Dysregulation of protein translation is a key driver for the pathogenesis of many cancers. Eukaryotic initiation factor 4A (eIF4A), an ATP-dependent DEAD-box RNA helicase, is a critical component of the eIF4F complex, which regulates capdependent protein synthesis. The flavagline class of natural products (i.e., rocaglamide A) has been shown to inhibit protein synthesis by stabilizing a translation−incompetent complex for select messenger RNAs (mRNAs) with eIF4A. Despite showing promising anticancer phenotypes, the development of flavagline derivatives as therapeutic agents has been hampered because of poor drug-like properties as well as synthetic complexity. A focused effort was undertaken utilizing a ligand-based design strategy to identify a chemotype with optimized physicochemical properties. Also, detailed mechanistic studies were undertaken to further elucidate mRNA sequence selectivity, key regulated target genes, and the associated antitumor phenotype. This work led to the design of eFT226 (Zotatifin), a compound with excellent physicochemical properties and significant antitumor activity that supports clinical development.

KRW were employees and shareholders when the studies were performed.

Zincke aldehydes, which are readily available from the ring-opening reaction of pyridinium salts, are easily converted into delta-tributylstannyl-alpha,beta,gamma,delta-unsaturated aldehydes (stannyldienals) by the action of tributylstannyllithium. This reaction appears to proceed via 1,6-stannyllithium addition/elimination of lithium dialkylamide. Several stannyldienals of significant utility for the synthesis of polyene natural products have been made by this route, which proceeds in modest yields, but is successful on multigram scale using inexpensive reagents. Simple stannylenals and stannylenones are similarly available from the corresponding vinylogous amides.

The synthesis of natural products of unprecedented structure can drive innovation in strategy and provide opportunities to test the limits of new methodology; therefore, it remains a worthy venture even when the targets are not yet known to possess important biological activity. In that context, we felt that the synthesis of the structurally unusual echinopines (Scheme 1) was warranted for the opportunity to evaluate metal-catalyzed polycyclizations in complex settings, and to access these natural products and structural analogues for a broader evaluation of their biological properties.Echinopines A and B (1 and 2) are sesquiterpenes isolated by Kiyota and co-workers from the root of the plant Echinops spinosus [1] and they probably originate from biosynthetic modification of the guaiane framework (see 3). In spite of the lack of reported biological activity, their novel structure inspired several research groups to embark upon and complete syntheses of these compounds. First, in 2009, Magauer, Mulzer, and Tiefenbacher reported a clever enantioselective route beginning from 1,5-cyclooctadiene; this work served to determine the absolute configuration of these natural products. [2] Shortly thereafter in 2010, Nicolaou, Chen, and co-workers in Singapore reported an asymmetric synthesis of these targets. [3] A formal synthesis followed later that year from Chen and co-workers. [4] We felt that a strategy related to the presumed biogenesis of the echinopines might yield a more direct synthesis than these previous routes. We posited that a bioinspired conversion of a suitably functionalized cis-fused guaiane-like precursor into the tetracyclic core of the echinopines might take place through a transitionmetal catalyzed bicyclization reaction; the cyclopropane acetic acid/ester functional group would then be introduced directly, thus avoiding the multi-step homologation of cyclopropane carboxylate ester intermediates that was employed in previous syntheses. In a third-generation route to the echinopines, Chen and co-workers recently reported the successful execution of a related strategy, providing echinopine B in 25 steps. [5] Herein, we report our synthesis of echinopine B, which proceeds through a concise sequence featuring a one-step conversion of a guaiane-like intermediate to the natural product.Initially, much effort was put forth to generate the fused tricyclic motif, which consisted of the cyclopropane and two cyclopentane rings, and involved either a carbonylative Heck cascade (4!5, Scheme 2a) or a Heck bicyclization terminating in b-hydride elimination (6!7); unfortunately, these approaches were never successful. [6] In late 2009, we were inspired by a PtCl 2 -catalyzed reaction of alkene-tethered propargylic ethers that was disclosed by Michelet and coworkers. [7] In the simple enyne model system 8 (Scheme 2 b), Scheme 1. The echinopines and the related guaiane framework.Scheme 2. a) Attempted Heck cascades to access tricycles relevant to the echinopines. b) Successful enyne cycloisomerization. Bn = benzyl,...

Survival of the human pathogen Streptococcus pneumoniae requires a functional mevalonate pathway, which produces isopentenyl diphosphate, the essential building block of isoprenoids. Flux through this pathway appears to be regulated at the mevalonate kinase (MK) step, which is strongly feedback-inhibited by diphosphomevalonate (DPM), the penultimate compound in the pathway. The human mevalonate pathway is not regulated by DPM, making the bacterial pathway an attractive antibiotic target. Since DPM has poor drug characteristics, being highly charged, we propose to use unphosphorylated, cell-permeable prodrugs based on mevalonate that will be phosphorylated in turn by MK and phosphomevalonate kinase (PMK) to generate the active compound in situ. To test the limits of this approach, we synthesized a series of C 3 -substituted mevalonate analogues to probe the steric and electronic requirements of the MK and PMK active sites. MK and PMK accepted substrates with up to two additional carbons, showing a preference for small substitutents. This result establishes the feasibility of using a prodrug strategy for DPM-based antibiotics in S. pneumoniae and identified several analogues to be tested as inhibitors of MK. Among the substrates accepted by both enzymes were cyclopropyl, vinyl, and ethynyl mevalonate analogues that, when diphosphorylated, might be mechanism-based inactivators of the next enzyme in the pathway, diphosphomevalonate decarboxylase.