1 d. a. evans’ asymmetric synthesis — from 80’s chiral auxiliary to 90’s copper complexes...
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1
D. A. Evans’ Asymmetric Synthesis
— From 80’s Chiral Auxiliary to 90’s Copper Complexes and Their Applications in Total Synthesis
Supervisor: Professor Yang Zhen Chen Jiahua
Reporter: Lin Guang
2
Introduction
CV of David A. EvansDavid A. Evans was born in Washington D.C, He received his A.B. degree from Oberlin College in 1963. He obtained Ph.D. at the California Institute of Technology in 1967, where he worked under the direction of Professor Robert E. Ireland. In that year he joined the faculty at the University of California, Los Angeles. In 1973 he was promoted to the rank of Full Professor and shortly there after returned to Caltech where he remained until 1983. He then joined the Faculty at Harvard University and in 1990 he was appointed as the Abbott and James Lawrence Professor ofChemistry.
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Part 1: Enantioselective reactions using chiral auxiliary
Part 2: Catalysis of enantioselective reactions using chiral copper complexes
Part 3: The application of Evans’ asymmetric methodologies in his total syntheses
Outline
4
Part 1:Enantioselective Reactions Induced by Chiral Auxiliary
The Optimization of the Chiral Imide Auxiliary
Asymmetric Aldol Reaction
Asymmetric Alkylation
Asymmetric Diels-Alder Reaction
Initial reports of asymmetric induction from chiral imides
5
Initial Reports of Asymmetric Induction from Chiral Imides
6
The Optimization of the Chiral Imide Auxiliary
Stereoselective Aldol Condensation via Boron Enolates (1979)Stereoselective Aldol Condensation via Boron Enolates (1979)
Stereoselective Aldol Condensation via Stereoselective Aldol Condensation via ZZirconium Enolates (1980)irconium Enolates (1980)
O
MO
L
L
R1
R2
H3C
Why boron? M = Li, MgL, ZnL, AIL2 Metal-oxygen bond lengths: (1.9-2.2Å ) M-L bond lengths: ( 2-2.2Å ) M = BR2
Metal-oxygen bond lengths:(1.36-1.47Å) M-L bond lengths:(1.5-1.6Å)
Result: the boron enolates are superior to the corresponding lithium enolates in stereoselective bond construction.
Zr OEN
Cl
O
H R
1. From Li to Zr the loss of enolate geometry was not significant2. Product selective aldol condensations independent of enolate geometry3. Pseudo-boat VS pseudo-chair
D. A. Evans et al, J. Am. Chem. Soc., 1979,101,6120D. A. Evans et al, Tetrahedron Lett., 1980, 21,7975
7
Transition states and relative products:
O
MO
L
L
R1R2
H3C
H
O
MO
L
L
R1R2
CH3H
O
MO
L
L
R1
R2
H3C
H
O
MO
L
L
R1
R2CH3
H
R2CHO
O
R1
H
H3C
M
R2CHO
O
R1
H
H3C
M
R1 R2
O OH
±
R1 R2
O OH
±
syn
anti
Favor
Favor
The Optimization of the Chiral Imide Auxiliary
D. A. Evans et al, J. Am. Chem. Soc., 1979, 101, 6120
8
