Showing papers on "Total synthesis published in 2020"

Transition Metal-Mediated C-C Single Bond Cleavage: Making the Cut in Total Synthesis.

Abstract: Transition-metal-mediated cleavage of C-C single bonds can enable entirely new retrosynthetic disconnections in the total synthesis of natural products. Given that C-C bond cleavage inherently alters the carbon framework of a compound, and that, under transition-metal catalysis, the generated organometallic or radical intermediate is primed for further complexity-building reactivity, C-C bond-cleavage events have the potential to drastically and rapidly remodel skeletal frameworks. The recent acceleration of the use of transition-metal-mediated cleavage of C-C single bonds in total synthesis can be ascribed to a communal recognition of this fact. In this Review, we highlight ten selected total syntheses from 2014 to 2019 that illustrate how transition-metal-mediated cleavage of C-C single bonds at either the core or the periphery of synthetic intermediates can streamline synthetic efforts.

Recent Advances in the Total Synthesis of Natural Products Containing Eight-Membered Carbocycles (2009–2019)

Abstract: Natural products containing eight-membered carbocycles constitute a class of structurally intriguing and biologically important molecules such as the famous diterpenes taxol and vinigrol. Such natu...

Total Synthesis of Natural Products with Bridged Bicyclo[m.n.1] Ring Systems via Type II [5 + 2] Cycloaddition.

Abstract: ConspectusNatural products containing bridged ring systems are widely identified and show significant biological activity. The development of efficient synthesis reactions and strategies to constru...

Regio- and Enantioselective Synthesis of Sulfone-Bearing Quaternary Carbon Stereocenters by Pd-Catalyzed Allylic Substitution

Abstract: Chiral sulfones are of great importance in medicinal chemistry and chemical synthesis. Efficient methods for preparing enantiomerically enriched sulfone-containing molecules can therefore be of significant value; such methods, however, are uncommon. Herein, we report the first general palladium-catalyzed sulfonylation of vinyl cyclic carbonates with sodium sulfinates. A series of enantiomerically enriched tertiary allylic sulfones were synthesized in good yields with excellent enantiomeric ratios. Both aliphatic- and aryl-substituted vinyl cyclic carbonates are suitable reactants with excellent results. This reaction features broad substrates scope, readily available starting materials, excellent regio- and enantioselectivity, and synthesis of sulfone-bearing quaternary carbon stereocenters. Through the sulfonylation of geranyl derived cyclic carbonate 1 h, we achieve the formal total synthesis of (+)-agelasidine A.

Total synthesis of the complex taxane diterpene canataxpropellane

Abstract: Canataxpropellane belongs to the medicinally important taxane diterpene family. The most prominent congener, Taxol, is one of the most commonly used anticancer agent in clinics today. Canataxpropellane exhibits a taxane skeleton with three additional transannular C-C bonds, resulting in a total of six contiguous quaternary carbons, of which four are located on a cyclobutane ring. Unfortunately, isolation of canataxpropellane from natural sources is inefficient. Here, we report a total synthesis of (-)-canataxpropellane in 26 steps and 0.5% overall yield from a known intermediate corresponding to 29 steps from commercial material. The core structure of the (-)-canataxpropellane (2) was assembled in two steps using a Diels-Alder/ortho-alkene-arene photocycloaddition sequence. Enantioselectivity was introduced by designing chiral siloxanes to serve as auxiliaries in the Diels-Alder reaction.

Asymmetric Total Synthesis of (−)-Arborisidine and (−)-19-epi-Arborisidine Enabled by a Catalytic Enantioselective Pictet–Spengler Reaction

