Straightforward and general Passerini and Ugi procedures have been developed to incorporate four-membered heterocycles into highly functionalized scaffolds. Additionally, toslymethyl isocyanide (TosMIC)-derived Ugi adducts have been prepared, showcasing the prospect of the multicomponent reaction.
Mitragynine pseudoindoxyl, a kratom metabolite, has attracted increasing attention due to its favorable side effect profile as compared to conventional opioids. Herein, we describe the first enantioselective and scalable total synthesis of this natural product and its epimeric congener, speciogynine pseudoindoxyl. The characteristic spiro-5-5-6-tricyclic system of these alkaloids was formed through a protecting-group-free cascade relay process in which oxidized tryptamine and secologanin analogues were used. Furthermore, we discovered that mitragynine pseudoindoxyl acts not as a single molecular entity but as a dynamic ensemble of stereoisomers in protic environments; thus, it exhibits structural plasticity in biological systems. Accordingly, these synthetic, structural, and biological studies provide a basis for the planned design of mitragynine pseudoindoxyl analogues, which can guide the development of next-generation analgesics.
Mitragyna , Secologanin Tryptamine Alkaloids , Mitragyna/chemistry , Mitragyna/metabolism , Secologanin Tryptamine Alkaloids/chemistry , Analgesics, Opioid
Diastereoselective and diastereoconvergent syntheses of 2- and 3-substituted morpholine congeners are reported. Starting from tosyl-oxazatedine 1 and α-formyl carboxylates 2, base catalysis is utilized to yield morpholine hemiaminals. Their further synthetic elaborations allowed the concise constructions of conformationally rigid morpholines. The observed diastereoselectivities and the unusual diastereoconvergence in the photoredox radical processes seem to be the direct consequence of the avoidance of pseudo A1,3 strain between the C-3 substituent and the N-tosyl group and the anomeric effect of oxygen atoms.
Prenylation is a ubiquitous late-stage modification in nature that often confers significantly improved bioactivity for secondary metabolites. While this lipophilic modification renders enhanced potency, the lipophilic tag(s) can diminish bioavailability and adversely alter drug transportation and metabolism. Thus, a functional-group-tolerant, mild, and selective late-stage C-H functionalization of prenyl tags would present a great potential in drug discovery programs but could also impact other fields, such as agrochemistry and chemical biology. Herein we report an exocyclic-strain-driven cross-metathesis reaction of prenyl tags, a formal double C-H oxidation protocol, that can be used for the selective late-stage derivatization of prenylated compounds and natural products. This methodology avoids the need for prefunctionalization of target molecules and affords ready access to an unprecedented library of oxo- and aza-prenylated complex molecules. Thus, in a broader context, this methodology extends late-stage functionalization beyond that available to nature.
Azetidines , Biological Products , Prenylation
A widely applicable, practical, and scalable synthetic method for efficient ene-type double oxidation of alkenes is reported via a two-step alkenyl thianthrenium umpolung/Kornblum-Ganem oxidation strategy. This chemo- and stereoselective procedure allows easy access to various α,ß-unsaturated carbonyls that may be otherwise difficult or cumbersome to synthesize by conventional methods. For α-olefins, this metal-free transformation can be tuned according to synthetic needs to produce either the elusive (Z)-unsaturated aldehydes or their (E) counterparts. Moreover, this strategy has enabled streamlined synthesis of distinct butadienyl pheromones and kairomones.
A recently proposed strategy to overcome multidrug resistance (MDR) in cancer is to target the collateral sensitivity of otherwise resistant cells. We designed a library of 120 compounds to explore the chemical space around previously identified 8-hydroxyquinoline-derived Mannich bases with robust MDR-selective toxicity. We included compounds to study the effect of halogen and alkoxymethyl substitutions in R5 in combination with different Mannich bases in R7, a shift of the Mannich base from R7 to R5, as well as the introduction of an aromatic moiety. Cytotoxicity tests performed on a panel of parental and MDR cells highlight a strong influence of experimentally determined pKa values of the donor atom moieties, indicating that protonation and metal chelation are important factors modulating the MDR-selective anticancer activity of the studied compounds. Our results identify structural requirements increasing MDR-selective anticancer activity, providing guidelines for the development of more effective anticancer chelators targeting MDR cancer.
