Cyclization Step Research Articles

Anodic Olefin Coupling Reactions: Elucidating Radical Cation Mechanisms and the Interplay between Cyclization and Second Oxidation Steps.

Anodic olefin coupling reactions generate new bonds and ring skeletons through a net two electron process that reverses the polarity of a known, electron-rich functional group. While much of the early work on the mechanism of these reactions focused on the initial oxidation and cyclization steps of the process, the second oxidation step also plays a central role in determining the success of the reaction. Evidence supporting this observation is presented, along with evidence that optimization of this second oxidation step is not enough to pull a poor cyclization to the desired product. Successful cyclization reactions require optimization of both processes.

Asymmetric Total Synthesis of Norzoanthamine

AbstractWe report herein the asymmetric total synthesis of norzoanthamine using radical reactions as key steps for rapid access to the congested carbocyclic core, which is the major synthetic challenge for most zoanthamine alkaloids. (1) The Ueno–Stork radical cyclization was applied to construct the adjacent quaternary centers at the C‐9 and C‐22 positions; (2) a Co‐catalyzed HAT radical reaction was successfully applied to construct the quaternary center at C‐12 via Csp3‐Csp2 bond formation; (3) a Mn‐catalyzed HAT radical reaction was used to stereospecifically reduce the tetra‐substituted olefin (C13=C18) and install the contiguous stereocenters in proximity to the quaternary center. A one‐pot bio‐inspired cyclization step was finally applied to forge the unstable bis‐amino acetal skeleton. Our approach can precisely control the stereochemistry of seven vicinal stereocenters and effectively construct the highly congested heptacyclic skeleton.

Asymmetric Total Synthesis of Norzoanthamine

We report herein the asymmetric total synthesis of norzoanthamine using radical reactions as key steps for rapid access to the congested carbocyclic core, which is the major synthetic challenge for most zoanthamine alkaloids. (1) The Ueno-Stork radical cyclization was applied to construct the adjacent quaternary centers at the C-9 and C-22 positions; (2) a Co-catalyzed HAT radical reaction was successfully applied to construct the quaternary center at C-12 via Csp3 -Csp2 bond formation; (3) a Mn-catalyzed HAT radical reaction was used to stereospecifically reduce the tetra-substituted olefin (C13=C18) and install the contiguous stereocenters in proximity to the quaternary center. A one-pot bio-inspired cyclization step was finally applied to forge the unstable bis-amino acetal skeleton. Our approach can precisely control the stereochemistry of seven vicinal stereocenters and effectively construct the highly congested heptacyclic skeleton.

A new synthesis of tafamidis via zinc-MsOH mediated reductive cyclisation strategy

A practical zinc-MsOH mediated intra-molecular reductive cyclisation and its application in the synthesis of tafamidis is presented starting from the readily available 3-hydroxy-4-nitrobenzoic acid as a precursor. The key reductive cyclization step involves the use of a combination of the readily available zinc and MsOH as the catalyst system. This methodology provides an attractive route to 2-aryl benzoxazoles from ortho-nitro phenols under mild reaction conditions. This methodology is developed on a multi-gram scale and without the need for column chromatography. A new and alternative zinc-MsOH mediated intra-molecular reductive cyclisation and its application in the synthesis of tafamidis is reported starting from the readily available 3-hydroxy-4-nitrobenzoic acid as precursor. This method provides an attractive route to 2-aryl benzoxazoles from ortho-nitro phenols under mild reaction conditions.

Celebrating Professor Barry M. Trost's 80th Birthday

Celebrating Professor Barry M. Trost's 80^th Birthday

Transformation of 3-(Furan-2-yl)-1,3-di(het)arylpropan-1-ones to Prop-2-en-1-ones via Oxidative Furan Dearomatization/2-Ene-1,4,7-triones Cyclization.

