Stereoselective Total Synthesis Research Articles

Stereoselective Total Synthesis of Natural Decanolides Bellidisin C and Pinolidoxin

Stereoselective Total Synthesis of Natural Decanolides Bellidisin C and Pinolidoxin

The first enantioselective total synthesis of the eremophilane-type sesquiterpenoid (−)-peniroqueforin C

Herein, we report the first stereoselective total synthesis of the eremophilane-type sesquiterpenoid (−)-peniroqueforin C using a chiral-pool strategy. This synthetic route features the use of readily available (S)-(+)-carvone as a chiral building block, Robinson annulation to construct the decalin system, substrate-controlled stereoselective methylation, single-step annulative construction of a tricyclic γ-ylidene-butenolide with concomitant alkene transposition, and direct lactone-to-lactam conversion as key transformations.

Stereoselective Total Synthesis of Rhodocoranes I and J.

We report the stereoselective total synthesis of rhodocoranes I and J in 10 steps and 16.4% overall yield from (S)-limonene. The synthesis was accomplished through the convergent assembly of a highly substituted chiral cyclopentanone and a lithiated furanyl silyl ketene acetal. The requisite cyclopentanone framework was strategically constructed from the chiral pool, (S)-limonene, through a sequence of steps that included a hydroboration/oxidation, ozonolysis, aldol condensation, reduction, and palladium-catalyzed diastereoselective allylic transposition. This study provides a general approach to the synthesis of the rhodocorane family, known for their antibacterial, antifungal, and cytotoxic properties.

Unified, Biosynthesis-Inspired, Completely Stereocontrolled Total Synthesis of All Highest-Order [n + 1] Oligocyclotryptamine Alkaloids.

We describe the unified enantioselective total synthesis of the polycyclotryptamine natural products (+)-quadrigemine H, (+)-isopsychotridine C, (+)-oleoidine, and (+)-caledonine. Inspired by our hypothesis for the biogenesis of these alkaloids via an iterative concatenative addition of homochiral cyclotryptamines to a meso-chimonanthine headcap, we leverage the modular, diazene-directed assembly of stereodefined cyclotryptamines to introduce successive C3a-C7' quaternary stereocenters on a heterodimeric meso-chimonanthine surrogate with full stereochemical control at each quaternary linkage. We developed a new strategy for iterative aryl-alkyl diazene synthesis using increasingly complex oligomeric hydrazide nucleophiles and a bifunctional cyclotryptamine bearing a C3a leaving group and a pendant C7 pronucleophile. The utility of this strategy is demonstrated by the first total synthesis of heptamer (+)-caledonine and hexamer (+)-oleoidine. Enabled by our completely stereoselective total syntheses and expanded characterization data sets, we provide the first complete stereochemical assignment of pentamer (+)-isopsychotridine C, provide evidence that it is identical to the alkaloid known as (+)-isopsychotridine B, and report that tetramer (+)-quadrigemine H is identical to the alkaloid called (+)-quadrigemine I, resolving longstanding questions about the structures of the highest-order [n + 1] oligocyclotryptamine alkaloids.

Biology and Total Synthesis of n-3 Docosapentaenoic Acid-Derived Specialized Pro-Resolving Mediators.

Research over the last 25 years related to structural elucidations and biological investigations of the specialized pro-resolving mediators has spurred great interest in targeting these endogenous products in total synthesis. These lipid mediators govern the resolution of inflammation as potent and stereoselective agonists toward individual G-protein-coupled receptors, resulting in potent anti-inflammatory activities demonstrated in many human disease models. Specialized pro-resolving mediators are oxygenated polyunsaturated products formed in stereoselective and distinct biosynthetic pathways initiated by various lipoxygenase and cyclooxygenase enzymes. In this review, the reported stereoselective total synthesis and biological activities of the specialized pro-resolving mediators biosynthesized from the polyunsaturated fatty acid n-3 docosapentaenoic acid are presented.

