Showing papers on "Total synthesis published in 2014"
TL;DR: An electrochemical oxidative dimerization method was developed and applied as the pivotal step of the first total synthesis of dixiamycin B, providing entry into seldom explored chemical space.
Abstract: N–N-linked dimeric indole alkaloids represent an unexplored class of natural products for which chemical synthesis has no practical solution. To meet this challenge, an electrochemical oxidative dimerization method was developed, which was applied as the pivotal step of the first total synthesis of dixiamycin B. This method is also general for N–N dimerization of substituted carbazoles and β-carbolines, providing entry into seldom explored chemical space.
243 citations
TL;DR: A facile multicomponent catalytic process that begins with a chemoselective, site-selective and diastereoselectively copper–boron addition to a monosubstituted allene and the resulting boron-substituting organocopper intermediates then participate in a similarly selective allylic substitution.
Abstract: Efficient catalytic reactions that can generate C–C bonds enantioselectively, and ones that can produce trisubstituted alkenes diastereoselectively, are central to research in organic chemistry. Transformations that accomplish these two tasks simultaneously are in high demand, particularly if the catalysts, substrates and reagents are inexpensive and if the reaction conditions are mild. Here we report a facile multicomponent catalytic process that begins with a chemoselective, site-selective and diastereoselective copper–boron addition to a monosubstituted allene; the resulting boron-substituted organocopper intermediates then participate in a similarly selective allylic substitution. The products, which contain a stereogenic carbon centre, a monosubstituted alkene and an easily functionalizable Z-trisubstituted alkenylboron group, are obtained in up to 89 per cent yield, with more than 98 per cent branch-selectivity and stereoselectivity and an enantiomeric ratio greater than 99:1. The copper-based catalyst is derived from a robust heterocyclic salt that can be prepared in multigram quantities from inexpensive starting materials and without costly purification procedures. The utility of the approach is demonstrated through enantioselective synthesis of gram quantities of two natural products, namely rottnestol and herboxidiene (also known as GEX1A). A catalytic process is reported that begins with a highly selective copper–boron addition to a monosubstituted allene, and in which the resulting boron-substituted organocopper intermediate then participates in a chemoselective, site-selective and enantioselective allylic substitution; this approach is used in the enantioselective synthesis of gram quantities of two natural products. This paper reports a catalytic process that combines two simple unsaturated organic molecules — a highly selective copper–diboron reagent and a monosubstituted allene — to produce a boron-substituted organocopper intermediate that then participates in a chemoselective, site-selective and enantioselective allylic substitution. The authors use this approach in the enantioselective synthesis of gram quantities of two natural products: the anti-tumour agent herboxidiene and stereoisomerically pure rottnestol, a hemiketal originally isolated from a marine sponge. Further development of this procedure should lead to economical protocols for the synthesis of other difficult-to-access alkenylboron-containing organocopper compounds.
171 citations
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02 Mar 2014TL;DR: The first total synthesis of Maoecrystal V (1) was reported in this paper, which features a Wessely oxidative dearomatization of a phenol, an intramolecular Diels−Alder reaction, and a Rh-catalyzed O−H bond insertion as key steps.
Abstract: A concise first total synthesis of (±) maoecrystal V (1) is reported. The synthesis features a Wessely oxidative dearomatization of a phenol, an intramolecular Diels−Alder reaction, and a Rh-catalyzed O−H bond insertion as key steps.
127 citations
TL;DR: The first and asymmetric total synthesis of Rubriflordilactone A, a bisnortriterpenoid isolated from Schisandra rubriflora, has been accomplished in a convergent manner as discussed by the authors.
Abstract: The first and asymmetric total synthesis of rubriflordilactone A, a bisnortriterpenoid isolated from Schisandra rubriflora, has been accomplished in a convergent manner. Two enantioenriched fragments were forged together to give a functionalized cis-triene. A 6π-electrocyclization/aromatization sequence assembled the penta-substituted arene, and a formal vinylogous Mukaiyama aldol reaction introduced the butenolide side chain.
