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Formation of Enolates
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Formation of Enolates
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Formation of Enolates
pKa for active methylene compounds
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Formation of Enolates
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Popular Strong Bases
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Explanation of Diastereoselectivity
Configuration of enolate controls the diastereoselectivity : Z-enolate leads to syn-aldol adduct.
Zimmerman–Traxler transition state models
Synthetic Organic Chemistry
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Lecture 02 Enolate Chemistry: Aldol and Related Reactions Dr. Shouyun Yu 俞寿云 副教授
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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.
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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
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Explanation of Diastereoselectivity
Configuration of enolate controls the diastereoselectivity: E-enolate leads to anti-aldol adduct.
Zimmerman–Traxler transition state models
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.
A solution to polyketides —— Aldol Condensation
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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.
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Why Hindered Base
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Regioselectivity
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E- or Z- Lithium Enolates
Z-enolate: Bulky substrate and base, chelating additive (HMPA) E-enolate: Less hindered substate and base, polar R’
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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)
■ Radical
Correlated movement of single electrons
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Ionic Organic Reactions
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Reaction with Carbonyl Group
Nucleophilic addition of aldehydes or ketones
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Explanation of Diastereoselectivity
Z-boron enolate leads to syn-aldol adduct
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Explanation of Diastereoselectivity
E-boron enolate leads to anti-aldol adduct
the Chemists’ Solutions
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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
Nucleophiles Hydride Organometallic species Enolates Electron-deficient alkenes Nitro alkane Allyl silane
Reactions Reduction 1,2-addition Aldol Baylis-Hillman Henry Sakurai
Wurts Coupling
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Enols and Enolates
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General Mechanism
The enol pathway
The enolate pathway
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Classic Examples
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Modern Examples
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Selectivity of Aldol: the Challenge
♣ 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
Wurtz, C. A. Bull. Soc. Chim. Fr. 1872, 17, 436−442.
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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.