stereoselective reactions of enolates: auxiliariesgjrowlan/stereo2/lecture8.pdfchiral auxiliaries,...
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123.702 Organic Chemistry
ON
O
MeMe
MeOLi
LDA
LDA ON
O
MeMe
O
Me
Li
1. n-BuLi2. EtCOCl
ON
O
MeMe
MeO
ON
O
MeMe
O
Me
OHN
O
MeMe
valine derivative
Stereoselective reactions of enolates: auxiliaries• 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
123.702 Organic Chemistry
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
123.702 Organic Chemistry
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
3
iso-propyl group blocks bottom face
123.702 Organic Chemistry
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
4
KN(SiMe3)2KHMDS
ON
O
Ph
MeO
KSO2N3
i-Pr
i-Pr
i-Pr
ON
O
Ph
MeO
HN3
>90% de
123.702 Organic Chemistry
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
5
ON
O
MeMe
MeO
Ph
OHMe
O
Ph
OMe
O
Ph
Bn
OHMe
Ph
OHN
O
MeMe
+
LiOOH
LiOBn
LiAlH4H H
123.702 Organic Chemistry
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
6
NNH2
H
OMeSAMP
NNH2
H
OMeRAMP
H3O+orO3Me Pr
O
Me
123.702 Organic Chemistry
BnOH
O
H
1. LiBH42. DMSO, (COCl)2, Et3N
96% (2 steps)C31
ON
O
MeMe
BnOO
ON
O
i-Pr
BnOO
H
I
NaHMDS, THF, –78°C
81%96%de
C31
Chiral auxiliaries in total synthesis
• Bistramide A was isolated from the marine ascidian (sea squirt) Lissoclinum bistratum and has profound effects on cell cycle regulation & sodium channels
• It has potential in the treatment of slowly evolving tumours• Auxiliary used to control C31 stereocentre• M. T. Crimmins & A. C. DeBaille, J. Am. Chem. Soc. 2006, 128, 4936
7
NH
HN
OO
MeMeMe
OH
H
Me
HO
Me
OHOMe
OMe
HH
O
bistramide A
C31
123.702 Organic Chemistry
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
8
B
Bu
O OMe
NH
Ph
Bu
H
O
OMe
Me
disfavoured
123.702 Organic Chemistry
ON
O
MeMe
MeO
BBu Bu
H
Me
H
N
O
O H
R
Et2AlCl
O
O
MeMe
ON
O
MeMe
O
R
OH
Me
RCHOEt2AlCl
BBu Bu
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
9
123.702 Organic Chemistry
Chiral auxiliaries, the aldol reaction & total synthesis
• Cytovaricin is an antineoplastic (anti-tumour) antibiotic isolated from Streptomyces diastatochromogenes
• Chiral auxiliaries used to set a number of stereocentres
• D. A. Evans, S. W. Kaldor, T. K. Jones, J. Clardy, Stout, T. J. J. Am. Chem. Soc. 1990, 112, 7001
10
ONO
O
MeO
Ph Me
MeO
N
O
MeO
Me
OH
O
Me
Ph
OB
NH
Me
H
O
O
Ph
Bu
Bu
Me
Me
1. Bu2BOTf, Et3N2.
92%100%de
C28
C29C30
OH
OH
MeH
O
OMeOH H
H
Me
HMe
H
OMe
OH
MeOH
HO
O O
OH
MeOH
H
MeOH
H
MeO
O
cytovaricin
C29
C30
C21
C19
C17
NO
OMe
O
Ph Me
1. Bu2BOTf, Et3N2.
N
O
OPMB
O
Me
OH
O
Me
PhC21 C19
C17
O
OPMB
87%100%de
123.702 Organic Chemistry
OMe
O
chiral≥95%ee
OH
Et
OMe
OEt
chiral
LDA
OMe
OEt
prochiral
Li
O
Me Me
S N
OO
Cl
Cl
Chiral reagents and enolate chemistry
• A number of forms of chiral reagent in enolate chemistry...chiral electrophiles (as shown above)chiral enolates (effectively a very short lived chiral auxiliary - shown next slide)chiral bases for the selective formation of chiral enolates
11
123.702 Organic Chemistry
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
12
Me
Me
B
2
Me
OMe
Me≡ ≡
123.702 Organic Chemistry
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
13
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
123.702 Organic Chemistry
CHiral reagents and total synthesis
• (–)-Laulimalide is an antimitotic (prevents mitosis - cancer chemotherapy) isolated from the Pacific sponges Hyatella sp. and Spongia mycofijiensis and the Okinawan sponge Fasciospongia rimosa
• I. Paterson, C. De Savi, M. Tudge Org. Lett. 2001, 3, 3149
14
O
OB[(+)-Ipc]2
CO2MeHHMe H O
O
HOTBS
OPMB
MeO
OHCO2MeOPMB
O
Me
HOTBS
HHMe
O
86%62%de
+
O
OH O O
O
Me
HOH
HHMe
O
(–)-laulimalide(fijianolide B)
Fasciospongia rimosa
123.702 Organic Chemistry
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
15
NCu
N
OO
t-Bu t-BuL L
L = CF3SO2amino acid / alcohol
derivative
MeMe
t-BuS
OSiMe3
+ Me
Ocat. (10%)
t-BuS
O
regioselectivity 98:297% ee86% de
Me
Et
O Me
OHMeEt
O
N BO
NH
O
BuTs
Lewis acid derived from tryptophan
HNH
NO B Ts
OO
R
H
Bu
Re
Si
Nuc
Si face blocked
R1
OSiMe3
+H R2
O cat. (20%)
R1 R2
O OH
86-93% ee
123.702 Organic Chemistry
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
16
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
123.702 Organic Chemistry
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)
17
acid aids enamine formation
acid activates aldehyde
acid positions aldehyde
123.702 Organic Chemistry
O
Me
OMesNH
CO2H
D-proline(0.4eq)PhN=O
O
Me
OMes
OPhHN
Me
OMes
HO
CO2Me
56%O2CO
NH
N
RPh
Organocatalysts in total synthesis
• Extracts of Verbena littoralis have interesting activity as enhancers for the neurotrophic properties of nerve growth factor (NGF) and contain the compound (–)-brasoside
• I. K. Mangion and D. W. C. MacMillan J. Am. Chem. Soc. 2005, 127, 3696
18
H
O
OBnH
O
OBn
+NH
CO2H
78%98%ee
H
O
OBn
OHOBn
O OBnOBnTMSO
ROOBn
OH
H
Me O O OHOH
OHHO
OO
(–)-brasoside