Cinchona Alkaloids
Asymmetric phase transfer catalysis (PTC) is now widely used as a "green" alternative route to numerous homogeneous synthesizer transformations as well. The typical chiral organocatalyst for asymmetric phase transfer catalysis is the synthesis of modified cinchona alkaloids. Several generations of O-alkyl N-arylmethyl derivatives have been developed that can catalyze the alkylation of glycine imines with high enantioselectivity and generate a series of α-amino acid derivatives (Table 1).
Figure 1. Alkylation reactions of glycine imines
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Table 1. Alkylation reactions of glycine imines
To further improve the enantioselectivity of the catalyst, Jew and Park attached two cinchona alkaloid molecules via a spacer unit. With the use of this dimeric cinchona alkaloid catalysis, the enantioselectivity of the glycine imine alkylation described in the table above was improved to as high as 97-99% ee.1-3
Nucleophilic catalysts have played an important role in the development of novel synthetic methods. In particular, the cinchona alkaloids can catalyze many practical synthetic processes with high enantioselectivity. Cinchona alkaloids can act as bases that allow the deprotonation of substrates with relatively acidic protons, which in turn leads to the formation of tight ion pairs between the resulting anion and the protonated amine. The interaction of the two leads to a chiral environment around the anion and allows it to react enantioselectively with the electrophilic reagent.
Among the many such processes carried out, how to control the generation of quaternary carbon asymmetric centers with high enantiomers excesses is of utmost importance. Using (DHQD)2AQN catalysts, the α-functionalization of ketones can be influenced by the addition of TMSCN to the corresponding cyanohydrin in excellent yields and enantiomeric excess (Scheme 1).4
Scheme 1
Metal-free allylic amination reactions provide a practical extension to the traditional palladium-catalyzed π-allyl approach. The use of (DHQ)2PYR allows amination reactions with diimides at the remote γ-position (Scheme 2), which in turn leads to the formation of various highly functionalized amino compounds. 5
Scheme 2
Finally, Jørgensen and his colleagues developed the first enantioselective acetylenic ketone conjugate addition reaction catalyzed using (DHQ)2PHAL.6 For aliphatic acetylenes and aromatic compounds, the addition of β-diketones prompted the generation of mixtures of (E)- and (Z)-enones in high yields and enantioselectivity (Scheme 3).
Scheme 3
Reference
1.O'Donnell MJ. 2004. The Enantioselective Synthesis of Amino Acids by Phase-Transfer Catalysis with Achiral Schiff Base Esters. Acc. Chem. Res.. 37(8):506-517. https://doi.org/10.1021/ar0300625
2.Lygo B, Andrews BI. 2004. Asymmetric Phase-Transfer Catalysis Utilizing Chiral Quaternary Ammonium Salts: Asymmetric Alkylation of Glycine Imines. Acc. Chem. Res.. 37(8):518-525. https://doi.org/10.1021/ar030058t
3.Jew S, Jeong B, Yoo M, Huh H, Park H. 2001. Synthesis and application of dimeric Cinchona alkaloid phase-transfer catalysts:bis[O(9)-allylcinchonidinium]-o, m, or p-xylene dibromide. Chem. Commun..(14):1244-1245. https://doi.org/10.1039/b102584h
4.Tian S, Hong R, Deng L. 2003. Catalytic Asymmetric Cyanosilylation of Ketones with Chiral Lewis Base. J. Am. Chem. Soc.. 125(33):9900-9901. https://doi.org/10.1021/ja036222p
5.Poulsen TB, Alemparte C, Jørgensen KA. 2005. Enantioselective Organocatalytic Allylic Amination. J. Am. Chem. Soc.. 127(33):11614-11615. https://doi.org/10.1021/ja0539847
6.Bella M, Jørgensen KA. 2004. Organocatalytic Enantioselective Conjugate Addition to Alkynones. J. Am. Chem. Soc.. 126(18):5672-5673. https://doi.org/10.1021/ja0493594