Cinchona Alkaloids

By: William Sommer and Daniel Weibel, Aldrich ChemFiles 2008, 8.2, 74.

Cinchona alkaloids and their derivatives have proven to catalyze an astonishing array of enantioselective transformations, providing access to chiral products of high enantiopurity.1 The presence of the tertiary quinuclidine nitrogen renders them effective ligands for a variety of metal-catalyzed processes. Of these reactions, the osmium-catalyzed asymmetric dihydroxylation of olefins (Scheme 1), developed by Sharpless in 1988, has had the greatest impact in synthetic chemistry.2

Scheme 1

Bis-(cinchona alkaloid) ligands (which are generally the better catalysts) catalyze the formation of diols of high enantiopurity from a very broad range of olefins. A recent example stems from O'Doherty et al. where (E,E)- and (E,Z)-1,3‑dienoates were dihydroxylated regioselectively in good yields and excellent enantioselectivities using (DHQD)2PHAL 392731 (Scheme 2).3

Scheme 2

Subsequently, these cinchona alkaloids were used for the osmium-catalyzed asymmetric aminohydroxylation of olefins.4 The significance of this reaction is immediately apparent as the asymmetric aminohydroxylation provides straightforward access to the aminoalcohols present in a wide variety of biologically active agents and natural products.

Kim et al. have published recently a practical new synthetic route to (–)-cassine, which shows antimicrobial activity against Staphylococcus aureus, via asymmetric aminohydroxylation followed by reductive amination (Scheme 3).5

Scheme 3

The nucleophilic quinuclidine nitrogen can also be used directly as a reactive center for enantioselective catalysis. Cinchona alkaloids therefore can be used as bases to deprotonate substrates with relatively acidic protons forming a contact ion pair between the resulting anion and protonated amine. This interaction leads to a chiral environment around the anion and permits enantioselective reactions with electrophiles.

Important in many of these processes is the ability to control the formation of quaternary asymmetric centers with high enantiomeric excesses. Using the (DHQD)2AQN (456713) catalyst it is possible to affect the α-functionalization of ketones by the addition of TMSCN to the corresponding cyanohydrin in excellent yield and enantiomeric excess (Scheme 4).6

Scheme 4

The metal-free, allylic amination reaction provides a useful extension to the conventional palladium catalyzed π-allylic methodology. Amination with diimides at the remote γ-position can be carried out using (DHQ)2PYR (418978) to form a diverse range of highly functionalized amine compounds (Scheme 5).7

Scheme 5

Jørgensen et al. have developed the first catalytic enantioselective conjugate addition to alkynones using (DHQ)2PHAL (392723).8 For both aromatic and aliphatic alkynones the addition of β-diketones proceeds in high yields and enantioselectivity giving a mixture of (E)- and (Z)-enones (Scheme 6).

Scheme 6

Dimeric (DHAD)2AQN catalyzes the enantioselective desymmetrization of meso anhydrides with methanol by a nucleophilic mechanism (Scheme 7). The scope of the reaction was found to be very general, with excellent enantioselectivity obtained in the desymmetrization of monocyclic, bicyclic, and tricyclic prochiral and meso anhydrides.9

Scheme 7

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  1. Kacprzak, K.; Gawronski, J. Synthesis 2001, 961‑998.
  2. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.Rev. 1994, 94, 2483.
  3. Ahmed, Md. M.; Mortensen, M. S.; O'Doherty, G. A. J. Org. Chem. 2006, 71, 7741‑7746.
  4. Bodkin, J. A.; McLeod, M. D. J. Chem. Soc., Perkin Trans. 1, 2002, 2733‑2746.
  5. Kim, G.; Kim, N. Tetrahedron Lett. 2007, 48, 4481‑4483.
  6. Tian, S.-K.; Hong, R.; Deng, L. J. Am. Chem. Soc. 2003, 125, 9900‑9901.
  7. Poulsen, T.B.; Alemparte, C.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 11614‑11615.
  8. (a) Bella, M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 5672‑5673. (b) Chen, Y.; Tian, S.-K.; Deng, L. J. Am. Chem. Soc. 2000, 122, 9542‑9543.

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