Antineoplastic Agents , Neoplasms , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Chelating Agents/pharmacology , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Humans , Mannich Bases/chemistry , Mannich Bases/pharmacology , Oxyquinoline/chemistry , Oxyquinoline/pharmacology , Structure-Activity Relationship
Porcine reproductive and respiratory syndrome (PRRS) is a globally spread, highly infectious viral disease. Live, attenuated vaccines against PRRS virus (PRRSV) decrease virus excretion and evoke protective immunity reducing the economic damage caused by the disease. In a longitudinal molecular epidemiological study accompanying ongoing national eradication programme we evaluated the suitability of PRRSV ORF5 and ORF7 sequences to identify possible field strains of vaccine-origin. In total, 2342 ORF5 sequences and 478 ORF7 sequences were analysed. Vaccine strains were identified by sequence identity values and phylogenetic network analysis. Strains that shared greater than 98% nucleotide identity within ORF5 and/or ORF7 were considered to have originated from vaccine. A total of 882 (37.6%) ORF5 and 88 (18.4%) ORF7 sequences met these criteria. In detail, 618, 179 and 35 ORF5 and 51, 29 and 8 ORF7 sequences were related to Porcilis PRRS vaccine, Unistrain PRRS vaccine, and ReproCyc PRRS EU vaccine, respectively. Data showed that the Porcilis vaccine was genetically more stable. Whereas, the variability of the Unistrain and the ReproCyc strains was significantly higher. Given that ORF7 shares, in some instances, complete identity between a particular vaccine strain and some historic variants of field PRRSV strains, care must be taken when evaluating vaccine relatedness of a field isolate based on the ORF7. On the contrary, ORF5 sequences were more suitable to predict the vaccine origin making a distinction more robustly between field and vaccine strains. We conclude that ORF5 based molecular epidemiological studies support more efficiently the ongoing PRRS eradication programmes. The conclusions presented in this large-scale PRRS molecular epidemiological study provides a framework for future eradication programmes planned in other countries.
We report a novel reductive interrupted Fischer indolization process for the concise assembly of the 20-oxoaspidospermidine framework. This rapid complexity generating route paves the way toward various dihydroindole Aspidosperma alkaloids with different C-5 side chain redox patterns. The end-game redox modulations were accomplished by modified Wolff-Kishner reaction and photo-Wolff rearrangement, enabling the total synthesis of (-)-aspidospermidine, (-)-limaspermidine, and (+)-17-demethoxy-N-acetylcylindrocarine and the formal total synthesis of (-)-1-acetylaspidoalbidine.
We report 8-step syntheses of (-)-minovincine and (-)-aspidofractinine using easily available and inexpensive reagents and catalyst. A key element of the strategy was the utilization of a sequence of cascade reactions to rapidly construct the penta- and hexacyclic frameworks. These cascade transformations included organocatalytic Michael-aldol condensation, a multistep anionic Michael-SN 2 cascade reaction, and Mannich reaction interrupted Fischer indolization. To streamline the synthetic routes, we also investigated the deliberate use of steric effect to secure various chemo- and regioselective transformations.
The reductive Ireland-Claisen rearrangement through borane-mediated hydrosilylation is reported. The method employs a borane catalyst with a special structural design and affords access to synthetically relevant products with high diastereoselectivity. Depending on electronic and structural parameters, the reaction can be coupled with a 1,3-allylic shift, thus the valence isomer of the Ireland-Claisen product is formed.
An inexpensive and chromatography-free Mitsunobu methodology has been developed using low molecular weight and orthogonally phase-tagged reagents, a tert-butyl-tagged highly apolar phosphine, and a water-soluble DIAD analogue. The byproduct of the Mitsunobu reactions can be removed by sequential liquid-liquid extractions using traditional solvents such as hexanes, MeOH, water, and EtOAc. Owing to the orthogonal phase labeling, the spent reagents can be regenerated. This new variant of the Mitsunobu reaction promises to provide an alternative and complementary solution for the well-known separation problem of the Mitsunobu reaction without having to resort to expensive, large molecular weight reagents and chromatography.
The development of a boron/nitrogen-centered frustrated Lewis pair (FLP) with remarkably high water tolerance is presented. As systematic steric tuning of the boron-based Lewis acid (LA) component revealed, the enhanced back-strain makes water binding increasingly reversible in the presence of relatively strong base. This advance allows the limits of FLP's hydrogenation to be expanded, as demonstrated by the FLP reductive amination of carbonyls. This metal-free catalytic variant displays a notably broad chemoselectivity and generality.
Herein we report that a single frustrated Lewis pair (FLP) catalyst can promote the reductive etherification of aldehydes and ketones. The reaction does not require an exogenous acid catalyst, but the combined action of FLP on H2 , R-OH or H2 O generates the required Brønsted acid in a reversible, "turn on" manner. The method is not only a complementary metal-free reductive etherification, but also a niche procedure for ethers that would be either synthetically inconvenient or even intractable to access by alternative synthetic protocols.
