
Me
O
O
H
H
O
Me
Me
H
O
Me
+H
O
Me
Me cat (10%)H Me
MeO
Me
OH
88%anti / syn 3 / 1
97% ee
NH
O
OHL-proline
Organocatalysis II
• Proline can catalyse the direct aldol reaction of simple aldehydes• Other simple amino acids can also be used in this reaction• In addition a number of derivatives have been prepared that show more ‘practical’
characteristics• Those interested in this are directed towards the work of List, Barbas III and the
excellent review of Dalko & Moisan (2004Angew5138)
13
acid aids enamine formation
acid activates aldehyde
acid positions aldehyde