Showing papers on "Total synthesis published in 2017"
TL;DR: The first enantioselective synthesis of (-)-himalensine A has been achieved in 22 steps, enabled by a novel catalytic, enantiOSElective prototropic shift/furan Diels-Alder cascade to construct the ACD tricyclic core.
Abstract: The first enantioselective synthesis of (−)-himalensine A has been achieved in 22 steps. The synthesis was enabled by a novel catalytic, enantioselective prototropic shift/furan Diels–Alder (IMDAF) cascade to construct the ACD tricyclic core. A reductive radical cyclization cascade was utilized to build the B ring, and end-game manipulations featuring a molecular oxygen mediated γ-CH oxidation, a Stetter cyclization to access the pendant cyclopentenone, and a highly chemoselective lactam reduction delivered the natural product target.
126 citations
TL;DR: Examples of palladium-catalyzed carbonylation reactions found broad application in total synthesis of natural products, including macrolide and spirocyclic molecule synthesis are presented to highlight recent progress.
Abstract: Carbon monoxide is an important one-carbon source and can be incorporated in complex molecules via various transition-metal-catalyzed carbonylation reactions. In particular, palladium-catalyzed carbonylation reactions have found broad application in total synthesis of natural products. Examples are presented in this Synopsis to highlight recent progress in this area, including our own work in macrolide and spirocyclic molecule synthesis. In these selected cases, carbon monoxide functions as a one-carbon linchpin to facilitate building structural complexity and improving synthetic efficiency.
114 citations
TL;DR: This review aims to highlight the origins, structures, biological potencies, and synthetic approaches of those natural products bearing at least one benzofuran in their complex structures and especially focus on the step in which this key heterocycle is installed during the total synthesis of a natural product as the desired target.
Abstract: Research on natural products containing benzofuran has remarkably increased during the past few decades. Newly isolated natural products with complex structures are being studied, characterized and screened for possible biological activities. Several of such compounds have exhibited various biological activities, thus their total syntheses have attracted much attention from synthetic organic chemists. In this review, we aim to highlight the origins, structures, biological potencies, and synthetic approaches of those natural products bearing at least one benzofuran in their complex structures. Furthermore, we especially focus on the step in which this key heterocycle is installed during the total synthesis of a natural product as the desired target.
111 citations
TL;DR: The efficiency of the NHKT reaction in the synthesis of a great number of different scaffolds present in complex natural products is analyzed and the preparation of enol and allylic and propargylic alcohol motifs is discussed, highlighting factors such as yield, chemoselectivity, stereoselectivities, or the importance of protecting groups.
Abstract: The Nozaki–Hiyama–Takai–Kishi (NHTK) reaction was discovered in the late 1970s and, since then, its main application has been its use in total synthesis. In this comprehensive review, the efficiency of the NHKT reaction in the synthesis of a great number of different scaffolds present in complex natural products is analyzed. The preparation of enol and allylic and propargylic alcohol motifs is discussed, highlighting factors such as yield, chemoselectivity, stereoselectivity, or the importance of protecting groups. The review is divided into two main sections: intermolecular and intramolecular NHTK reactions. A final discussion about the current “state-of-art” and future perspectives for the use of this transformation in total synthesis is also included.
106 citations
TL;DR: The first catalytic asymmetric total synthesis of the heptacyclic alkaloid (-)-communesin F is described, featuring an iridium-catalyzed asymmetric intermolecular cascade cyclization and the closure of final ring system (A ring) via a facile reduction of a twisted amide and concomitant cyclization activated by mesylation of N,O-hemiaminal intermediate.
Abstract: The first catalytic asymmetric total synthesis of the heptacyclic alkaloid (−)-communesin F is described. A key step features an iridium-catalyzed asymmetric intermolecular cascade cyclization, constructing the lower N,N-aminal-containing CDEF tetracyclic core in one step. Another notable element is the closure of final ring system (A ring) via a facile reduction of a twisted amide and concomitant cyclization activated by mesylation of N,O-hemiaminal intermediate.
96 citations
TL;DR: This review will summarize recent applications of asymmetric organocatalysis in the enantioselective synthesis of indole alkaloids.
