1,720,979 research outputs found
Biomimetic synthesis of fluvirosaone A
No full textOver the past century, biomimetic synthesis has significantly enhanced our understanding of the biosynthetic pathways involved in the formation of natural products. In this article, we present a two-step biomimetic synthesis of fluvirosaone A from 2,3-dehydroallosecurinine, featuring a Nazarov-type cyclization as the key step. Based on our synthetic results and computational analysis, we propose an alternative biosynthetic route for fluvirosaone A, identifying pyruvaldehyde as the likely source of the extraneous three carbons incorporated into the securinega skeleton.
Synthesis of Suffranidine B
No full textEfficiently generating intricate molecular complexity is a coveted goal in organic synthesis. This can be realized through the implementation of inventive and audacious strategies coupled with the exploration and advancement of novel molecular reactivity pathways. Herein, we present a concise two-step synthesis of a high-oxidation state heterotrimeric securinega alkaloid, suffranidine B, from 2,3-dehydroallosecurinine and the vinylogous ketoaldehyde compound derived from kojic acid. Key to the success was the astute selection of appropriate acids during both the heterotrimerization and the desymmetrizing cyclization steps. This study underscores the value of biomimicry in the synthesis of complex natural products.
Total Synthesis of (−)-FD-838 and (−)-Cephalimysin A
No full textWe completed a nine-step total synthesis of (−)-FD-838 and (−)-cephalimysin A. Our synthesis features a biogenetically guided assembly of the highly oxidized spirocyclic core by Snider-type tandem epoxidations of the chiral substrate derived from an amino acid derivative. Our synthetic approach provides a general and versatile solution to access spirocyclic PKS-NRPS-based secondary fungal metabolites.
Syntheses of Post-Iboga Alkaloids
No full textPost-iboga alkaloids are secondary metabolites that are biosynthetically derived from iboga-type alkaloids via rearrangements of the indole and/or isoquinuclidine moieties. Herein, we categorize post-iboga alkaloids into five types based on the biosynthetic mode of transformation of the iboga scaffold. We then describe reported syntheses of post-iboga alkaloids, including our laboratory’s recent contributions, based on our own categorization.
Total Synthesis of (+)-Herpotrichones A-C
No full textEpoxyquinoids herpotrichones A-C exhibit unique 6/6/6/6/3 pentacyclic frameworks and potent neuroprotective effects. Inspired by their proposed biosynthetic origins, we completed a total synthesis of herpotrichones A-C by devising a de novo synthesis of epoxyquinol monomer and leveraging a key Diels-Alder (DA) reaction between epoxyquinol monomer-based dienophiles and delitpyrone C-derived dienes. DFT calculations anticipated competing pathways, including homodimerization and regio- and stereoisomers formation, necessitating precise control over reaction selectivity during the key DA reaction. We discovered that the C2 ' hydroxyl configuration of delitpyrone C is critical in directing the desired DA reaction, with hydrogen bonding playing a decisive role in product formation. This strategy enabled synthetic access to the herpotrichone core and facilitated the first total synthesis of all known herpotrichones.
Divergent synthesis of conidiogenones B–F and 12β-hydroxyconidiogenone C
No full textSince the initial discovery of conidiogenone in 2002, over 20 highly congested 6/5/5/5-fused cyclopianes have been isolated and have served as an arena for the development of new synthetic strategies. While the D-ring with distinct oxidative decorations serves as a fingerprint region of these natural products, most synthetic approaches focused on the construction of the highly congested tetracyclic structure, and a divergent synthetic approach amenable to D-ring modifications remains unknown. Herein, we describe a synthetic strategy that enabled a divergent synthesis of six conidiogenones, including three first total syntheses. Trimethylenemethane (TMM) diyl-mediated cycloaddition expediently forged the tetracyclic conidiogenone core. The olefin moiety that was formed as a result of the TMM-based cycloaddition served as a synthetic handle for subsequent stereoselective D-ring diversifications. © 2023 Elsevier Inc.
