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Novel Applications of Imidazolidinone Chiral Auxiliaries

Gregory H. P. Roosa and Sundari Balasubramaniamb

a Chemistry Department, College of Science, Sultan Qaboos University, P O Box 36, Al-Khod, Sultanate of Oman 123.
b Chemistry Department, Murdoch University, South Street, Murdoch 6150, Western Australia.

The utility of homochiral imidazolidin-2-ones in synthesis has only recently been reviewed for the first time.1 Members of this class of readily accessible chiral adjuncts have now proven themselves as competitive control elements in both stoichiometric diastereoselective processes as well as in the role of ligands for catalytic asymmetric synthesis.
This contribution describes some ongoing extensions in the use of the ephedrine-derived (4R,5S)-imidazolidin-2-one auxiliaries 1 and 2 in further highly stereoselective coupling reactions.

This current work has followed 2 distinct directions:
A. The stereoselective entry to [alpha]-amino phosphonates.
B. The stereoselective synthesis of [beta]-amino acids.


In a recent publication, Chung and Kang have reported an investigation of a range of chiral auxiliaries to control the stereoselectivity of phosphite addition to imines.2 Unfortunately, greatest control was achieved with the relatively labour-intensive Oppolzer camphorsulfonamide auxiliary.3 As depicted in Scheme 1, this one-pot procedure may be performed in a highly stereoselective manner with the corresponding urea derivatives of auxiliaries 1 and 2. As might be anticipated, the poorest diastereomeric excess was obtained in the low sterically demanding case of acetaldehyde (leading to 5c) where facial discrimination in the intermediate N-acylimine is most challenging.

Scheme 1 Stereoselective [alpha]-Amino Phosphonate Formation



Yield 5 (%)a





5a (70)





5b (52)





5c (42)





5d (68)



a Isolated yield after recrystallization. b As determined by HPLC on a silica column

The correlation of the absolute sense of stereochemistry of the [alpha]-aminophosphonates was provided by hydrolysis of 5a to give the corresponding phosphophenylglycine. This product gave a rotation that is in agreement with reported values for the (S)-configuration, and is consistent with frontside attack of the phosphorous nucleophile on the s-cis/E conformation of the N-acylimine intermediate.


One of the three primary strategies to [beta]-amino acids has been the addition of enolate equivalents to imines.4 In an example of this approach, a recent contribution by Wyatt and co-workers has sought to exploit the lithium and titanium enolates of an Evans N-acyloxazolidin-2-one in this role.5 This prompts us to report our findings in this area. Here, whilst use of the ephedrine-derived auxiliary 1 again improved stereoselectivity, the complete preference for syn selectivity is in contrast to the reported work. The results in Scheme 2 are only for the enolate based on auxiliary 1, since the alternative cyclohexyl analogue proved to be extremely unreactive, possibly due to severe steric crowding during approach of the Ti-complexed imine to the Ti-chelated enolate.

Scheme 2 Stereoselective Imine Coupling


Ratio 7 : 8

7 Yield%

8 Yield%









a Not isolated

As can be seen, the reactions produced only 2 of the possible 4 stereoisomers (as judged by 300MHz NMR) with good selectively between the minor anti and major syn diastereomers. The high degree of crystallinity of these high-melting products allowed for their ready separation by crystallisation. The absolute stereochemistry of the products was confirmed by hydrolytic removal of the auxiliary and comparison of the rotation of the N-Tos amino acids with reported values.
1. Roos, G. H. P., S. Afr. J. Chem., 1998, 51, 1
2. Chung, S-K., Kang, D-H., Tetrahedron: Asymmetry., 1996, 7, 21.
3. Oppolzer, W., Chapius, C., Bernardinelli, G., Tetrahedron Lett., 1984, 25, 5885.
4. Hart, D. J., Ha, D-C., Chem. Rev., 1989, 89, 1447.
5. Abrahams, I., Motevalli, M., Robinson, A. J., Wyatt, P. B., Tetrahedron, 1994, 50, 12755.
6. Drewes, S. E., Malissar, D. G., Roos, G. H. P., Chem. Ber., 1993, 126, 2663.
The imidazolidin-2-one auxiliaries 1 and 2, as well as derivatives 6 were prepared as previously described.6
Preparation of Ureas (3): A stirred solution of the appropriate imidazolidin-2-one (1 equiv.) in dry THF was treated with n-BuLi at 0°C. After 30 min, ethyl chloroformate (1 equiv.) was added and the mixture stirred for 1 hr at 0°C before quenching with saturated NaHCO3. The THF was removed under reduced pressure and the residue partitioned between H2O and CH2Cl2. The organic phase was dried (MgSO4) and concentrated to give the crude ethyl formate derivative. This intermediate was taken up in further THF and treated with excess concentrated aqueous NH3 (~25 equiv) and the mixture stirred at room temperature overnight. The white precipitated product was filtered, washed with H2O, and recrystallized from EtOAc. (3a 95% yield, m.p.240°C, [[alpha]]D -2.3°; 3b 95% yield, m.p.130°C, [[alpha]]D -1.1°).
Preparation of [alpha]-Amino Phosphonates (5): A mixture of urea (1mmol), diethyl phosphite (1.5mmol), and acetyl chloride (5ml) at 0°C under dry argon, was treated with the aldehyde (1.5mmol) over 10 min. The reaction mixture was stirred at this temperature for 30 min, and then for 1 hr at room temperature. Standard extractive workup afforded the products. (refer to Scheme 1).
Imine Coupling: To a stirred solution of the appropriate imidazolidin-2-one (1 equiv.) in dry CH2Cl2 (4 ml) at 0°C were added iPr2NEt (1.2 equiv.) and TiCl4 (1.1 equiv.). The resultant purple enolate was stirred at 0°C for 20 minutes, cooled to 55°C, and treated with a premixture of TiCl4 (1.5 mmol) and N-(benzylidene) toluene-4-sulphonamide (1.5 mmol) in CH2Cl2 (4 ml). The mixture was stirred at - 55°C for 3h, quenched with saturated aqueous ammonium chloride (20 ml), warmed to room temperature, and extracted with CH2Cl2 (3x20 ml). The organic phase was dried (MgSO4) concentrated and purified. (7 R = Me, m.p.210°C, [[alpha]]D -7.8°; 8 R = Me, m.p.242°C, [[alpha]]D -178°; 8 R = Ph, m.p.262°C, [[alpha]]D -118°)