BF₃·Et₂O-Mediated Cascade Cyclizations: Synthesis of Schweinfurthins F and G

Abstract

The total synthesis of the natural stilbene (+)-schweinfurthin G (8) has been accomplished through a sequence based on an efficient cationic cascade cyclization. This cascade process is initiated by Lewis acid promoted ring opening of an epoxide and terminated through a novel reaction with a phenolic oxygen “protected” as its MOM ether. Several Lewis acids have been examined for their ability to induce this new reaction, and BF3·Et2O was found to be the most effective. The only major by-product under these conditions was one where the expected secondary alcohol was found as its MOM ether derivative (e.g. 30). While this by-product could be converted to the original target compound through hydrolysis, it also could be employed as a protected alcohol to allow preparation of a benzylic phosphonate (43) without dehydration of the secondary alcohol. The resulting phosphonate was employed in a Horner-Wadsworth-Emmons condensation with an aldehyde representing the right half of the target compounds, an approach complementary to previous studies based on condensation of a right half phosphonate and a left half aldehyde.

Biomimetic Synthesis of Polyether Natural Products via Polyepoxide Opening

“…Epoxide-opening cascades are, however, in no way limited only to the synthesis of polycyclic polyether natural products. Cascade cyclizations that involve epoxide-opening steps have, in fact, found use in many syntheses of natural products outside the polyether families discussed herein (i.e., schweinfurthins and wortmannin) [220][221][222][223][224].…”

Functional Evaluation of a Fluorescent Schweinfurthin: Mechanism of Cytotoxicity and Intracellular Quantification

“…Until relatively recently, a scheme for schweinfurthin B synthesis was unknown (Topczewski et al, 2009). Although early attempts failed to yield the natural products, closely related schweinfurthin analogs did provide insight into the structure-function relationships of schweinfurthin-like compounds Mente et al, 2007Mente et al, , 2008Ulrich et al, 2010). The left half of the molecule is required for potent biological activity, although some conservative substitutions are allowed (Fig.…”

Synthesis of the cis-fused hexahydroxanthene system via cationic cascade cyclization

“…16 Based on these studies, we hypothesized that starting with an aryl epoxide containing the 2Z-olefin geometry (e.g., 5, Fig. 2) would result in a cis ring fusion through the cascade process via one of two reasonable transition states, affording either hexahydroxanthene 6 or 7.…”

“…In a similar sense, addition of an electrophile could initiate a cationic cascade leading to the cis-fused natural products if Br + (for cymobarbatol) or H + (for ugonstilbene B) were added to the terminal olefin of a neryl system (i.e., a 2Z-olefin). Biomimetic syntheses leading from E-olefins to trans-fused hexahydroxanthenes have been reported, [14][15][16] but there is little information on the synthesis of these cis-fused natural products. During the course of their elegant studies on Lewis acid-assisted chiral Bronsted acids, 17,18 Yamamoto and co-workers have shown that achiral nerylphenol cyclizes in modest yield and low ee when treated with a nonracemic catalyst, but does give only the cis-fused skeleton.…”

“…Saponification of ester 11 afforded (R)-6,7-epoxynerol (12) which was then converted to the desired allylic bromide 13 via the mesylate. Immediate coupling of this allylic bromide with the presumed cuprate 23 formed from known aryl bromide 14 16 afforded the desired cyclization precursor, aryl epoxide 15, in moderate yield.…”