Total Synthesis of (+)-Schweinfurthins B and E

Abstract

The first total synthesis of (+)-schweinfurthin B, a potent and differentially active cytotoxic agent, has been accomplished. Completion of the synthesis required just 16 steps in the longest linear sequence from commercially available vanillin. Key synthetic transformations included a Shi epoxidation and an efficient cascade cyclization initiated by treatment of the resulting epoxide with BF(3).OEt(2). Furthermore, use of a methyl ether as a stable protecting group for benzylic alcohols dramatically increased the efficiency of the overall sequence. The benzylic ether can be removed from this electron-rich aromatic system through oxidation with DDQ that provided the desired aldehyde intermediate in quantitative yield and shortened the synthetic sequence. Introduction of the A-ring diol in the required cis stereochemistry then became viable through a short sequence highlighted by an aldol condensation with benzaldehyde to introduce an olefin as a latent carbonyl group at the C-3 position. This synthesis established for the first time the absolute stereochemistry of the natural product, and provides access to material on a scale that will advance biological studies. The total synthesis of the closely related compound (+)-schweinfurthin E also is reported.

Synthesis of amide isosteres of schweinfurthin-based stilbenes

“…The complementary carboxylic acid 24 could be prepared by simple oxidation of the aldehyde 23 , a hexahydroxanthene we have used in past syntheses of numerous schweinfurthin analogues. 14 An EDC-mediated condensation of the acid 24 and the amine 22 gave the expected amide 25 , and a final acid-catalyzed hydrolysis of the MOM protecting groups gave the target compound 11 .…”

“…12 The combination of a unique profile of activity with the limited success of efforts to obtain more of the schweinfurthins by isolation from the plant source, has led us to an extended effort to prepare these natural products by chemical synthesis. Our efforts to date have afforded seven of the natural products (schweinfurthins A, 13 B, 14 C, 15 E, 14 F, 16 G 16 and vedelianin 17 ), as well as 3-deoxyschweinfurthin B 18 ( 10 ) which we have used as a lead for a number of structure-activity studies. 19,20 All of the optically active synthetic materials were prepared in high ee through reagent level control of absolute stereochemistry via an enantioselective epoxidation followed by a cascade cyclization to the tricyclic core.…”

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

“…1). 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).…”