Abstract: A five-step total synthesis of arborisidine, a caged pentacyclic monoterpene indole alkaloid, has been accomplished in both racemic and enantioselective manners. The synthesis features the following three key steps: (a) a regioselective Pictet-Spengler reaction of tryptamine with 2,3-pentanedione; (b) a chemo- and stereoselective intramolecular oxidative cyclization; and (c) a complexity-generating aza-Cope/Mannich cascade followed by in situ oxidation and epimerization. A chiral pyrenylpyrrolidino-squaramide catalyzed enantioselective Pictet-Spengler reaction between tryptamine and 2,3-pentanedione is subsequently uncovered, allowing us to develop a five-step asymmetric synthesis of (-)-arborisidine, an enantiomer of the natural substance. Both (±)-19-epi-arborisidine and (-)-19-epi-arborisidine are also synthesized, which undergo epimerization at room temperature in the presence of aqueous 2 N KOH to (±)-arborisidine and (-)-arborisidine, respectively. The 19-epi-isomer is also partially epimerized to arborisidine upon preparative TLC purification (eluent: MeOH/CHCl3 saturated with NH3) and equilibrium studies indicate that arborisidine is thermodynamically more stable than its 19-epimer. In line with Kam's biosynthesis proposal and their purification protocol, we suspect that 19-epi-arborisidine could also be a natural product.

Asymmetric Total Synthesis of (+)-Waihoensene

Abstract: The asymmetric total synthesis of (+)-waihoensene, which has a cis-fused [6,5,5,5] tetracyclic core bearing an angular triquinane, a cis-fused six-membered ring, and four contiguous quaternary carbon atoms, was achieved through a sequence of chemical reactions in a stereochemically well-defined manner. The total synthesis features the following: (1) Cu-catalyzed asymmetric conjugated 1,4-addition; (2) diastereoselective Conia-ene type reaction; (3) diastereoselective intramolecular Pauson-Khand reaction; (4) Ni-catalyzed diastereoselective conjugated 1,4-addition; and (5) radical-initiated intramolecular hydrogen atom transfer (HAT). Control experiments and density functional theory calculations support the proposed HAT process.

Applications of Knoevenagel condensation reaction in the total synthesis of natural products

Abstract: The Knoevenagel condensation reaction is a prominent organic reaction commonly being utilized in the total synthesis of natural and biologically potent products as a vital and frequently beginning step. Naturally occurring compounds having complex structures were demonstrated to exhibit significant biological properties. Due to numerous biological potencies, the total syntheses of them has fascinated and attracted much attention of synthetic organic chemists. In this review, we try to highlight the applications of the Knoevenagel reaction as the key step in the total synthesis of biologically active natural products.

Total synthesis of brevianamide A.

Abstract: The fungal-derived bicyclo[2.2.2]diazaoctane alkaloids are of interest to the scientific community for their potent and varied biological activities. Within this large and diverse family of natural products, the insecticidal metabolite (+)-brevianamide A is particularly noteworthy for its synthetic intractability and inexplicable biogenesis. Despite five decades of research, this alkaloid has remained an elusive target for chemical synthesis due to insurmountable issues of reactivity and selectivity associated with all previously explored strategies. We herein report the chemical synthesis of (+)-brevianamide A (seven steps, 7.2% overall yield, 750 mg scale), which involves a bioinspired cascade transformation of the linearly fused (−)-dehydrobrevianamide E into the topologically complex bridged-spiro-fused structure of (+)-brevianamide A. Despite five decades of research, the alkaloid (+)-brevianamide A has remained an elusive target for chemical synthesis. Now, it has been shown that the total synthesis of (+)-brevianamide A can be achieved in seven steps and 7.2% overall yield to give 750 mg of the target compound.

Nature of the Nucleophilic Oxygenation Reagent Is Key to Acid-Free Gold-Catalyzed Conversion of Terminal and Internal Alkynes to 1,2-Dicarbonyls.

Abstract: 2,3-Dichloropyridine N-oxide, a novel oxygen transfer reagent, allows the conductance of the gold(I)-catalyzed oxidation of alkynes to 1,2-dicarbonyls in the absence of any acid additives and under mild conditions to furnish the target species, including those derivatized by highly acid-sensitive groups. The developed strategy is effective for a wide range of alkyne substrates such as terminal- and internal alkynes, ynamides, alkynyl ethers/thioethers, and even unsubstituted acetylene (40 examples; yields up to 99%). The oxidation was successfully integrated into the trapping of reactive dicarbonyls by one-pot heterocyclization and into the synthesis of six-membered azaheterocycles. This synthetic acid-free route was also successfully applied for the total synthesis of a natural 1,2-diketone.

Total Synthesis of (-)-Rhodomollanol A.

