Bis(cyclohexyl isocyanide)gold(I) Tetrafluoroborate-(R)-N-[2-(N,N-Dimethylamino)ethyl]-N-methyl-1-[(S)-1,2-bis(diphenylphosphino)ferrocenyl]ethylamine1

[-]  · C41H44AuBF4FeN2P2  · Bis(cyclohexyl isocyanide)gold(I) Tetrafluoroborate-(R)-N-[2-(N,N-Dimethylamino)ethyl]-N-methyl-1-[(S)-1,2-bis(diphenylphosphino)ferrocenyl]ethylamine  · (MW 966.38) (gold component)

[43067-36-3]  · C14H22AuBF4N2  · Bis(cyclohexyl isocyanide)gold(I) Tetrafluoroborate-(R)-N-[2-(N,N-Dimethylamino)ethyl]-N-methyl-1-[(S)-1,2-bis(diphenylphosphino)ferrocenyl]ethylamine  · (MW 502.14) (ferrocene component)

[119477-31-5]  · C41H44FeN2P2  · Bis(cyclohexyl isocyanide)gold(I) Tetrafluoroborate-(R)-N-[2-(N,N-Dimethylamino)ethyl]-N-methyl-1-[(S)-1,2-bis(diphenylphosphino)ferrocenyl]ethylamine  · (MW 682.62)

(chiral catalyst for asymmetric aldol reactions giving high diastereo- and enantioselectivity;2 enantioselective synthesis of b-hydroxy-a-aminophosphonates;3 asymmetric allylation4)

Solubility: sol dichloromethane, 1,2-dichloroethane, and diethylene glycol dimethyl ether; insol diethyl ether and pentane.

Preparative Method: the complex is prepared in situ by the reaction of bis(cyclohexyl isocyanide)gold(I) tetrafluoroborate5 with (R)-N-[2-(N,N-Dimethylamino)ethyl]-N-methyl-1-[(S)-1,2-bis(diphenylphosphino)ferrocenyl]ethylamine,6 typically in dichloromethane.7

Handling, Storage, and Precautions: prepare under anhydrous conditions and use under a dry inert atmosphere of nitrogen.

Enantioselective Aldol Reactions.

The development of synthetic methodology for the diastereoselective and enantioselective formation of C-C bonds through the use of catalytic quantities of chiral transition-metal catalysts is a topic of fundamental importance. In 1986, Ito and Hayashi reported an elegant asymmetric synthesis of dihydrooxazolines by the gold(I)-catalyzed aldol reaction (more correctly a Knoevenagel reaction) of an aldehyde with an isocyanoacetate ester in the presence of a chiral ferrocenylamine ligand.7 The chiral catalyst (R)-(S)-(1) is conveniently prepared in situ as described above.5,6 The dihydrooxazolines obtained provide a convenient precursor to enantiomerically pure b-hydroxy-a-amino acid derivatives. The trans (4S,5R)-oxazoline in high ee is obtained predominantly in the reaction of aldehydes with a-isocyanoacetate esters catalyzed by (R)-(S)-(1) (eqs 1-3).7-9 High stereoselectivity is retained with alkyl-substituted a-isocyanoacetate esters (eq 4), although reduced diastereoselectivity and enantioselectivity is often obtained with large a-substituents.10

A wide variety of ester functionalities are tolerated (eq 5).11 A single stereocenter is formed in high ee when formaldeyde is utilized as a reaction component, which leads to an efficient asymmetric synthesis of a-alkylserines (eq 6).12 The utilization of a-keto esters provides a facile route to b-alkyl-b-hydroxyaspartic acid. Higher diastereo- and enantioselectivity are obtained by the reaction of the a-keto ester with the corresponding N,N-dimethyl-a-isocyanoacetamide (eq 7).13 In certain cases, the use of a-isocyanoacetamides is advantageous for improving stereoselectivity in the corresponding reaction with aldehydes.14 The presence of a-heteroatoms or certain electronegative groups in the aldehyde component of the reaction may lead to dramatic changes in diastereo- and enantioselectivity.8,11 Opposite product chirality can be obtained in the gold(I)-catalyzed aldol reaction by using the (S)-(R) enantiomer of (1).