Total Synthesis of Macrocyclolipopeptide Dysoxylactam A.

A highly stereoselective total synthesis of potent multidrug-resistant reverser dysoxylactum A has been accomplished in the longest linear sequences of 20 steps with an overall 10.2% yield. The key steps of this synthesis included Brown's crotylation, Evans alkylation, the Carreira protocol to generate the stereogenic center, and Yamaguchi macrolactonization.

Easy and Accessible Synthesis of Cannabinoids from CBD.

Cannabidiol (CBD), a prominent phytocannabinoid found in various Cannabis chemotypes, is under extensive investigation for its therapeutic potential. Moreover, because it is nonpsychoactive, it can also be utilized as a functional ingredient in foods and supplements in certain countries, depending on its legal status. From a chemical reactivity point of view, CBD can undergo conversion into different structurally related compounds both during storage and after the consumption of CBD-based products. The analytical determination of these compounds is of paramount concern due to potential toxicity and the risk of losing the active ingredient (CBD) title. Consequently, the complete stereoselective total synthesis of representative CBD-derived compounds has become a matter of great interest. The synthesis of pure CBD-derived compounds, achievable in a few synthetic steps, is essential for preparing analytical standards and facilitating biological studies. This paper details the transformation of the readily available CBD into Δ8-THC, Δ9-THC, Δ8-iso-THC, CBE, HCDN, CBDQ, Δ6-iso-CBD, and 1,8-cineol cannabinoid (CCB). The described protocols were executed without the extensive use of protecting groups, avoiding tedious purifications, and ensuring complete control over the structural features.

Biological Evaluations, NMR Analyses, Molecular Modeling Studies, and Overview of the Synthesis of the Marine Natural Product (-)-Mucosin.

Natural products obtained from marine organisms continue to be a rich source of novel structural architecture and of importance in drug discovery, medicine, and health. However, the success of such endeavors depends on the exact structural elucidation and access to sufficient material, often by stereoselective total synthesis, of the isolated natural product of interest. (-)-Mucosin (1), a fatty acid derivative, previously presumed to contain a rare cis-bicyclo[4.3.0]non-3-ene moiety, has since been shown to be the trans-congener. Analytically, the fused bicyclic ring system in (-)-1 constitutes a particular challenge in order to establish its relative and absolute stereochemistry. Herein, data from biological evaluations, NMR and molecular modeling studies of (-)-1 are presented. An overview of the synthetic strategies enabling the exact structural elucidation of (-)-mucosin (1) is also presented.

Stereoselective convergent total synthesis of oxylipins.

We synthesized stereoselectively four stereoisomers of oxylipins (1a-d) by a convergent approach based on chiral catalysis. The synthetic approach involved sequential assembly of two key fragments - ene-diol and allyl alcohol - for an intended convergent cross-metathesis reaction to join these fragments. The key steps include Sharpless kinetic resolution, asymmetric dihydroxylation and Grubbs cross-metathesis. The characterization of the synthesized oxylipins revealed spectroscopic data that were consistent with previously reported values.

Unlocking a reductive hydroalkoxylation cascade for the stereoselective synthesis of cyclic ethers: total synthesis of (±)-isolaurepan and (±)-cis-lauthisan.

A Lewis acid-mediated, 5/6/7/8-endo-dig reductive hydroalkoxylation cascade on enynols gives expeditious, diastereoselective access to small and medium ring cyclic ethers with a long aliphatic side chain. The brevity of the approach allowed a 4-step, stereoselective total synthesis of (±)-isolaurepan and (±)-cis-lauthisan.

Concise Stereoselective Total Synthesis of (-)-Hedycoropyran A.

A concise and stereoselective total synthesis of (-)-hedycoropyran A was accomplished in a substrate-controlled manner from a readily available alkene. Highlights of the synthesis include a highly diastereoselective dehydrogenative cycloetherification to construct the trans-2-aryl-6-alkyl-3,6-dihydro-2H-pyran framework and late-stage substrate-controlled trans-dihydroxylation at C(3,4).