Abstract: An asymmetric approach for the first total synthesis of (-)-rhodomollanol A, a highly oxidized diterpenoid, is described. The efficient synthetic strategy features three key transformations: (1) an oxidative dearomatization-induced (5 + 2) cycloaddition/pinacol-type 1,2-acyl migration cascade to build up the bicyclo[3.2.1]octane skeleton; (2) a retro-Dieckmann fragmentation/vinylogous Dieckmann cyclization cascade to assemble the bicyclo[3.3.0]octane subunit; and (3) a photo-Nazarov cyclization/intramolecular cycloetherification cascade to forge the 7-oxabicyclo[4.2.1]nonane core structure of the natural product.

Tris(pentafluorophenyl)borane-Catalyzed Cyclopropanation of Styrenes with Aryldiazoacetates

Abstract: Methods for the synthesis of cyclopropanes are critical for drug discovery, chemical biology, total synthesis, and other fields. Herein, we report the use of the strong sterically encumbered Lewis ...

Total Synthesis of Talatisamine

Abstract: Talatisamine (1) is a member of the C19 -diterpenoid alkaloid family, and exhibits K+ channel inhibitory and antiarrhythmic activities. The formidable synthetic challenge that 1 presents is due to its highly oxidized and intricately fused hexacyclic 6/7/5/6/6/5-membered-ring structure (ABCDEF-ring) with 12 contiguous stereocenters. Here we report an efficient synthetic route to 1 by the assembly of two structurally simple fragments, chiral 6/6-membered AE-ring 7 and aromatic 6-membered D-ring 6. AE-ring 7 was constructed from 2-cyclohexenone (8) through fusing an N-ethylpiperidine ring by a double Mannich reaction. After coupling 6 with 7, an oxidative dearomatization/Diels-Alder reaction sequence generated fused pentacycle 4 b. The newly formed 6/6-membered ring system was then stereospecifically reorganized into the 7/5-membered BC-ring of 3 via a Wagner-Meerwein rearrangement. Finally, Hg(OAc)2 induced an oxidative aza-Prins cyclization of 2, thereby forging the remaining 5-membered F-ring. The total synthesis of 1 was thus accomplished by optimizing and orchestrating 33 transformations from 8.

Asymmetric total synthesis of yuzurimine-type Daphniphyllum alkaloid (+)-caldaphnidine J.

Abstract: Ever since Hirata's report of yuzurimine in 1966, nearly fifty yuzurimine-type alkaloids have been isolated, which formed the largest subfamily of the Daphniphyllum alkaloids. Despite extensive synthetic studies towards this synthetically challenging and biologically intriguing family, no total synthesis of any yuzurimine-type alkaloids has been achieved to date. Here, the first enantioselective total synthesis of (+)-caldaphnidine J, a highly complex yuzurimine-type Daphniphyllum alkaloid, is described. Key transformations of this approach include a highly regioselective Pd-catalyzed hydroformylation, a samarium(II)-mediated pinacol coupling, and a one-pot Swern oxidation/ketene dithioacetal Prins reaction. Our approach paves the way for the synthesis of other yuzurimine-type alkaloids and related natural products.

Pot and time economies in the total synthesis of Corey lactone

Abstract: The Corey lactone is a highly versatile intermediate for the synthesis of a variety of prostaglandin hormones that natively control a multitude of important physiological processes. Starting from commercially available compounds, we herein disclose a time-economical, one-pot enantioselective preparation of the Corey lactone by virtue of a new diphenylprolinol silyl ether-mediated domino Michael/Michael reaction to afford the substituted cyclopentanone core in a formal (3 + 2) cycloadditive fashion. More broadly, this work advances the on-demand, gram-scale synthesis of high-value targets involving chemically orthogonal transformations, whereby distinct reactions of acids, bases, organometalics, reductants and oxidants can be carried out in a single reaction vessel in a sequential fashion.

Deconstructive Reorganization: De Novo Synthesis of Hydroxylated Benzofuran

Abstract: An unprecedented deconstructive reorganization strategy for the de novo synthesis of hydroxylated benzofurans from kojic acid- or maltol-derived alkynes is reported. In this reaction, both the benzene and furan rings were simultaneously constructed, whereas the pyrone moiety of the kojic acid or maltol was deconstructed and then reorganized into the benzene ring as a six-carbon component. Through this strategy, at least one free hydroxyl group was introduced into the benzene ring in a substitution-pattern tunable fashion without protection-deprotection and redox adjustment. With this method, a large number of hydroxylated benzofuran derivatives with different substitution-patterns have been prepared efficiently. This methodology has also been shown as the key step in a collective total synthesis of hydroxylated benzofuran-containing natural products (11 examples).