The approach to 3-(furan-2-yl)-1,3-di(het)arylprop-2-en-1-ones based on the oxidative dearomatization of 3-(furan-2-yl)-1,3-di(het)arylpropan-1-ones followed by an unusual cyclization of the formed di(het)aryl-substituted 2-ene-1,4,7-triones has been developed. The cyclization step is related to the Paal–Knorr synthesis, but the furan ring formation is accompanied in this case by a formal shift of the double bond through the formation of a fully conjugated 4,7-hydroxy-2,4,6-trien-1-one system or its surrogate.

Synthesis and Properties of Partially Saturated Fluorenyl-Derived [n]Helicenes Featuring an Overcrowded Alkene.

The straightforward, multigram-scale synthesis of the partially saturated H6 -fluoreno[n]helicenes (n=5 or 7) featuring a central, overcrowded alkene is described. The key cyclization step was based on an intramolecular McMurry reaction from the corresponding 1,5-diketones. Chiral stationary phase HPLC analysis and isomer separation indicate that each helicenic compound is constituted of three diastereoisomers at room temperature, i. e. the configurationally stable (R,R,P)/(S,S,M) pair of enantiomers and an apparently achiral compound resulting from the rapid interconversion between the (R,S,P) and (S,R,M) enantiomers. The partially saturated H6 -fluoreno[n]helicenes are oxidatively aromatized to give an efficient access to the corresponding fluoreno[n]helicenes. The chiroptical properties (vibrational and electronic circular dichroism) of the chiral, enantiopure compounds have been measured and analyzed by quantum-chemical calculations, confirming their helicoidal nature.

Synthesis of 2-aryl-1,2,4-triazol-3-one derivatives from β-nitroenamines

The preparation of representatively selected 2-aryl-4,5-disubstituted-1,2,4-triazol-3-ones from cyclic β-nitroenamines in four steps is provided, with an overall yield of 8–70%. The nitrazone to amidrazone conversion (third step) could not proceed in absence of LiBr catalyst, and the crucial role of this mild Lewis acid is emphasized. The last cyclization step required the boosting effect of N-methylimidazole and elevated reaction temperature, as well. This reliable synthesis is highly versatile as well, and it could furnish a chemical library of 2,4,5-trisubstituted-1,2,4-triazol-3-ones with potential pharmacological activities. The usefulness of the umpolung that is accompanied by a wide transformability of nitroenamines is highlighted.

Optical Purity as a Programmable Variable for Controlling Polyolefin Tacticity in Living Coordinative Chain Transfer Polymerization: Application to the Stereomodulated LCCTP of α,ω-Nonconjugated Dienes

Two-state, stereomodulated living coordinative chain transfer polymerization (LCCTP) of 1,6-heptadiene has been achieved to produce a series of cis-poly(methylene-1,3-cyclohexane) (cis-PMCH) with stereochemical microstructures that vary between two limiting forms as a function of the optical purity of the chiral C1-symmetric hafnium preinitiator 1 when activated by the borate co-initiator B1 in the presence of a fixed excess amount of ZnEt2. Optical purity as a programmable variable was demonstrated by premixing the pure homochiral (SC,SHf) and (RC,RHf) enantiomers of 1 in different ratios prior to activation. In contrast, the LCCTP of 1,5-hexadiene using a “racemic” mixture of 1 to produce cis/trans-poly(methylene-1,3-cyclopentane) (cis/trans-PMCP) was less successful due to the loss of stereocontrol for insertion under chain transfer conditions that arises with site epimerization at the transition metal center. A correlation is proposed between the diastereoselectivity and efficiency for the cyclization step in propagation and the magnitude of site epimerization due to reversible chain transfer. These results serve to validate the strategy of using the optical purity of an initiator as a programmable parameter for controlling polyolefin tacticity as well as to better establish the criteria that are required for achieving successful stereomodulated LCCTP for the production of next generation polyolefin materials.

