有机合成化学第二章
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Synthetic Organic Chemistry
合成化学
Lecture 02 Enolate Chemistry: Aldol and Related Reactions Dr. Shouyun Yu 俞寿云 副教授
1
Reading Assignment
Trost, B. M.; Brindle, C. S. Chem. Soc. Rev. 2010, 39, 1600. Geary, L. M.; Hultin, P. G. Tetrahedron Asymm. 2009, 20, 131. Guillena, G.; Najera, C.; Ramon, D. J. Tetrahedron Asymm. 2007, 18, 2249. Schetter, B.; Mahrwald, R. Angew. Chem. Int. Ed. 2006, 45, 7506. Cordova, A et al, Chem. Eur. J. 2006, 12, 5383. Palomo, C.; Oiarbide, M.; Garcia, J. M. Chem. Soc. Rev. 2004, 33, 65. Notz, W.; Tanaka, F.; Barbas, C. F. Acc. Chem. Res. 2004, 37, 580. Mahrwald, R. Curr. Org. Chem. 2003, 7, 1713. Alcaide, B.; Almendros, P. Eur. J. Org. Chem. 2002, 1595. Machajewski, T. D.; Wong, C. H. Angew. Chem. Int. Ed. 2000, 39, 1352. Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325. Denmark, S. E.; Stavenger, R. A. Acc. Chem. Res. 2000, 33, 432.
2
Classification of Organic Reactions
■ Ionic
Ions or electrons moving in pairs
■ Pericyclic
Cyclic transition structures Concerted bond forming/breaking (not always synchronous) Single step with no intermediate
A solution to polyketides —— Aldol Condensation
6
Aldol Condensation
The Aldol condensation is the coupling of an enolate ion with a carbonyl compound to form a -hydroxycarbonyl, and sometimes, followed by dehydration to give a conjugated enone. A simple case is addition of an enolate to an aldehyde to afford an alcohol, thus the name aldol.
27
E- or Z- Boron Enolates
♣ The joint power of dialkyl boron triflates bearing small alkyl ligands (such as n-butyl) and sterically emanding amine bases (such as i-Pr2NEt) provides Z-enolates
28
Explanation of Diastereoselectivity
Z-boron enolate leads to syn-aldol adduct
29
Explanation of Diastereoselectivity
E-boron enolate leads to anti-aldol adduct
■ Radical
Correlated movement of single electrons
3
Ionic Organic Reactions
4
Reaction with Carbonyl Group
Nucleophilic addition of aldehydes or ketones
26
Explanation of Diastereoselectivity
Configuration of enolate controls the diastereoselectivity: E-enolate leads to anti-aldol adduct.
Zimmerman–Traxler transition state models
25
Explanation of Diastereoselectivity
Configuration of enolate controls the diastereoselectivity : Z-enolate leads to syn-aldol adduct.
Zimmerman–Traxler transition state models
21
Why Hindered Base
22
Regioselectivity
23
E- or Z- Lithium Enolates
Z-enolate: Bulky substrate and base, chelating additive (HMPA) E-enolate: Less hindered substate and base, polar R’
16
Formation of EnoБайду номын сангаасates
17
Formation of Enolates
18
Formation of Enolates
pKa for active methylene compounds
19
Formation of Enolates
20
Popular Strong Bases
Nucleophiles Hydride Organometallic species Enolates Electron-deficient alkenes Nitro alkane Allyl silane
Reactions Reduction 1,2-addition Aldol Baylis-Hillman Henry Sakurai
the Chemists’ Solutions
15
Selectivity of Aldol
D. Seebach
@ ETH
T. Mukaiyama 向山 光昭
D. A. Evans
@ Harvard
G. Stork
@ Columbia
Preformed enolates: a solution to chemo- and regioselectivity
♣ The use of dialkyl boron chloride reactants with large ligands (such as a cyclohexyl ring) in combination with small bases (such as Et3N) affords E-enolates
Although the Aldol reaction that Wurtz discovered in 1872 has C. A. Wurtz become a staple in organic synthesis. Alexander P. Borodin is (1817−1884) also credited with the discovery of the Aldol reaction together with Wurtz. In 1872 he announced to the Russian Chemical Society the discovery of a new byproduct in aldehyde reactions with properties like that of an alcohol, and he noted similarities with compounds already discussed in publications by Wurtz from the same year.