126 citations
TL;DR: The chemical connections that have been realized as a result of the syntheses of citrinalin and cyclopiamine support the existence of a common bicyclo-containing biogenetic precursor to these compounds, as has been proposed previously.
Abstract: Many natural products that contain basic nitrogen atoms—for example alkaloids like morphine and quinine—have the potential to treat a broad range of human diseases. However, the presence of a nitrogen atom in a target molecule can complicate its chemical synthesis because of the basicity of nitrogen atoms and their susceptibility to oxidation. Obtaining such compounds by chemical synthesis can be further complicated by the presence of multiple nitrogen atoms, but it can be done by the selective introduction and removal of functional groups that mitigate basicity. Here we use such a strategy to complete the chemical syntheses of citrinalin B and cyclopiamine B. The chemical connections that have been realized as a result of these syntheses, in addition to the isolation of both 17-hydroxycitrinalin B and citrinalin C (which contains a bicyclo[2.2.2]diazaoctane structural unit) through carbon-13 feeding studies, support the existence of a common bicyclo[2.2.2]diazaoctane-containing biogenetic precursor to these compounds, as has been proposed previously. Natural products citrinalin B and cyclopiamine B, which contain basic nitrogen atoms that are susceptible to oxidation during synthesis, can be synthesized by the selective introduction and removal of functional groups. This paper reports the first syntheses of the natural products citrinalin B and cyclopiamine B. And as a by-product of this work, the authors propose a revision of the structure initially assigned to citrinalin B. The presence of nitrogen atoms in a target molecule can complicate its synthesis because of nitrogen's basicity and susceptibility to oxidation. This can be circumvented by the selective introduction and removal of functional groups that mitigate basicity. The prenylated indole alkaloids citrinalin B and cyclopiamine B were produced using a refinement of the technique, opening up a class of compounds that includes therapeutics such as quinine and morphine to synthetic chemistry.
119 citations
TL;DR: A number of novel flow-through processes for reactions commonly encountered in natural product synthesis programs are developed to achieve the first total synthesis of spirodienal A and the preparation of spirangien A methyl ester.
Abstract: Over the past decade, the integration of synthetic chemistry with flow processing has resulted in a powerful platform for molecular assembly that is making an impact throughout the chemical community. Herein, we demonstrate the extension of these tools to encompass complex natural product synthesis. We have developed a number of novel flow-through processes for reactions commonly encountered in natural product synthesis programs to achieve the first total synthesis of spirodienal A and the preparation of spirangien A methyl ester. Highlights of the synthetic route include an iridium-catalyzed hydrogenation, iterative Roush crotylations, gold-catalyzed spiroketalization and a late-stage cis-selective reduction.
117 citations
TL;DR: A short total synthesis of podophyllotoxin, the prototypical aryltetralin lignan natural product, is reported, which allows for access to the natural product in five steps from commercially available bromopiperonal, and sheds light on subtle conformational effects governing reductive elimination pathways from high-valent palladium centers.
Abstract: A short total synthesis of podophyllotoxin, the prototypical aryltetralin lignan natural product, is reported. Key to the success of this synthetic pathway is a Pd-catalyzed C(sp3)–H arylation reaction enabled by a conformational biasing element to promote C–C reductive elimination over an alternative CN bond-forming pathway. This strategy allows for access to the natural product in five steps from commercially available bromopiperonal, and sheds light on subtle conformational effects governing reductive elimination pathways from high-valent palladium centers.
116 citations
TL;DR: The first phosphine-catalyzed enantioselective γ-addition with prochiral nucleophiles and 2,3-butadienoates as the reaction partners has been developed and the synthetic value was demonstrated by the formal total synthesis of two natural products and by the preparation of biologically relevant molecules and structural scaffolds.