Prins cyclization: new strategy for the stereoselective total synthesis of Polyrhacitide A

A highly stereoselective total synthesis of polyrhacitide A, a polyketide natural product, has been accomplished by means of Prins cyclisation. The key precursor i.e. anti-1,3-diol for polyrhacitide A has been prepared from trans-2,6-disubstituted-3,4-dihydropyrans. In this approach, Prins cyclisation has successfully been utilised twice for the construction of 1,3-diol unit of polyrhacitide A. The key steps involved in this approach are Jacobsen hydrolytic kinetic resolution, Mitsunobu inversion, Prins cyclisation and Ring-closing metathesis (RCM).

Structure Confirmation of Dechlorotrichotoxin A through Stereoselective Total Synthesis.

The stereoselective total synthesis of dechlorotrichotoxin A, alongside the synthesis of a 1:1 10E/Z mixture of trichotoxin A, was successfully achieved, commencing from the natural monoterpenoid (-)-citronellal. Key steps in the synthesis involved introducing three alkenes and establishing a stereogenic secondary alcohol center. These transformations were accomplished through olefin cross-metathesis, Tebbe olefination, and enantioselective allylation using a chiral phosphoric acid. A comparison of the spectroscopic data between the synthetic dechlorotrichotoxin A and the reported spectra confirmed that the polyketide isolated from a Smenospongia species corresponds to trichotoxin A rather than dechlorotrichotoxin A.

Total Synthesis of the Reported Structure of Neaumycin B.

The stereoselective total synthesis of structure 1 assigned to the macrolide natural product neaumycin B is reported in a 2.3% overall yield on 90 mg scale. The synthesis features a gram-scale nickel-catalyzed reductive cross-coupling/spiroketalization tactic to construct the spiroketal core of neaumycin B. The stereostructures of the C3-C6, C8-C14, and C20-C41 segments of synthetic neaumycin B were unambiguously verified by X-ray crystallography.

Total Synthesis of Pyrrolidine and Piperidine Natural Products via TMSOTf-Mediated "5/6-endo-dig" Reductive Hydroamination of Enynyl Amines.

Stereoselective syntheses of pyrrolidines and piperidines bearing hydrophobic chains have been achieved through a metal free, Lewis acid-mediated 5/6-endo-dig reductive hydroamination cascade of enynyl amines. The brevity of the developed strategy allowed for the collective stereoselective total synthesis of various alkaloids, including (±)-pyrrolidine cis-225H, (±)-epi-197B, (±)-epi-225C, the family of (+)-solenopsins and (+)-isosolenopsins, and the formal synthesis of (±)-bgugaine and (+)-azimic acid.

Sulfamidate-Based Stereoselective Total Synthesis of (+)-Preussin Using Gold(I)-Catalyzed Intramolecular Dehydrative Amination: Dead End and Detour.

A sulfamidate-based stereoselective total synthesis of (+)-preussin has been developed. The key step involves a gold(I)-catalyzed intramolecular dehydrative amination of sulfamate esters tethered to allylic alcohols, which allows for the construction of the cyclic sulfamidate with high stereoselectivity. Further manipulation to highly constrained bicyclic sulfamidate and the following ring-opening process afford 3-hydroxypyrrolidine motif stereoselectively. The energy of the constrained bicyclic ring system is relieved by the subsequent ring-opening process, which leads to a stereoselective formation of the 3-hydroxypyrrolidine motif under mild reaction conditions. The success of this approach not only provides a new method for the total synthesis of enantiomerically pure (+)-preussin but also highlights the synthetic utility of sulfamidates in constructing valuable natural product architectures.

