Showing papers on "Total synthesis published in 2008"
TL;DR: It is demonstrated that a complicated mixture of racemic and meso diastereomers may be smoothly converted to a synthetically useful intermediate with exceptional enantiomeric excess by employing a technique for independent, selective formation of two stereocentres in a single stereoconvergent operation.
Abstract: Double catalytic enantioselective transformations are powerful synthetic methods that can facilitate the construction of stereochemically complex molecules in a single operation. In addition to generating two or more stereocentres in a single reaction, multiple asymmetric reactions also impart increased enantiomeric excess to the final product in comparison with the analogous single transformation. Furthermore, multiple asymmetric operations have the potential to independently construct several stereocentres at remote points within the same molecular scaffold, rather than relying on pre-existing chiral centres that are proximal to the reactive site. Despite the inherent benefits of multiple catalytic enantioselective reactions, their application to natural product total synthesis remains largely underutilized. Here we report the use of a double stereoablative enantioselective alkylation reaction in a concise synthesis of the marine diterpenoid (-)-cyanthiwigin F (ref. 8). By employing a technique for independent, selective formation of two stereocentres in a single stereoconvergent operation, we demonstrate that a complicated mixture of racemic and meso diastereomers may be smoothly converted to a synthetically useful intermediate with exceptional enantiomeric excess. The stereochemical information generated by means of this catalytic transformation facilitates the easy and rapid completion of the total synthesis of this marine natural product.
244 citations
TL;DR: Use of the recently developed direct indole coupling enabled an efficient, practical, scalable, and protecting-group-free synthesis of each of the hapalindole family of natural products.
Abstract: Full details are provided for the total synthesis of several members of the hapalindole family of natural products, including hapalindole Q, 12-epi-hapalindole D, 12-epi-fischerindole U, 12-epi-fischerindole G, 12-epi-fischerindole I, and welwitindolinone A. Use of the recently developed direct indole coupling enabled an efficient, practical, scalable, and protecting-group-free synthesis of each of these natural products. The original biosynthetic proposal is reviewed, and a revised biosynthetic hypothesis is suggested, validated by the above syntheses. The syntheses are also characterized by an adherence to the concept of “redox economy”. Analogous to “atom economy” or “step economy”, “redox economy” minimizes the superfluous redox manipulations within a synthesis; rather, the oxidation state of intermediates linearly and steadily increases throughout the course of the synthesis.
243 citations
TL;DR: The isolation, structure elucidation, and confirmatory biomimetic total synthesis of the first member of the paraherquamide-stephacidin family to possess the rare anti-relative stereochemistry within the bicyclo-diazaoctane ring system are described.
Abstract: Prenylated indole alkaloids containing, the bicyclo[2.2.2]diazaoctane ring system as a structural core, now number more than thirty-eight family members. These natural substances, produced by various genera of fungi, in particular Aspergillus sp. and Penicillium spp., among others, exhibit a range of interesting structural and stereochemical features. Significantly, a myriad of biological activities are displayed by members of this family including insecticidal, anti-tumor, anthelmintic, calmodulin inhibitory, and anti-bacterial activities. Structurally, these substances arise from the oxidative condensation of one or two isoprene units, tryptophan and another cyclic amino acid residue, such as proline, β-methylproline or pipecolic acid. With respect to the relative stereochemistry within the core bicyclo[2.2.2]diazaoctane ring system, all of the known members of the paraherquamides (e.g., 1, 2)/stephacidins (e.g., 3, 4)/asperparalines and notoamides (e.g., 5, 6) have been shown to possess the syn-stereochemistry, while only the brevianamides (9, 10) have been shown to possess the anti-relative configuration (Schemes 1 and and2).2). The syn-/anti-relationship refers to the relative stereochemistry between the C-19 stereogenic center (sclerotiamide numbering) and the cyclic amino acid residue (proline, β-methylproline, or pipecolic acid; Scheme 2). This reveals that in the oxidative cyclization process(es) to construct this core ring system biosynthetically, both faces of the isoprene-derived dienophile participate in the ring-forming process. However, until now, this stereochemical divergence was cleanly separated between the brevianamides and all other members of this growing family of natural products. Herein, we describe the isolation, structure elucidation, and confirmatory biomimetic total synthesis of the first member of the paraherquamide-stephacidin family to possess the rare anti-relative stereochemistry within the bicyclo[2.2.2]diazaoctane ring system. We propose the new name versicolamide B for this natural product (8), a minor metabolite of Aspergillus versicolor NRRL 35600, Based on CD spectra, we have assigned the absolute configuration to this compound, and have concluded that it possesses the ent-configuration with respect to the bicyclo[2.2.2]diazaoctane core. Surprisingly and as striking, we have also isolated (−)-stephacidin A and (+)-notoamide B from Aspergillus versicolor NRRL 35600 and conclude that these substances are produced as the corresponding antipodes to the structures that have been previously described for these natural products. The provocative biogenetic implications of these stereochemical findings are discussed herein.