5
Structurally Diverse Polyketides
Erythromycin, with all our advantages, looks at present hopelessly complex, particularly in view of its plethora of asymmetric centers. by R B Woodward (1954)
Wurts Coupling
8
Enols and Enolates
9
General Mechanism
The enol pathway
The enolate pathway
10
Classic Examples
11
Modern Examples
12
Selectivity of Aldol: the Challenge
Geometry of lithium enolate depends on the structure of base and substrate.
24
Diastereoselectivity of Aldol
Z-enolate leads to syn-aldol adduct
E-enolate leads to anti-aldol adduct
Wurtz, C. A. Bull. Soc. Chim. Fr. 1872, 17, 436−442.
7
About Wurts
Charles Adolphe Wurtz (1817−1884) was born in Strasbourg, France. After his doctoral training, he spent a year under Liebig in 1843. In 1874, Wurtz became the Chair of Organic Chemistry at the Sorbonne, where he educated many illustrious chemists such as Crafts, Fittig, Friedel, and van’t Hoff.
13
Selectivity of Aldol
The nature’s solution: the enzyme
14
Selectivity of Aldol
■ Preformed enolates: a solution to chemo- and regioselectivity ♣ Lithium enolates ♣ Boron enolates ♣ Enol silanes ■ Substrate control: a solution to Diastereoselectivity ♣ Geometry of enolates control syn/anti selectivity ♣ Chiral enolates or/and chiral aldehydes control face selectivity (1,2-asymmetric induction or chiral auxiliary) ■ Asymmetric catalysis: a solution to enantioselectivity ♣ Biocatalysis ♣ Transition metal catalysis ♣ Organocatalysis
合成化学
Lecture 02 Enolate Chemistry: Aldol and Related Reactions Dr. Shouyun Yu 俞寿云 副教授
1
Reading Assignment
Trost, B. M.; Brindle, C. S. Chem. Soc. Rev. 2010, 39, 1600. Geary, L. M.; Hultin, P. G. Tetrahedron Asymm. 2009, 20, 131. Guillena, G.; Najera, C.; Ramon, D. J. Tetrahedron Asymm. 2007, 18, 2249. Schetter, B.; Mahrwald, R. Angew. Chem. Int. Ed. 2006, 45, 7506. Cordova, A et al, Chem. Eur. J. 2006, 12, 5383. Palomo, C.; Oiarbide, M.; Garcia, J. M. Chem. Soc. Rev. 2004, 33, 65. Notz, W.; Tanaka, F.; Barbas, C. F. Acc. Chem. Res. 2004, 37, 580. Mahrwald, R. Curr. Org. Chem. 2003, 7, 1713. Alcaide, B.; Almendros, P. Eur. J. Org. Chem. 2002, 1595. Machajewski, T. D.; Wong, C. H. Angew. Chem. Int. Ed. 2000, 39, 1352. Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325. Denmark, S. E.; Stavenger, R. A. Acc. Chem. Res. 2000, 33, 432.
2
Classification of Organic Reactions
■ Ionic
Ions or electrons moving in pairs
■ Pericyclic
Cyclic transition structures Concerted bond forming/breaking (not always synchronous) Single step with no intermediate
A solution to polyketides —— Aldol Condensation
6
Aldol Condensation
The Aldol condensation is the coupling of an enolate ion with a carbonyl compound to form a -hydroxycarbonyl, and sometimes, followed by dehydration to give a conjugated enone. A simple case is addition of an enolate to an aldehyde to afford an alcohol, thus the name aldol.
