[130-95-0]  · C20H23N2O2  · Quinine  · (MW 324.45)

(chiral catalyst1-14)

Physical Data: mp 173-175 °C.

Solubility: sol hot water, methanol, benzene, chloroform, ether, glycerol; insol pet ether.

Form Supplied in: crystalline solid; 90% purity.

Analysis of Reagent Purity: NMR, mp.

Preparative Methods: commercially available from several sources.

Purification: recrystallize from absolute ethanol.

Handling, Storage, and Precautions: toxic; irritant.

Asymmetric Diels-Alder Reactions.

Chiral bases, including quinine, have been used as catalysts in Diels-Alder reactions (eq 1).1 The reactions take place at room temperature or below and require 1-10% equiv of the alkaloid. The asymmetric induction that is observed can be attributed to complex formation between the achiral dienolate and the chiral amine.1

Preparation of Chiral Sulfinates.

Optically active sulfinates can be prepared by reaction of a symmetrical sulfite with t-Butylmagnesium Chloride in the presence of an optically active amino alcohol. The best enantioselectivity has been observed using quinine as the optically active amine (eq 2).2 An alternative approach to this new enantioselective asymmetric synthesis of alkyl t-butylsulfinates would be reaction of a racemic sulfinate with t-butylmagnesium chloride complexed by optically active alkaloids (eq 3).2 In this case, kinetic resolution of the racemic sulfinate leads to an optically active sulfinate and an optically active sulfoxide.

Stereoselective Addition of Diethylzinc to Aldehydes.

Wynberg has found that the cinchona alkaloids catalyze the reaction of Diethylzinc and aldehydes to form optically active alcohols (eq 4).3 The highest enantiomeric excess obtained was from reactions which used quinine as the catalyst. Results show that the hydroxyl group of the catalyst hydrogen bonds with the aldehyde and that the diethylzinc interacts with the vinyl group of the catalyst as well, but it has not been determined if one or two catalyst molecules are involved in the transition state. Similar results have been obtained using a furan aldehyde.4

Synthesis of Optically Active Epoxides.

Alkaloids and alkaloid salts have been successfully used as catalysts for the asymmetric synthesis of epoxides. The use of chiral catalysts such as quinine or quinium benzylchloride (QUIBEC) have allowed access to optically active epoxides through a variety of reaction conditions, including oxidation using Hydrogen Peroxide (eq 5),5 Darzens condensations (eq 6),6 epoxidation of ketones by Sodium Hypochlorite (eq 7),6 halohydrin ring closure (eq 8),6 and cyanide addition to a-halo ketones (eq 9).6 Although the relative stereochemistry of most of the products has not been determined, enantiomerically enriched materials have been isolated. A more recent example has been published in which optically active 2,3-epoxycyclohexanone has been synthesized by oxidation with t-Butyl Hydroperoxide in the presence of QUIBEC and the absolute stereochemistry of the product established (eq 10).7

Asymmetric Michael Reactions.

Asymmetric induction has been observed in Michael-type addition reactions that are catalyzed by chiral amines.8 The N-benzyl fluoride salt of quinine has been particularly successful since the fluoride ion serves as a base and the aminium ion as a source of chirality.9 Drastic improvements in optical purity (1-23%) have resulted by changing from quinine to the N-benzyl fluoride salt (eq 11).9

Asymmetric Synthesis of b-Keto Sulfides.

Quinine can be used to catalyze asymmetrically the addition of thiols to cyclohexenone, thus forming b-keto sulfides (eq 12).10 The absolute stereochemistry of the products has not been determined.

Asymmetric Reduction of Ketones.

Alkyl phenyl ketones can be asymmetrically reduced to the corresponding alcohol using Sodium Borohydride under phase-transfer conditions in the presence of a catalytic amount of QUIBEC (eq 13).11 The results indicate that the asymmetric reduction is due to the rigidity of the catalyst as well as the b-position of the hydroxyl group on the quinine molecule. The asymmetric induction is much lower with a g-hydroxyl group.11

Synthesis of Optically Active b-Hydroxy Esters.

Chiral amino alcohols such as quinine have been used in the enantioselective synthesis of b-hydroxy esters via an indium-induced Reformatsky reaction (eq 14).12 Although the enantioselectivities are not particularly high, aromatic aldehydes have produced the best results to date. The absolute stereochemistry of the products has not yet been assigned.

Preparation of Polymeric Catalyst.

A quinine/Acrylonitrile copolymer has been successfully synthesized via radical polymerization using Azobisisobutyronitrile (AIBN) as initiator (eq 15).13 The polymer can be prepared such that the vinyl group is the connecting site and the amino alcohol portion can either be free or protected. These copolymers are thermally stable and are soluble in polar aprotic solvents such as DMF and DMSO, but insoluble in common organic solvents. Preliminary experiments have shown that these copolymers can be used as asymmetric catalysts.13

Asymmetric Addition of Thioglycolic Acid to Nitro Alkenes.

Quinine has been used to catalyze the addition of thioglycolic acid to nitro alkenes (eq 16).14 Enantiomerically enriched materials have been isolated, although the absolute stereochemistry of the products has not been assigned. The direction and extent of asymmetric induction seems to be dependent on the catalyst/acid ratio, thereby pointing to interaction between the carbonyl of the acid and the alkaloid nitrogen as being responsible for the asymmetric induction.14

1. Riant, O.; Kagan, H. B. TL 1989, 30, 7403.
2. Drabowicz, J.; Legedź, S.; Mikolajczyk, M. T 1988, 44, 5243.
3. Smaardijk, A. A.; Wynberg, H. JOC 1987, 52, 135.
4. van Oeveren, A.; Menge, W.; Feringa, B. L. TL 1989, 30, 6427.
5. Helder, R.; Hummelen, J. C.; Laane, R. W. P. M.; Wiering, J. S.; Wynberg, H. TL 1976, 1831.
6. Hummelen, J. C.; Wynberg, H. TL 1978, 1089.
7. Wynberg, H.; Marsman, B. JOC 1980, 45, 158.
8. Wynberg, H.; Helder, R. TL 1975, 4057.
9. Colonna, S.; Hiemstra, H.; Wynberg, H. CC 1978, 238.
10. Helder, R.; Arends, R.; Bolt, W.; Hiemstra, H.; Wynberg, H. TL 1977, 2181.
11. Colonna, S.; Fornasier, R. JCS(P1) 1978, 371.
12. Johar, P. S.; Araki, S.; Butsugan, Y. JCS(P1) 1992, 711.
13. Kobayashi, N.; Iwai, K. JACS 1978, 100, 7071.
14. Kobayashi, N.; Iwai, K. JOC 1981, 46, 1823.

Ellen M. Leahy

Affymax Research Institute, Palo Alto, CA, USA

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.