De Novo Synthesis of Dihydrobenzofurans and Indolines and Its Application to a Modular, Asymmetric Synthesis of Beraprost

Dihydrobenzofurans and indolines are important constituents of pharmaceuticals. Herein, we describe a novel strategy for their construction in which the aromatic ring is created de novo through an inverse-electron demand Diels-Alder reaction and cheletropic extrusion sequence of a 2-halothiophene-1,1-dioxide with an enol ether/enamide, followed by aromatization. Unusually, the aromatization process proved to be highly challenging, but it was discovered that treatment of the halocyclohexadienes with a base effected an α-elimination-aromatization reaction. Mechanistic investigation of this step using deuterium-labeling studies indicated the intermediacy of a carbene which undergoes a 1,2-hydrogen shift and subsequent aromatization. The methodology was applied to a modular and stereoselective total synthesis of the antiplatelet drug beraprost in only 8 steps from a key enal-lactone. This lactone provided the core of beraprost to which both its sidechains could be appended through a 1,4-conjugate addition process (lower ω-sidechain), followed by de novo construction of beraprost's dihydrobenzofuran (upper α-sidechain) using our newly developed methodology. Additionally, we have demonstrated the breadth of our newly established protocol in the synthesis of functionalized indolines, which occurred with high levels of regiocontrol. According to density-functional theory (DFT) calculations, the high selectivity originates from attractive London dispersion interactions in the TS of the Diels-Alder reaction.

Stereoselective Total Synthesis of Stereoisomers of Entecavir

AbstractPractical methods for the synthesis of three stereoisomers of Entecavir have been developed. Starting from the reported intermediate (1S,2R)-2-((benzyloxy)methyl)cyclopent-3-en-1-ol and (1R,2S)-2-((benzyloxy)methyl)cyclopent-3-en-1-ol, respectively, three stereoisomers of Entecavir have been prepared with 17–20% overall yields. In principle, other stereoisomers could also be prepared by using the materials and reactions described in this article.

Structural Requirements for Ga3+ Coordination in Synthetic Analogues of the Siderophore Piscibactin Deduced by Chemical Synthesis and Density Functional Theory Calculations.

Stereoselective total synthesis of several analogues of piscibactin (Pcb), the siderophore produced by different pathogenic Gram-negative bacteria, was performed. The acid-sensitive α-methylthiazoline moiety was replaced by a more stable thiazole ring, differing in the configuration of the OH group at the C-13 position. The ability of these Pcb analogues to form complexes with Ga3+ as a mimic of Fe3+ showed that the configuration of the hydroxyl group at C-13 as 13S is crucial for the chelation of Ga3+ to preserve the metal coordination, while the presence of a thiazole ring instead of the α-methylthiazoline moiety does not affect such coordination. A complete 1H and 13C NMR chemical shift assignment of the diastereoisomer mixtures around C9/C10 was done for diagnostic stereochemical disposition. Additionally, density functional theory calculations were performed not only for confirming the stereochemistry of the Ga3+ complex among the six possible diastereoisomers but also for deducing the ability of these to form octahedral coordination spheres with gallium. Finally, the lack of antimicrobial activity of Pcb and Pcb thiazole analogue Ga3+ complexes against Vibrio anguillarum agrees with one of the roles of siderophores in protecting pathogens from metal ion toxicity. The efficient metal coordination shown by this scaffold suggests its possible use as a starting point for the design of new chelating agents or vectors for the development of new antibacterials that exploit the "Trojan horse" strategy using the microbial iron uptake mechanisms. The results obtained will be of great help in the development of biotechnological applications for these types of compounds.

The Stereoselective Total Synthesis of the Elusive Cephalosporolide F

Here we report a seven-step protecting-group-free stereoselective total synthesis of the elusive (+)-cephalosporolide F from d-glucose. A microwave-assisted reaction between the Meldrum's acid and the d-glucose to the respective octono-1,4-lactone derivative, and a low temperature visible-light photoredox spirocyclization of a chiral N-alkoxyphthalimide to ceph F, are the two key chemical reactions that allowed the accomplishment of this unprecedented feat under an environmentally friendly processes.