Daniel Romo

Eukaryotic Initiation Factor 2α-independent Pathway of Stress Granule Induction by the Natural Product Pateamine A

Stress granules are aggregates of small ribosomal subunits, mRNA, and numerous associated RNA-binding proteins that include several translation initiation factors. Stress granule assembly occurs in the cytoplasm of higher eukaryotic cells under a wide variety of stress conditions, including heat shock, UV irradiation, hypoxia, and exposure to arsenite. Thus far, a unifying principle of eukaryotic initiation factor 2α phosphorylation prior to stress granule formation has been observed from the majority of experimental evidence. Pateamine A, a natural product isolated from marine sponge, was recently reported to inhibit eukaryotic translation initiation and induce the formation of stress granules. In this report, the protein composition and fundamental progression of stress granule formation and disassembly induced by pateamine A was found to be similar to that for arsenite. However, pateamine A-induced stress granules were more stable and less prone to disassembly than those formed in the presence of arsenite. Most significantly, pateamine A induced stress granules independent of eukaryotic initiation factor 2α phosphorylation, suggesting an alternative mechanism of formation from that previously described for other cellular stresses. Taking into account the known inhibitory effect of pateamine A on eukaryotic translation initiation, a model is proposed to account for the induction of stress granules by pateamine A as well as other stress conditions through perturbation of any steps prior to the rejoining of the 60S ribosomal subunit during the entire translation initiation process.

Biosynthesis, asymmetric synthesis, and pharmacology, including cellular targets, of the pyrrole-2-aminoimidazole marine alkaloids

The pyrrole-2-aminoimidazole (P-2-AI) alkaloids are a growing family of marine alkaloids, now numbering well over 150 members, with high topographical and biological information content. Their intriguing structural complexity, rich and compact stereochemical content, high N to C ratio (~1 : 2), and increasingly studied biological activities are attracting a growing number of researchers from numerous disciplines world-wide. This review surveys advances in this area with a focus on the structural diversity, biosynthetic hypotheses with increasing, but still rare, verifying experimental studies, asymmetric syntheses, and biological studies, including cellular target receptor isolation studies, of this stimulating and exciting alkaloid family.

Enantioselective, organocatalyzed, intramolecular aldol lactonizations with keto acids leading to bi- and tricyclic β-lactones and topology-morphing transformations.

The ability to rapidly assemble complex carbocyclic frameworks in a catalytic, asymmetric manner has garnered great interest in recent years. This type of cascade process, which generates multiple C C and C X bonds and stereogenic centers, including quaternary carbon atoms, is highly useful in chemical biology, for example when attempting to synthesize a family of compounds around a natural product lead. We developed intramolecular nucleophile-catalyzed aldol lactonization (NCAL) processes that deliver bicyclic b-lactones from aldehyde acid substrates by using Cinchona alkaloid catalysts and modified Mukaiyama activating agents. The NCAL methodology was more recently applied to keto acid substrates by using stoichiometric nucleophiles including 4-pyrrolidinopyridine (4-PPY), which led to a variety of racemic biand tricyclic b-lactones, and a nine-step enantioselective synthesis of salinosporamide A from d-serine. Tricyclic-b-lactones ( )-4 (Scheme 1) were also found to participate in a novel dyotropic process leading to spirocyclic g-lactones. In the latter report, we described a single example of an enantioselective NCAL process with keto acids leading to b-lactone ( )-4, by employing stoichiometric quantities of commercially available tetramisole (Scheme 1). Herein, we report a significant advance in the NCAL methodology with keto acids involving the use of catalytic homobenzotetramisole (S)-HBTM (6, Scheme 2) as chiral nucleophile (Lewis base), a tetramisole analogue, and p-toluenesulfonyl chloride rather than Mukaiyama s reagent, which led to biand tricyclic b-lactones in good yields and excellent enantioselectivities. In addition, we report transformations of these systems that lead to dramatically different topologies. Overall, the reported process provides an expedient route to useful templates for chemical biology through rapid synthesis of carbocyclic frameworks in optically active

Concise Synthesis of Spirocyclic, Bridged γ-Butyrolactones via Stereospecific, Dyotropic Rearrangements of β-Lactones Involving 1,2-Acyl and δ-Lactone Migrations

Dyotropic processes involving unprecedented 1,2-acyl migrations provide access to novel spirocyclic, bridged keto-gamma-lactones from a series of fused, tricyclic-beta-lactones, available via biscyclization of ketoacids including a new asymmetric variant. In addition, a spirocyclic bis-gamma-lactone was generated via a dyotropic process involving a 1,2-beta-lactone/sigma-lactone interchange. Overall, this sequence provides a simple, two-step process for conversion of diketoacids to complex spiro[5.n]alkanes bearing a contiguous tertiary carbon center, a quaternary carbon center, and a tertiary alcohol in the form of a bridging gamma-lactone.

Bioinspired total synthesis and human proteasome inhibitory activity of (-)-salinosporamide A, (-)-homosalinosporamide A, and derivatives obtained via organonucleophile promoted bis-cyclizations.

