1 糸状菌の生産するアシルCoA : コレステロールアシル基転移酵素(ACAT)阻害剤ピリピロペンの全合成研究(口頭発表の部)

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Rccently we disclosed the isolation, biological properties, and structures of the pyripyropenes which apparently represent the most potent naturally ACAT inhibitors reported to date. Importanly, pyripyropene A 1 proved to be orally active in a hamsters, reducing cholesterol. Herein, we describe the first total synthesis of pyripyropene A 1. The key step is the coupling reaction between α-pyrone-pyridine moiety 4 and the acid chloride of sesquiterpene moiety 3 in the presence of Lewis acid to construct ketone 2. The sesquiterpene moiety has been synthesized via stereoselective reductive formylation, palladium associated carbonylation, and allylic oxidation started from (+)-Wieland-Wiescher ketone. As our point of departure, keto alcohol 7 was treated with tetramethylammonium triacetoxyborohydride to furnish the trans-diol 8 stereoselectively. The benzyl protection of 8 followed by dekatalization gave 9. Treatment of the enol silyl ether derived from 9 (KDA/Me_3SiCl) with methyl iodide and benzyltrimethylammonium fluoride (BTAF) afforded mono-methylated ketone 10. 10 was treated with triflic anhydride in the presence of di-t-butyl-4-methylpyridine to give enol triflate 11. Next, palladium-catalyzed carbonylation (CO atomosphere, Pd(OAc)_2, PPh_3, Et_3N, MeOH, DMF) of 11 as described by Stille obtained the methyl ester 12. Allylic oxidation (SeO_2, in dioxane, reflux) of 12 followed by PCC oxidation gave ketone 13. Stereoselective reduction (NaBH_4, CeCl_3 in MeOH) of 13 afforded 14. Deprotection (H_2, Pd(OH)_2 in MeOH, and 1-propanethiol, NaH in DMF) of 14 followed by per-acetylation (Ac_2O, DMAP in pyridine) gave carboxylic acid 15. 15 was converted to acid chloride 3 in treatment with SOCl_2. Next, the key reaction, the coupling reaction between acid chloride 3 and α-pyrone-pyridine 4 was treated with CF_3COOH to obtain ketone 2. Finally, stereoselective reduction of 2 (NaBH_4, CeCl_3 in MeOH) gave pure (+)-pyripyropene A 1. In summary, the first total synthesis of pyripyropene A 1, which were effective and concise convergent approach, designed to afford easy access to both the natural products and a variety of analogs, has been achieved.
天然有機化合物討論会の論文
1995-09-01

1 糸状菌の生産するアシルCoA : コレステロールアシル基転移酵素(ACAT)阻害剤ピリピロペンの全合成研究(口頭発表の部)

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