Brucine1

[357-57-3]  · C23H26N2O4  · Brucine  · (MW 394.47)

(reagent for the resolution of acids, alcohols, and other neutral compounds1)

Physical Data: colorless needles (acetone/water) mp 178 °C; [a]D -79.3° (c 1.3, EtOH).

Solubility: very sol methanol, ethanol, and chloroform; mod sol ethyl acetate or benzene.

Form Supplied in: colorless needles or plates. The free base, which is available from multiple commercial sources, is usually hydrated. Dihydrated and tetrahydrated forms have been characterized. Anhydrous brucine can be obtained by heating at 100-120 °C in vacuo for 24 h. The hydrated forms can be used for most applications.

Purification: the commercial reagent is often used without further purification. However, the reagent can be purified by recrystallization from ethanol/water (1:1).2 Recovered reagent3 should be purified before reuse.

Handling, Storage, and Precautions: EXTREMELY POISONOUS. Oral LD50 in rats is 1 mg kg-1. Handle in well-ventilated hood only.

Introduction.

The alkaloid brucine has been a key resolving agent for over a century, in spite of its highly toxic nature. The group of chiral bases represented primarily by brucine, its homolog strychnine, and the cinchona alkaloids quinine, quinidine, cinchonidine, and cinchonine, has been extremely useful for the resolution of all types of acids.1 No empirical rules have emerged from all of this work to help in predicting the optimal resolving agent for a given type of acid. Acid resolution is still primarily an empirical process that requires the evaluation of several diastereomeric salts. An inherent limitation to the use of alkaloids as resolving agents for acids is the availability of only one antipode, which sometimes allows the practical isolation of only one of the acid enantiomers in a pure form. Nevertheless, there are reports of resolutions with brucine that are so efficient that the less crystalline enantiomer can be isolated directly from the mother liquors (see below for examples). In other cases, pairs of pseudoenantiomeric cinchona alkaloids (i.e. quinine and quinidine, cinchonine and cinchonidine), or brucine and another alkaloid, display opposite selectivities for the enantiomers of a racemic acid (see below).1a

Resolution of Acids.

The number of acids resolved with brucine is too large to attempt to list even a small portion of them in this synopsis. An excellent tabulation of all published resolutions with brucine up to 1972 is available.1a Only a few representative examples will be described here (eqs 1-4).4-9 In all these cases, the resolved acids were obtained in high yield and with almost absolute enantiomeric purity. The solvents most frequently used for brucine resolutions are acetone and alcohol solvents. However, water, hexane, and others have also been used as cosolvents.

Additional types of carboxylic acids that have been successfully resolved with brucine are represented by structures (1)-(5).10-14

As mentioned above, one of the limitations of using naturally occurring resolving agents is that only one enantiomer of the compound being resolved may be readily accessible by resolution. However, many examples have been described where brucine and some other alkaloid favor crystallization with opposite enantiomers of a given acid. For example, resolution of acid (6) with brucine yields the (+)-enantiomer, while cinchonidine provides material that is enriched in the (-)-enantiomer of the acid.15 Similarly, diacid (7) is resolved into its (-)-enantiomer by brucine and into its (+)-enantiomer by strychnine.16 The (+)-enantiomer of acid (8) can be obtained with brucine, while the (-)-enantiomer crystallizes with cinchonidine.17 Additional examples of the same phenomenon can be found in the literature.1a

Resolution of Alcohols.

Although not a well exploited use of brucine, a variety of secondary benzylic alcohols have been resolved by complexation and crystallization with brucine (eq 5).18 About a dozen alcohols were obtained in close to enantiomeric purity by this procedure.18 Also resolved by crystallization of their brucine inclusion complexes were a series of tertiary propargylic alcohols (eq 6).19 In this case, the enantiomer that does not crystallize with brucine can be obtained in almost complete optical purity from the mother liquors.

A more traditional and general approach to the resolution of alcohols is the formation of the corresponding hemiphthalate or hemisuccinate esters, followed by resolution of these acidic derivatives with brucine or some other chiral base (eqs 7-9).20-23 The resolved alcohols are liberated by alkaline hydrolysis of the esters. High enantiomeric purity is frequently achieved by this procedure, which has been applied successfully to primary, secondary, and tertiary alcohols.

Resolution of Ketones.

Brucine has not been used very extensively for the resolution of neutral compounds. However, in some cases, ketones or ketone derivatives may form diastereomeric inclusion complexes with brucine, providing an opportunity for their resolution. For example, the cyanohydrin of a bicyclic ketone has been resolved by this procedure (eq 10).24 Following resolution of the cyanohydrin, the ketone was regenerated and determined to be of 94% ee.

Resolution of Sulfoxides.

Although it can be considered as the resolution of an unique type of carboxylic acid, some racemic sulfoxides containing carboxylic acids have been resolved via diastereomeric crystalline complexes with brucine (eq 11).25

Chiral Catalysis.

Brucine has been utilized as chiral catalyst in a variety of reactions. For example, its incorporation into a polymer support provides a chiral catalyst for performing enantioselective benzoin condensations.26 It has also been used as a chiral catalyst in the asymmetric synthesis of (R)-malic acid via the corresponding b-lactone, which results from the asymmetric cycloaddition of chloral and ketene (eq 12).27 Though brucine yields malic acid with 68% ee, quinidine was found to be a more selective catalyst (98% ee).

