Vitamin B121-3

[68-19-9]  · C63H88CoN14O14P  · Vitamin B12  · (MW 1355.40)

(radical source via carbon-cobalt bond homolysis; stoichiometric and catalytic radical C-C bond formation; enantioselective catalyst for molecular rearrangements)

Physical Data: odorless and tasteless, hygroscopic, dark red solid; does not have a defined melting point; darkens at 210-220 °C but is not melted at 300 °C.

Solubility: sol H2O (1 g/80 mL), alcohol; insol acetone, chloroform, ether.

Form Supplied in: powder or crystalline solid; available from biologically oriented chemical suppliers.

Handling, Storage, and Precautions: hygroscopic; absorbs moisture from air. Hydrated crystals are air stable. Aqueous solutions slowly decompose. May be harmful by inhalation, ingestion, or skin absorption and can cause eye and skin irritation. Keep containers tightly closed and store in a cool dry place. Use in a fume hood with safety goggles and chemically resistant gloves and clothing.

Stoichiometric Processes.

In 1964, Schrauzer published the first of many papers on the synthesis and properties of alkyl cobaloximes.1 This work led to the development of cobaloximes and related compounds as vitamin B12 model compounds, e.g. (1)-(4), summarized in a review in 1976.2 By the mid 1970's, many of the fundamental reactions of vitamin B12 and model complexes were well established. This work is summarized in several reviews.3

Alkylcobalt complexes provide an easy bridge between two-electron ionic chemistry and one-electron radical chemistry. This has made them popular and useful radical precursors; ionic reactions provide alkylcobalt complexes which then provide alkyl radicals via C-Co bond homolysis. In the mid 1970s and early 1980s, radical chain SH2 reactions of allylcobaloximes were studied (eq 1).4 These reactions were not applied to specific synthetic problems.5

In the late 1980s, and early 1990s, stoichiometric nonchain organocobalt reactions have been developed.6 Cobalt-based radicals, formed by carbon-cobalt bond homolysis, continue to participate in multistep radical processes to guide reaction pathways into particular directions.7 The main practical benefits are: (1) radical-alkene additions are possible; (2) polymerization is inhibited; and (3) the alkene is regenerated in the final product by cobalt-mediated b-H elimination. A tandem radical cyclization (eq 2)8 illustrates the main features. Oxidative addition of the cobalt anion to the alkyl bromide generates the alkyl radical which undergoes cyclization followed by trapping by the CoII radical. This type of reaction was first observed in earlier studies of the mechanism of oxidative addition of CoI to hindered alkyl halides.9 Photolytic homolysis of the C-Co bond produces the alkyl radical which undergoes cyclization followed by CoII-mediated b-H elimination.

A similar strategy has been applied to the synthesis of kainoids and related compounds (eq 3).10 Both stoichiometric and catalytic amounts of cobalt reagents have been used in these and other cyclization studies. Several examples of these types of cyclizations have been published,11 including cyclizations using aryl halides as precursors to aryl radicals.12

Alkylcobalt reagents are often prepared from the reaction of anionic CoI complexes with alkyl halides or sulfonate esters. They can also be prepared by conjugate addition of anionic CoI complexes to a,b-unsaturated carbonyl compounds and nitriles, placing the cobalt b to the activating group, or by addition of neutral CoIII hydrides to activated alkenes (carbonyl, nitrile, and aryl activating groups), placing the cobalt a to the activating group.13 Anionic CoI anions open epoxides regioselectively and the resulting cobaloximes show different patterns of reactivity under thermolysis versus photolysis (eq 4).14 A mechanistic study indicates that cobalt-mediated cyclizations proceed via radicals,15 but the reaction mechanism in the reactions in eq 4 has not been studied in detail. Acyl radicals can be generated from readily prepared acyl cobalt complexes.16 The key step in a formal synthesis of racemic thienamycin is illustrative (eq 5).17

Intermolecular cross-coupling reactions have been developed.18 One application to the synthesis of KDO takes advantage of alkene regeneration to allow further synthetic elaboration (eq 6).19 Similar reactions have been developed for C-C bond constructions at the anomeric center of hexopyranoses,20 leading to the production of C-glycosides, at C-1 of an open-chain pentose, leading to a synthesis of KDO,21 and at C-3 of ribofuranoses.22 Nonalkene cross-coupling partners have been used, specifically protonated heteroaromatics23 and nitroalkyl anions.24 Nitroalkyl anion cross couplings have been used to prepare C-disaccharides (eq 7).25

Catalytic Processes.

