《Asymmetric Organocatalysis》英文版不对称有机催化反应讲义

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