Total synthesis of the potent anticancer Aglaia metabolites (-)-silvestrol and (-)-episilvestrol and the active analogue (-)-4'-desmethoxyepisilvestrol | Health & Environmental Research Online (HERO)

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Citation
Tags

HERO ID

3537651

Reference Type

Journal Article

Title

Total synthesis of the potent anticancer Aglaia metabolites (-)-silvestrol and (-)-episilvestrol and the active analogue (-)-4'-desmethoxyepisilvestrol

Author(s)

Adams, TE; El Sous, M; Hawkins, BC; Hirner, S; Holloway, G; Khoo, ML; Owen, DJ; Savage, GP; Scammells, PJ; Rizzacasa, MA

Year

2009

Is Peer Reviewed?

Yes

Journal

Journal of the American Chemical Society
ISSN: 0002-7863
EISSN: 1520-5126

Book Title

Journal of the American Chemical Society

Volume

131

Issue

Page Numbers

1607-1616

Language

English

PMID

19140688

DOI

10.1021/ja808402e

Web of Science Id

WOS:000264791800058

URL

https://pubs.acs.org/doi/10.1021/ja808402e
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Abstract

Total synthesis of the anticancer 1,4-dioxane containing natural products silvestrol (1) and episilvestrol (2) is described by an approach based on the proposed biosynthesis of these novel compounds. The key steps included an oxidative rearrangement of the protected d-glucose derivative 11 to afford the 1,4-dioxane 12, which could be elaborated to the coupling partner 5 and a photochemical [3 + 2]-cycloadditon between the 3-hydroxyflavone 27 and methyl cinnamate followed by base-induced alpha-ketol rearrangement and reduction to give the cyclopentabenzofuran core 33. The core (-)-6 and 1,4-dioxane fragment 5 were united by a highly stereoselective Mitsunobu coupling with the modified azodicarboxylate DMEAD to afford the axial coupled product 36. Deprotection then gave episilvestrol (2). Silvestrol (1) was synthesized by a coupling between core (-)-6 and the dioxane 44 followed by deprotection. Compound 1 was also synthesized from episilvestrol (2) by a Mitsunobu inversion. In addition, the analogue 4'-desmethoxyepisilvestrol (46) was synthesized via the same route. It was found that 46 and episilvestrol 2 displayed an unexpected concentration-dependent chemical shift variation for the nonexchangeable dioxane protons. Synthetic compounds 1, 2, 38, 46, and 54 were tested against cancer cells lines, and it was found that the stereochemistry of the core was critical for activity. Synthetic analogue 4'-desmethoxyepisilvestrol (46) was also active against lung and colon cancer cell lines.