We report an expedient approach to highly functionalized cis- and trans-decalines that could function as key structural subunits toward the synthesis of various classes of terpenoids. Key to the strategy is an organocatalyzed Robinson annulation reaction of the Nazarov reagent that affords chiral enone building blocks with high enantioselectivities. The quaternary carbon stereogenic center can direct the subsequent reactions and allow the rapid and diastereoconvergent assembly of complex decalines with contiguous stereocenters.
An organocatalytic iterative assembly line has been developed in which nitromethane was sequentially coupled with two different enones using a combination of pseudoenantiomeric cinchona-based thiourea catalysts. Application of unsaturated aldehydes and ketones in the second step of the iterative sequence allows the construction of cyclic syn-ketols and acyclic compounds with multiple contiguous stereocenters. The combination of the multifunctional substrates and ambident electrophiles rendered some organocatalytic transformations possible that have not yet been realized in bifunctional noncovalent organocatalysis.
Owing to the ring strain and α-heteroatom effect, the four-membered heterocyclic ketones can undergo direct cross-aldol and -ketol reactions without the need for preformed enol or "enolate-like" intermediates. Besides the organocatalyzed cross-ketol addition onto their highly active carbonyl group, their ability to act as a nucleophilic donor has also been explored. As a result, a number of discrete aldol adducts were synthesized and the distinct reactivities were successfully combined into a double-aldol one-pot reaction.
Alcohols/chemical synthesis , Aldehydes/chemical synthesis , Heterocyclic Compounds/chemistry , Ketones/chemistry , Ketones/chemical synthesis , Alcohols/chemistry , Aldehydes/chemistry , Molecular Structure
3-Isopropylmalate dehydrogenase (IPMDH) from Mycobacterium tuberculosis (Mtb) may be a target for specific drugs against this pathogenic bacterium. We have expressed and purified Mtb IPMDH and determined its physicalchemical and enzymological properties. Size-exclusion chromatography and dynamic light scattering measurements (DLS) suggest a tetrameric structure for Mtb IPMDH, in contrast to the dimeric structure of most IPMDHs. The kinetic properties (kcat and Km values) of Mtb IPMDH and the pH-dependence of kcat are very similar to both Escherichia coli (Ec) and Thermus thermophilus (Tt) IPMDHs. The stability of Mtb IPMDH in 8 M urea is close to that of the mesophilic counterpart, Ec IPMDH, both of them being much less stable than the thermophilic (Tt) enzyme. Two known IPMDH inhibitors, O-methyl oxalohydroxamate and 3-methylmercaptomalate, have been synthesised. Their inhibitory effects were found to be independent of the origin of IPMDHs. Thus, experiments with either Ec or Tt IPMDH would be equally relevant for designing specific inhibitory drugs against Mtb IPMDH.
3-Isopropylmalate Dehydrogenase/metabolism , Antitubercular Agents/metabolism , Bacterial Proteins/metabolism , Mycobacterium tuberculosis/enzymology , 3-Isopropylmalate Dehydrogenase/chemistry , 3-Isopropylmalate Dehydrogenase/drug effects , 3-Isopropylmalate Dehydrogenase/genetics , Antitubercular Agents/pharmacology , Bacterial Proteins/chemistry , Bacterial Proteins/drug effects , Bacterial Proteins/genetics , Catalytic Domain , Drug Discovery , Hydrogen-Ion Concentration , Kinetics , Models, Molecular , Mycobacterium tuberculosis/genetics , Protein Refolding
How do skilled synthetic chemists develop good intuitive expertise? Why can we only access such a small amount of the available chemical space-both in terms of the reactions used and the chemical scaffolds we make? We argue here that these seemingly unrelated questions have a common root and are strongly interdependent. We performed a comprehensive analysis of organic reaction parameters dating back to 1771 and discovered that there are several anthropogenic factors that limit reaction parameters and thus the scope of synthetic chemistry. Nevertheless, many of the anthropogenic limitations such as narrow parameter space and the opportunity for rapid and clear feedback on the progress of reactions appear to be crucial for the acquisition of valid and reliable chemical intuition. In parallel, however, all of these same factors represent limitations for the exploration of available chemistry space and we argue that these are thus at least partly responsible for limited access to new chemistries. We advocate, therefore, that the present anthropogenic boundaries can be expanded by a more conscious exploration of "off-road" chemistry that would also extend the intuitive knowledge of trained chemists.
