(R)-N-[2-(N,N-Dimethylamino)ethyl]-N-methyl-1-[(S)-1,2-bis(diphenylphosphino)ferrocenyl]ethylamine

[119477-31-5]  · C41H43FeN2P2  · (R)-N-[2-(N,N-Dimethylamino)ethyl]-N-methyl-1-[(S)-1,2-bis(diphenylphosphino)ferrocenyl]ethylamine  · (MW 682.62)

(chiral ligand for asymmetric synthesis;1 gold(I)-catalyzed asymmetric aldol reaction;2 silver(I)-catalyzed asymmetric aldol reaction;3 enantioselective synthesis of b-hydroxy-a-aminophosphonates;4 asymmetric allylic alkylation;5 asymmetric allylic aminations;6 asymmetric hydrogenations;7 asymmetric [3 + 2] cycloaddition reactions8)

Physical Data: viscous liquid, [a]25D +313° (c = 0.3, CHCl3).

Solubility: sol dichloromethane, 1,2-dichloroethane, toluene, diethyl ether.

Preparative Methods: can be prepared9 in two steps from commercially available (-)-(R)-N,N-dimethyl-1-[(S)-1,2-bis(diphenylphosphino)ferrocenyl]ethylamine.

Handling, Storage, and Precautions: although air stable at rt, storage under anhydrous conditions under an inert atmosphere is recommended both to prevent the slow air oxidation of the phosphorus(III) ligating groups and absorption of atmospheric moisture.

Chiral Ferrocenylamine Ligands.

Chiral ferrocenylamine ligands typified by the title reagent (1) have played a key role in the development of both methodology and ligand design10 for asymmetric synthesis, particularly for the enantioselective formation of C-C bonds using catalytic quantities of chiral transition-metal catalysts. In the following discussion, both (1) and close analogs will be discussed and compared because small structural modifications of the alkyl side-chain of (1) can lead to significant increases in stereoselectivity.11

Gold(I)-Catalyzed Aldol Reaction.

In 1986 an elegant enantioselective and diastereoselective synthesis of dihydrooxazolines was reported, using the aldol reaction of an aldehyde with an a-isocyanoacetate ester (formally a Knoevenagel reaction) using a cationic gold(I) complex of (1) (eq 1).2

The gold(I) complex is prepared in situ by the reaction of (1) with bis(cyclohexyl isocyanide)gold(I) tetrafluoroborate (2),12 typically in anhydrous dichloromethane. The dihydrooxazolines obtained provide a ready access to enantiomerically pure b-hydroxy-a-amino acid derivatives. High diastereo- and enantioselectivity are generally maintained with a wide variety of substituted aldehydes,2,13,14 and a-isocyanoacetate esters.15-17 N,N-Dimethyl-a-isocyanoacetamides18 and a-keto esters19 have been substituted for the a-isocyanoacetate ester and aldehyde component, respectively, sometimes with improved stereoselectivity. The effect of both the central and planar chirality of (1) on the diastereo- and enantioselectivity of the gold(I)-catalyzed aldol reaction has been studied.20 The modification of the terminal dialkylamino group of (1) can lead to improvements in the stereoselectivity of the reaction, which in certain cases can be dramatic (eq 2).11,21 The utility of the gold(I)-catalyzed aldol reaction in the synthesis of natural products has been demonstrated.22,23 The gold(I)-catalyzed reaction of an a-isocyanomethylphosphonate ester with an aldehyde provides an enantioselective synthesis of b-hydroxy-a-aminophosphonic acid derivatives.24-26

Silver(I)-Catalyzed Aldol Reaction.

In 1991 the silver(I)-catalyzed aldol reaction of an aldehyde with an a-isocyanoacetate ester was reported, analogous to the above mentioned gold(I)-catalyzed reaction.3 The catalyst was prepared in situ from (2) and Silver(I) Perchlorate. The stereoselectivity of the silver(I)-catalyzed reaction was shown to be temperature dependent, which was attributed to the variation of the degree of metal coordination with temperature. Slow addition of the a-isocyanoacetate ester to a mixture of the aldehyde and catalyst, which favored the preferred tricoordinate AgI, gave high diastereo- and enantioselectivity (eq 3).

Earlier workers reported the silver(I)-catalyzed reaction of an aldehyde with p-Tolylsulfonylmethyl Isocyanide (eq 4).27 The (R)-(R)-dihydrooxazolines formed can be reduced with Lithium Aluminum Hydride to provide a facile route to a-alkyl-b-(N-methylamino)ethanols in good to excellent yield.

Asymmetric Allylations.

The asymmetric allylation of b-diketones with p-allyl PdII complexes using the chiral ligand (1) was reported to proceed with low stereoselectivity.5 Modification of the alkyl side-chain of (1) led to significant improvements in enantioselectivity (eq 5).5,28-31

The in situ formed PdII catalyst system prepared with the hydroxyalkyl-substituted ferrocenylamine (7) led to the opposite absolute configuration at the carbon stereocenter (eq 6).28 A similar inversion of stereochemistry is observed with ferrocenylamine ligands containing a free hydroxyl substituent in the gold(I)-catalyzed aldol reaction.21b Although asymmetric allylic aminations can be achieved using the chiral ligand (7), significantly improved enantioselectivity is obtained with the bis(hydroxyalkyl)-substituted ligand (8) (eq 7).6

An interesting intramolecular variation of this reaction provides oxazolidones, which may be hydrolyzed to synthetically useful optically active 2-amino-3-butenols (eq 8).32 The absolute stereochemistry of the stereocenter formed is dependent upon the geometry about the double bond of the 2-butenylene dicarbamate substrate. A related PdII-promoted [3 + 2] cycloaddition of an activated alkene with a 2-(sulfonylmethyl)-2-propenyl carbonate, using the bis(hydroxyalkyl)-substituted ligand (8), gave methylenecyclopentane derivatives with high asymmetric induction.8

Asymmetric Hydrogenations.