Catalytic processes lead to intramolecular and intermolecular C-C bond constructions which are usually directly analogous to the stoichiometric reactions. This topic was reviewed in 1983.26 Catalytic processes often lead to reduction rather than alkene regeneration; this is more likely to happen with B12 as a catalyst than it is with a cobaloxime. Scheffold pioneered the use of vitamin B12 as a catalyst for C-C bond formation,27 and Tada pioneered the use of model complexes such as cobaloximes.28 Several of the reactions described in the section on stoichiometric reactions have also been performed catalytically, as mentioned in that section. Commonly used chemical reductants include Sodium Borohydride and Zinc metal. Electrochemical reduction has also been used.29 A novel catalytic system with a RuII trisbipyridine unit covalently tethered to a B12 derivative has been used for photochemically driven catalytic reactions using triethanolamine as the reductant.30 A catalytic system using DODOH complexes can lead to reduction products or alkene regeneration depending upon the reaction conditions.31 These catalytic B12 and model complex systems all utilize a CoI-CoII-CoIII redox shuttle, shown in eq 8. Several other publications have described catalytic systems such as these,32 including B12-catalyzed alkene acylations via addition of acyl radicals to activated alkenes33 and the use of hydrophobic B12 derivatives which are designed to provide a binding pocket for enzyme-like catalytic reactions, usually skeletal rearrangement reactions designed to mimic reactions catalyzed by B12-containing enzymes.34 A catalytic system utilizing a CoII-CoIII redox shuttle has been described.35 A catalytic system for alkene oligomerization has been developed.36 Cobalt complexes are known to catalyze radical alkene polymerization.37

Examples of the use of vitamin B12 as a catalyst for enantioselective processes have been reported. The rearrangement of aziridines can proceed catalytically with ee's of up to 95% (eq 9).38 Analogous rearrangements on achiral epoxides (typically 60% ee)39 and achiral peroxides (low ee's)40 have been reported.


