Asymmetric Organocatalysis Sarah maifeld September 19, 2002
Asymmetric Organocatalysis Sarah Maifeld September 19, 2002
Approaches to Asymmetric Catalysis Organometallic catalysis Broad scope Ligand control Inert conditions Cost and toxicity Bioorganic catalysis Highly selective High rate of reaction Limited scope
Approaches to Asymmetric Catalysis • Organometallic catalysis – Broad scope – Ligand control – Inert conditions – Cost and toxicity • Bioorganic catalysis – Highly selective – High rate of reaction – Limited scope
Organocatalysis Similar modes of action Lewis acidic/Lewis basic functionality Enzyme mimetics Advantages Preparative expensive Amenable to combinatorial approaches
Organocatalysis • Similar modes of action – Lewis acidic/Lewis basic functionality – Enzyme mimetics • Advantages – Preparative – Inexpensive – Amenable to combinatorial approaches
History and Development Early example OH catalytic Hcn quInine CN Applications 10%ee -Kinetic resolutions -Phase transfer catalysis -Asymmetric synthesis Bredig, G; Fiske, P S. Biochem. Z. 1912, 46,7 Prelog, V. Wilhelm, M. He/v. Chim. Acta 1954, 37, 1634
History and Development • Early example Bredig, G.; Fiske, P. S. Biochem. Z. 1912, 46, 7. Prelog, V.; Wilhelm, M. Helv. Chim. Acta 1954, 37, 1634. H O HCN CN OH + 10% ee catalytic quinine •Applications –Kinetic resolutions –Phase transfer catalysis –Asymmetric synthesis
Outline Cinchona alkaloids Proline Amino acid derivatives Peptide-like Catalysts Heteroazolium species
Outline • • Cinchona Alkaloids • Proline • Amino Acid Derivatives • Peptide-like Catalysts • Heteroazolium Species
Cinchona alkaloids OMe OMe H N OH MOH N R 8S, 9R-quinine 8R, 9s-quinidine Enantiomeric B-hydroxyamine functionality Nucleophilic catalysts Wynberg, H Top. Stereochem. 1986, 16, 87
Cinchona Alkaloids • Enantiomeric b-hydroxyamine functionality • Nucleophilic catalysts Wynberg, H. Top. Stereochem. 1986, 16, 87. S H N N OMe OH H N H H OH N OMe R 8S, 9R - quinine 8R, 9S - quinidine
ASymmetricβ- Lactones H H 1-2 mol% quinidine Clc H toluene,-25°C O 89% yield Clc (S)98%ee Requires electron deficient aldehydes and aromatic ketones 68-98%yied 89-98%ee Alkyl aryl ketones react in trace amounts Staring, E.G.J.: Wynberg, H.J. Am. Chem. Soc. 1982, 104, 166 Staring, E.G. J; Wynberg, H J. Org. Chem. 1985, 50, 1977
Asymmetric b-Lactones Staring, E. G. J.; Wynberg, H. J. Am. Chem. Soc. 1982, 104, 166. Staring, E. G. J.; Wynberg, H. J. Org. Chem. 1985, 50, 1977. O Cl 3 C H O H H O O Cl 3 C + 1-2 mol% quinidine toluene, -25 °C 89% yield (S) 98% ee Requires electron deficient aldehydes and aromatic ketones 68 – 98% yield 89 – 98% ee Alkyl aryl ketones react in trace amounts
Aldol- lactonization mechanism NR NR CCI 3 0 OAC NR OCH Re face of enolate blocked Aldehyde approaches the si face of enolate Dijkstra, G. D. H. Kellog, R. M; Wynberg, H. Svendsen, J. S; Marko, I; Sharpless, K. B J.Am.chem.Soc.1989.111.8069 Cortez, G.S., Tennyson, R L Romo, D.J. Am. Chem. Soc. 2001, 123, 7945
Aldol - Lactonization Mechanism Dijkstra, G. D. H.; Kellog, R. M.; Wynberg, H.; Svendsen, J. S.; Marko, I.; Sharpless, K. B. J. Am. Chem. Soc. 1989, 111, 8069. Cortez, G. S.; Tennyson, R. L.; Romo, D. J. Am. Chem. Soc. 2001, 123, 7945. NR3 O H H O NR3 H H O H CCl3 O H NR3 O Cl3C NR3 O O Cl3C O O NR3 Cl3C H N H OAc H N H OCH3 O + * * * * Aldehyde approaches the Si face of enolate * Re face of enolate blocked
Methyl Ketene Dimerization Me Zn 1 mol%amine Me Br THF,-78°C Br MeH Me OH LIAIH Me 20% yield Me Me uridine (R)98%ee (trimethyl quInine (S)93%ee Calter, M. A.J. Org. Chem. 1996, 61, 8006
Methyl Ketene Dimerization Calter, M. A. J. Org. Chem. 1996, 61, 8006. O Br Me Br Zn O Me H O O Me Me LiAlH4 (S) 93% ee (R) 98% ee O Me Me OH O R3 N Me O Me 1 mol% amine THF, -78 °C * * quinidine (trimethylsilyl)quinine 20% yield * *
Polypropionate Synthesis 0.3mo% 500° quinidine THF.-78°C Me - OLi Meo Me N MeMe THF,-78° Me Me THF,-78°C oO OH Meo OHC N MeMe MeMe Me Me MeMeMeMe 55% yield siphonarienal Guo, X ; Liao, W; Calter, M. A. Org. Lett. 2001, 3, 1499
Polypropionate Synthesis Guo, X.; Liao, W.; Calter, M. A. Org. Lett. 2001, 3, 1499. O Me O Me N MeO Li O Me H Me N O MeO Me OLi Me O H Me Me O O Me Me Me Me Me Me N O MeO Me O OH Me OHC Me Me Me Me 55% yield siphonarienal THF, -78 °C THF, -78 °C THF, -78 °C 0.3 mol% quinidine 2 500 °C
