97(P-30) Synthesis and Determination of the Absolute Configurations of Pentenocins, Novel Inhibitors of Caspase-1
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Pentenocins A (1) and B (2) were isolated by Omura et al. in 1999. The planar structures of 1 and 2 were determined by NMR spectral analysis, however, the relative and absolute configurations of these cyclopentenones were not elucidated. We report here the syntheses of the four possible racemic pentenocins B 3〜6 and the first synthesis of (+)-pentenocin B, and the determination of the relative and absolute configurations of natural pentenocin B. We synthesized the four possible racemic pentenocins B 3〜6 to determine the relative configuration of pentenocin B using racemic ketodicyclopentadiene (KDP) 8 as the common starting material. 8 was converted to the 1,4-diols 10a and 10b as an 86:14 mixture of diastereomers. Although the configurations of the diastereomers 10a and 10b were not determined, the major alcohol of 10a was transformed to the ketone 13a. The retro Diels-Alder reaction of 13a was performed to the cyclopentenone 14a. Finally, 14a was treated with 90% TFA to give (±)-pentenocin B 3 or 4. The minor alcohol 10b was transformed to (±)-pentenocin B 4 or 3 by the same procedures as those for the major alcohol 10a to (±)-pentenocin B 3 or 4. To synthesize (±)-pentenocin B 5 or 6, the mixture of the 1,4-diols 10a and 10b was converted to the α,β-unsaturated ketones 18a and 18b via a Wharton rearrangement. 18a was then converted to (±)-pentenocin B 5. The Z-isomer 18b was transformed to (±)-pentenocin B 6 by the same procedures as those for 18a to 5. The NMR spectrum of synthetic pentenocin B 3 or 4 from the major alcohol 10a was in agreement with those of natural pentenocin B from the comparison of NMR spectra between reported natural pentenocin B and synthetic (±)-pentenocins B 3〜6. Having secured the diastereoselective route to pentenocin B, we then conducted the enantioselective synthesis to determine the absolute stereochemistry of natural pentenocin B. (-)-KDP 8 was transformed to (+)-pentenocin B 3 as shown in scheme 4 with the same procedures as described for the synthesis of the racemic pentenocin B 3 or 4. The (R)-stereochemistry of the C-6 secondary alcohol in (+)-pentenocin B 3 was determined using the modified Mosher method and the X-ray analysis. We then developed new synthetic routes to (+)-pentenocin B 3 from (-)-KDP 8 as shown in the scheme 5 to improve the synthetic yield. In conclusion, we have realized the first enantiocontrolled synthesis of (+)-pentenocin B and determined its absolute stereochemistry to be 4S,5R,6R as compared with the value of optical rotation with natural pentenocin B.
