The convergent total syntheses of three 14membered macrolide natural products, mutolide, nigrosporolide and (4S,7S,13S)-4,7-dihydroxy-13-tetradeca-2,5,8-trienolide have been achieved. The key synthetic features include Shiina macrolactonization to assemble the 14-membered macrocyclic core, Wittig or Still-Gennari olefination and selective reduction of propargylic alcohol to construct the Eor Z-olefins. Cross metathesis was also highlighted as an efficient tool to forge the formation of E-olefin. The three synthetic macrolides were evaluated for their cytotoxic activity against three human cancer cell lines as well as for inhibitory effect on CFTR-mediated chloride secretion in human intestinal epithelial (T84) cells. Mutolide displayed significant cytotoxic activity against HCT116 colon cancer cells with an IC 50 of ~12 μM as well as a potent CTFR inhibitory effect with an IC 50 value of ~1 μM.
An efficient and convergent synthesis of 5′‐hydroxyzearalenone and 5′β‐hydroxyzearalenone, 14‐membered β‐resorcylic acid lactone (RAL) natural products, has been achieved in a longest linear sequence of 19 steps, and a total of 29 steps, starting from commercially available 5‐hexen‐1‐ol and methyl 2‐(3,5‐dimethoxyphenyl)acetate. The key features of our synthesis include a Jacobsen hydrolytic kinetic resolution, a Mitsunobu esterification and (an E)‐selective ring‐closing metathesis (RCM). Our synthesis also highlights the utility of the acetal protecting group for the resorcylate moiety, and its compatibility with RCM reactions for the synthesis of 14‐membered RALs. The cytotoxic activity of both synthetic compounds was evaluated against seven human cancer cell lines. 5′‐Hydroxyzearalenone shows more potent cytotoxic activity against most of the cancer cell lines tested than its epimer, 5′β‐hydroxyzearalenone. Both compounds show significant cytotoxic activity against the C33A cervical cancer cell line, with IC50 values of 21.33 ± 6.43 µm and 16.00 ± 12.17 µm, respectively.
A convergent total synthesis of 7-O-methylnigrosporolide and pestalotioprolide D has been accomplished in 17 longest linear steps starting with 1.7% and 2.6% overall yields, respectively, starting from (S)-propylene oxide and known (S)-benzyl glycidyl ether. Our synthesis exploited acetylide addition and Shiina macrolactonization to assemble the macrocycle, Lindlar reduction, Wittig and Still–Gennari olefination to construct the three olefins as well as a Jacobsen hydrolytic kinetic resolution to install the stereogenic center. The selection of silyl protecting group of C-4 alcohol was crucial for final deprotection step. Our synthesis also led to a hypothesis that pestalotioprolide D could be an artifact of 7-O-methylnigrosporolide. Cytotoxic activity of both synthetic compounds against six human cancer cell lines was evaluated. Synthetic pestalotioprolide D showed more potent cytotoxic activity against all cancer cell lines tested than 7-O-methylnigrosporolide, and the SiHa cervical cancer cell line was the most sensitive cell to both synthetic compounds.
A new variation of Prins cyclization to directly and stereoselectively synthesize cis-2,6-disubstituted tetrahydropyran-4-ones from 3-chlorohomoallylic alcohols and aldehydes catalyzed by perrhenic acid is reported. The reaction is generally compatible with...
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