Showing papers on "Total synthesis published in 2023"

Total synthesis of lissodendoric acid A via stereospecific trapping of a strained cyclic allene

Abstract: Small rings that contain allenes are unconventional transient compounds that have been known since the 1960s. Despite being discovered around the same time as benzyne and offering a number of synthetically advantageous features, strained cyclic allenes have seen relatively little use in chemical synthesis. We report a concise total synthesis of the manzamine alkaloid lissodendoric acid A, which hinges on the development of a regioselective, diastereoselective, and stereospecific trapping of a fleeting cyclic allene intermediate. This key step swiftly assembles the azadecalin framework of the natural product, allows for a succinct synthetic endgame, and enables a 12-step total synthesis (longest linear sequence; 0.8% overall yield). These studies demonstrate that strained cyclic allenes are versatile building blocks in chemical synthesis. Description Synthesis by strain Chemists often rely on strained intermediates to drive reactions that relieve the strain. In this context, however, cyclic allenes that cram adjacent double bonds into tight carbon rings have been underexploited. Ippoliti et al. now report a synthetic route to lissodendoric acid A, a marine natural product that relies on transient generation of a cyclic allene to prepare the fused ring core (see the Perspective by Jankovic and West). They accessed a single mirror-image form of the allene from a chiral precursor by fluoride attack on a silicon substituent and displacement of an adjacent bromide, setting up a stereospecific Diels-Alder cycloaddition with a pyrone reagent. —JSY Strain relief of adjacent double bonds in a carbon ring enables a key cycloaddition in the synthesis of a marine natural product.

Enantioselective Total Synthesis of (−)-Himalensine A via a Palladium and 4-Hydroxyproline Co-catalyzed Desymmetrization of Vinyl-bromide-tethered Cyclohexanones

Abstract: Herein, we describe the convergent enantioselective total synthesis of himalensine A in 18 steps, enabled by a highly enantio- and diastereoselective construction of the morphan core via a palladium/hydroxy proline co-catalyzed desymmetrization of vinyl-bromide-tethered cyclohexanones. The reaction pathway was illuminated by density functional theory calculations, which support an intramolecular Heck reaction of an in situ-generated enamine intermediate, where exquisite enantioselectivity arises from intramolecular carboxylate coordination to the vinyl palladium species in the rate- and enantio-determining carbopalladation steps. The reaction tolerates diverse N-derivatives, all-carbon quaternary centers, and trisubstituted olefins, providing access to molecular scaffolds found in a range of complex natural products. Following large-scale preparation of a key substrate and installation of a β-substituted enone moiety, the rapid construction of himalensine A was achieved using a highly convergent strategy based on an amide coupling/Michael addition/allylation/ring-closing metathesis sequence which allowed the introduction of three of the five rings in only three synthetic steps (after telescoping). Moreover, our strategy provides a new enantioselective access to a known tetracyclic late-stage intermediate that has been used previously in the synthesis of many Daphniphyllum alkaloids.

A Convergent Total Synthesis of (+)-Ineleganolide.

Abstract: We report the total synthesis of the furanobutenolide-derived diterpenoid (+)-ineleganolide. The synthetic approach relies on a convergent strategy based on the coupling of two enantioenriched fragments, which are derived from (-)-linalool and (+)-norcarvone, respectively. A high-yielding, one-step Michael addition and aldol cascade furnishes a pentacyclic framework as a single diastereomer, thereby overcoming previous challenges in controlling stereochemistry. The endgame features an O2-facilitated C-H oxidation and a samarium diiodide-induced semipinacol rearrangement to furnish the highly rigid central seven-membered ring.

Intramolecular Rhodium-Catalyzed [(3+2+2)] Carbocyclization Reactions with Dienylidenecyclopropanes: A Concise and Stereoselective Total Synthesis of the Sesquiterpene (+)-Zizaene.

