1997 Volume 55 Issue 10 Pages 858-867
A novel chiral benzoxazinone auxiliary was developed and applied to the synthesis of carbapenem antibiotics. The auxiliary 2 was easily accessible by the synthesis involving dehydrative condensation of l-menthone with salicylamide followed by stereospecific isomerization with a catalytic amount of 1, 8 -diazabicyclo [5. 4. 0] undec-7-ene (DBU). Excellent diastereoselectivity was observed in the auxiliary-mediated aldol reaction, affording syn-aldols 10 in high yields. A dramatic reversal in diastereofacial selectivities was attained simply by changing the metal, permitting either enantiomeric form of β- hy dr oxy -α-methylcarboxylic acid derivatives 10a or 10b to form from a single readily available benzoxazinone derivative 9. The highly stereoselective aldol reaction was successfully applied to the synthesis of acetoxyazetidinone 3, a key intermediate for penems and carbapenems. The propionate enolate derived from the benzoxazinone derivative 28, 31 reacted smoothly with the acetoxyazetidinone 3 to furnish the intermediate 29 carrying four contiguous asymmetric centers of the 1-β-methylcarba-penems 4 in a high yield with a virtually complete β-selectivity. The high-yield Dieckmann-type cyclization thanks to the high leaving group ability of the auxiliary, and subsequent efficient removal of the protective groups completed a practical synthetic scheme of the 1-β-methylcarbapenems 4 of recent pharmaceutical interest.
