Asymmetric Synthesis of a New Monocyclic β-Lactam as a potential biological active compound

The asymmetric synthesis of monocyclic β-lactams belong to five categories: a) asymmetric induction from the imine component; b) asymmetric induction from the ketene component; c) double stereodifferentiating cycloadditions; d) carbacephem intermediates and e) 2-oxaisocephems and 2-isocephems. The asymmetric induction in the reaction of achiral ketenes with chiral imines has been effected from imines derived from chiral aldehydes and achiral amines and also from imines derived from chiral amines and achiral aldehydes[1,2,3,4,5,6]. Hashimoto and his coworkers have used chiral imines derived from erythro 2-methoxy-1,2-diphenylethylamine and aromatic aldehydes to prepare β-lactams in good yields with high diastereoselectivity [7]. Recently high levels of asymmetric induction has also been reported for monocyclic β-lactam formation [8,9]. Thus, we decided to synthesize a diastereoselective monocyclic β-lactam using the asymmetric induction by the chiral imine component and achiral ketene.

Treatment of S- (-)-tyrosine ethyl ester hydrochloride with 2-hydroxybenzaldehyde (salicylaldehyde) in the presence of triethylamine in dry benzene afforded Schiff base 1 as a yellow crystal. This chiral Schiff base was then transformed into the monocyclic β-lactam 2 bytreatment with achiral ketene which was prepared in situ from phthaloylglycyl chloride and triethylamine in dry methylene chloride.

To the cold solution of mixture of Schiff base 1 (3.13 g, 10.00 mmol) and phthaloylglycyl chloride (2.37 g, 10.00 mmol) in dry methylene chloride (30 ml/g of phthaloyl), was added slowly triethylamine (1.31 g, 13.00 mmol) in methylene chloride (10 ml/g of the base). The reaction mixture was stirred at room temperature for 24 hours. The formation of new product was confirmed by the presence of β-lactam carbonyl group at 1780 cm^-1 in its IR spectrum. Then it was washed with water (3×30 ml). The organic layer was separated and dried (Na₂SO₄), filtered and the solvent was evaporated under reduced pressure. The crude β-lactam 2 was recrystalized from ether-hexane (3.13 g, 61%).

This [2+2] cycloaddition (Staudinger reaction) afforded the cis stereoisomer. The coupling costant for H₃ and H₄ was 6.19 Hz which is consistent with this kind of geometry. The other stereoisomer was not detected in TLC and NMR. Its biological activities such as antibacterial, antifungal, antiproliferative are under study.

Melting point: 158-160°C.

IR(KBr, cm^-1): 1725; 1775 (Phthalimido CO); 1740 (CO₂Et); 1784 (β-lactam CO); 3180-3300 (OH).

¹H-NMR (250MHz, CDCl₃): δ= 1.09-1.14 (3H, t, CH₃); 3.11-3.20 (1H, t, CHCO₂Et); 4.10-4.32 (4H, m, PhCH₂, OCH₂); 4.40-4.54 (1H, d, J=6.19 Hz, H₄); 4.61-4.88 (1H, d, J=6.19, H₃); 6.99-7.92 (12H, m, ArH).

MS (m/z, %): 500 (M⁺, 3.6%); 499 (M⁺ -1, 3.9%); 174 (PhthCH₂CH_2, 100.00%).