Abstract: The development of an intramolecular rhodium-catalyzed [(3+2+2)] carbocyclization reaction of alkylidenecyclopropanes (ACPs) tethered to 1,4- and 1,5-skipped dienes is described. This transformation offers a new approach for the construction of bridged tricyclic compounds with up to three quaternary centers, which are suitable for the synthesis of challenging bioactive natural products. For instance, the synthetic utility of this transformation is illustrated through a concise asymmetric total synthesis of the sesquiterpene (+)-zizaene in ten steps from a commercially available starting material.

Asymmetric Total Synthesis of Twin Bufogargarizins A and B.

Abstract: The first and asymmetric total synthesis of bufogargarizins A and B, two unusual and highly oxygenated twin steroids with rearranged A/B rings, was achieved. The synthetically challenging [7-5-6-5] tetracyclic ring system of bufogargarizin A was efficiently constructed by the first intramolecular Ru-catalyzed [5 + 2] cycloaddition reaction of a vinyl ether cyclopropane-yne. Notably, the interesting [5-7-6-5] tetracyclic skeleton of bufogargarizin B was diastereoselectively reassembled by unique retro-aldol/transannular aldol cascade reactions from the [7-5-6-5] tetracyclic framework.

Combining the best of both worlds: radical-based divergent total synthesis

Abstract: A mature science, combining the art of the total synthesis of complex natural structures and the practicality of delivering highly diverged lead compounds for biological screening, is the constant aim of the organic chemistry community. Delivering natural lead compounds became easier during the last two decades, with the evolution of green chemistry and the concepts of atom economy and protecting-group-free synthesis dominating the field of total synthesis. In this new era, total synthesis is moving towards natural efficacy by utilizing both the biosynthetic knowledge of divergent synthesis and the latest developments in radical chemistry. This contemporary review highlights recent total syntheses that incorporate the best of both worlds.

Total Synthesis of Taxol Enabled by Inter- and Intramolecular Radical Coupling Reactions.

Abstract: Taxol is a clinically used drug for the treatment of various types of cancers. Its 6/8/6/4-membered ring (ABCD-ring) system is substituted by eight oxygen functional groups and flanked by four acyl groups, including a β-amino acid side chain. Here we report a 34-step total synthesis of this unusually oxygenated and intricately fused structure. Inter- and intramolecular radical coupling reactions connected the A- and C-ring fragments and cyclized the B-ring, respectively. Functional groups of the A- and C-rings were then efficiently decorated by employing newly developed chemo-, regio-, and stereoselective reactions. Finally, construction of the D-ring and conjugation with the β-amino acid delivered taxol. The powerful coupling reactions and functional group manipulations implemented in the present synthesis provide new valuable information for designing multistep target-oriented syntheses of diverse bioactive natural products.

Asymmetric Total Synthesis of Illisimonin A

Abstract: The discovery of illisimonin A in 2017 extended the structural repertoire of the Illicium sesquiterpenoids—a class of natural products known for their high oxidation levels and neurotrophic properties—with a new carbon backbone combining the strained trans-pentalene and norbornane substructures. We report an asymmetric total synthesis of (−)-illisimonin A that traces its tricyclic carbon framework back to a spirocyclic precursor, generated by a tandem-Nazarov/ene cyclization. As crucial link between the spirocyclic key intermediate and illisimonin A, a novel approach for the synthesis of tricyclo[5.2.1.01,5]decanes via radical cyclization was explored. This approach was applied in a two-stage strategy consisting of Ti(III)-mediated cyclization and semipinacol rearrangement to access the natural product’s carbon backbone. These key steps were combined with carefully orchestrated C–H oxidations to establish the dense oxidation pattern.

Enantioselective Total Synthesis of (+)-Stephadiamine.

