Dyotropic Rearrangement of ß-Lactams: Reaction Development, Mechanistic Study, and Application to the Total Syntheses of Tricyclic Marine Alkaloids.

An unprecedented dyotropic rearrangement of ß-lactams has been developed, which provides an enabling tool for the synthesis of structurally diverse γ-butyrolactams. Unlike the well-established dyotropic rearrangements of ß-lactones, the present reaction probably proceeds through a dual-activation mode, and thus displays unusual reactivity and chemoselectivity. The combined computational and experimental results suggest that the dyotropic rearrangement of ß-lactams may proceed through different mechanisms depending on the nature of migrating groups (H, alkyl, or aryl). Hinging on a chemoselective H-migration dyotropic rearrangement of ß-lactams, we have completed the divergent synthesis of tricyclic marine alkaloids (-)-lepadiformine A, (+)-cylindricine C, and (-)-fasicularin within 11-12 longest linear steps.

The synthetic chemistry of sarpagine-ajmaline-type alkaloids.

The sarpagine-ajmaline type monoterpenoid indole alkaloids are among the most important groups of natural alkaloids, and the complex polycyclic and cage-like architectures present significant synthetic challenges. Because of their characteristic indole-fused azabicyclo[3.3.1]nonane structures and prominent biological activities, sarpagine-ajmaline related alkaloids have captured the attention of organic synthetic chemists for decades. In this chapter, the strategies employed in the synthesis of sarpagine-ajmaline related alkaloids are outlined, and the synthetic progress during the period of 2019-2023 is provided in detail. To provide potential targets for future synthetic endeavors, some sarpagine/ajmaline type alkaloids isolated in recent years with novel structures and biological activities are also summarized.

Cyclization by Intramolecular Suzuki-Miyaura Cross-Coupling - A Review.

Ring systems of all sizes are frequent core or substructures in natural products and they are important elements of many drug molecules, as they often confer high binding affinity to and selectivity for disease-relevant biological targets. A uniform key transformation in the synthesis of such structures is the cyclization step. Among the various approaches that have been developed for ring closure, the intramolecular Suzuki-Miyaura reaction has emerged as a powerful option for the construction of normal- and medium-sized rings as well as macrocycles, due to its stereospecificity, the mild reaction conditions, and the non-toxic nature of the boron by-products. In this review, we summarize the state-of-the-art of the application of intramolecular Suzuki-Miyaura cross-coupling reactions in the construction of (macro)cyclic frameworks of natural products and bioactive molecules of synthetic origin, covering (mostly) examples that have been reported since 2015. Target molecules prepared via intramolecular Suzuki-Miyaura cross-coupling as a key step range from natural products / natural product analogs to synthetic drug candidates, featuring ring sizes from 4 to >>12. We highlight the utility, scope, and limitations of the reaction for different ring sizes and arrays of functional groups. Where possible, comparisons with other methods of cyclization are provided.

Total Synthesis of Ryanodane Diterpenoids Garajonone and 3-epi-Garajonone.

Ryanodane diterpenes are structurally complex natural products that are well-known for their high degree of oxidation and the challenges associated with synthesizing them within the terpene class. Herein, we present a two-stage synthetic strategy that draws inspiration from the broad biosynthesis of terpenes, allowing us to successfully achieve the first chemical synthesis of garajonone, a ryanodane diterpenoid that occurs naturally at low abundance, as well as its epimer, 3-epi-garajonone. The key to this success lies in the rapid construction of the carbon framework of target molecule by employing an early-stage palladium-catalyzed Heck/carbonylative esterification cascade annulation, followed by successive late-stage selective redox manipulation to establish the desired oxidation state of the molecule. This research not only showcases the synthesis of garajonone and its epimer but also provides a platform for the chemical synthesis of other members and analogs within this complex diterpenoid family.

Direct Catalytic Asymmetric Conjugate Addition of Benzofuran-3(2H)-ones to α,ß-Unsaturated Thioamides: Stereodivergent Synthesis of Rocaglaol.

Rocaglaol, a representative flavagline, has attracted significant attention because of its unique chemical structure and biological activities. This paper reports a mild and scalable copper-catalyzed enantioselective conjugate addition of benzofuran-3(2H)-one to α,ß-unsaturated thioamides. This method allows for the concise synthesis of all possible stereoisomers of a key intermediate of rocaglaol and its derivatives in a highly diastereo- and enantioselective manner using different chiral phosphine ligands. Theoretical insights into the reaction mechanism and the origin of ligand-dependent diastereodivergence were obtained using density functional theory calculations.

