The removal of intervening sequences from transcripts is catalyzed by the spliceosome, a multicomponent complex that assembles on the newly synthesized pre-mRNA. Pre-mRNA translation in the cytoplasm leads to the generation of aberrant proteins that are potentially harmful. Therefore, tight control to prevent undesired pre-mRNA export from the nucleus and its subsequent translation is an essential requirement for reliable gene expression. Here, we show that the natural product FR901464 (1) and its methylated derivative, spliceostatin A (2), inhibit in vitro splicing and promote pre-mRNA accumulation by binding to SF3b, a subcomplex of the U2 small nuclear ribonucleoprotein in the spliceosome. Importantly, treatment of cells with these compounds resulted in leakage of pre-mRNA to the cytoplasm, where it was translated. Knockdown of SF3b by small interfering RNA induced phenotypes similar to those seen with spliceostatin A treatment. Thus, the inhibition of pre-mRNA splicing during early steps involving SF3b allows unspliced mRNA leakage and translation.

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Keywords natural products; pyrans; polyethers; metathesisThe halichondrin family of marine polyethers, first defined by the isolation and structure elucidation of norhalichondrin A by Uemura and co-workers in 1985, now numbers ~ 15 compounds.[1] The structures of the halichondrins, as exemplified by norhalichondrin B (Figure 1) are characterized by a 53-55 carbon backbone that is defined by two domains: the spiroketal containing C31-C53/55 region and a C1-C30 macrolactone that also contains a 2,6,9-trioxatricyclo[3.3.2.0 3,7 ]decane. The structures, in conjunction with impressive levels of cytotoxicity, have attracted significant scientific attention [2,3] highlighted by the total syntheses of halichondrin B and norhalichondrin B by Kishi in 1992, [3,5] and the current efforts of Eisai Pharmaceuticals to establish E7389,[6] a truncated analog of the macrolactone, as an anti-cancer therapeutic. In this communication we describe our studies that have culminated in the total synthesis of norhalichondrin B.Our overall plans are defined in Figure 1, and involve a late stage Horner-Wadsworth-Emmons coupling of C40-C53 domain, 2 with phosphonate 3. Phosphonate 3 can be traced back to C1-C13 domain 5 and C12-C38 domain 4. In the forward sense, we envisioned that these two domains would be connected by a combination of cross-metathesis and macrolactonization as the key reactions. The C12-C38 domain 4 could be further dissected to arrive at pyranopyran 6 and the C14-C26 THF-ring containing domain 7.[7] Pyran 2 and pyranopyran 6 would ultimately be prepared by the application of our recently reported furan→pyranone conversion, [8] and pyranopyran 5 would arise from a tandem ring-opening-ring-closing metathesis of an oxabicyclo[3.2.1]octene. [9]

Cut it out! Convenient procedures have been delineated for the synthesis of optically active, functionalized 1,1‐diarylethanes by decarbonylation of β,β‐diarylpropionaldehydes. The process can be conducted as a one‐pot 1,4‐addition/decarbonylation sequence. Aldehydes are used as removable steering groups in this new strategy for the preparation of optically active building blocks.

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Without a trace: Benzylic nitroalkanes are reduced to the corresponding parent alkanes in good yields by using a simple procedure involving heterolytic CN bond cleavage (see scheme). Traceless removal of the nitro group leaves behind a stereogenic center that may otherwise be difficult to install. This reaction significantly expands the scope of building blocks that can be accessed.

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