Double stereodifferentiation (double asymmetric induction) between a chiral substrate and the chiral ferrocenylamine ligand has been demonstrated (eq 8).11 The stereocenter (central chirality) as well as the stereoaxis (axial chirality) affects both product diastereoselectivity and enantioselectivity.15 Chiral cooperativity (or internal cooperativity) refers to individual chirotopic segments of the ligand molecule acting in a cooperative manner to promote a particular diastereo- and enantioselectivity in the product.8,15-18 The effects of distant stereocenters in ligands analogous to (R)-(S)-(1) upon the stereoselectivity of the gold(I)-catalyzed aldol reaction has been studied.19,20 Improvements in stereoselectivity can be obtained in certain cases by modification of the terminal N,N-dimethylamino substituent in the side chain of (R)-(S)-(1),2,9,10,12,21 (compare eqs 4 and 9) as well as the aryl substituents on phosphorus.22 Several recent studies have appeared dealing with the elucidation of the stereoselective transition-state geometry.8,23-25 An elegant study of aldol stereochemistry has important implications on the stereoselective transition-state geometry for the gold(I)-catalyzed aldol reaction.26 A report has appeared describing the use of a neutral gold(I) ferrocenylamine catalyst for asymmetric aldol reactions, albeit in lower diastereo- and enantioselectivity.27

The gold(I)-catalyzed aldol reaction has been applied to the synthesis of several natural products including cyclosporin's unusual amino acid MeBmt, in which two of the three product stereocenters were generated by the reaction of 2-(R)-methyl-4-hexenal with ethyl a-isocyanoacetate (eq 10).28 Although either enantiomer of the trans-dihydrooxazole can be obtained by using (R)-(S)-(1) or (S)-(R)-(1), a modest effect due to matching and mismatching of substrate and ligand chirality is apparent (double stereodifferentiation).29 Methylation of the trans-dihydrooxazole with Trimethyloxonium Tetrafluoroborate followed by aqueous sodium bicarbonate hydrolysis gives the formamido ester enantiomerically pure after crystallization. The absolute configuration of the two stereocenters formed was confirmed by X-ray crystallography. Careful hydrolysis of the formamido ester to avoid skeletal rearrangement yields MeBmt. In this kilogram scale synthesis, the catalyst can be recovered by precipitation with either diethyl ether or pentane, and can be recycled a number of times without any loss of activity or selectivity.

The gold(I)-catalyzed asymmetric aldol reaction with the chiral ligand (R)-(S)-(2) has been applied in the synthesis of D-erythro- and threo-sphingosines (eq 11).30 The D-erythro-sphingosine can be prepared from the threo isomer by inversion of the C-3 hydroxyl group.

Chiral b-Hydroxy-a-Aminophosphonic Acids.

An enantioselective synthesis of substituted dihydrooxazolin-4-yl phosphonates was reported by the reaction of an aldehyde with a-isocyanomethylphosphonate ester catalyzed by (R)-(S)-(1) (eq 12).31 The enantiomeric purity of the product was determined by 31P{1H} NMR spectroscopy using the chiral solvating reagent (S)-(+)-2,2,2-trifluoro-1-(9-anthryl)ethanol. Independently, an asymmetric synthesis of a-aminophosphonic acids was reported using the chiral ferrocenylamine catalyst (R)-(S)-(3) (eq 13).32

Asymmetric Allylation.