1. Schrauzer, G. N.; Kohlne, J. CB 1964, 97, 3056.
2. Schrauzer, G. N. AG(E) 1976, 15, 417.
3. (a) Dodd, D.; Johnson, M. D. JOM 1973, 52, 1. (b) Kemmitt, R. D. W.; Russell, D. R. In Comprehensive Organometallic Chemistry; Wilkinson, G.; Stone, F. G. A.; Abel, E. W., Eds.; Pergamon: New York, 1982; Vol. 5, pp 80-131. (c) Toscano, P.; Marzilli, L. G. Prog. Inorg. Chem. 1984, 31, 105. (d) Gupta, B. D.; Roy, S. ICA 1988, 146, 209.
4. (a) Johnson, M. D. ACR 1983, 16, 343, and references cited therein. (b) Veber, M.; Duong, K. N. V.; Gaudemer, F.; Gaudemer, A. JOM 1979, 177, 231.
5. Work continues in this area: Gupta, B. D.; Roy, S. JCS(P2) 1988, 2, 1377.
6. A review of Pattenden's early contributions: Pattenden, G. CSR 1988, 17, 361.
7. This phenomenon has been termed the persistent radical effect. See Branchaud, B. P.; Yu, G.-X. OM 1993, 12, 4262, and references cited therein.
8. Ali, A.; Harrowven, D. C.; Pattenden, G. TL 1992, 33, 2851.
9. (a) Tada, M.; Okabe, M. CL 1980, 201. (b) Okabe, M.; Tada, M. BCJ 1982, 55, 1498.
10. (a) Baldwin, J. E.; Li, C. S. CC 1987, 166. See also: (b) Baldwin, J. E.; Moloney, M. G.; Parsons, A. F. T 1991, 47, 155. (c) Baldwin, J. E.; Moloney, M. G.; Parsons, A. F. T 1990, 46, 7263. (d) Baldwin, J. E.; Li, C. S. CC 1988, 261.
11. (a) Bhandal, H.; Patel, V. F.; Pattenden, G.; Russell, J. J. JCS(P1) 1990, 2691. (b) Patel, V. F.; Pattenden, G. JCS(P1) 1990, 2703. (c) Begley, M. J.; Bhandal, H.; Hutchinson, J. H.; Pattenden, G. TL 1987, 28, 1317. (d) Patel, V. F.; Pattenden, G. TL 1987, 28, 1451. (e) Branchaud, B. P.; Meier, M. S.; Malekzadeh, M. N., JOC 1987, 52, 212. (f) Bhandal, H.; Pattenden, G.; Russell, J. J. TL 1986, 27, 2299.
12. (a) Clark, A. J.; Jones, K. T 1992, 33, 6875, and references cited therein. The first publication on cobalt-mediated aryl radical cyclizations: (b) Patel, V. F.; Pattenden, G.; Russell, J. J. TL 1986, 27, 2303.
13. (a) Howell, A. R.; Pattenden, G. JCS(P1) 1990, 2715. (k) Bhandal, H.; Pattenden, G. CC 1988, 1110.
14. Harrowven, D. C.; Pattenden, G. TL 1991, 32, 243.
15. Giese, B.; Hartung, J.; He, J.; Hueter, O.; Koch, A. AG(E) 1989, 28, 325.
16. (a) Patel, V. F.; Pattenden, G.; Thompson, D. M. JCS(P1) 1990, 2729. (b) Coveney, D. J.; Patel, V. F.; Pattenden, G.; Thompson, D. M. JCS(P1) 1990, 2721. (c) Gill, G. B.; Pattenden, G.; Reynolds, S. J. TL 1989, 30, 3229. (d) Patel, V. F.; Pattenden, G. TL 1988, 29, 707. (e) Coveney, D. J.; Patel, V. F.; Pattenden, G. TL 1987, 28, 5949.
17. Pattenden, G.; Reynolds, S. J. TL 1991, 32, 259.
18. (a) Patel, V. F.; Pattenden, G. CC 1987, 871. (b) Branchaud, B. P.; Meier, M. S.; Choi, Y. L. TL 1988, 29, 167. (c) Bhandal, H.; Howell, A. R.; Patel, V. F.; Pattenden, G. JCS(P1) 1990, 2709.
19. (a) Branchaud, B. P.; Meier, M. S. TL 1988, 29, 3191. (b) Branchaud, B. P.; Meier, M. S. JOC 1989, 54, 1320.
20. Ghosez, A.; Göbel, T.; Giese, B. CB 1988, 121, 1807.
21. (a) Giese, B.; Carboni, B.; Göbel, T.; Muhn, R.; Wetterich, F. TL 1992, 33, 2673. (b) Veit, A.; Giese, B. SL 1990, 166.
22. Branchaud, B. P.; Yu, G.-X. TL 1991, 32, 3639.
23. Branchaud, B. P.; Choi, Y. L. JOC 1988, 53, 4638.
24. (a) Branchaud, B. P.; Yu, G.-X. TL 1988, 29, 6545. (b) Ref. 22.
25. Martin, O. R.; Xie, F.; Kakarla, R.; Benhamza, R. SL 1993, 165.
26. Scheffold, R.; Rytz, G.; Walder, L., In Modern Synthetic Methods; Scheffold, R., Ed.; Wiley: New York, 1983; Vol. 3, pp 355-440.
27. (a) Auer, L.; Weymuth, C.; Scheffold, R. HCA 1993, 76, 810. (b) Yamamoto, K.; Abrecht, S.; Scheffold, R. C 1991, 45, 86. (c) Scheffold, R. Nachr. Chem., Tech. Lab. 1988, 36, 261. (c) Scheffold, R.; Abrecht, S.; Orlinski, R.; Ruf, H. R.; Stamouli, P.; Tinembart, O.; Walder, L.; Weymuth, C. PAC 1987, 59, 363. (d) Scheffold, R. C 1985, 39, 203.
28. (a) Okabe, M.; Abe, M.; Tada, M. JOC 1982, 47, 1775. (b) Okabe, M.; Tada, M. JOC 1982, 47, 5382.
29. In addition to the work of Scheffold, see: (a) Fry, A. J.; Sirisoma, U. N.; Lee, A. S. TL 1993, 34, 809. (b) Fry, A. J.; Sirisoma, U. N. JOC 1993, 58, 4919.
30. Steiger, B.; Eichenberger, E.; Walder, L. C 1991, 45, 32.
31. Giese, B.; Erdmann, P.; Göbel, T.; Springer, R. TL 1992, 33, 4545.
32. (a) Hu, C.-M.; Qui, Y.-L. JOC 1992, 57, 3339. (b) Erdmann, P.; Schäfer, J.; Springer, R.; Zeitz, H.-G.; Giese, B. HCA 1992, 75, 638. (c) Inokuchi, T.; Tsuji, M.; Kawafuchi, H.; Torii, S. JOC 1991, 56, 5945.
33. Walder, L.; Orlinski, R. OM 1987, 6, 1606.
34. Murakami, Y.; Hisaeda, Y.; Song, X.-M.; Takasaki, K.; Ohon, T. CL 1991, 977. (b) Murakami, Y.; Hisaeda, Y. PAC 1988, 60, 1363.
35. Branchaud, B. P.; Detlefsen, W. D. TL 1991, 32, 6273.
36. Bandaranayake, W. M.; Pattenden, G. CC 1988, 1179.
37. (a) Suddaby, K. G.; O'Driscoll, K. F.; Rudin, A. J. Polym. Sci., Part A: Polym. Chem. 1992, 30, 643. (b) Suddaby, K. G.; Sanayei, R. Amin; Rudin, A.; O'Driscoll, K. F. J. Appl. Polym. Sci. 1991, 43, 1565. (c) Sanayei, R. A.; O'Driscoll, K. F. J. Macromol. Sci., Chem. 1989, A26, 1137.
38. Zhang, Z.; Scheffold, R. HCA 1993, 76, 2602.
39. Bonh&obreve;te, P.; Scheffold, R. HCA 1991, 74, 1425.
40. Essig, S.; Scheffold, R. C 1991, 45, 30.

Bruce P. Branchaud & Gregory K. Friestad

University of Oregon, Eugene, OR, USA



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