Approach to enatioselective alkylation via initial chiral auxiliary (1980)Approach to enatioselective alkylation via initial chiral auxiliary (1980)
R1N
O OH
R1N
O OHLi
H
R1N
O OR2
R1N
O OR2
E
E
R2=Li
R2=alkyl
R2=Li Major product is 3; 3:4 high selective ratioR2=alkyl Major product is 4;
4:3 moderate selective ratio
R1N
O OR2
E
R1
O
E H2N
O
R1OH
O
E
H3O
Easy to Easy to hydrolysishydrolysis
The Optimization of the Chiral Imide Auxiliary
D. A. Evans et al, Tetrahedron Letters, 1980, 31, 7975
3
4
9
Approach to enatioselective aldol condensation via initial chiral auxiliary (1980)Approach to enatioselective aldol condensation via initial chiral auxiliary (1980)
RL R1
O
RSH
RL R1
OM
RSH
RL
R1
O
RSH
R2
OH
Seebach: M=Li, RL=Et, RS=Me, R1=H (1976)Heathcock: M=Li, RL=t-Bu, RS=OSiMe3, R1=Me (1979) Evans: M=B, RL=Et, Rs=Me, R1=H or Me (1980)
N R1
OMTsH
N R1
OTsH
R2CHON
R1
OTsH
R2
OHN
R1
OTsH
R2
OH
HO
R1
O
R2
OH
M=BBu2; R1=Me or H;R2=Ph or i-Pr,
O
BO
Bu
BuR2
HRL
Rs
R1
O
BO
Bu
Bu
R1
RS
H
RL
R2
R1
O
R2
OH
RL(R)
RSH R1
O
R2
OH
RL(R)
RSH
The Optimization of the Chiral Imide Auxiliary
D.A Evans et al, Tetrahedron Lett., 1980, 21, 4675
10
The completion of the Evans’ auxiliary (1981)The completion of the Evans’ auxiliary (1981)
D. A. Evans et al, Pure and Applied Chemistry, 1981,53,1109
NO
O
NO
O
Ph
O
BO
L
L
CH3
N
R
O
OR2
O
BO
L
L
H3C
N
R
O
O
R2
B
OO
N
O
O
R2
L
L
RCH3
B
OO
N
L
L
RCH3
O
R2
N
O
N
OO
R
OH
R
OH
O
R2
R2
The Optimization of the Chiral Imide Auxiliary
N O
O
R1
O
N O
O
R1
O
N O
O
R1
O
N
O
R1O
N O
O
R1
O
O
N
O
R1O
O
BB
BBO O
OO
B
L
L
L
L
L
L
L
L
LL
R2
H
R2
H
R2 R2
L2BOTf
EtN(i-Pr)2
-78°C
R2CHO
-face -faceA B
DC
11
NO
O
R
Ph
NO
O
R
1 2
O
N
O
R1
OH
O
O
N
O
R1
OH
O
Ph
O
R1
OH O
R1
OH
MeO MeO
MeOH/ MeO-MeOH/ MeO-3 4
5b 6b
Asymmetric Aldol Reaction
D. A. Evans et al, J. Am. Chem. Soc., 1981,103, 8
Metal=B(Bu)2
a, R=H b, R=C(O)Etc, R=C(O)Me d, R=C(O)CH2SMe
12D. A. Evans et al, J. Am. Chem. Soc., 1990, 112, 866
Asymmetric Aldol Reaction
N
OO O
Me
Me
Bn
Sn(OTf)2
TiCl4
Et3N
i-PrNEt
N
OO O
Me MeBn
N
OO O
Me MeBn
R
R
OH
OH
O
TiO
OHMe
ClCl
Cl
Me
H
Xp
Sn
OO
R
H
Me
H
Xp
OHMe
L
L
N
OO O
Me MeBn
R
OH
N
OO O
Me MeBn
R
OH
Anti-Syn
Syn-Syn
Sn(II) Aldol and Ti(IV) AldolSn(II) Aldol and Ti(IV) Aldol
13
Asymmetric Aldol Reaction
D. A. Evans et al, J. Am. Chem. Soc., 2002, 124, 392
14
Asymmetric Aldol Reaction
15
Asymmetric Aldol Reaction
D.A. Evans et al, Org. Lett., 2002, 4, 1127
16
Asymmetric Alkylation
NOR
OO
NOR
OO
Ph
NOR
OO
Ph
E
NOR
OO
E
Major
Major
Minor
NOR
OO
NOR
OOM
D. A. Evans et al, J. Am. Chem. Soc., 1982, 104, 1737
17
Asymmetric Diels-Alder Reaction
O
N
OAl
O
R
RH
Me
Ca-si Face
Ca-re Face
R2AlHCl2
Endo Ca-Si FaceMe
COXv
COXv
Me
COOH
Me
LiOBnH2 Pd/C
N O
O O
N O
O O
R2
Major
Major
Minor
Ph
R1
R1
COX
R1
COX
R1
D. A. Evans et al, J. Am. Chem. Soc., 1984, 106, 4261
D. A. Evans et al, J. Am. Chem. Soc., 1988, 110, 1238
18