Abstract: The first phosphine-catalyzed enantioselective γ-addition with prochiral nucleophiles and 2,3-butadienoates as the reaction partners has been developed. Both 3-alkyl- and 3-aryl-substituted oxindoles could be employed in this process, which is catalyzed by a chiral phosphine that is derived from an amino acid, thus affording oxindoles that bear an all-carbon quaternary center at the 3-position in high yields and excellent enantioselectivity. The synthetic value of these γ-addition products was demonstrated by the formal total synthesis of two natural products and by the preparation of biologically relevant molecules and structural scaffolds.
114 citations
TL;DR: All four stereoisomers of Δ(9)-tetrahydrocannabinol (Δ( 9)-THC) were synthesized in concise fashion using stereodivergent dual catalysis using identical synthetic sequences and applying identical reaction conditions to the same set of starting materials.
Abstract: All four stereoisomers of Δ(9)-tetrahydrocannabinol (Δ(9)-THC) were synthesized in concise fashion using stereodivergent dual catalysis. Thus, following identical synthetic sequences and applying identical reaction conditions to the same set of starting materials, selective access to the four stereoisomers of THC was achieved in five steps.
109 citations
TL;DR: This work reviews the application of the Diels-Alder reaction of quinones in the total synthesis of natural products, spanning some 60 years from the landmark syntheses of morphine and reserpine by Gates and Woodward through to the present day examples, such as the tetracyclines.
Abstract: In the canon of reactions available to the organic chemist engaged in total synthesis, the Diels–Alder reaction is among the most powerful and well understood. Its ability to rapidly generate molecular complexity through the simultaneous formation of two carboncarbon bonds is almost unrivalled, and this is reflected in the great number of reported applications of this reaction. Historically, the use of quinones as dienophiles is highly significant, being the very first example investigated by Diels and Alder. Herein, we review the application of the Diels–Alder reaction of quinones in the total synthesis of natural products. The highlighted examples span some 60 years from the landmark syntheses of morphine (1952) and reserpine (1956) by Gates and Woodward, respectively, through to the present day examples, such as the tetracyclines.
106 citations
TL;DR: Highlights of the synthesis include a Et2AlCl-promoted, highly stereoselective, susbtrate-controlled intramolecular Diels-Alder reaction, a transannular enolate alkylation, an effective Stille carbonylation/Nazarov cyclization sequence, and a high-risk diastereoselectives hydrogenation of a fully substituted conjugated diene ester.
Abstract: The total synthesis of the architecturally complex Daphniphyllum alkaloid (−)-calyciphylline N has been achieved. Highlights of the synthesis include a Et2AlCl-promoted, highly stereoselective, susbtrate-controlled intramolecular Diels–Alder reaction, a transannular enolate alkylation, an effective Stille carbonylation/Nazarov cyclization sequence, and a high-risk diastereoselective hydrogenation of a fully substituted conjugated diene ester.
TL;DR: A diastereoselective reverse prenylation of tryptophan methyl ester is disclosed, and its synthetic utility is demonstrated in the synthesis of (+)-aszonalenin and (-)-brevicompanine B.
Abstract: The selective reverse prenylation of 3-substituted-1H-indoles at C3 is described. The iridium-catalyzed reaction proceeds with high branched to linear selectivity (>20:1) for a variety of indoles. In addition, a diastereoselective reverse prenylation of tryptophan methyl ester is disclosed, and its synthetic utility is demonstrated in the synthesis of (+)-aszonalenin and (−)-brevicompanine B.
TL;DR: The total syntheses of cyclopeptide alkaloids, pacidamycin D, and yaku'amide A exemplify the versatility of the Cu-catalyzed cross-coupling reaction in comparison to other synthetic methods.
TL;DR: This chemoselective approach minimized the use of protecting-group manipulations and redox reactions, which resulted in the most concise and efficient total synthesis of (±)-gephyrotoxin described to date.
Abstract: A chemoselective approach for the total synthesis of (±)-gephyrotoxin has been developed. The key to success was the utilization of N-methoxyamides, which enabled the direct coupling of the amide with an aldehyde and selective reductive nucleophilic addition to the amide in the presence of a variety of sensitive and electrophilic functional groups, such as a methyl ester. This chemoselective approach minimized the use of protecting-group manipulations and redox reactions, which resulted in the most concise and efficient total synthesis of (±)-gephyrotoxin described to date.
