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

Synthesis and structure activity relationships of schweinfurthin indoles

“…While efforts to secure more material from the natural source have met with limited success, a program to synthesize these natural products has been more rewarding. Our synthesis efforts have determined the absolute stereochemistry of the natural products, 7 provided access to most of the tetracyclic examples in the correct natural stereochemistry, 8–11 and afforded a host of analogues designed to gather information on structure-activity relationships 12–15 and to afford fluorescent 16 or biotinylated 17 probes. From the results of these studies it is now clear that: a) the C-3 hydroxyl group is not essential for activity; b) compounds with a free phenol at C-5 show greater activity than the corresponding methoxy compounds, although both are active; c) methylation of one D-ring phenol improves chemical stability but does not diminish activity greatly; and, d) the para position on the D-ring is tolerant of a variety of substituents.…”

Electrophilic aromatic prenylation via cascade cyclization

“…Various compounds in the broad family display activity as anti-proliferative, 1,2 anti-oxidant, 3-5 chemopreventative, 6 CNS modulating, 7,8 or immunosuppressant agents, 9 and as insect repellents. 10,11 Common methods for incorporation of a prenyl moiety into an aromatic system include the use of lithiated intermediates, 12-15 an approach which displays limited functional group tolerance, Friedel-Crafts alkylation, 12,16-18 which often proceeds in modest yield even with an excess of the arene, or Claisen rearrangements, 19-22 where the regiochemistry both about the allylic system and in the arene can be difficult to control. Our preliminary account 23 of a new reaction sequence based on cascade cyclization with tandem electrophilic aromatic substitution (Figure 1) suggested a route to prenylated aromatic compounds with the potential to overcome at least some of these limitations.…”

Relevance of the C-5 position to schweinfurthin induced cytotoxicity

“…Several portions of the schweinfurthin structure have shown tolerance to modification, including the presence or absence of a hydroxyl group at C-3, 10 methylation of one D-ring phenol 11 (Figure 1, “tolerant”), and especially incorporation of substituents at the para position of the D-ring, including hydrogen or an alkyl, allyl, prenyl, or geranyl group (“highly tolerant”). 12–15 Conversely, modification of other regions resulted in a significant loss of activity, including a cis -fused A/B system, 16 a cis -stilbene or a saturated linkage, 13 and simultaneous methylation of both D-ring phenols (Figure 1, “intolerant”). 11 …”