Concise and Stereospecific Total Synthesis of Arenastatin A and Its Segment B Analogs.

A novel and concise synthetic method for arenastatin A, a cytotoxic cyclic depsipeptide of marine origin, was developed in this study. The convergent assembly of the four segments, including the cross-metathesis reaction, gave a cyclization precursor, and Fmoc deprotection caused simultaneous macrocyclization. The Corey-Chaykovsky reaction using a chiral sulfur ylide afforded arenastatin A with complete stereoselectivity in the longest linear sequence of seven reaction steps from the known compound. Using this synthetic method, some analogs of segment B were prepared through a late-stage diversification strategy. The simple SN2 reaction of the thiolate toward the tosylate precursor, prepared using almost the same synthetic method as described above, provided the desired sulfide analogs.

Fun With Unusual Functional Groups: Sulfamates, Phosphoramidates, and Di-tert-butyl Silanols.

Compared to ubiquitous functional groups such as alcohols, carboxylic acids, amines, and amides, which serve as central "actors" in most organic reactions, sulfamates, phosphoramidates, and di-tert-butyl silanols have historically been viewed as "extras". Largely considered functional group curiosities rather than launch-points of vital reactivity, the chemistry of these moieties is under-developed. Our research program has uncovered new facets of reactivity of each of these functional groups, and we are optimistic that the chemistry of these fascinating molecules can be developed into truly general transformations, useful for chemists across multiple disciplines. In the ensuing sections, I will describe our efforts to develop new reactions with these "unusual" functional groups, namely sulfamates, phosphoramidates, and di-tert-butyl silanols.

Expeditious chemical synthesis of xylomannans disproves the proposed antifreeze activities.

Cold-adapted species are able to generate cryoprotective proteins and glycoproteins to prevent freezing damage. The [→4)-ß-D-Manp-(1→4)-ß-D-Xylp-(1→] n xylomannan from the Alaska beetle Upis ceramboides was disclosed by Walters and co-workers in 2009 as the first glycan-based antifreeze agent, which was later reported to be found in diverse taxa. Here, we report the rapid synthesis of four types of xylomannans, including the proposed antifreeze xylomannan up to a 64-mer (Type I), the regioisomeric [→3)-ß-D-Manp-(1→4)-ß-D-Xylp-(1→] n 16-mer (Type II), the diastereomeric [→4)-ß-L-Manp-(1→4)-ß-D-Xylp-(1→] n 16-mer (Type III) and the block-wise [→4)-ß-D-Manp-(1→] m [→4)-ß-D-Xylp-(1→] n 32-mer (Type IV), by employing a strategic iterative exponential glycan growth (IEGG) process. The nuclear magnetic resonance spectral data of the alleged natural xylomannan are in accordance only to those of the block-wise Type IV glycan and none of these synthetic xylomannans has been found to be capable of inducing thermal hysteresis. These results disprove the previous reports about the natural occurrence of antifreeze xylomannans.

Diversity oriented total synthesis (DOTS) of pyridoquinazolinone alkaloids and their analogues.

A short diversity oriented total synthesis (DOTS) of substituted rutaecarpines, homo-luotonins, homo-vasicinone, homo-isaindigotones and homo-vasnetine has been achieved from the key tricyclic intermediate. The [6,6,6] tricyclic ketone, the mackinazolindione, was accessed from simple substrates i.e., quinazolinone diester obtained from the disubstituted anthranilamide which in turn was prepared from the coupling of amino acid ester and ethyl oxalyl chloride with isatoic anhydride and Dieckmann condensation chemistry.

Synthesis of (-)-Cannabidiol (CBD), (-)-Δ9- and (-)-Δ8-Tetrahydrocannabinols, Encapsulation of CBD with Nanoparticles for Controlled Delivery and Biological Evaluation.