01 Jan 2014
TL;DR: A 15-step synthesis of Aspidophylline from readily available starting materials is described in this article, where the key elements of the synthesis include an intramolecular oxidative coupling to create the tetracyclic furoindoline motif of the natural product and a [Ni(cod)(2)]-mediated cyclization to install its piperidine ring.
Abstract: AspidophyllineA belongs to the akuammiline alkaloid family, the members of which possess intriguing cagelike structures and diverse biological activities. Herein we report a 15-step synthesis of this alkaloid from conveniently available starting materials. The key elements of the synthesis include an intramolecular oxidative coupling to create the tetracyclic furoindoline motif of the natural product and a [Ni(cod)(2)]-mediated cyclization to install its piperidine ring.
TL;DR: A practical method for a "one-pot" native chemical ligation of peptide hydrazides that would circumvent the need for the isolation of the intermediate products and draws attention to the potential applications of the thus far under-exploited boron-based functionalities in protein chemical synthesis.
Abstract: One of the rising demands in the field of protein chemical synthesis is the development of facile strategies that yield the protein in workable quantities and homogeneity, with fewer handling steps. Although the native chemical ligation of peptide hydrazides has recently been shown to be useful for the chemical synthesis of proteins carrying acid-sensitive modification groups, previous hydrazide-based protein synthesis studies have used sequential ligation strategies. Here, we report a practical method for a “one-pot” native chemical ligation of peptide hydrazides that would circumvent the need for the isolation of the intermediate products. This method employed a fast and selective arylboronate oxidation reaction mediated by H2O2, which draws attention to the potential applications of the thus far under-exploited boron-based functionalities in protein chemical synthesis. To demonstrate the practicality and efficiency of the new one-pot method, we report its application to a scalable total synthesis of modified histones (with five analogues of H3 and H4 as examples) on a multi-milligram scale, with good homogeneity.
TL;DR: A 15-step synthesis of Aspidophylline A from conveniently available starting materials includes an intramolecular oxidative coupling to create the tetracyclic furoindoline motif of the natural product and a [Ni(cod)2 ]-mediated cyclization to install its piperidine ring.
Abstract: Aspidophylline A belongs to the akuammiline alkaloid family, the members of which possess intriguing cagelike structures and diverse biological activities. Herein we report a 15-step synthesis of this alkaloid from conveniently available starting materials. The key elements of the synthesis include an intramolecular oxidative coupling to create the tetracyclic furoindoline motif of the natural product and a [Ni(cod)2 ]-mediated cyclization to install its piperidine ring.
TL;DR: The first total syntheses of taiwaniadducts B, C, and D have been accomplished, and two diterpenoid segments were prepared with high enantiopurity, both through Ir-catalyzed asymmetric polyene cyclization.
Abstract: The first total syntheses of taiwaniadducts B, C, and D have been accomplished. Two diterpenoid segments were prepared with high enantiopurity, both through Ir-catalyzed asymmetric polyene cyclization. A sterically demanding intermolecular Diels–Alder reaction promoted by Er(fod)3 assembled the scaffold of taiwaniadducts B and C. A carbonyl-ene cyclization forged the cage motif of taiwaniadduct D at a late stage, providing over 200 mg of this compound.
TL;DR: A unified and bioinspired oxidative cyclization strategy was used in the first total syntheses of naturally occurring 12-epi-hapalindole Q isonitrile, hapalonamide H, deschloro 12-EPi-fischerindoles I nitrile, and deschloric acid W nitril, as well as the structural revision of the latter.
Abstract: A unified and bioinspired oxidative cyclization strategy was used in the first total syntheses of naturally occurring 12-epi-hapalindole Q isonitrile, hapalonamide H, deschloro 12-epi-fischerindole I nitrile, and deschloro 12-epi-fischerindole W nitrile, as well as the structural revision of the latter. Hapalindoles H and Q were also synthesized.