Biosynthesis of the Tricyclic Aromatic Type II Polyketide Rishirilide: New Potential Third Ring Oxygenation after Three Cyclization Steps

Rishirilides are a group of PKS II secondary metabolites produced by Streptomyces bottropensis Gö C4/4. Biosynthetic studies in the past have elucidated early and late steps of rishirilide biosynthesis. This work is aiming to solve the remaining steps in the rishirilide biosynthesis. Inactivation of the cyclase gene rslC3 in Streptomyces bottropensis resulted in an interruption of rishirilide production. Instead, accumulation of the tricyclic aromatic galvaquinones was observed. Similar results were observed after deletion of rslO4. Closer inspection into RslO4 crystal structure in addition to site-directed mutagenesis and molecular dynamic simulations revealed that RslO4 might be responsible for quinone formation on the third ring. The RslO1 three-dimensional structure shows a high similarity to FMN-dependent luciferase-like monooxygenases such as the epoxy-forming MsnO8 which acts with the flavin reductase MsnO3 in mensacarcin biosynthesis in the same strain. The high sequence similarity between RslO2 and MsnO3 suggests that RslO2 provides RslO1 with reduced FMN to form an epoxide that serves as substrate for RslO5.

Ce-introduced effects on modification of acidity and Pt electronic states on Pt-Sn/γ-Al2O3 catalysts for catalytic reforming

Catalytic reforming of n-heptane over a series of Pt-based catalysts modified by Sn and Ce has been conducted in a fixed-bed reactor. Introducing Sn and Ce resulted in changes in the electronic environment of the Pt particles and acidity properties of the γ-Al2O3 support, causing changes in product distribution. Results from in-situ Diffusion Reflectance Infrared Fourier Transform Spectroscopy (DRIFTS), X-ray Photoelectron Spectroscopy (XPS) and density functional theory (DFT) evidenced that the metal promoters altered the metal-support interaction, endowing the generation of negatively charged Pt particles which favored the adsorption of n-heptene, a commonly accepted intermediate for n-heptane aromatization. A mechanistic study on the interaction of n-heptene and the Pt clusters with different chemical states based on n-heptene- Temperature Programmed Desorption (TPD) and Density-function theory (DFT) calculations suggested that negatively charged Pt clusters (Ptδ−) were thermodynamically favorable for the adsorption of n-heptene and its further cyclization step.

Reaction of N-allenyl-1H-pyrrole-2-yl-carbaldehyde with hydroxylamine: a quantum-chemical model

The mechanism of the reaction between hydroxylamine and N-allenylpyrrole-2-carbaldehyde has been studied using quantum-chemical methods (B2PLYP-D2/6-311+G**//B3LYP/6-31+G*). It is shown that the calculations should take into account the solvent molecules. Solvent molecules provide both proton transfer and adequate reproduction of activation barriers. It is found that two solvent molecules are necessary for modeling oximation reaction, whereas only one solvent molecule is sufficient for the cyclization step.

Theoretical Studies of Rare-Earth-Catalyzed [3 + 2] Annulation of Aromatic Aldimine with Styrene: Mechanism and Origin of Diastereoselectivity.

The synthesis of multisubstituted 1-aminoindanes through catalyst-controlled diastereodivergent [3 + 2] annulation of aromatic imines with alkenes is of great interest and importance. An understanding of the exact reaction mechanism, especially for the origin of diastereoselectivity, is an essential aspect for further development of such reactions. In this study, density functional theory calculations have been carried out on the rare-earth-catalyzed diastereodivergent [3 + 2] annulation of benzaldimine with styrene. The results show that the reaction mainly involves generation of active species, olefin insertion, cyclization, and protonation steps. The noncovalent interactions, such as C-H···π and metal···π interactions, play an important role in stabilizing the key transition state or intermediate. Both steric and electronic factors account for the diastereoselectivity. The preferred cis-diastereoselectivity could be ascribed to more efficient orbital interaction, while the crowded space will induce the formation of a C-H···π interaction between the NtBu group and benzene ring in a trans-diastereoselectivity manner, thus stabilizing the trans-selective transition state. Therefore, the stereospecific product could be obtained by fine-tuning the ligand/metal combination of the catalysts.

Enhanced Lutein Production in Chlamydomonas reinhardtii by Overexpression of the Lycopene Epsilon Cyclase Gene.