Enantioselective Synthesis of cis‐Decalin Derivatives by the Inverse‐Electron‐Demand Diels–Alder Reaction of 2‐Pyrones

Abstract: A novel strategy for the synthesis of cis-decalins by an ytterbium-catalyzed asymmetric inverse-electron-demand Diels-Alder reaction of 2-pyrones and silyl cyclohexadienol ethers is reported here. A broad range of synthetically important cis-decalin derivatives with multiple contiguous stereogenic centers and functionalities are obtained in good yields and stereoselectivities. A full set of diastereomeric substituted cis-decalin motifs are readily accessible by tuning the absolute configurations of substituted silyl cyclohexadienol ethers (R or S) as well as the ligands (R or S). The synthetic potential is showcased by the enantioselective total synthesis of 4-amorphen-11-ol, and further demonstrated by the first total synthesis of cis-crotonin.

A Concise Total Synthesis of (+)‐Waihoensene Guided by Quaternary Center Analysis

Abstract: The four contiguous all-carbon quaternary centers of waihoensene, coupled with the absence of any traditional reactive functional groups other than a single alkene, render it a particularly challenging synthetic target among angular triquinane natural products. Here, we show that its polycyclic frame can be assembled concisely by using a strategically chosen quaternary center to guide the formation of the other three through judiciously selected C-C bond formation reactions. Those events, which included a unique Conia-ene cyclization and a challenging Pauson-Khand reaction, afforded a 17-step synthesis of the molecule in enantioenriched form.

Stereoselective Construction of (E,Z)‐1,3‐Dienes and Its Application in Natural Product Synthesis

Abstract: The E,Z-configured 1,3-diene unit is a common motif in numerous bioactive natural products. Although several powerful methods are available to produce these motifs with high levels of selectivity, their construction within a complex, polyfunctionalised structure, such as a natural product, requires well-defined strategies to avoid undesirable reactions and low-to-moderate selectivities. The aim of this review is to provide a full account of the stereoselective strategies for building E,Z-configured 1,3-dienes, as well as to highlight selected total syntheses that employ them.

N-Methylated Peptide Synthesis via Generation of an Acyl N-Methylimidazolium Cation Accelerated by a Brønsted Acid.

Abstract: The development of a robust amide-bond formation remains a critical aspect of N-methylated peptide synthesis. In this study, we synthesized a variety of dipeptides in high yields, without severe racemization, from equivalent amounts of amino acids. Highly reactive N-methylimidazolium cation species were generated in situ to accelerate the amidation. The key to success was the addition of a strong Bronsted acid. The developed amidation enabled the synthesis of a bulky peptide with a higher yield in a shorter amount of time compared with the results of conventional amidation. In addition, the amidation can be performed by using either a microflow reactor or a conventional flask. The first total synthesis of naturally occurring bulky N-methylated peptides, pterulamides I-IV, was achieved. Based on experimental results and theoretical calculations, we speculated that a Bronsted acid would accelerate the rate-limiting generation of acyl imidazolium cations from mixed carbonic anhydrides.

Total Synthesis of Farnesin through an Excited-State Nazarov Reaction.

Abstract: The asymmetric total synthesis of farnesin, a rearranged ent-kaurenoid, was achieved through a convergent approach involving photo-Nazarov and intramolecular aldol cyclizations to build the syn-syn-syn hydrofluorenol ABC ring system and bicyclo[3.2.1]octane CD ring system in the first application of a UV-light-induced excited-state Nazarov cyclization of a non-aromatic dicyclic divinyl ketone in a total synthesis. Unlike the conventional acid-promoted ground-state Nazarov reaction, the excited-state Nazarov reaction enables stereospecific formation of the highly strained syn-syn-syn-fused hydrofluorenone scaffold through a disrotatory cyclization.

Catalytic Hydroxycyclopropanol Ring-Opening Carbonylative Lactonization to Fused Bicyclic Lactones.

