Chemical asymmetric syntheses of the key intermediates (4,6,8) for the __ synthesis of monobactam antibiotics ( SQ 26776 (azthreonam), sulfazecin, and SQ 26180 ) are accomplished from I*)-4-phenylsulfonyl-2-azetidinone. Recently much attention have been focused on the nonclassical B-lactam antibiotics, particularly carbapenem' and monobactam* antibiotics, because of their significant potency for the antibacterial activity. In the course of our synthetic studies on the B-lactam antibiotics, we have established the simple asymmetric synthesis of (+)-4-phenylthio-Z-azetidinone ((+)-2) from (f)-4-phenylsulfonyl-2-azetidinone (1) as well as the formal total synthesis of (+)thienamycin.3 In this communication, we wish to report the simple and efficient synthesis of the chiral key intermediates (4,6,8) for the synthesis of monobactam antibiotics. ___ An introduction of the required functionalities at the C(3) position of a B-lactam ring would be carried out in a stereospecific trans manner by using the optically active 4-phenylthio--2-azetidinone (2). After functionalization at C(3), the phenylthio group at C(4) can be removed by reduction, and it also can serve as a suitable leaving group for stereospecific alkylation at C(4) by appling the chiral functionality at C(3). Thus, the phenylthio group of 2 is expected to work as an anchor in the transfer of the chirality. Firstly, the synthesis of the possible intermediate (4,) for the synthesis of SQ 26776 (z), which is a synthetic monobactam antibiotic developed by Squibb group, 2b,2c,2d was attempted. Since the intermediate (4) has an amino group with B-configuration at C(3), it is required to use (4S)-4-phenylthio-2-azetidinone ((-)-2) as a starting material. (-)-2 was effectively synthesized from (+)-1 by the similar reaction used to the synthesis of (+)-2_. Namely, treatment of (*)-1 with thiophenol (1.2 equiv) in the presence of cinchonine (1.2 equiv) in benzene (190 ml/g) at 33f2"C under an argon atmosphere for 150 hrs afforded (-)-2, [a]k5-63.00 (c=1.03, CHC13), in 97% yield.4 Repeated recrystallization from ether-n-hexane gave the essentially optically pure (-)-2, [~]~5-134.6"(c=l.21, CHC13),5 in ~a. 30% yield from l_. With optically pure (-)-z in hand, it was necessary to introduce the other functional groups. After the zsilyl protection of (-)-2, the lithium enolate of 2 was reacted with 2-naphthalenesulfonyl azide to give the stereochemically pure azide (1Q)6y7 . in 66% yield from 2, which was reduced to the amine (11) by exposure with hydrogen sulfide.8 Because of its instability, 11 was directly acylated by treatment with benzyloxycarbonyl chloride to afford the protected product (12).6 Then 12 was converted to the sulfone (13) by the desilylation, followed by mCPBA oxidation in 61% yield from 10. Finally, treatment of 12 with lithium dimethylcuprate gave the desired g6 stereospecifically in 92% yield. Thus, the conversion of (-)-2 to 4 in 7 steps was accomplished in 38% overall yield. We are grateful to Miss J. Yamamoto and Mr. T. Kasaka for their technical assistance.
We also thank Miss K. Takahashi for NMR spectral measurement.