Abstract: Indole and its structural analogues have been frequently found in numerous alkaloids, pharmaceutical products and related materials. The enantioselective construction of these structures allows efficient total synthesis of optically pure indole alkaloids, and hence has received worldwide interest. In the past decade, asymmetric organocatalysis has been recognized as one of the most powerful strategies to create chiral molecules with high levels of stereoselectivity. In particular, organocatalytic asymmetric cascade reactions often occur with multiple bond-breaking and forming events simultaneously or sequentially, leading to the appearance of various straightforward approaches to access core structures for asymmetric total synthesis. This review will summarize recent applications of asymmetric organocatalysis in the enantioselective synthesis of indole alkaloids.
92 citations
TL;DR: One of the oldest and most useful reactions in organic chemistry is the Fischer indole synthesis (FIS) as discussed by the authors, which is known to have a wide variety of applications including the synthesis of indole rings, often present as the framework in the total synthesis of natural products.
Abstract: One of the oldest and most useful reactions in organic chemistry is the Fischer indole synthesis (FIS). It is known to have a wide variety of applications including the synthesis of indole rings, often present as the framework in the total synthesis of natural products, particularly those found in the realm of alkaloids, which comprise a ring system known as an indole alkaloid. In this review, we are trying to emphasize the applications of FIS as an old reaction, which is currently applied to the total synthesis of biologically active natural products and some other complex targets.
91 citations
TL;DR: A ligand-promoted catalytic [4+2] annulation reaction using indole derivatives and donor-acceptor (D-A) cyclobutanes is reported, thus providing an efficient and atom-economical access to versatile cyclohexa-fused indolines with excellent levels of diastereoselectivity and a broad substrate scope.
Abstract: A ligand-promoted catalytic [4+2] annulation reaction using indole derivatives and donor-acceptor (D-A) cyclobutanes is reported, thus providing an efficient and atom-economical access to versatile cyclohexa-fused indolines with excellent levels of diastereoselectivity and a broad substrate scope. In the presence of a chiral SaBOX ligand, excellent enantioselectivity was realized with up to 94 % ee. This novel synthetic method is applied as a general protocol for the total synthesis of (±)-akuammicine and the formal total synthesis of (±)-strychnine from the same common-core scaffold.
90 citations
TL;DR: The catalyst system PC-Phos/AuNTf2 proved to be specifically efficient to promote the desymmetrization of N-allenamides in excellent yields with satisfactory ee values.
Abstract: Highly enantioselective gold-catalyzed intramolecular cyclization of N-allenamides was implemented by utilizing a designed chiral sulfinamide phosphine ligand (PC-Phos). This represents the first example of highly enantioselective intramolecular cyclization of N-allenamides. The practicality of this reaction was validated in the total synthesis of (R)-desbromoarborescidine A and formal synthesis of (R)-desbromoarborescidine C and (R)-deplancheine. Moreover, the catalyst system PC-Phos/AuNTf2 proved to be specifically efficient to promote the desymmetrization of N-allenamides in excellent yields with satisfactory ee values.
90 citations
TL;DR: The first and asymmetric total synthesis of longeracinphyllin A, a hexacyclic Daphniphyllum alkaloid, has been accomplished and the cyclopentenone motif was assembled by using intramolecular Horner-Wadsworth olefination.
Abstract: The first and asymmetric total synthesis of longeracinphyllin A, a hexacyclic Daphniphyllum alkaloid, has been accomplished. A tetracyclic intermediate was prepared through silver-catalyzed alkyne cyclization and Luche radical cyclization. A phosphine-promoted [3 + 2] cycloaddition reaction was exploited to construct the sterically congested E ring bearing vicinal tertiary and quaternary centers. The cyclopentenone motif was assembled by using intramolecular Horner–Wadsworth–Emmons olefination. Raney Ni reduction delivered the tertiary amine from a thioamide precursor at a late stage.
89 citations
TL;DR: An engineered cytochrome P450 enzyme was employed to effect a chemo- and regioselective allylic C-H oxidation in the presence of four oxidizable positions of the norditerpenoid alkaloid nigelladine A.