Abstract: A novel palladium-catalyzed ring opening carbonylative lactonization of readily available hydroxycyclopropanols was developed to efficiently synthesize tetrahydrofuran (THF) or tetrahydropyran (THP)-fused bicyclic γ-lactones, two privileged scaffolds often found in natural products. The reaction features mild reaction conditions, good functional group tolerability, and scalability. Its application was demonstrated in a short total synthesis of (±)-paeonilide. The fused bicyclic γ-lactone products can be easily diversified to other medicinally important scaffolds, which further broadens the application of this new carbonylation method.

Evolution of Pauson-Khand Reaction: Strategic Applications in Total Syntheses of Architecturally Complex Natural Products (2016–2020)

Abstract: Metal-mediated cyclizations are important transformations in a natural product total synthesis. The Pauson-Khand reaction, particularly powerful for establishing cyclopentenone-containing structures, is distinguished as one of the most attractive annulation processes routinely employed in synthesis campaigns. This review covers Co, Rh, and Pd catalyzed Pauson-Khand reaction and summarizes its strategic applications in total syntheses of structurally complex natural products in the last five years. Additionally, the hetero-Pauson-Khand reaction in the synthesis of heterocycles will also be discussed. Focusing on the panorama of organic synthesis, this review highlights the strategically developed Pauson-Khand reaction in fulfilling total synthetic tasks and its synthetic attractiveness is aimed to be illustrated.

Total Synthesis of Daphniphyllum Alkaloids: From Bicycles to Diversified Caged Structures.

Abstract: Native to the Asia-Pacific region and widely applied in traditional Chinese medicine, the genus Daphniphyllum has produced over 330 known Daphniphyllum alkaloids. Investigations into these alkaloids have shown an exceptional range of interesting bioactivities. Challenging and caged polycyclic architectures and the promising biological profiles make Daphniphyllum alkaloids intriguing synthetic targets. Based on their backbones, these alkaloids can be categorized into 13-35 structurally distinct subfamilies. In addition to our work, almost 30 impressive total syntheses of Daphniphyllum alkaloids from seven subfamilies, namely, daphniphylline-type, secodaphniphylline-type, daphnilactone A-type, bukittinggine-type, daphmanidin A-type, calyciphylline A-type, and calyciphylline B-type alkaloids, have been reported by 11 research groups. However, many Daphniphyllum alkaloid subfamilies remain inaccessible by chemical synthesis.In this Account, we summarize our recent endeavors in the total synthesis of Daphniphyllum alkaloids commencing from simple chiral bicyclic synthons. Daphniphyllum alkaloids with diversified skeletons from four different subfamilies, namely, calyciphylline A-type, daphnezomine A-type, bukittinggine-type, and yuzurimine-type alkaloids, have been achieved. Furthermore, the tricyclic core structure of daphniglaucin C-type alkaloids daphnimacropodines was also synthesized. First, we describe a 14-step synthesis of calyciphylline A-type alkaloid (-)-himalensine A, which features a mild Cu-mediated nitrile hydration, an intramolecular Heck reaction to assemble the pivotal 2-azabicyclo[3.3.1]nonane moiety, and a Meinwald rearrangement to introduce the critical oxidative state into the skeleton. We then introduce the synthesis of daphnezomine A-type alkaloid dapholdhamine B, which possesses a unique aza-adamantane core. This target molecule was fabricated using key reactions including Huang's amide-activation-annulation. An unexpected radical detosylation during the synthesis of dapholdhamine B further inspired an ambitious radical cyclization cascade strategy, which eventually led to an efficient total synthesis of bukittinggine-type alkaloid (-)-caldaphnidine O. This highly chemo-, regio-, and stereoselective radical reaction cascade also shed light on the synthetic strategy of other alkaloids with caged structures. We next describe the first total synthesis of yuzurimine-type alkaloid (+)-caldaphnidine J. The key steps in our approach include a Pd-catalyzed regioselective hydroformylation and a novel Swern oxidation/ketene dithioacetal Prins reaction cascade. The work has achieved the first synthesis of a member of the largest subfamily of Daphniphyllum alkaloids. Finally, we show our efforts toward the total synthesis of daphniglaucin C-type alkaloids. Overall, we hope that the interesting strategies and synthetic methods demonstrated in our efforts could inspire a wide variety of additional applications to natural product synthesis.