Chlamydomonas reinhardtii is a well-established microalgal model species with a shorter doubling time, which is a promising natural source for the efficient production of high-value carotenoids. In the microalgal carotenoid biosynthetic pathway, lycopene is converted either into β-carotene by lycopene β-cyclase or into α-carotene by lycopene ε-cyclase (LCYE) and lycopene β-cyclase. In this study, we overexpressed the LCYE gene in C. reinhardtii to estimate its effect on lycopene metabolism and lutein production. Chlamydomonas transformants (CrLCYE#L1, #L5, and #L6) produced significantly increased amounts of lutein per culture (up to 2.6-fold) without a decrease in cell yields. Likewise, the expression levels of LCYE gene in transformants showed a significant increase compared with that of the wild-type strain. These results suggest that LCYE overexpression enhances the conversion of lycopene to α-carotene, which in turn improves lutein productivity. Interestingly, their β-carotene productivity appeared to increase slightly rather than decrease. Considering that the inhibition of the lycopene cyclization steps often induces higher expression in genes upstream of metabolic branches, this result implies that the redirection from β-carotene to α-carotene by LCYE overexpression might also enhance upstream gene expression, thereby leading to auxiliary β-carotene production.

In Pursuit of Synthetic Efficiency: Convergent Approaches.

The field of total synthesis has reached a stage in which emphasis has been increasingly focused on synthetic efficiency rather than merely achieving the synthesis of a target molecule. The pursuit of synthetic efficiency, typically represented by step count and overall yield, is a rich source of inspiration and motivation for synthetic chemists to invent innovative strategies and methods. Among them, convergent strategy has been well recognized as an effective approach to improve efficiency. This strategy generally involves coupling of fragments with similar complexity to furnish the target molecule via subsequent cyclization or late-stage functionalization. Thus, methodologies that enable effective connection of fragments are critical to devising a convergent plan. In our laboratory, convergent strategy has served as a long-standing principle for pursuing efficient synthesis during the course of planning and implementing synthetic projects. In this Account, we summarize our endeavors in the convergent synthesis of natural products over the last ten years. We show how we identify reasonable bond disconnections and employ enabling synthetic methodologies to maximize convergency, leading to the efficient syntheses of over two-dozen highly complex molecules from eight disparate families.In detail, we categorize our work into three parts based on the diverse reaction types for fragment assembly. First, we demonstrate the application of a powerful single-electron reducing agent, SmI2, in a late-stage cyclization step, forging the polycyclic skeletons of structurally fascinating Galbulimima alkaloids and Leucosceptrum sesterterpenoids. Next, we showcase how three different types of cycloaddition reactions can simultaneously construct two challenging C-C bonds in a single step, providing concise entries to three distinct families, namely, spiroquinazoline alkaloids, gracilamine, and kaurane diterpenoids. In the third part, we describe convergent assembly of ent-kaurane diterpenoids, gelsedine-type alkaloids, and several drug molecules via employing some bifunctional synthons. To access highly oxidized ent-kaurane diterpenoids, we introduce the hallmark bicyclo[3.2.1]octane ring system at an early stage, and then execute coupling and cyclization by means of a Hoppe's homoaldol reaction and a Mukaiyama-Michael-type addition, respectively. Furthermore, we showcase how the orchestrated combination of an asymmetric Michael addition, a tandem oxidation-aldol reaction and a pinacol rearrangement can dramatically improve the efficiency in synthesizing gelsedine-type alkaloids, with nary a protecting group. Finally, to address the supply issue of several drugs, including anti-influenza drug zanamivir and antitumor agent Et-743, we exploit scalable and practical approaches to provide advantages over current routes in terms of cost, ease of execution, and efficiency.

Synthesis of New Cyclopeptide Analogues of the Miuraenamides.

