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Organic Chemistry Highlights

Total Synthesis

Monday, September 3, 2007
Douglass F. Taber
University of Delaware

The Pettus Synthesis of (+)-Rishirilide B

(+)-Rishirilide (4), an inhibitor of α2-macroglobulin, a tetrameric serum glycoprotein that is an irreversible protease inhibitor, has a deceptively simple structure. Thomas R. R. Pettus of the University of California at Santa Barbara has reported (J. Am. Chem. Soc. 2006, 128, 15625. DOI: 10.1021/ja062987w a concise route to 4, based on the highly regioselective Diels-Alder addition of the enantiomerically-pure dienophile 2 to the diene derived from 1.

The preparation of 2 was carried out from the aldehyde 5. Selective protection of the less hindered phenol followed by reduction gave the benzyl alcohol 6. On exposure to excess Grignard reagent 7, the primary alcohol of 6 apparently underwent elimination to give the o-quinone methide 8, conjugate addition to which gave 9. Mitsunobu coupling of 9 with the lactic acid amide 10 proceeded with clean inversion, to give 11. The methoxy methyl amide of 11 was required for the oxidative dearomatization to 2 to proceed efficiently.

The preparation of the masked diene 1 started with the aldehyde 12. Following the Comins procedure, metalation of the derived hemiaminal alkoxide and subsequent addition of methyl iodide gave 13. Addition of SO2 to the photoenol derived from 13 followed by etherification of the labile secondary alcohol so formed then gave 1.

The dienophile 2 should undergo cycloaddition with high facial selectivity. That is not relevant in this application, as addition to the intermediate quinone methide 14 was followed by elimination and oxidative aromatization. The regioselectivity of the addition, delivering 2, was, however, critical for the success of the synthesis.

With 3 in hand, what remained was a one-carbon homologation. This was accomplished by selective O-acylation with dimethyl carbamoyl chloride 16. Subsequent addition of an excess of anion 17 led, via alkoxide-directed addition to the remaining ketone carbonyl followed by deacylation, to the desired adduct 18. Careful cleavage, to avoid lactone formation, then delivered 4. Note that this synthesis of (+)-rishirilide B (4) would be classified as enantioselective, since the intial stereogenic center of 2, that set the absolute configuration of the dearomatized ring of 2, was not included in the final product.

D. F. Taber, Org. Chem. Highlights 2007, September 3.