D. A. Evans’ Asymmetric Synthesis — From 80’s Chiral Auxiliary to 90’s Copper Complexes and Their Applications in Total Synthesis

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D. A. Evans Asymmetric Synthesis From 80s
Chiral Auxiliary to 90s Copper Complexes and
Their Applications in Total Synthesis

• Supervisor Professor Yang Zhen
• Chen Jiahua
• Reporter Lin Guang

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Introduction
CV of David A. Evans David 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 of Chemistry.
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Outline
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
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Part 1Enantioselective Reactions Induced by
Chiral Auxiliary

• Initial reports of asymmetric induction from
  chiral imides

• The Optimization of the Chiral Imide Auxiliary

• Asymmetric Aldol Reaction

• Asymmetric Alkylation

• Asymmetric Diels-Alder Reaction

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Initial Reports of Asymmetric Induction from
Chiral Imides
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The Optimization of the Chiral Imide Auxiliary
Stereoselective Aldol Condensation via Boron
Enolates (1979)
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.
Stereoselective Aldol Condensation via Zirconium
Enolates (1980)
1. From Li to Zr the loss of enolate geometry was
not significant 2. Product selective aldol
condensations independent of enolate
geometry 3. Pseudo-boat VS pseudo-chair
D. A. Evans et al, J. Am. Chem. Soc.,
1979,101,6120 D. A. Evans et al, Tetrahedron
Lett., 1980, 21,7975
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The Optimization of the Chiral Imide Auxiliary
Transition states and relative products
D. A. Evans et al, J. Am. Chem. Soc., 1979, 101,
6120
8
The Optimization of the Chiral Imide Auxiliary
Approach to enatioselective alkylation via
initial chiral auxiliary (1980)
3
4
R2Li Major product is 3
34 high selective ratio R2alkyl Major product
is 4 43 moderate selective
ratio
Easy to hydrolysis
D. A. Evans et al, Tetrahedron Letters, 1980, 31,
7975
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The Optimization of the Chiral Imide Auxiliary
Approach to enatioselective aldol condensation
via initial chiral auxiliary (1980)
Seebach MLi, RLEt, RSMe, R1H
(1976) Heathcock MLi, RLt-Bu, RSOSiMe3,
R1Me (1979) Evans MB, RLEt,
RsMe, R1H or Me (1980)
MBBu2 R1Me or H R2Ph or i-Pr,
D.A Evans et al, Tetrahedron Lett., 1980, 21, 4675
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The Optimization of the Chiral Imide Auxiliary
The completion of the Evans auxiliary (1981)
A
B
D
C
D. A. Evans et al, Pure and Applied Chemistry,
1981,53,1109
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Asymmetric Aldol Reaction
2
1
MetalB(Bu)2
a, RH b, RC(O)Et c, RC(O)Me
d, RC(O)CH2SMe
D. A. Evans et al, J. Am. Chem. Soc., 1981,103, 8
12
Asymmetric Aldol Reaction
Sn(II) Aldol and Ti(IV) Aldol
Anti-Syn
Syn-Syn
D. A. Evans et al, J. Am. Chem. Soc., 1990, 112,
866
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Asymmetric Aldol Reaction
D. A. Evans et al, J. Am. Chem. Soc., 2002, 124,
392
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Asymmetric Aldol Reaction
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Asymmetric Aldol Reaction
D.A. Evans et al, Org. Lett., 2002, 4, 1127
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Asymmetric Alkylation
D. A. Evans et al, J. Am. Chem. Soc., 1982, 104,
1737
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Asymmetric Diels-Alder Reaction
D. A. Evans et al, J. Am. Chem. Soc., 1984, 106,
4261
D. A. Evans et al, J. Am. Chem. Soc., 1988, 110,
1238
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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
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Part 2 Catalysis of Enantioselective Reactions
Using Chiral Copper Complexes