A full account of concise, enantioselective syntheses of the anticancer agent (-)-salinosporamide A and derivatives, including (-)-homosalinosporamide, that was inspired by biosynthetic considerations is described. The brevity of the synthetic strategy stems from a key bis-cyclization of a β-keto tertiary amide, which retains optical purity enabled by A(1,3)-strain rendering slow epimerization relative to the rate of bis-cyclization. Optimization studies of the key bis-cyclization, enabled through byproduct isolation and characterization, are described that ultimately allowed for a gram scale synthesis of a versatile bicyclic core structure with a high degree of stereoretention. An optimized procedure for zincate generation by the method of Knochel, generally useful for the synthesis of salino A derivatives, led to dramatic improvements in side-chain attachment and a novel diastereomer of salino A. The versatility of the described strategy is demonstrated by the synthesis of designed derivatives including (-)-homosalinosporamide A. Inhibition of the human 20S and 26S proteasome by these derivatives using an enzymatic assay are also reported. The described total synthesis of salino A raises interesting questions regarding how biosynthetic enzymes leading to the salinosporamides proceeding via optically active β-keto secondary amides, are able to maintain the stereochemical integrity at the labile C2 stereocenter or if a dynamic kinetic resolution is operative.

Rapid assembly of complex cyclopentanes employing chiral, α,β-unsaturated acylammonium intermediates.

With the intention of improving synthetic efficiency, organic chemists have turned to bioinspired organocascade or domino processes that generate multiple bonds and stereocentres in a single operation. However, despite the great importance of substituted cyclopentanes, given their prevalence in complex natural products and pharmaceutical agents, the rapid, enantioselective assembly of these carbocycles lags behind cyclohexanes. Here, we describe a Michael–aldol-β-lactonization organocascade process for the synthesis of complex cyclopentanes utilizing chiral α,β-unsaturated acylammonium intermediates, readily generated by activation of commodity unsaturated acid chlorides with chiral isothiourea catalysts. This efficient methodology enables the construction of two C–C bonds, one C–O bond, two rings and up to three contiguous stereogenic centres delivering complex cyclopentanes with high levels of relative and absolute stereocontrol. Our results suggest that α,β-unsaturated acylammonium intermediates have broad utility for the design of organocascade and multicomponent processes, with the latter demonstrated by a Michael–Michael–aldol-β-lactonization. Despite their appearance in a number of bioactive natural products, the synthesis of 5-membered carbocycles has received much less attention than synthesis of their 6-membered counterparts. Here, a Michael-aldol-β-lactonization cascade is used to forge two C-C bonds, one C-O bond, two rings and up to three contiguous stereocentres and deliver complex cyclopentanes with high levels of relative and absolute stereocontrol.

Double Diastereoselective, Nucleophile-Catalyzed Aldol Lactonizations (NCAL) Leading to β-Lactone Fused Carbocycles and Extensions to β-Lactone Fused Tetrahydrofurans

A double diastereoselective variant of the nucleophile-catalyzed aldol lactonization (NCAL) process is described. This strategy delivers beta-lactone-fused carbocycles with good to excellent diastereoselectivities using cinchona alkaloid catalysts with enantioenriched aldehyde acids, which gave low diastereoselectivity based on substrate control alone. beta-Lactone-fused tetrahydrofurans are also prepared for the first time via the NCAL process; however, diastereoselectivity was only modestly improved when applying double diastereodifferentiation to these systems.

A1,3-strain enabled retention of chirality during bis-cyclization of β-ketoamides: total synthesis of (−)-salinosporamide A and (−)-homosalinosporamide A

A concise, enantioselective synthesis of the Phase I anticancer agent, (-)-salinosporamide A, is described. The brevity of the described strategy stems from a key bis-cyclization of a beta-keto tertiary amide, accomplished on gram scale, which retains optical purity enabled by A(1,3)-strain rendering epimerization slow relative to the rate of bis-cyclization. The versatility of the strategy for derivative synthesis is demonstrated by the synthesis of (-)-homosalinosporamide A.

Direct Catalytic Asymmetric Synthesis of N‐Heterocycles from Commodity Acid Chlorides by Employing α,β‐Unsaturated Acylammonium Salts

Taming the beast, asymmetrically: Modulation of the reactivity of acid chlorides, using cinchona alkaloid catalysts, results in chiral α,β-unsaturated acylammoniums, which react with nucleophiles enantioselectively to give pyrrolidinones, piperid-2-ones, and dihydropyridinones. This nucleophile-catalyzed Michael/proton transfer/lactamization or lactonization organocascade leads to chiral intermediates previously employed for the synthesis of bioactive pharmaceuticals.

Mild arming and derivatization of natural products via an In(OTf) 3-catalyzed arene iodination

Iodination of arene-containing natural products employing N-iodosuccinimide catalyzed by In(OTf)(3) at ambient temperature is reported as a versatile and mild method for natural product derivatization amenable to small scale. This process facilitates natural product derivatization of arene moieties for SAR studies, homo- and heterodimerization of natural products, and also conjugation with reporters such as biotin via subsequent metal-mediated coupling reactions.