Abstract: An enantioselective total synthesis of the norditerpenoid alkaloid nigelladine A is described. Strategically, the synthesis relies on a late-stage C–H oxidation of an advanced intermediate. While traditional chemical methods failed to deliver the desired outcome, an engineered cytochrome P450 enzyme was employed to effect a chemo- and regioselective allylic C–H oxidation in the presence of four oxidizable positions. The enzyme variant was readily identified from a focused library of three enzymes, allowing for completion of the synthesis without the need for extensive screening.
TL;DR: The development of asymmetric, in particular catalytic enantioselective intramolecular aza-Diels-Alder reaction in the total synthesis of natural products remains highly challenging, and will no doubt see enormous advances in the future.
Abstract: The Diels-Alder reaction that involves a nitrogen atom in the diene or dienophile is termed the aza-Diels-Alder reaction. As well as the powerful all-carbon Diels-Alder reaction, the aza-Diels-Alder reaction has also played an important role in the total synthesis of natural products. Herein, we review various natural products using an aza-Diels-Alder reaction as a key step to their total synthesis, and divide the syntheses into inter- and intra-molecular aza-Diels-Alder reactions and a retro-aza-Diels-Alder reaction. Inter- and intra-molecular aza-Diels-Alder reactions involve an imine as an electron deficient dienophile and an imine as an electron deficient azadiene. The significance of the aza-Diels-Alder reaction for the construction of a six-membered ring containing nitrogen is tremendous, but the development of asymmetric, in particular catalytic enantioselective intramolecular aza-Diels-Alder reaction in the total synthesis of natural products remains highly challenging, and will no doubt see enormous advances in the future.
TL;DR: This Tutorial Review describes the organocatalytic methods available to furnish THPs as well as the application of these methodologies in the total synthesis of THP-based natural products.
Abstract: Recent advancement in the area of asymmetric organocatalysis led to the development of new methodologies for the construction of valuable enantiopure molecules, including various heterocycles. As one of the latter class of compounds tetrahydropyrans (THPs) constitute a core structure of a wide array of bioactive natural products. A noticeable growth has been observed in the asymmetric synthesis of THPs using small organic molecules as catalysts. This Tutorial Review describes the organocatalytic methods available to furnish THPs as well as the application of these methodologies in the total synthesis of THP-based natural products.
TL;DR: A unified total synthesis of stemoamide-type alkaloids is reported, which features the chemoselective convergent assembly of five-membered building blocks viastemoamide as the common precursor to tetracyclic natural products.
Abstract: A unified total synthesis of stemoamide-type alkaloids is reported. Our synthetic approach features the chemoselective convergent assembly of five-membered building blocks via stemoamide as the common precursor to tetracyclic natural products. The synthesis consists of two successive coupling reactions of the three five-membered building blocks. The first coupling reaction is the vinylogous Michael addition/reduction sequence, which enables the gram-scale synthesis of stemoamide. The second coupling reaction is a chemoselective nucleophilic addition to stemoamide. While the lactone-selective nucleophilic addition to stemoamide affords saxorumamide and isosaxorumamide, the lactam-selective reductive nucleophilic addition leads to the formation of stemonine. Both chemoselective nucleophilic additions enable direct modification of stemoamide, resulting in highly concise and efficient total syntheses of the stemoamide-type alkaloids.
TL;DR: In total and formal syntheses of dictyodendrins B, C, E, and F, the key step involved the direct construction of the pyrrolo[2,3-c]carbazole core by the gold-catalyzed annulation of a conjugated diyne with a pyrrole to form three bonds and two aromatic rings.
Abstract: Total synthesis of dictyodendrins A–E was achieved on the basis of a novel gold-catalyzed cascade reaction for the construction of pyrrolo[2,3-c]carbazole scaffold. The synthetic strategy features functionalization of pyrrole pyrrolo[2,3-c]carbazole scaffold at the C1 (arylation), C2 (acylation), N3 (alkylation), and C5 (oxidation) positions. This synthetic method could be used for the diversity-oriented synthesis of dictyodendrin derivatives for medicinal applications.
TL;DR: An enantioselective iridium-catalyzed allylic substitution with a set of highly unstabilized nucleophiles generated in situ from 2-methylpyridines is described, demonstrating the synthetic utility of the pyridine products and the synthesis of (-)-lycopladine A.
