Synthesis of (5S)-Tricyclic Penems as Novel and Potent Inhibitors of Bacterial Signal Peptidases

Abstract

(5S)-Tricyclic penems were synthesized for the first time via intramolecular cyclization of penem epoxy amides catalyzed by a weak Lewis acid [Mg(ClO₄)₂]. Due to the high degree of ring strain in these molecules, mild reaction conditions were developed to successfully construct penem intermediates and the tricyclic penem final products. These tricyclic penems and other newly synthesized (5S)-penem esters and amides exhibited good-to-high potency when tested as inhibitors of bacterial signal peptidases.

Key words

tricyclic penems - β-lactams - cyclization - epoxidation - signal peptidase - inhibitors

References

• 1a Trias J. Gordon EM. Curr. Opin. Biotechnol.  1997,  8:  757 
• 1b Brickner SJ. Chem. Ind. (London)  1997,  131 
• 2 Dalbey RE. Lively MG. Bron S. van Dijl JM. Protein Sci.  1997,  6:  1120 
• 3a Dulbey RE. Wickner W. J. Biol. Chem.  1985,  260:  15925 
• 3b Dalbey RE. Features  1995,  61:  586 
• 3c Stephens C. Shapiro L. Chem. Biol.  1997,  4:  637 
• 4a Allsop AE. Brooks G. Bruton G. Coulton S. Edwards PD. Hatton IK. Kaura AC. McLean SD. Pearson ND. Smale TC. Southgate R. Bioorg. Med. Chem. Lett.  1995,  5:  444 
• 4b Allsop AE. Brooks G. Edwards PD. Kaura AC. Southgate R. , J. Antibiotics  1996,  49:  921 
• 4c Black MT. Bruton G. Curr. Pharm. Des.  1998,  4:  133 
• 5 Date T. J. Bacteriol.  1983,  154:  76 
• 6a Ernst I. Gosteli J. Greengrass CW. Holick W. Jackman DE. Pfaendler HR. Woodward RB. J. Am. Chem. Soc.  1978,  100:  8214 
• 6b McCombie SW. Ganguly AK. Med. Res. Rev.  1988,  8:  393 
• 7 Georg GI. The Organic Chemistry of β-Lactams   VCH; Weinheim: 1993. 
• 8 Tanaka R. Iwata H. Ishiguro M. J. Antibiotics  1990,  43:  1608 
• For review, see:
• 11a Fatiadi AJ. Synthesis  1976,  65 
• 11b Fatiadi AJ. Synthesis  1976,  133 
• 11c See also for an experimental procedure: Gilow HM. Jones G. Org. Synth., Coll. Vol. 7   Wiley; New York: 1990.  p.102 
• 12a Dess DB. Martin JC. J. Org. Chem.  1983,  48:  4155 
• 12b Dess DB. Martin JC. J. Am. Chem. Soc.  1991,  113:  7277 
• 13 For a review, see: Gutsche D. Org. React.  1954,  8:  364 
• 15 Personal communication with Professor Henry Rapoport at University of California, Berkeley
• 16 Seki M. Kondo K. Kuroda T. Yamanaka T. Iwasaki T. Synlett  1995,  609 
• 17 Unpublished results.
• 19 Cregg KM. Wilding EI. Black MT. J. Bacteriology  1996,  178:  5712 
• 20 Tschantz WR. Paetzel M. Cao G. Suciu D. Inouye M. Dalbey RE. Biochemistry  1995,  34:  3935 
• 22 Paetzel M. Dalbey RE. Strynadka NCJ. Nature (London)  1998,  396:  186 

9

The characterization of (5S)-Penems was based on MS and NMR analyses. In the ¹H NMR spectrum, both 5S- and 5R-isomers show similar peak patterns, but different chemical shifts. The most diagnostic peaks are CH-5, CH-6 and CH₃-8. In the 5S-isomer, a large coupling constant J = >4 Hz (vs J = <2 Hz for 5R-isomer) for CH-5 indicated a cis relationship with CH-6.

10

A thiozone by-product was isolated and characterized. Similar observation was descried by authors in Ref. [5]

14

Although the initially formed penem sodium salt was readily isolated and found relatively stable under ambiguous conditions, the acid was obtained in <5% yield after flash chromatography separation.

18

All compounds showed satisfactory analytical data.

21

The E. coli SPase was kindly provided by Dr. R. E. Dalbey (Ohio State University).