Cannabidiol (CBD) is garnering increasing interest due to its significant biological activity. This natural compound is one of the major cannabinoids in Cannabis sativa L. In this work, we describe the encapsulation of CBD in solid and hollow pH-sensitive poly(4-vinylpyridine) (solid@p4VP and hollow@p4VP) nanoparticles, and temperature-sensitive poly(N-isopropylacrylamide) (solid@pNIPAM and hollow@pNIPAM) nanoparticles for transport and release CBD in a controlled manner. The CBD loading into these smart polymeric systems was effective and their release profiles, solubility and resistance to stomach and intestinal conditions were evaluated, showing satisfactory properties and improved bioavailability with respect to free CBD. Finally, the A549 human lung cancer cell line was used as lung adenocarcinoma epithelial cellular model to carry out preliminary assays of the in vitro activity of the vehiculized CBD. For all these studies, synthetic CBD was employed, for which a new efficient and scalable synthesis of cannabinoids has been developed.

An overview: total synthesis of arborisidine, and arbornamine.

Arborisidine and Arbornamine are two monoterpenoid indole alkaloids that were isolated from the Malayan Kopsia arborea plant. This review provides valuable information about the total and formal syntheses of these alkaloids. The synthesis strategies discussed in this review, such as Pictet-Spengler cyclization, chemo- and stereoselective oxidative cyclization, Michael/Mannich cascade process, and intramolecular N-alkylation, can be useful for developing new methods to synthesize these and other similar compounds.

Copper(II)-Amine Complex-Mediated Intramolecular Coupling of Gallates: A Bioinspired Solution to the Atroposelective Synthesis of Ellagitannins.

Total syntheses of the C-glucosidic ellagitannins (-)-punicacortein A, (-)-epipunicacortein A and (+)-castalin were accomplished for the first time, and those of the glucopyranosic ellagitannins (+)-tellimagrandin I and (+)-pedunculagin were revisited. The atroposelective construction of their characteristic hexahydroxydiphenoyl (HHDP) and nonahydroxyterphenoyl (NHTP) units relied on the use of different cupric-amine complexes under different reaction conditions to mediate the intramolecular dehydrogenative coupling of galloyl groups at different positions of glucose cores. In particular, the monodentate n-butylamine and the bidentate (-)-sparteine were found to be complementary in their capacity to promote the regio- and atroposelective coupling of galloyl groups on a 4C1-glucopyranosic core into 2,3-O-(S)- and/or 4,6-O-(S)-HHDP units. Furthermore, replacing (-)-sparteine by its optical antipode not only counteracted the substrate-controlled induction of atroposelectivity to forge a 4,6-O-(R)-HHDP unit, but it also enabled a 4C1 to 1C4 ring flip of the glucopyranosic core and hence the formation of 2,4-O-(R)- and 3,6-O-(R)-HHDP units, such as those featured in the glucopyranosic ellagitannins phyllanemblinin B and geraniin.

Natural resorcylic lactones derived from alternariol.

In this overview, naturally occurring resorcylic lactones biosynthetically derived from alternariol and almost exclusively produced by fungi, are discussed with view on their isolation, structure, biological activities, biosynthesis, and total syntheses. This class of compounds consists until now of 127 naturally occurring compounds, with very divers structural motifs. Although only a handful of these toxins (i.e., alternariol and its 9-O-methyl ether, altenusin, dehydroaltenusin, altertenuol, and altenuene) were frequently found and isolated as fungal contaminants in food and feed and have been investigated in significant detail, further metabolites, which were much more rarely found as natural products, similarly show interesting biological activities.

The Quinine Odyssey: A Barometer of the State of Organic Synthesis Over Centuries.

The year 2024 marks the 80th anniversary of the landmark formal synthesis of (±)-quinine completed by Woodward and Doering. This article examines the evolution of approaches to access this storied Cinchona alkaloid natural product which represent a microcosm the progress that has been made in organic synthesis over the past ~170 years. Seminal contributions led by Pasteur, Rabe, Woodward, Uskokovic, Stork, Jacobsen, Hayashi, Maulide and others are discussed.

A Formal Synthesis of (+)-Hannokinol Using a Chiral Horner-Wittig Reagent.

Herein, we report a concise and efficient formal synthesis of (+)-hannokinol. Key to this new strategy is the use of a chiral Horner-Wittig reagent, readily available from 2-deoxy-D-ribose, to introduce the chiral 1,3-diol motif.

Total Synthesis of Cyclosenegalin A.