Abstract: An asymmetric synthesis of (+)-stephadiamine has been accomplished featuring (a) an enantioselective dearomatizative Michael addition to generate a quaternary stereocenter; (b) a domino sequence involving reductive generation of nitrone from γ-nitro ketone followed by a highly regio- and diastereo-selective intramolecular [3 + 2] cycloaddition to construct the aza[4,3,3]propellane core with concurrent generation of two quaternary stereocenters and two functional groups ready for subsequent transformations; (c) the Curtius rearrangement of the sensitive α,α-disubstituted malonic acid mono ester for the installation of α,α-disubstituted amino ester moiety; (d) a benzylic C-H oxidation under photoredox catalytic conditions; and (e) a highly diastereoselective ketone reduction affording δ-hydroxyester preorganized for lactonization.

Total Synthesis of Vilmoraconitine.

Abstract: Vilmoraconitine belongs to one of the most complex skeleton types in the C19-diterpenoid alkaloids, which architecturally features an unprecedented heptacyclic core possessing a rigid cyclopropane unit. Here, we report the first total synthesis of vilmoraconitine relying on strategic use of efficient ring-forming reactions. Key steps include an oxidative dearomatization-induced Diels-Alder cycloaddition, a hydrodealkenylative fragmentation/Mannich sequence, and an intramolecular Diels-Alder cycloaddition.

Concise Enantioselective Total Synthesis of Isopavine Alkaloids.

Abstract: Herein, we report a concise asymmetric total synthesis of isopavine alkaloids, which feature a special azabicyclo[3.2.2]nonane tetracyclic skeleton. The key steps include iridium-catalyzed asymmetric hydrogenation of unsaturated carboxylic acids, Curtius rearrangement, and Eschweiler-Clarke methylation, which enable an enantioselective approach to isopavine alkaloids in 6-7 linear steps. Furthermore, for the first time, isopavine alkaloids, especially (-)-reframidine (3), are found to display effective antiproliferative effects on various cancer cell lines.

Total Syntheses of Kopsaporine, Kopsinol and Kopsiloscine A.

Abstract: Kopsia alkaloids represent a complex class of natural products bearing polycyclic ring system with two or three consecutive quaternary carbon centers. In this article, we report the first total synthesis of Kopsaporine related alkaloids. Features of our structure-unit-based strategy are an intramolecular Pummerer rearrangement induced cascade nucleophilic cyclization/aza-Prins cyclization to construct the highly functional hexahydrocarbazole skeleton, an olefin deconjugated vinylogous alkylation to establish the all-carbon quaternary center, an iridium complex mediated radical addition to fuse the aspidofractine framework, an unprecedented IBX oxidation to introduce the α-hydroxyketone moiety, and a bio-inspired retro-Aldol/Aldol reaction to convert kopsaporine to kopsiloscine A.

Antrodiellin B/hypnophilin/coriolin and strained 5/5/5 and 5/6/4 skeletons via [5+2+1]/epoxidation/transannular radical cyclization

Abstract: Many natural products contain compact cis-anti-cis-configurated 5/5/5 and 5/6/4 tricycles, and efficient access to these molecules is posing many hurdles to the synthetic community. Accessing molecules with more strained trans-anti-cis-configurated 5/5/5 tricycles (which are rarely found in nature) was envisioned to be more challenging, and no solution to this has been reported. We describe here a [5+2+1]/epoxidation/transannular radical cyclization strategy to solve the above-mentioned challenges, as demonstrated by the first total synthesis of (+)-antrodiellin B, the asymmetric total synthesis of (−)-hypnophilin, and the formal synthesis of (−)-coriolin, all of which contain a cis-anti-cis-configurated 5/5/5 skeleton, together with the synthesis of compounds with 5/6/4 and trans-anti-cis-configurated 5/5/5 tricycles. The present strategy is helpful for obtaining these and other molecules and their analogs for future downstream studies dependent on synthetic molecules with unusual scaffolds.

Total Synthesis of (+)-Shearilicine.