TL;DR: Although the constitution and stereochemistry of the synthetic samples are unambiguous, the spectra of 1 as well as of 11-epi-1 deviate from those of the natural product, which implies a subtle but deep-seated error in the original structure assignment.
Abstract: A concise synthesis of the putative structure assigned to the highly cytotoxic marine macrolide mandelalide A (1) is disclosed. Specifically, an iridium-catalyzed two-directional Krische allylation and a cobalt-catalyzed carbonylative epoxide opening served as convenient entry points for the preparation of the major building blocks. The final stages feature the first implementation of terminal-acetylene metathesis into natural product synthesis, which is remarkable as this class of substrates was beyond reach until very recently; key to success was the use of the highly selective molybdenum alkylidyne complex 42 as the catalyst. Although the constitution and stereochemistry of the synthetic samples are unambiguous, the spectra of 1 as well as of 11-epi-1 deviate from those of the natural product, which implies a subtle but deep-seated error in the original structure assignment.
TL;DR: This work reports the first total synthesis of the complex akuammiline alkaloid picrinine, which was first isolated nearly five decades ago, and constitutes a formal synthesis ofThe related polycyclic alkaloids strictamine.
Abstract: We report the first total synthesis of the complex akuammiline alkaloid picrinine, which was first isolated nearly five decades ago. Our synthetic approach features a concise assembly of the [3.3.1]-azabicyclic core, a key Fischer indolization reaction to forge the natural product’s carbon framework, and a series of delicate late-stage transformations to complete the synthesis. Our synthesis of picrinine also constitutes a formal synthesis of the related polycyclic alkaloid strictamine.
TL;DR: A total synthesis of aspidophylline A, a pentacyclic akuammiline-type monoterpene indole alkaloid, is described, and an intramolecular azidoalkoxylation of an enecarbamate is described to install both the furoindoline ring and the azido functionality.
Abstract: A total synthesis of aspidophylline A, a pentacyclic akuammiline-type monoterpene indole alkaloid, is described. The synthesis features: 1) rapid access to a fully functionalized dihydrocarbazole through the desymmetrization of readily available 2-allyl-2-(o-nitrophenyl)cyclohexane-1,3-dione; 2) an intramolecular azidoalkoxylation of an enecarbamate to install both the furoindoline ring and the azido functionality; and 3) an intramolecular Michael addition for the construction of the 2-azabicyclo[3.3.1]nonane ring system.
TL;DR: The first total syntheses of the proposed structure of cycloinumakiol and its C5 epimer are achieved in a concise and efficient fashion and demonstrates the potential of C-C activation for streamlining complex natural product synthesis.
Abstract: The first total syntheses of the proposed structure of cycloinumakiol (1) and its C5 epimer (18) are achieved in a concise and efficient fashion. Starting from the known 3-hydroxybenzocyclobutenone, 1 and 18 are obtained in nine and five steps with overall yields of 15 % and 33 %, respectively. The key for the success of this approach is the use of a catalytic CC activation strategy for constructing the tetracyclic core of 1 through carboacylation of a sterically hindered trisubstituted olefin with benzocyclobutenone. In addition, the structure of the natural cycloinumakiol was reassigned to 19-hydroxytotarol (7) through X-ray diffraction analysis. This work demonstrates the potential of CC activation for streamlining complex natural product synthesis.
TL;DR: The selective C5-alkenylation was successfully applied to the total synthesis of (±)-rhazinilam and achieved good yields with high regioselectivities.
TL;DR: The first successful effort to replicate the beginning of the Taxol oxidase phase in the laboratory is reported, culminating in the total synthesis of taxuyunnanine D, itself a natural product.
Abstract: The first successful effort to replicate the beginning of the Taxol oxidase phase in the laboratory is reported, culminating in the total synthesis of taxuyunnanine D, itself a natural product. Through a combination of computational modeling, reagent screening, and oxidation sequence analysis, the first three of eight C–H oxidations (at the allylic sites corresponding to C-5, C-10, and C-13) required to reach Taxol from taxadiene were accomplished. This work lays a foundation for an eventual total synthesis of Taxol capable of delivering not only the natural product but also analogs inaccessible via bioengineering.