A Pro-Gly-typed cyclopeptide, cyclosenegalin A, was firstly isolated from Annona senegalensis and Annona scleroderma. In this study, we reported synthesis the cycloheptapeptide with a combination of solid- and solution-phase synthetic methods. This study also compared the effectiveness of ß-turn inducer type I and II in cyclosenegalin A to facilitate the cyclization process. The synthesis of cyclosenegalin A were prepared using two different sequences of linear peptides for cyclization. First sequence employed ß-turn type I inducer (Ser-Ala-Val-Thr) as turning point and second sequence employed ß-turn type II inducer (Thr-Pro-Gly-Leu). The successful cyclization was obtained using the linear sequence of NH2-Ala-Val-Thr-Pro-Gly-Leu-Ser-OH with ß-turn type II. The final product was obtained in 8.2 % yield with PyBOP/DIEA act as coupling agent. The synthetic cyclosenegalin A were characterized with HR-ToFMS, 1H NMR, 13C NMR, HSQC, HMBC, TOCSY, and ROESY. The synthetic product was also evaluated for its antimicrobial activity.

Convenient Access to a Strained Bicyclic Enone: A Concise and Improved Formal Synthesis of Ineleganolide.

The norcembranoid and cembranoid diterpenoids represent an intriguing class of natural products isolated from marine sources. Their chemical synthesis has been a challenging and exciting field of research over the past two decades, owing largely to their structural complexity. We recently disclosed a total synthesis of a member of this class, ineleganolide, in a 23 step longest linear sequence. In search of a shorter, more efficient route, we have devised a new strategy for the synthesis of a key bicyclic enone. Disclosed herein is our improved synthesis of this strained intermediate, completing the formal synthesis of ineleganolide in only 14 steps, thereby shortening our previous synthesis by 9 steps. Dedicated to Prof. Thomas Maimone on his receipt of the Tetrahedron Young Investigator Award 2024.

Collective Asymmetric Synthesis of Thiosilvatins.

Thiosilvatins are a family of biologically active sulfenylated diketopiperazine natural products. The first members were reported over 40 years ago, but total synthesis of a thiosilvatin has remained elusive. Here, we describe the first, collective, synthesis of the parent epidithiodiketopiperazine (-)-dithiosilvatin and ten related thiosilvatins. Several of the targets are structurally revised. A catalytic asymmetric sulfenylation of triketopiperazines efficiently controls absolute configuration at the thioaminal units. Further synthetic highlights include a diastereoconvergent installation of the requisite cis-orientation of the sulfur atoms and a tandem epidisulfide formation/O-prenylation under mild Mitsunobu conditions. The described methods for late-stage diversification of sensitive bis(methylthio)diketopiperazines offer a blueprint for systematically exploring this interesting 3D-pharmacophore in stereochemically pure form.

Total Syntheses and Anti-Inflammatory Studies of Three Natural Coumarins: Glycycoumarin, Glycyrin, and 3-O-Methylglycyrol.

Licorice (Glycyrrhiza uralensis Fisch), a significant traditional Chinese herbal medicine, has been extensively utilized in China to treat various ailments. Natural bioactive coumarins, glycycoumarin, glycyrin, and 3-O-methylglycyrol, were isolated from licorice, and they exhibited various pharmacological properties. In this report, we have accomplished the total synthesis of glycycoumarin, glycyrin, and 3-O-methylglycyrol in 5-7 linear steps from commercially available 2,4,6-trihydroxybenzaldehyde with yields of 12.3-21.2%. Additionally, their anti-inflammatory activities were studied and compared. Glycycoumarin, glycyrin, and 3-O-methylglycyrol exhibited different levels of anti-inflammatory activities, with glycyrin being the most potent. Mechanistic studies indicated that glycyrin exerted its anti-inflammatory properties by inhibiting the activation of TNF-α, IL-6, and IL-1ß, making it a potential anti-inflammatory lead compound for further optimization and discovery of new agents.

Isolation and Total Synthesis of PM170453, a New Cyclic Depsipeptide Isolated from Lyngbya sp.

In our continuing search for biologically active new chemical entities from marine organisms, we have isolated a new cyclic depsipeptide, PM170453 (1), from a cyanobacterium of the genus Lyngbya sp., collected in the Indo-Pacific Ocean. Structure elucidation of the isolated compound was determined by spectroscopic methods including MS, 1H, 13C and 2D-NMR. To solve the supply problem for 1 and progress pharmaceutical development, the total synthesis of 1 that involves a total of 20 chemical steps in a convergent process was carried out. Its in vitro cytotoxic activity against four human tumor cell lines, as well as the inhibition of the interaction between the programmed cell death protein 1 PD-1 and its ligand PD-L1 were also evaluated.