Alkaloids
No full textSecurinega alkaloids, composed of more than 100 members characterized by the compact tetracyclic scaffold, have fascinated the synthetic community with their structural diversity and notable bioactivities. On the basis of the structural phenotype, oligomerizations and oxidations are major biosynthetic diversification modes of the basic Securinega framework. Despite the rich history of synthesis of basic monomeric Securinega alkaloids, the synthesis of oligomeric Securinega alkaloids, as well as oxidized derivatives, has remained relatively unexplored because of their extra structural complexity. In the first half of this Account, our synthetic studies toward high-order Securinega alkaloids are described. We aimed to establish a reliable synthetic method to form C14-C15′ and C12-C15′ bonds, which are prevalent connection modes between monomers. During our total synthesis of flueggenine C (9), we have invented an accelerated Rauhut-Currier reaction capable of forming the C14-C15′ bond stereoselectively. Installation of the nucleophilic functionality to the Michael acceptor, which ushers the C-C bond forming conjugate addition to follow the intramolecular pathway, was the key to success. The C12-C15′ linkage, which was inaccessible via an accelerated Rauhut-Currier reaction, was established by devising a complementary cross-coupling/conjugate reduction-based dimerization strategy that enabled the total synthesis of flueggenines D (11) and I (14). In this approach, the C12-C15′ linkage was established via a Stille cross-coupling, and the stereochemistry of the C15′ position was controlled during the following conjugate reduction step. In the later half of this Account, our achievements in the field of high-oxidation state Securinega alkaloids synthesis are depicted. We have developed oxidative transformations at the N1 and C2-C4 positions, where the biosynthetic oxidation event occurs most frequently. The discovery of a VO(acac)2-mediated regioselective Polonovski reaction allowed us to access the key 2,3-dehydroallosecurinine (112). Divergent synthesis of secu′amamine A (62) and fluvirosaones A (60) and B (61) was accomplished by exploiting the versatile reactivities of the C2/C3 enamine moiety in 112. We have also employed a fragment-coupling strategy between menisdaurilide and piperidine units, which allowed the installation of various oxygen-containing functionality on the piperidine ring. Combined with the late-stage, light-mediated epimerization and well-orchestrated oxidative modifications, collective total synthesis of seven C4-oxygenated securinine-type natural products was achieved. Lastly, the synthesis of flueggeacosine B (70) via two synthetic routes from allosecurinine (103) was illustrated. The first-generation synthesis (seven overall steps) employing Pd-catalyzed cross-coupling between stannane and thioester to form the key C3-C15′ bond enabled the structural revision of the natural product. In the second-generation synthesis, we have invented visible-light-mediated, Cu-catalyzed cross-dehydrogenative coupling (CDC) between an aldehyde and electron-deficient olefin, which streamlined the synthetic pathway into four overall steps. Organisms frequently utilize dimerization (oligomerization) and oxidations during the biosynthesis as a means to expand the chemical space of their secondary metabolites. Therefore, methods and strategies for dimerizations and oxidations that we have developed using the Securinega alkaloids as a platform would be broadly applicable to other alkaloids. It is our sincere hope that lessons we have learned during our synthetic journey would benefit other chemists working on organic synthesis. © 2023 American Chemical Society.
Transformation of (allo)securinine to (allo)norsecurinine via a molecular editing strategy
Full text linkSecurinega alkaloids have intrigued chemists since the isolation of securinine in 1956. This family of natural products comprises a securinane subfamily with a piperidine substructure and norsecurinane alkaloids featuring a pyrrolidine core. From a biosynthetic perspective, the piperidine moiety in securinane alkaloids derives from lysine, whereas the pyrrolidine moiety in norsecurinane natural products originates from ornithine, marking an early biogenetic divergence. Herein, we introduce a single-atom deletion strategy that enables the late-stage conversion of securinane to norsecurinane alkaloids. Notably, for the first time, this method enabled the transformation of piperidine-based (allo)securinine into pyrrolidine-based (allo)norsecurinine. Straightforward access to norsecurinine from securinine, which can be readily extracted from the plant Flueggea suffruticosa, abundant across the Korean peninsula, holds promise for synthetic studies of norsecurinine-based oligomeric securinega alkaloids
(+)-Dimericbiscognienyne A: Total Synthesis and Mechanistic Investigations of the Key Heterodimerization
No full textThe first total synthesis of (+)-dimericbiscognienyne A is described. Key to the successful access to (+)-dimericbiscognienyne A was a biosynthetically inspired Diels-Alder reaction between two differential epoxyquinoid monomers and the subsequent intramolecular hemiacetal formation. The selective formation of the natural product among other possible diastereomers during the late-stage [4+2] cycloaddition reaction was investigated by DFT calculations and experimental control studies.
Lithiation and electrophilic substitution of dimethyl triazones
Full text linkThe lithiation and electrophilic substitution of dimethyl triazones is described. Directed lithiation or tin–lithium exchange of dimethyl triazones afforded the corresponding dipole stabilized nucleophiles that were trapped with various electrophiles. Keto-triazone derivatives accessed by acylation of such nucleophiles were readily converted into the corresponding imidazolone heterocycles.National Institutes of Health (U.S.) (National Institute of General Medical Sciences (U.S.) GM074825
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