Miuraenamides belong to natural marine compounds with interesting biological properties. Miuraenamides initiate polymerization of monomeric actin and therefore show high cytotoxicity by influencing the cytoskeleton. New derivatives of the miuraenamides have been synthesized containing an N-methylated amide bond instead of the more easily hydrolysable ester in the natural products. Incorporation of an aromatic side chain onto the C-terminal amino acid of the tripeptide fragment also led to highly active new miuraenamides. In this study, we showed that the ester bond of the natural product miuraenamide can be replaced by an N-methyl amide. The yields in the cyclization step were high and generally much better than with the corresponding esters. On the other hand, the biological activity of the new amide analogs was lower compared to the natural products, but the activity could significantly be increased by incorporation of a p-nitrophenyl group at the C-terminus of the peptide fragment.

Construction of Peptide Macrocycles via Radical-Mediated Intramolecular C-H Alkylations.

Enzyme-catalyzed radical-mediated C-H functionalization reactions allow nature to create natural products of unusual three-dimensional structures from simple linear peptide precursors. In comparison, chemist's ability to harness radical C-H functionalization reactions for synthesis of complex peptides remains limited. In this work, new methods have been developed to construct peptide macrocycles via radical-mediated intramolecular C-H alkylation reactions under photoredox catalysis. Linear peptide precursors equipped with a C-terminal N-(acyloxy)phthalimide ester can cyclize with the α C-H bond of N-terminal glycine or aryl C-H bond of N-heteroarene capping units in high yield and selectivity under mild conditions. The strategy uses the C-H cyclization step to incorporate lysine, homolysine, and various heteroarene-derived amino acid linchpins into peptide macrocycles, enabling convergent and flexible synthesis of complex peptide macrocycles from simple building blocks.

Synthesis, crystal structure, and DFT study of 4-(2-chlorobenzyl)-1-(5-nitro-2-(pyrrolidin-1-yl)phenyl)- [1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one

4-(2-Chlorobenzyl)-1-(5-nitro-2-(pyrrolidin-1-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazo-lin-5(4H)-one is a derivative of quinazolinones with antitumor, antibacterial, anti-inflammatory, and antimicrobial effects. Using diabetic jujube as a raw material, the title compound is synthesized by substitution and cyclization steps. The structure of the target compound is confirmed by FTIR, 1H and 13C NMR, and MS spectroscopies. The precise structure of the 4-(2-chlorobenzyl)-1-(5-nitro-2-(pyrrolidin-1-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one compound is analyzed by single crystal X-ray diffraction (XRD). The molecular structure is further calculated using density functional theory (DFT) and the result is compared with the XRD value. The molecular electrostatic potential and frontier molecular orbitals of the title compound are investigated using DFT. In addition, the obtained atomic coordinates for the single crystal of the compound are then applied in a molecular docking simulation, and the title compound is found to participate in a number of important binding interactions in the SHP2 binding sites.

Synthesis of Pyrrolo[1,2-a][1,6]- and [1,8]naphthyridines by Alkyne-Carbonyl Metathesis

AbstractA concise and modular synthesis of pyrrolo[1,2-a][1,6]- and [1,8]naphthyridines by a one-pot two-step reaction consisting of electrophilic acylation followed by an alkyne-carbonyl-metathesis reaction as the final cyclization step is reported. This developed synthetic methodology allows the facile synthesis of these heterocyclic core structures in mainly high overall yields under metal-free conditions. Reaction conditions are carefully optimized and display a novel supplement to access these tricyclic heterocyclic compounds.

Base Promoted Three-Component Annulation of 4-Diazoisochroman-3-imines with Dimethylsulfonium Ylides: Synthesis of Highly Functionalized Isochromeno[4,3-c]pyridazines.

A novel method has been developed to synthesize a unique class of highly functionalized isochromeno[4,3-c]pyridazines. This reaction features an intermolecular functionalization of terminal nitrogen atom of diazo group of 4-diazoisochoman-3-imine with two dimethylsulfonium ylide components, followed by a base promoted 6-exo-trig cyclization step. Readily available starting materials, a broad substrate scope, and operationally simple, mild, and catalyst-free reaction conditions are the prominent features of this method.