A novel Diels-Alder approach to carbapenems

✍ Scribed by Richard Bayles; Anthony P. Flynn; Ronald H.B. Galt; Susan Kirby; Ralph W. Turner

• Publisher: Elsevier Science
• Year: 1988
• Tongue: French
• Weight: 231 KB
• Volume: 29
• Category: Article
• ISSN: 0040-4039
• DOI: 10.1016/s0040-4039(00)82342-4

✦ Synopsis

An inverse electron demand heter*Diels-Alder reaction between 2-acylaminc+ methylen&-oxobutanoic acid derivatives (5land ketene acetals (61yields crystalline dihydropyrans, which are versatile intermediates in the synthesis of carbapenems. Synthetic carbapenem analogues related to thienamycin show broad spectrum anti-bacterial activity but are rapidly metabolfsed by kidney dehydropeptidase (~~~-111. A second generation of l-B-substituted carbapenems have emerged which show both improved chemical stability and resistance to DHP-12. Recent publications in this area3 have prompted us to reveal some of our synthetic work which has been directed mainly at a commercially viable route to (114. The great interest in carbapenems has produced a wide variety of synthetic approaches to the new p-lactam skeleton 5. The azetidinones (31 have been key intermediates and our retrosynthetic analysis led, via (21 and (3). to the 6-lactones (4) which have four contiguous chiral centres. The lactone (4,Rl=H) was an intermediate in an ingenious synthesis of thienamycin6 but the approach required the inversion of the stereochemistry at C6. Also, in a recent synthesis of 4(Rl=Mel,3b the stereochemistry at C5 had to be inverted. In this communication we describe the facile preparation of the dihydropyrans (7) and (81 utilfsfng a Diels-Alder reaction between the dienes (51 and the ketene acetals (61.7 These dihydropyrans are direct precursors of the lactams (31 or the lactones (4) as described in the next paper.