Conclusion of Part 1
The gradual approach to the enantioselectivity
The variety of aldol reactions
Applications in other reactions such as alkylation and D-A reaction
Transition states
19
Enantioselective Cycloaddition
Enantioselective Aldol
Enantioselective Michael Addition
Enantioselective Carbonyl Ene Reactions
Part 2: Catalysis of Enantioselective Reactions Using Chiral Copper Complexes
20
N
O
N
O
R R
N
O
N
O
R R
N
O
N
O
R R
N
O
N
O
R R
N
Metal center: Cu, Mg, Zn, Sc, Ni……
Why copper?Why copper?1.Cu(II) forms the most stable ligand-metal complexes (Mn < Fe < Co <Ni < Cu > Zn)2.The exchange rate is greater than those of other first row divalent transition metalSome Bis(oxazo1ines) Ligands
D.A.Evans et al, Acc. Chem. Res. 2000, 33, 325
Basic Knowledge
21
A, R=Ph B, R=α-NpC, R=CHMe2 D, R=CMe3
D R=CMe3 is the best: 1. endo:exo=98:2 2. Endo e.e.>98%
Enantioselective Cycloaddition
N
O
N
O
R R
CuOTf22OTf-
N
O
N
O
R R
O
N
OO
Cu
2
N
O
N
O
CMe3 CMe3Cu
2
2X-
O
N
OO
-78oC
1%mol 1N
OO
OH
X=SbF6, PF6 , BF4 , OTf--
X=SbF6 is the best
Diels-Alder Reactions
Cu: Square-planarZn & Mg: Tetrahedral
D. A. Evans et al, J. Am. Chem. Soc., 1999, 121, 7559
22
Enantioselective Cycloaddition
Hetero Diels-Alder Reactions
D.A. Evans et al, J. Am. Chem. Soc., 2000, 122, 1635D.A. Evans et al, J. Am. Chem. Soc., 1998, 120, 4895
23
Ene Reactions of Glyoxylate Esters
Enantioselective Carbonyl Ene Reactions
N
O
N
O
Me3C CMe3
Cu
2
2OT f
1a
Low catalyst loading (0.2-10 mol %)
Moderate temperatures (0-25 )℃
Practical utility:
Commercially available undistilled glyoxylate
D.A. Evans et al, J. Am. Chem. Soc., 2000, 122, 7936
24
Ene Reaction of Pyruvate Esters
N
O
N
O
Me3C CMe3
Cu
2
2OT f
a
Enantioselective Carbonyl Ene Reactions
D.A. Evans et al, J. Am. Chem. Soc., 2000, 122, 7936
25
Enantioselective Aldol Reactions
Some incorporate additional stabilizing interactions: hydrogen, bonding, chelation
D.A. Evans, et al, J. Am. Chem. Soc., 1999, 121, 669
26
Enantioselective Aldol Reactions
D. A. Evans et al, J. Am. Chem. Soc., 1999, 121, 686
27
Alkylidene Malonates
D. A. Evans et al, J. Am. Chem. Soc., 2001, 123, 4480
Enantioselective Michael Addition
28
Enantioselective Michael Addition
D.A. Evans et al, J. Am. Chem. Soc., 2001, 123, 4480
Alkylidene Malonates
29David A. Evans et al, Org. Lett., 1999, 1, 865
Enantioselective Michael Addition
Fumaroyl Oxazolidinone
30
Conclusion of Part 2
The character and advantage of catalytic reactions
The character of these Cu(II) complexes
Different reactions catalyzed by Cu(II) complexes
31
Part 3:The applications of Evans’ asymmetric methodologies in his total synthesis
6-Deoxyerythronolide B (1998)
Cytovaricin (1990)
Callipeltoside A (2002)
Oasomycin A (2006)
32
OO
OH
O
H
Me
OH
Me
O
Me
OH
H
OHHO
O
Me
OH
OH
Me
H
H
MeH
O
H
Me
H
OH
HH
OOH
OH
HMe
OH
Me
H
H
MeH
HO
OH
CHO
OH
