Cinchona Alkaloids

Chemfiles Volume 6 Article 4

Desymmetrization

Abundant in nature, cinchona alkaloids are readily accessible chiral amine catalysts that exist in pseudoenantiomeric forms. Indeed, some of the very first examples of organocatalyzed reactions were mediated by O-acetylated quinine.1a Deng has used modified cinchona alkaloids as ligands in Sharpless’ asymmetric dihydroxylation catalyst system and in the desymmetrization of anhydrides (Scheme 11).


Scheme 11

A high degree of asymmetric induction using cinchona catalysts can be achieved in desymmetrization of meso anhydrides to form the corresponding hemiesters (Scheme 12). Biscinchona alkaloids such as (DHQD)2AQN (456713) were more efficient in this transformation.2


Scheme 12

Other highly enantioselective reactions using cinchona alkaloids include cyanation of ketones,2 1,4-additions of thiols to enones,2dimerizations of methylketene,3 asymmetric Baylis–Hillman reactions,4 synthesis of β-lactams,5 α-halogenations,6 aza-Henryreactions, 7 and intramolecular aldol reactions.8

Nonracemic planar chiral (arene)Cr(CO)3 complexes are increasingly important chiral building blocks in highly diastereoselective transformations and they can also serve as ligands in catalytic reactions.9 Kündig has shown that chiral diamine (07317) performed well in the asymmetric benzoylation/desymmetrization of a meso Cr complex.10 Enantiomeric excess only marginally decreased (to 98%) when diamine (39867) was employed in the same reaction (Scheme 13).


Scheme 13

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Asymmetric Phase-Transfer Reactions

Asymmetric phase-transfer catalysis (PTC) has been recognized as a “green” alternative to many homogeneous synthetic organic transformations, and has found widespread application. Synthetically modified cinchona alkaloids are typical chiral organocatalysts used in asymmetric PTC. Several generations of O-alkyl Narylmethyl derivatives were developed, which finally led to highly enantioselective alkylation reactions of glycine imines to generate a range of α-amino acid derivatives (Table 2).11


Table 2

In an attempt to further improve catalyst enantioselectivities, Jew and Park linked two cinchona alkaloid moieties via spacer units.12 With such a dimeric cinchona alkaloid (06542), enantioselectivity for the above mentioned glycine imine alkylation was optimized to 97–99% ee.

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Materials

     

References

  1. For early examples of organocatalyzed reactions, see: (a) Pracejus, H. Justus Liebigs Ann. Chem. 1960, 634, 9. (b) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615. (c) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem. Int. Ed. Engl. 1971, 10, 496.
  2. Tian, S.-K.; Chen, Y.; Hang, J.; Tang, L.; McDaid, P.; Deng, L. Acc. Chem. Res. 2004, 37, 621.
  3. Calter, M. A. J. Org. Chem. 1996, 61, 8006.
  4. Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatekeyama, S. J. Am. Chem. Soc. 1999, 121, 10219.
  5. Taggi, A. E.; Hafez, A. M.; Wack, H.; Young, B.; Drury, W. J.; Leckta, T. J. Am. Chem. Soc. 2000, 122, 7831.
  6. Wack, H.; Taggi, A. E.; Hafez, A. M.; Drury, W. J.; Leckta, T. J. Am. Chem. Soc. 2001, 123, 1531.
  7. Bernardi, L.; Fini, F.; Herrera, R. P.; Ricci, A.; Sgarzani, V. Tetrahedron 2006, 62, 375.
  8. Cortez, G. S.; Tennyson, R. L.; Romo, D. J. Am. Chem. Soc. 2001, 123, 7945.
  9. Pape, A.; Kaliappan, K.; Kündig, E. P. Chem. Rev. 2000, 100, 2917.
  10. Kündig, E. P.; Lomberget, T.; Bragg, R.; Poulard, C.; Bernardinelli, G. Chem. Commun. 2004, 1548.
  11. (a) O’Donnell, M. J. Acc. Chem. Res. 2004, 37, 506. (b) Lygo, B.; Andrews, B. J. Acc. Chem. Res. 2004, 37, 518.
  12. Jew, S.-S.; Jeong, B.-S.; Yoo, M.-S.; Huh, H.; Park, H.-G. Chem. Commun. 2001, 1244.

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