Asymmetric allylation of b-diketones using the palladium analog of (1) has been described.4 Higher enantioselectivity can be achieved in this case using ferrocenylamines with a modified alkyl side chain.4 For synthetically useful ferrocenylamine complexes of other metals, see (R)-N-[2-(N,N-Dimethylamino)ethyl]-N-methyl-1-[(S)-1,2-bis(diphenylphosphino)ferrocenyl]ethylamine.


1. Sawamura, M.; Ito, Y. CRV 1992, 92, 857.
2. Hayashi, T.; Sawamura, M.; Ito, Y. T 1992, 48, 1999.
3. Mastalerz, P. in Handbook of Organophosphorus Chemistry; Engel, R., Ed.; Dekker: New York, 1992; pp 336-339.
4. Sawamura, M.; Nagata, H.; Sakamoto, H.; Ito, Y. JACS 1992, 114, 2586.
5. Bonati, F.; Minghetti, G. G 1973, 103, 373.
6. 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.
7. Ito, Y.; Sawamura, M.; Hayashi, T. JACS 1986, 108, 6405.
8. Togni, A.; Pastor, S. D. JOC 1990, 55, 1649.
9. Ito, Y.; Sawamura, M.; Hayashi, T. TL 1987, 28, 6215.
10. Ito, Y.; Sawamura, M.; Shirakawa, E.; Hayashizaki, K.; Hayashi, T. T 1988, 44, 5253.
11. Togni, A.; Pastor, S. D. HCA 1989, 72, 1038.
12. Ito, Y.; Sawamura, M.; Shirakawa, E.; Hayashizaki, K.; Hayashi, T. TL 1988, 29, 235.
13. Ito, Y.; Sawamura, M.; Hitoshi, H.; Emura, T.; Hayashi, T. TL 1989, 30, 4681.
14. Ito, Y.; Sawamura, M.; Kobayashi, M.; Hayashi, T. TL 1988, 29, 6321.
15. Pastor, S. D.; Togni, A. JACS 1989, 111, 2333.
16. Togni, A.; Pastor, S. D. Chirality 1991, 3, 331.
17. (a) Togni, A.; Häusel, R. SL 1990, 633. (b) Togni, A.; Rihs, G.; Blumer, R. E. OM 1992, 11, 613.
18. (a) Nagel, U.; Rieger, B. OM 1989, 8, 1534. (b) Burgess, K.; Ohlmeyer, M. J.; Whitmire, K. H. OM 1992, 11, 3588 and references therein.
19. Pastor, S. D.; Togni, A. TL 1990, 31, 839.
20. Pastor, S. D.; Togni, A. HCA 1991, 74, 905.
21. Hayashi, T. PAC 1988, 60, 7.
22. Hayashi, T.; Yamazaki, A. JOM 1991, 413, 295.
23. Sawamura, M.; Ito, Y.; Hayashi, T. TL 1990, 31, 2723.
24. Togni, A.; Blumer, R. E.; Pregosin, P. S. HCA 1991, 74, 1533.
25. Pastor, S. D.; Kesselring, R.; Togni, A. JOM 1992, 429, 415.
26. Denmark, S. E.; Henke, B. R. JACS 1991, 113, 2177.
27. Togni, A.; Pastor, S. D.; Rihs, G. JOM 1990, 381, C21.
28. Togni, A.; Pastor, S. D.; Rihs, G. HCA 1989, 72, 1471.
29. (a) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. AG(E) 1985, 24, 1. For earlier reports, see (b) Heathcock, C. H.; White, C. T. JACS 1979, 101, 7076. (c) Horeau, A.; Kagan, H.-B.; Vigneron, J.-P. BSF 1968, 3795.
30. Ito, Y.; Sawamura, M.; Hayashi, T. TL 1988, 29, 239.
31. Togni, A.; Pastor, S. D. TL 1989, 30, 1071.
32. Sawamura, M.; Ito, Y.; Hayashi, T. TL 1989, 30, 2247.

Stephen D. Pastor

Ciba-Geigy Corporation, Ardsley, NY, USA



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