Abstract: Herein we report the first total synthesis of the indole diterpenoid natural product shearilicine by an 11-step sequence via a generalizable precursor to the highly oxidized subclass of indole diterpenoids. A native chiral auxiliary strategy was employed to access the target molecule in an enantiospecific fashion. The formation of the key carbazole substructure was achieved through a mild intramolecular Heck cyclization, wherein a computational study revealed noncovalent substrate-ligand and ligand-ligand interactions that promoted migratory insertion.

Total Synthesis of Starfish Cyclic Steroid Glycosides. Part 3, Formal Total Synthesis of Luzonicosides A and D

Abstract: Luzonicosides A (1) and D (2) are the major saponins isolated from pacific starfish Echinaster Luzonicus, featuring a sterically congested 16-membered ring which is formed by bridging the C3 and C6 of a 3β,6β-dihydroxy-Δ7-ene steroid with a 1,2-trans-linked linear trisaccharide via glycosidic and ether bonds, respectively. Here, we describe a formal total synthesis of starfish cyclic steroid glycosides 1 and 2. The synthetic route is highly modular and versatile, involving construction of the 16-membered macrocycles via Au(I)-catalyzed intramolecular glycosylation, highly efficient installation of unsaturated sugar moieties with ortho-hexynylbenzoates, elaboration of glucuronic acid unit via post-oxidation, and a de novo synthesis of the ether-linked pyranose unit. Appendix S1: Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Enantioselective Total Synthesis of (+)-KB343.

Abstract: A concise total synthesis of the complex guanidinium toxin KB343 is reported traversing through an unusual sequence of chemoselective transformations and strategic skeletal reorganization. The absolute configuration is confirmed through an enantioselective route, and the structures of all key intermediates and the natural product itself are unassailably confirmed through X-ray crystallographic analysis.

Total Synthesis of Sculponin U through A Photoinduced Radical Cascade Cyclization.

Abstract: We have accomplished the total synthesis of sculponin U, a polycyclic C-20-oxygenated kaurane diterpenoid featuring a bridge of 7,20-lactone-hemiketal functionality, through a radical cascade cyclization triggered by photoinduced electron transfer (PET) of silyl enolate to form the cyclohexanone-fused bicyclo[3.2.1]octane skeleton. Other keypoints in our synthetic strategy encompass a Diels-Alder reaction to construct the middle six-membered ring of sculponin U, and an intramolecular radical cyclization induced by iron-catalyzed hydrogen atom transfer to close the western cyclohexane ring. Successful preparation of the enantiopure silyl enolate as the PET precursor enables the asymmetric total synthesis of sculponin U, opening a new avenue for divergent syntheses of structurally related C-20-oxygenated kaurane congeners and pharmaceutical derivatives thereof.

Enantioselective Total Synthesis of (+)-Pedrolide.

Abstract: The first total synthesis of (+)-pedrolide, a tigliane-derived diterpenoid featuring an unprecedented 5-5-6-6-3 carbon skeleton, is reported. Key to the approach is the construction of the bicyclo[2.2.1]heptane core via an intramolecular cyclopentadiene-Diels-Alder cycloaddition. To this end, a norbornadiene serves as an effective surrogate for cyclopentadiene, which is unmasked under mild conditions involving a complex Diels-Alder reaction cascade. In addition, the synthesis provides a novel approach to a densely functionalized carane in an efficient and enantioselective manner.

Palladium-Catalyzed Carbonylations: Application in Complex Natural Product Total Synthesis and Recent Developments

Abstract: Carbon monoxide is a cheap and abundant C1 building block that can be readily incorporated into organic molecules to rapidly build structural complexity. In this Perspective, we outline several recent (since 2015) examples of palladium-catalyzed carbonylations in streamlining complex natural product total synthesis and highlight the strategic importance of these carbonylation reactions in the corresponding synthesis. The selected examples include spinosyn A, callyspongiolide, perseanol, schizozygane alkaloids, cephanolides, and bisdehydroneostemoninine and related stemona alkaloids. We also provide our perspective about the recent advancements and future developments of palladium-catalyzed carbonylations.

Total Synthesis of (±)- and (-)-Daphnillonin B.