Abstract: An enantioselective iridium-catalyzed allylic substitution with a set of highly unstabilized nucleophiles generated in situ from 2-methylpyridines is described. Enantioenriched 2-substituted pyridines, which are frequently encountered in natural products and pharmaceuticals, could be easily constructed by this simple method in good yields and excellent enantioselectivity. The synthetic utility of the pyridine products is demonstrated through the synthesis of a key intermediate of a reported Na+/H+ exchanger inhibitor and the total synthesis of (−)-lycopladine A.
TL;DR: A highly efficient synthesis of the enantioenriched tetrahydro-β-carbolines was developed by using a chiral phosphoric acid catalyzed Pictet-Spengler reaction of indolyl dihydropyridines.
Abstract: A highly efficient synthesis of enantioenriched tetrahydro-β-carbolines is developed via chiral phosphoric acid-catalyzed Pictet-Spengler reaction of indolyl dihydropyridines. The reaction proceeds under mild conditions to afford the desired chiral tetrahydro-β-carbolines in good to excellent yields (up to 96%) and high enantioselectivity (up to 99% ee). With this method, a formal synthesis of Tangutorine and a total synthesis of Deplancheine were achieved in a highly efficient manner.
TL;DR: The present total synthesis of 1 demonstrates the advantages of radical reactions for linking hindered bonds within carbocycles without damaging preexisting functionalities, thereby offering a new strategic design for multistep target-oriented synthesis.
Abstract: Resiniferatoxin (1) belongs to a daphnane diterpenoid family and has strong agonistic effects on TRPV1, a transducer of noxious temperature and chemical stimuli. The densely oxygenated trans-fused 5/7/6-tricarbocycle (ABC-ring) of 1 presents a daunting challenge for chemical synthesis. Here we report the development of a novel radical-based strategy for assembling 1 from three components: A-ring 9, allyl stannane 18b, and C-ring 17b. The 6-membered 17b, prepared from d-ribose derivative 19, was designed to possess the caged orthoester structure with α-alkoxy selenide as a radical precursor. Upon treatment of 17b with 18b, 9, and V-40, the potently reactive α-alkoxy bridgehead radical was generated from 17b and then sequentially coupled with 9 and 18b to yield 16b. This first radical reaction formed the hindered C9,10-linkage between the A and C-rings and extended the C4-chain on the A-ring in a stereoselective fashion. After derivatization of 16b into 15, the remaining 7-membered B-ring was cyclized in th...
TL;DR: This review summarises the application of gold catalysis for the syntheses of spiro, bridged and fused ketal natural products.
Abstract: In the last decade the use of homogenous gold catalysts has rapidly grown and become a valuable tool for complex natural product synthesis. Spiroketal natural products are valuable targets for total synthesis and medicinal chemistry applications. The use of gold catalysts has emerged as a useful tool to synthesise these privileged scaffolds. This review summarises the application of gold catalysis for the syntheses of spiro, bridged and fused ketal natural products.
TL;DR: The first example of the palladium-catalyzed sequential nucleophilic addition followed by an intramolecular cyclization of functionalized nitriles with arylboronic acids has been achieved, providing an efficient synthetic pathway to access structurally diverseisoquinolines and isoquinolones.
TL;DR: In the synthesis, the triflamide served as not only an effective directing group for C-H bond activation but also a versatile functional group for further elaborations, enabling two different yet related approaches to a key intermediate 28 in excellent enantiopurity.
Abstract: Delavatine A (1) is a structurally unusual isoquinoline alkaloid isolated from Incarvillea delavayi. The first and gram-scale total synthesis of 1 was accomplished in 13 steps (the longest linear sequence) from commercially available starting materials. We exploited an isoquinoline construction strategy and developed two reactions, namely Rh-catalyzed asymmetric hydrogenation of indene-type tetrasubstituted olefins and kinetic resolution of β-alkyl phenylethylamine derivatives through Pd-catalyzed triflamide-directed C–H olefination. The substrate scope of the first reaction covered unfunctionalized olefins and those containing polar functionalities such as sulfonamides. The kinetic resolution provided a collection of enantioenriched indane- and tetralin-based triflamides, including those bearing quaternary chiral centers. The selectivity factor (s) exceeded 100 for a number of substrates. These reactions enabled two different yet related approaches to a key intermediate 28 in excellent enantiopurity. In ...