TL;DR: The combined efforts represent the total syntheses of members of four classes of natural products from a common intermediate functionalized for late-stage formation of four different key strategic bonds uniquely embedded in each natural product core structure.
Abstract: Divergent total syntheses of (-)-kopsifoline D and (-)-deoxoapodine are detailed from a common pentacyclic intermediate 15, enlisting the late-stage formation of two different key strategic bonds (C21-C3 and C21-O-C6) unique to their hexacyclic ring systems that are complementary to its prior use in the total syntheses of kopsinine (C21-C2 bond formation) and (+)-fendleridine (C21-O-C19 bond formation). The combined efforts represent the total syntheses of members of four classes of natural products from a common intermediate functionalized for late-stage formation of four different key strategic bonds uniquely embedded in each natural product core structure. Key to the first reported total synthesis of a kopsifoline that is detailed herein was the development of a transannular enamide alkylation for late-stage formation of the C21-C3 bond with direct introduction of the reactive indolenine C2 oxidation state from a penultimate C21 functionalized Aspidosperma-like pentacyclic intermediate. Central to the assemblage of the underlying Apidosperma skeleton is a powerful intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of a 1,3,4-oxadiazole that provided the functionalized pentacyclic ring system 15 in a single step in which the C3 methyl ester found in the natural products served as a key 1,3,4-oxadiazole substituent, activating it for participation in the initiating Diels-Alder reaction and stabilizing the intermediate 1,3-dipole.
TL;DR: The concise total syntheses of the bis(pyrroloindolines) (-)-lansai B and (+)-nocardioazines A and B are reported and the macrocycle of (+)- nocardioazine’A is constructed by an unusual intramolecular diketopiperazine formation.
Abstract: The concise total syntheses of the bis(pyrroloindolines) (−)-lansai B and (+)- nocardioazines A and B are reported. The key pyrroloindoline building blocks are rapidly prepared by enantioselective formal [3+2] cycloaddition reactions. The macrocycle of (+)-nocardioazine A is constructed by an unusual intramolecular diketopiperazine formation.
TL;DR: A direct catalytic synthesis of γ-butyrolactones from simple alkene and unsaturated acid starting materials is reported, and this method has been applied to the diastereoselective total synthesis of methylenolactocin and protolichesterinic acid.
TL;DR: Investigations on the aza-Prins cyclization imply that the C3 configuration of the hydroxyindolenine intermediate is crucial to the biosynthesis of sespenine and its congener xiamycin A.
Abstract: The first total synthesis of sespenine, a rare indole sesquiterpenoid from a mangrove endophyte, has been accomplished. A bioinspired aza-Prins/Friedel-Crafts/retro Friedel-Crafts cascade reaction assembles the bridged tetrahydroquinoline core. Further investigations on the aza-Prins cyclization imply that the C3 configuration of the hydroxyindolenine intermediate is crucial to the biosynthesis of sespenine and its congener xiamycin A.
TL;DR: In this paper, the authors describe the first application of their methodology for heterodimerization via diazene fragmentation towards the total synthesis of (−)-calycanthidine, meso-chimonanthine, and (+)-desmethyl-meso-methionanthine.
Abstract: We describe the first application of our methodology for heterodimerization via diazene fragmentation towards the total synthesis of (−)-calycanthidine, meso-chimonanthine, and (+)-desmethyl-meso-chimonanthine. Our syntheses of these alkaloids feature an improved route to C3a-aminocyclotryptamines, an enhanced method for sulfamide synthesis and oxidation, in addition to a late-stage diversification leading to the first enantioselective total synthesis of (+)-desmethyl-meso-chimonanthine and its unambiguous stereochemical assignment. This versatile strategy for directed assembly of heterodimeric cyclotryptamine alkaloids has broad implications for the controlled synthesis of higher order derivatives with related substructures.