• Enantioselective Cycloaddition

• Enantioselective Carbonyl Ene Reactions

• Enantioselective Aldol

• Enantioselective Michael Addition

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Basic Knowledge
Metal center Cu, Mg, Zn, Sc, Ni
Why copper? 1.Cu(II) forms the most stable
ligand-metal complexes (Mn lt Fe lt Co ltNi lt Cu gt
Zn) 2.The exchange rate is greater than those of
other first row divalent transition metal
Some Bis(oxazo1ines) Ligands
D.A.Evans et al, Acc. Chem. Res. 2000, 33, 325
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Enantioselective Cycloaddition
Diels-Alder Reactions
A, RPh B, Ra-Np C, RCHMe2 D, RCMe3
D RCMe3 is the best 1. endoexo982 2. Endo
e.e.gt98
Cu Square-planar Zn Mg Tetrahedral
XSbF6 is the best
D. A. Evans et al, J. Am. Chem. Soc., 1999, 121,
7559
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Enantioselective Cycloaddition
Hetero Diels-Alder Reactions
D.A. Evans et al, J. Am. Chem. Soc., 2000, 122,
1635 D.A. Evans et al, J. Am. Chem. Soc., 1998,
120, 4895
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Enantioselective Carbonyl Ene Reactions
Ene Reactions of Glyoxylate Esters
D.A. Evans et al, J. Am. Chem. Soc., 2000, 122,
7936
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Enantioselective Carbonyl Ene Reactions
Ene Reaction of Pyruvate Esters
D.A. Evans et al, J. Am. Chem. Soc., 2000, 122,
7936
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Enantioselective Aldol Reactions
Some incorporate additional stabilizing
interactions hydrogen, bonding, chelation
D.A. Evans, et al, J. Am. Chem. Soc., 1999, 121,
669
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Enantioselective Aldol Reactions
D. A. Evans et al, J. Am. Chem. Soc., 1999, 121,
686
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Enantioselective Michael Addition
Alkylidene Malonates
D. A. Evans et al, J. Am. Chem. Soc., 2001, 123,
4480
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Enantioselective Michael Addition
Alkylidene Malonates
D.A. Evans et al, J. Am. Chem. Soc., 2001, 123,
4480
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Enantioselective Michael Addition
Fumaroyl Oxazolidinone
David A. Evans et al, Org. Lett., 1999, 1, 865
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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
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Part 3The applications of Evans asymmetric
methodologies in his total synthesis

• Cytovaricin (1990)

• 6-Deoxyerythronolide B (1998)

• Callipeltoside A (2002)

• Oasomycin A (2006)

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Cytovaricin (1990)
D.A. Evans et al, J. Am. Chem. Soc., 1990, 112,
7001
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Cytovaricin (1990)
D.A. Evans et al, J. Am. Chem. Soc., 1990, 112,
7001
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Cytovaricin (1990)
D.A. Evans et al, J. Am. Chem. Soc., 1990, 112,
7001
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6-Deoxyerythronolide B (1998)
Erythromycins A ROH Erythromycins B RH
D.A. Evans et al, J. Am. Chem. Soc., 1990, 112,
7001
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6-Deoxyerythronolide B (1998)
D.A. Evans et al, J. Am. Chem. Soc., 1990, 112,
7001
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Callipeltoside A (2002)
D. A. Evans et al, J. Am. Chem. Soc., 2002, 124,
5654
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Callipeltoside A (2002)
D. A. Evans et al, J. Am. Chem. Soc., 2002, 124,
5654
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Oasomycin A (2006)
D. A. Evans et al, Angew. Chem. Int. Ed., 2007,
46, 537
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Oasomycin A (2006)
D. A. Evans et al, Angew. Chem. Int. Ed., 2007,
46, 537
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Oasomycin A (2006)
D. A. Evans et al, Angew. Chem. Int. Ed., 2007,
46, 537
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Summary
1.Chiral auxiliary
The Key Point How to control the transition
states!!!
2.Copper complexes
3. Total syntheses
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Acknowledgement
Professor Yang Zhen and Chen Jiahua All the
members in our group Professor Yu and Shi All
the members of IOC