TL;DR: A total synthesis of (-)-rhazinilam and formal syntheses of (+)-eburenine and (+)-aspidospermidine that rely on a copper(I)-catalyzed asymmetric propargylic substitution as the key step are reported.
TL;DR: The methodology was used in the total synthesis of the Stemona alkaloid (−)‐stemaphylline in just 11 steps (longest linear sequence), with high stereocontrol (>20:1 d.r.) and 11 % overall yield.
Abstract: Homologation of readily available α-boryl pyrrolidines with metal carbenoids is especially challenging even when good leaving groups (Cl−) are employed. By performing a solvent switch from Et2O to CHCl3, efficient 1,2-metalate rearrangement of the intermediate boronate occurs with both halide and ester leaving groups. The methodology was used in the total synthesis of the Stemona alkaloid (−)-stemaphylline in just 11 steps (longest linear sequence), with high stereocontrol (>20:1 d.r.) and 11 % overall yield. The synthesis also features a late-stage lithiation–borylation reaction with a tertiary amine containing carbenoid.
TL;DR: In this article, a compilation of the applications of aza-Prins cyclization in the preparation of natural products and selected analogues, especially compounds of potential biological interest, is presented, with emphasis placed on the key roles of this reaction in the total synthesis of these products.
TL;DR: Asymmetric total synthesis of the dimeric diterpenoid hispidanin A was accomplished by non-catalytic Diels-Alder cycloaddition at room temperature.
Abstract: Asymmetric total synthesis of the dimeric diterpenoid hispidanin A was accomplished by non-catalytic Diels–Alder cycloaddition at room temperature. The synthesis relies on iron-catalyzed coupling to construct a Z-configured trisubstituted alkene, an iron-catalyzed radical cascade to generate a labdane-type diene, and both Yamamoto cationic polyene cyclization and palladium-catalyzed Stille coupling to generate a totarane-type dienophile.
TL;DR: In this paper, a review summarises the applications of heteroatom substituted donor-acceptor cyclopropanes in the total synthesis of natural products, including cycloaddition, rearrangement and cascade reactions.
TL;DR: A novel one-pot reaction has been developed for the efficient synthesis of pyrrolo[2,1-a]isoquinolines and 1-dearyllamellarin core from (E)-(2-nitrovinyl)benzenes and azomethine ylides generated in situ.
TL;DR: The formal (3+2) cycloaddition between terminal allenes and aryl or styryl gold(I) carbenes generated by a retro‐Buchner reaction of 7‐substituted 1,3,5‐cycloheptatrienes led to indenes and cyclopentadienes, respectively.
Abstract: The formal (3+2) cycloaddition between terminal allenes and aryl or styryl gold(I) carbenes generated by a retro-Buchner reaction of 7-substituted 1,3,5-cycloheptatrienes led to indenes and cyclopentadienes, respectively. These cycloaddition processes have been applied to the construction of the carbon skeleton of the cycloaurenones and the dysiherbols as well as to the total synthesis of (±)-laurokamurene B.
TL;DR: A concise total synthesis of aristolactam alkaloids by a synergistic combination of C–H bond activation and dehydro-Diels–Alder reactions is described.
Abstract: A concise total synthesis of aristolactam alkaloids by a synergistic combination of C–H bond activation and dehydro-Diels–Alder reactions is described. To achieve the synthesis two new synthetic methodologies, namely the oxidative cyclization of benzamides with vinyl sulfone leading to 3-methyleneisoindolin-1-ones via a ruthenium-catalyzed C–H bond activation, and a dehydro-Diels–Alder reaction followed by the fluoride ion mediated desulfonylation of 3-methyleneisoindolin-1-ones with benzynes, were developed. The method presented allows the opportunity for the construction of all the rings of aristolactams from easily available starting materials.
TL;DR: Asymmetric total synthesis of structurally intriguing and highly oxygenated lancifodilactone G acetate has been achieved for the first time in 28 steps from a cheap commodity chemical, 2-(triisopropylsiloxy)-1,3-butadiene.
Abstract: Asymmetric total synthesis of structurally intriguing and highly oxygenated lancifodilactone G acetate (7) has been achieved for the first time in 28 steps from a cheap commodity chemical, 2-(triisopropylsiloxy)-1,3-butadiene.