Brucine has been used as an enantioselective catalyst in the kinetic resolution of alcohols. For example, an azirinylmethanol was reacted with 0.5 equiv of Acetic Anhydride in the presence of 25 mol % brucine. The resulting acetate was found to possess 24% ee (eq 13).28

Brucine has been used to produce enantiomerically enriched compounds by selective reaction with or destruction of one of the enantiomers. The optical purity of the resulting compound is usually modest, although some exceptions have been described. For example, dibromo compound (9) was obtained (enriched in the (-)-enantiomer) by selective destruction of the (+)-enantiomer with brucine in chloroform.29 The resolution of (±)-2,3-dibromobutane may have also been a case of enantioselective destruction,30 although more recent reports suggest that it is more likely a case of enantioselective entrapment in the brucine crystals (eq 14).31

Miscellaneous.

Brucine greatly accelerates the decarboxylation of certain b-oxo carboxylic acids at rt (eq 15),32 as well as the decarbalkoxylation of b-oxo esters.33 In some cases the products of these reactions possess some (modest) enantiomeric excess.34


1. (a) Wilen, S. H. In Tables of Resolving Agents and Optical Resolutions; Eliel, E. L., Ed.; University of Notre Dame Press: Notre Dame, 1972. (b) Jacques, J.; Collet, A. In Enantiomers, Racemates and Resolutions; Wilen, S. H., Ed.; Wiley: New York, 1981.
2. DePuy, C. H.; Breitbeil, F. W.; DeBruin, K. R. JACS 1966, 88, 3347.
3. Vogel, A. I. Practical Organic Chemistry; Longmans: London, 1957. p 507.
4. Allan, R. D.; Johnston, G. A. R.; Twitchin, B. AJC 1981, 34, 2231.
5. Kaifez, F.; Kovac, T.; Mihalic, M.; Belin, B.; Sunjic, V. JHC 1976, 13, 561.
6. Kanoh, S.; Hongoh, Y.; Motoi, M.; Suda, H. BCJ 1988, 61, 1032.
7. Hasaka, N.; Okigawa, M.; Kouno, I.; Kawano, N. BCJ 1982, 55, 3828.
8. Lévai, A.; Ott, J.; Snatzke, G. M 1992, 123, 919.
9. Puzicha, G.; Lévai, A.; Szilágyi, L. M 1988, 119, 933.
10. Tichy, M.; Sicher, J. TL 1969, 53, 4609.
11. Dvorken, L. V.; Smyth, R. B.; Mislow, K. JACS 1958, 80, 486.
12. McLamore, W. M.; Celmer, W. D.; Bogert, V. V.; Pennington, F. C.; Sobin, B. A.; Solomons, I. A. JACS 1953, 75, 105.
13. Sealock, R. R.; Speeter, M. E.; Schweet, R. S. JACS 1951, 73, 5386.
14. Dutta, A. S.; Morley, J. S. CC 1971, 883.
15. Mislow, K.; Strinberg, I. V. JACS 1955, 77, 3807.
16. Hoffman, T. D.; Cram, D. J. JACS 1969, 91, 1000.
17. Tanabe, T.; Yajima, S.; Imaida, M. BCJ 1968, 41, 2178.
18. Toda, F.; Tanaka, K.; Koshiro, K. TA 1991, 2, 873.
19. Toda, F.; Tanaka, K. TL 1981, 22, 4669.
20. Crout, D. H. G.; Morrey, S. M. JCS(P1) 1983, 2435.
21. Lukes, R. M.; Sarett, L. H. JACS 1954, 76, 1178.
22. MacLeod, R.; Welch, F. J.; Mosher, H. S. JACS 1960, 82, 876.
23. Eliel, E. L.; Kofron, J. T. JACS 1953, 75, 4585.
24. Black, K. A.; Vogel, P. HCA 1984, 67, 1612.
25. Barbieri, G.; Davoli, V.; Moretti, I.; Montanari, F.; Torre, G. JCS(C) 1969, 731.
26. Castells, J.; Duñach, E. CL 1984, 1859.
27. Wynberg, H.; Staring, E. G. J. JACS 1982, 104, 166.
28. Stegmann, W.; Uebelhart, P.; Heimgartner, H.; Schmid, H. TL 1978, 34, 3091.
29. Greene, F. D.; Remers, W. A.; Wilson, J. W. JACS 1957, 79, 1416.
30. Tanner, D. D.; Blackburn, E. V.; Kosugi, Y.; Ruo, T. C. S. JACS 1977, 99, 2714.
31. Pavlis, R. R.; Skell, P. S. JOC 1983, 48, 1901.
32. Hargreaves, M.; Khan, M. M 1978, 109, 799.
33. Miles, D. H.; Stagg, D. D. JOC 1981, 46, 5376.
34. Toussaint, O.; Capdevielle, P.; Maumy, M. TL 1987, 28, 539.

Juan C. Jaen

Parke-Davis Pharmaceutical Research, Ann Arbor, MI, USA



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