27
E- or Z- Boron Enolates
♣ The joint power of dialkyl boron triflates bearing small alkyl ligands (such as n-butyl) and sterically emanding amine bases (such as i-Pr2NEt) provides Z-enolates
28
Explanation of Diastereoselectivity
Z-boron enolate leads to syn-aldol adduct
29
Explanation of Diastereoselectivity
E-boron enolate leads to anti-aldol adduct
■ Radical
Correlated movement of single electrons
3
Ionic Organic Reactions
4
Reaction with Carbonyl Group
Nucleophilic addition of aldehydes or ketones
26
Explanation of Diastereoselectivity
Configuration of enolate controls the diastereoselectivity: E-enolate leads to anti-aldol adduct.
Zimmerman–Traxler transition state models
25
Explanation of Diastereoselectivity
Configuration of enolate controls the diastereoselectivity : Z-enolate leads to syn-aldol adduct.
Zimmerman–Traxler transition state models
21
Why Hindered Base
22
Regioselectivity
23
E- or Z- Lithium Enolates
Z-enolate: Bulky substrate and base, chelating additive (HMPA) E-enolate: Less hindered substate and base, polar R’
16
Formation of EnoБайду номын сангаасates
17
Formation of Enolates
18
Formation of Enolates
pKa for active methylene compounds
19
Formation of Enolates
20
Popular Strong Bases
Nucleophiles Hydride Organometallic species Enolates Electron-deficient alkenes Nitro alkane Allyl silane
Reactions Reduction 1,2-addition Aldol Baylis-Hillman Henry Sakurai
the Chemists’ Solutions
15
Selectivity of Aldol
D. Seebach
@ ETH
T. Mukaiyama 向山 光昭
D. A. Evans
@ Harvard
G. Stork
@ Columbia
Preformed enolates: a solution to chemo- and regioselectivity
♣ The use of dialkyl boron chloride reactants with large ligands (such as a cyclohexyl ring) in combination with small bases (such as Et3N) affords E-enolates
Although the Aldol reaction that Wurtz discovered in 1872 has C. A. Wurtz become a staple in organic synthesis. Alexander P. Borodin is (1817−1884) also credited with the discovery of the Aldol reaction together with Wurtz. In 1872 he announced to the Russian Chemical Society the discovery of a new byproduct in aldehyde reactions with properties like that of an alcohol, and he noted similarities with compounds already discussed in publications by Wurtz from the same year.
5
Structurally Diverse Polyketides
Erythromycin, with all our advantages, looks at present hopelessly complex, particularly in view of its plethora of asymmetric centers. by R B Woodward (1954)
Wurts Coupling
8
Enols and Enolates
9
General Mechanism
The enol pathway
The enolate pathway
10
Classic Examples
11
Modern Examples
12
Selectivity of Aldol: the Challenge
Geometry of lithium enolate depends on the structure of base and substrate.
24
Diastereoselectivity of Aldol
Z-enolate leads to syn-aldol adduct
E-enolate leads to anti-aldol adduct
Wurtz, C. A. Bull. Soc. Chim. Fr. 1872, 17, 436−442.
7
About Wurts
Charles Adolphe Wurtz (1817−1884) was born in Strasbourg, France. After his doctoral training, he spent a year under Liebig in 1843. In 1874, Wurtz became the Chair of Organic Chemistry at the Sorbonne, where he educated many illustrious chemists such as Crafts, Fittig, Friedel, and van’t Hoff.
13
Selectivity of Aldol
The nature’s solution: the enzyme
14
Selectivity of Aldol
■ Preformed enolates: a solution to chemo- and regioselectivity ♣ Lithium enolates ♣ Boron enolates ♣ Enol silanes ■ Substrate control: a solution to Diastereoselectivity ♣ Geometry of enolates control syn/anti selectivity ♣ Chiral enolates or/and chiral aldehydes control face selectivity (1,2-asymmetric induction or chiral auxiliary) ■ Asymmetric catalysis: a solution to enantioselectivity ♣ Biocatalysis ♣ Transition metal catalysis ♣ Organocatalysis