A concise, protecting group-free total synthesis of (−)-fusarisetin A (1) was efficiently achieved in 9 steps from commercially available (S)-(−)-citronellal. The synthetic approach was inspired by our proposed biosynthesis of 1. Key transformations of our strategy include a facile construction of the decalin moiety that sets the stage for a stereoselective IMDA reaction and a one-pot TEMPO induced radical cyclization/aminolysis that forms the C ring of 1. Our route is amenable to analogue synthesis for biological evaluation.

Fusarisetin A (1) is a recently isolated natural product that displays an unprecedented chemical motif and remarkable bioactivities as a potent cancer migration inhibitor. We describe here our studies leading to an efficient and scalable total synthesis of 1. Essential to the strategy was the development of a new route for the formation of a trans-decalin moiety of this compound and the application of an oxidative radical cyclization (ORC) reaction that produces fusarisetin A (1) from equisetin (2) via a bio-inspired process. TEMPO-induced and metal/O2-promoted ORC reactions were evaluated. Biological screening in vitro confirms the reported potency of (+)-1. Importantly, ex vivo studies show that this compound is able to inhibit different types of cell migration. Moreover, the C5 epimer of (+)-1 was also identified as a potent cancer migration inhibitor, while (−)-1 and 2 were found to be significantly less potent. The optimized synthesis is applicable on gram scale and provides a solid platform for analogue synthesis and methodical biological study.

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An enantioselective formal synthesis of (−)-englerin A (1) is reported. Key to the strategy is a Rhcatalyzed [4+3] cycloaddition reaction between furan 10 and diazoester 11 that, following an intramolecular aldol condensation, produces the tri-cyclic scaffold of englerin. This strategy also provides a rapid, efficient and stereoselective access to the biologically significant core motif of the guaiane sesquiterpenes.Renal cell carcinoma (RCC also known as hypernephroma) is a type of kidney cancer that originates in the small tubes in the kidneys that filter the blood and remove waste products. This cancer ranks among the ten leading cancer types in the United States and only in 2009, it was responsible for about 58000 new cases and 13000 deaths.1 Importantly, RCC is resistant to radiation and chemotherapy leaving partial or radical nephrectomy as the only means of treatment. Therefore the search for new compounds that can safely and effectively block or reverse RCC remains a high priority.Efforts to identify new small molecule leads against RCC led to the identification of englerin A (1) and B (2) (Figure 1) from the Tanzanian plant Phyllanthus engleri. 2 From the standpoint of biogenesis, the englerins are guaiane-type sesquiterpenes that contain an uncommon oxygenated motif (Figure 1). Structurally related members of this family include orientalols E (3) and F (4)3 and pubinernoid B (5)4 (Figure 1). Most likely, this motif originates from a more common bicyclic-sesquiterpenes core via a sequence of oxygenations and acid-induced oxo-cyclization reactions highlighted in Scheme 1.3Remarkably, englerin A (1) showed highly potent and selective cytotoxicities against various renal cancer cell lines at low nanomolar level.2 Preliminary biological investigations also showed a significant drop of potency and selectivity of englerin B (2), suggesting that the substitution at the C-9 position by the glycolate ester may be important for the activity and selectivity of englerins.2Correspondence to: Emmanuel A. Theodorakis, etheodor@ucsd.edu. Supporting Information Available: Experimental procedures and characteristic data of new compounds, as well as X-ray data of compound 13. This material is available free of charge via the Internet at http://pubs.acs.org. Due to its promising anticancer activity and its scarcity from natural sources, englerin A has become an intriguing target in synthetic and medicinal chemistry. The absolute configuration of 1 was confirmed by Christmann et al. in their first total synthesis of ent-1 in 2009.5 More recently, three additional syntheses were reported, by Ma,6 Echavarren7 and Nicolaou8 the first two of which were enantioselective. In addition, a stereoselective approach to the guaianolide core of these sesquiterpenes has been disclosed.9 NIH Public AccessInspired by the unusual tricyclic motif, we sought to design a general approach leading not only to the structures of 1 and 2 but also to various guaiane analogues, such as orientalols E (3) and F (4) and pubinernoid B (5). We env...

An efficient formal synthesis of (−)-englerin A (1) is reported. The target molecule is a recently isolated guaiane sesquiterpene that possesses highly potent and selective activity against renal cancer cell lines. The developed strategy proceeds in an enantioselective manner by constructing the BC ring system of 1 via a Rh(II)-catalyzed [4+3] cycloaddition and subsequently attaching the A ring via an intramolecular aldol condensation reaction. As such, this strategy allows the synthesis of truncated englerins. Evaluation of these analogues in A498 renal cancer cell line suggests that the A ring of englerin is crucial to its antiproliferative activity. Moreover, evaluation of these analogues led to the identification of potent growth inhibitors of CEM cells with GI50 values ranging from 1–3 μM.