Catalytic asymmetric hydrogenations of b-disubstituted-a-phenylacrylic acids have been achieved using the RhI complex of (4) (eq 9).7,33 Asymmetric hydrogenation of unsymmetrically substituted trisubstituted acrylic acids leads to the formation of two stereocenters in high ee.7 The variation of the terminal dialkylamino substituents has little effect on enantioselectivity.33 A study of a RuII complex of (1) was reported as a model for understanding the stereoselective transition state of asymmetric hydrogenations.34


1. Hayashi, T. PAC 1988 60, 7.
2. Ito, Y.; Sawamura, M.; Hayashi, T. JACS 1986, 108, 6405
3. Hayashi, T.; Uozumi, Y.; Yamazaki, A. TL 1991, 32, 2799.
4. Mastalerz, P. In Handbook of Organophosphorus Chemistry; Engel, R., Ed.; Dekker: New York, 1992; pp 277-375.
5. Sawamura, M.; Nagata, H.; Sakamoto, H.; Ito, Y. JACS 1992, 114, 2586.
6. Hayashi, T.; Yamamoto, A.; Ito, Y.; Nishioka, E.; Miura, H.; Yanagi, K. JACS 1989, 111, 6301.
7. Hayashi, T.; Kawamura, N.; Ito, Y. TL 1988, 29, 5969.
8. Yamamoto, A.; Ito, Y.; Hayashi, T. TL 1989, 30, 375.
9. Hayashi, T.; Mise, T.; Fukushima, M.; Kagotani, M.; Nagashima, N.; Hamada, Y.; Matsumoto, A.; Kawakami, S.; Konishi, M.; Yamamoto, K.; Kumada, M. BCJ 1980, 53, 1138.
10. Sawamura, M.; Ito, Y. CRV 1992, 92, 857.
11. Hayashi, T.; Sawamura, M.; Ito, Y. T 1992, 48, 1999.
12. Bonati, F.; Minghetti, G. G 1973, 103, 373.
13. Togni, A.; Pastor, S. D. JOC 1990, 55, 1649.
14. Ito, Y.; Sawamura, M.; Hayashi, T. TL 1987, 28, 6215.
15. Ito, Y.; Sawamura, M.; Shirakawa, E.; Hayashizaki, K.; Hayashi, T. T 1988, 44, 5253.
16. Togni, A.; Pastor, S. D. HCA 1989 72, 1038.
17. Ito, Y.; Sawamura, M.; Shirakawa, E.; Hayashizaki, K.; Hayashi, T. TL 1988, 29, 235.
18. Ito, Y.; Sawamura, M.; Kobayashi, M.; Hayashi, T TL 1988, 29, 6321.
19. Ito, Y.; Sawamura, M.; Hamashima, H.; Emura, T.; Hayashi, T TL 1989, 30, 4681.
20. Pastor, S. D.; Togni, A. JACS 1989, 111, 2333.
21. (a) Hayashi, T.; Yamazaki JOM 1991, 413, 295. (b) Pastor, S. D.; Togni, A. HCA 1991, 74, 905.
22. Togni, A.; Pastor, S. D.; Rihs, G. HCA 1989 72, 1471.
23. Ito, Y.; Sawamura, M.; Hayashi, T TL 1988, 29, 239.
24. Togni, A.; Pastor, S. D. TL 1989, 30, 1071.
25. Sawamura, M.; Ito, Y.; Hayashi, T. TL 1989, 30, 2247.
26. For a more detailed discussion, see Bis(cyclohexyl isocyanide)gold(I) Tetrafluoroborate-(R)-N-[2-(N,N-Dimethylamino)ethyl]-N-methyl-1-[(S)-1,2-bis(diphenylphosphino)ferrocenyl]ethylamine.
27. Sawamura, M.; Hamashima, H.; Ito, Y. JOC 1990, 55, 5935.
28. Hayashi, T.; Kanehira, K.; Hagihara, T.; Kumada, M. JOC 1988, 53, 113.
29. Hayashi, T.; Yamamoto, A.; Hagihara, T.; Ito, Y. TL 1986, 27, 191.
30. Hayashi, T.; Yamamoto, A.; Ito, Y. CC 1986 1090.
31. Ito, Y.; Sawamura, M.; Matsuoka, M.; Matsumoto, Y.; Hayashi, T. TL 1987, 28, 4849.
32. Hayashi, T.; Yamamoto, A.; Ito, Y. TL 1988, 29, 99.
33. Hayashi, T.; Kawamura, N.; Ito, Y. JACS 1987, 109, 7876.
34. Alcock, N. W.; Brown, J. M.; Rose, M.; Wienand, A. TA 1991, 2, 47.

Stephen D. Pastor

Ciba-Geigy Corporation, Ardsley, NY, USA



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