Me
Me OH
HO
O
MeHO
OH
O
H
Me
H
OH
HHO2SPh
+
14
1
4
16 17
2417
4
8
14
A B
Me
OH
HOOC
Cytovaricin (1990)
D.A. Evans et al, J. Am. Chem. Soc., 1990, 112, 7001
33
Me
OPMB OTES
Me
O NHNMe2
Me
O O
OPMB OH
Me
O
MeMe
O
Me
O O
X
N
OMe
O
O
Ph +O
OH
OH
H
Me
H
MeH
HO
OH
CHO
2417
A
1
2
3
4
H
Me
OH
Cytovaricin (1990)
D.A. Evans et al, J. Am. Chem. Soc., 1990, 112, 7001
34
OH
Me
X
Me OH
HO
O
MeHO
OH
O
H
Me
H
OH
HH
PhSO2
H
4
8
14
MeO
SiO
OH
t-Bu
t-BuMe
O NOPMB
OO
Ph
12
+
MeO
SiO
OH
t-Bu
t-BuMe
PMBO
OXN
MeO
SiO
OH
t-Bu
t-BuMe
PMBO
OXN
A B
Cytovaricin (1990)
D.A. Evans et al, J. Am. Chem. Soc., 1990, 112, 7001
35
6-Deoxyerythronolide B (1998)
OMe
Me
Me
O
OO
Et
Me
Me
O
R
Me
OH
O
O
HOH
NMe2
Me
OH
Me
MeOMe
Erythromycins A R=OHErythromycins B R=H
D.A. Evans et al, J. Am. Chem. Soc., 1990, 112, 7001
36
Et
Me
O
Me
O
Me Me
O
Me
O
Me
OTBSOH
O N
OO O O O
H
Bn
Me Me
EtMe
Me
OPMB
Me
OTBSOTMS
O N
OO
Ph
O
MeMe
Ti Evans aldol
O N
OO
Ph
O
MeMe
Sn Evans aldol
A
B
A+B
Deoxyerythronolide B
Mukaiyama aldol
Xp
O
MeOPh
Et
Me
O
Me
O
Me Me
O
Me
O
Me
OTBS
Xp
O
MeOPh
6-Deoxyerythronolide B (1998)
D.A. Evans et al, J. Am. Chem. Soc., 1990, 112, 7001
37
Callipeltoside A (2002)
O
O
OHH
O
Me
Me
MeO
Me
O
Cl
O
NH
O
O
MeO
MeH O
O
OHH
Me
Me
MeO
Me
O
OPMB
OH
Me
O O
MeMe
OTBS
OPMB
O
Me Me
EtO
O
Me
O O
MeMe
OTBS
OPMB
OH
N
O
Bn
5b 6
7
D. A. Evans et al, J. Am. Chem. Soc., 2002, 124, 5654
38
EtO
OTMS Me
H
OPMB
O
+
NO
N N
O
Ph Ph
CuH2O OH2
2+
2SbF6-2
1
a, 93%, 95% e.e.EtO
Me
OH
OPMB
O
H
Me
OTBS
OPMB
O
3 4
a
R
H
Me
OTBS
OPMB
O
R
H
Me
OTBS
OPMB
O
4b S
N
Me
OO O
BnMe
5
Xp
Me
O O
MeMe
OTBS
OPMB
OH
R
Xp
Me
O O
MeMe
OTBS
OPMB
OH
S
R:Diastereselection 55:45
S:Diastereselection 92:8
4a 5a
5b
Callipeltoside A (2002)
D. A. Evans et al, J. Am. Chem. Soc., 2002, 124, 5654
39
O
OHMe
Me
HO
OH
Me
OH OH OH OH OH OH
O
OOOH
Me
OH
Me Me
MeMeOH
OH
Me
29
46
D. A. Evans et al, Angew. Chem. Int. Ed., 2007, 46, 537
Oasomycin A (2006)
40
RO
H
O OR OR OR O
O
MeMe
OR
Me29
46
38
39
RO
S
O
O
Me
4639NN
N
NH
RO
OR OR OR
MeMe
OR29 38
O
H+
O N
OO
Bn
O
MeMe HOR
O OR OR
Sn(II) Aldol
1
2 3
45
OO
D. A. Evans et al, Angew. Chem. Int. Ed., 2007, 46, 537
Oasomycin A (2006)
41
O N
OO
Bn
O
MeMe
t-Bu
OTMS OTMS
HOBn
O
1 2t-Bu
OBn
O O OH
3
NO
N N
O
Ph Ph
Cu
2+
2SbF6-
a
HOBn
O OTBS OTBS
45
+
O N
OO
Bn
O
MeMe
OBn
OH OTBS OTBS
Sn(II) Aldol
a
D. A. Evans et al, Angew. Chem. Int. Ed., 2007, 46, 537
Oasomycin A (2006)
42
Summary
NO
O
R
Ph
NO
O
R
N
O
N
O
Me3C CMe3
Cu
2
O
OHMe
Me
HO
OH
Me
OH OH OH OH OH OH
O
OOOH
Me
OH
Me Me
MeMeOH
OH
Me
46
1.Chiral auxiliary
2.Copper complexes
3. Total syntheses
The Key Point:How to How to control control
the the transition transition states!!!states!!!
43
Acknowledgement
Professor Yang Zhen and Chen Jiahua
All the members in our group
Professor Yu and Shi
All the members of IOC
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