Abstract: The first total synthesis of (±)- and (-)-daphnillonin B, a daphnicyclidin-type alkaloid with a new [7-6-5-7-5-5] A/B/C/D/E/F hexacyclic core, has been achieved. The [6-5-7] B/C/D ring system was efficiently and diastereoselectively constructed via a mild type I intramolecular [5+2] cycloaddition, followed by a Grubbs II catalyst-catalyzed radical cyclization. The [5-5] fused E/F ring system was synthesized via a diastereoselective intramolecular Pauson-Khand reaction. Notably, the synthetically challenging [7-6-5-7-5-5] hexacyclic core was reassembled by a unique Wagner-Meerwein-type rearrangement from the [6-6-5-7-5-5] hexacyclic framework found in calyciphylline A-type Daphniphyllum alkaloids.

Asymmetric Total Synthesis of (+)-Phainanoid A and Biological Evaluation of the Natural Product and Its Synthetic Analogues.

Abstract: Here, we report our detailed efforts toward the synthesis of phainanoids, a novel class of dammarane-type triterpenoids with potent immunosuppressive activities and unique structural features. Systematic model studies have been carried out, and efficient approaches have been established to construct the benzofuranone-based 4,5-spirocycle, the D/E/F tricyclic core, the [4.3.1] propellane, and the 5,5-oxaspirolactone moieties. The asymmetric synthesis of (+)-phainanoid A has been achieved through kinetic resolution of the tricyclic core followed by diastereoselective installation of the A/B/C and G/H rings and fragment coupling with the enantioenriched I/J rings. In addition, novel estrone-derived phainanoid analogues have been prepared. The immunosuppressive and cell survival assays revealed that (+)-phainanoid A and some of its synthetic analogues can specifically inhibit stimulation-induced lymphocyte proliferation but not cell survival at their effective concentrations. Preliminary structure-activity relationship information has been obtained, which could inspire future design of immunosuppressive phainanoid analogues.

Divergent Total Syntheses of (-)-Daphnezomines A and B and (+)-Dapholdhamine B.

Abstract: The daphnezomine A-type subfamily of Daphniphyllum alkaloids structurally features a unique aza-adamantane core skeleton and anticipates efficient strategies for completing their syntheses to thoroughly investigate their biological activities. Herein, divergent total syntheses of (-)-daphnezomines A and B and (+)-dapholdhamine B have been accomplished in 16~20 steps from a known epoxide via rapid construction of a common core intermediate. The present work features a Ti-mediated radical cyclization to establish the azabicyclo[3.3.1]nonane ring system, an intramolecular Heck reaction to install the bridgehead all-carbon quaternary stereocenter, a tandem deprotection/reduction/keto amine-carbinolamine tautomerization to furnish the aza-adamantane backbone, and an NIS-promoted 6-endo-trig aminocyclization to assemble the (+)-dapholdhamine B backbone.

Fragment Coupling Approach to Diaporthein B.

Abstract: Pimarane diterpenes are produced by a diverse array of plants, fungi, and bacteria. Many members of this family possess antimicrobial and antiproliferative activities. The pimarane diterpenes are characterized by a tricyclic carbon scaffold comprising three fused six-membered rings and at least three quaternary centers. Here, we describe two convergent, fragment-based strategies toward the synthesis of diaporthein B (3), one of the most highly oxidized pimarane diterpenes. The first approach provided access to the tricyclic carbon scaffold of the target and featured a highly diastereoselective fragment coupling, a novel carbonylative Stille cross-coupling to directly access an α-hydroxyketone from a vinyl iodide, and a tandem aldol cyclization-deprotection cascade. The second route utilized a diastereoselective 1,4-addition of a silyloxyfuran to an unsaturated ketone, followed by an epoxidation-ring opening sequence, to access a highly oxidized intermediate containing two elaborated cyclohexane rings. The chemistry developed herein may ultimately be useful in an eventual synthesis of this class of natural products.