212 citations
TL;DR: Trost et al. as mentioned in this paper used atom economy and chemoselectivity to improve the efficiency of the synthesis of bryostatin 16, a biologically active, naturally occurring compound.
Abstract: The ideal in organic synthesis is to prepare complex molecules in the smallest possible number of steps. Also important is atom economy — limiting waste by ensuring that most of atoms present in the reactants end up in the product. Barry Trost and Guangbin Dong demonstrate these principles to good effect in a synthesis of the naturally occurring compound bryostatin 16 that takes about half as many steps as previous methods. A key reaction is the formation of a large ring, in a palladium-catalysed reaction between two alkynes (hydrocarbons containing carbon-carbon triple bonds). The bryostatins, a group of macrolide lactones originally isolated from coral-like marine organisms, display a range of biological activities including cytotoxicity, and have potential in anticancer and memory enhancement therapies. The ideal in organic synthesis is to prepare complex molecules using the smallest possible number of steps. Also important is atom economy, limiting waste by ensuring that most of atoms present in the reactants end up in the product. This paper demonstrates both of these principles to great effect in the synthesis of bryostatin 16, a biologically active, naturally occurring compound. The synthesis uses nearly half the number of steps of previously reported routes to bryostatins. Of the concepts used to improve the efficiency of organic syntheses, two have been especially effective: atom economy1 (the use of routes in which most of the atoms present in the reactants also end up in the product) and chemoselectivity2 (the use of reactions that take place only at desired positions in a molecule). Synthesis of complex natural products is the most demanding arena in which to explore such principles. The bryostatin family of compounds are especially interesting targets, because they combine structural complexity with promising biological activity3,4,5,6,7. Furthermore, synthetic routes to some bryostatins have already been reported9,10,11,12, providing a benchmark against which new syntheses can be measured. Here we report a concise total synthesis of bryostatin 16 (1), a parent structure from which almost all other bryostatins could in principle be accessed. Application of atom-economical and chemoselective reactions currently under development provides ready access to polyhydropyran motifs in the molecule, which are common structural features of many other natural products. The most notable transformations are two transition-metal-catalysed reactions. The first is a palladium-catalysed reaction of two different alkynes to form a large ring. The product of this step is then converted into a dihydropyran (the ‘C ring’ of bryostatins) in the second key reaction, which is catalysed by a gold compound. Analogues of bryostatin that do not exist in nature could be readily made by following this route, which might allow the biological activity of bryostatins to be fine-tuned.
212 citations
TL;DR: What is described in this report is the first total synthesis of elatol, a halogenated sesquiterpene in the chamigrene natural product family, which represents a general platform for accessing the chAMigrenenatural product family.
Abstract: Described in this report is the first total synthesis of elatol, a halogenated sesquiterpene in the chamigrene natural product family. The key disconnections in our synthetic approach include an enantioselective decarboxylative allylation to form the all-carbon quaternary stereocenter and a ring-closing olefin metathesis to concomitantly form the spirocyclic core as well as the fully substituted chlorinated olefin. This strategy represents a general platform for accessing the chamigrene natural product family, as demonstrated by the synthesis of (+)-laurencenone B as an intermediate in our route.
171 citations
TL;DR: A cascade catalytic asymmetric Heck-iminium cyclization was developed that rapidly provides 3,4-dihydro-9a,4a-(iminoethano)-9H-carbazoles in high enantiomeric purity and uses palladium-catalyzed reactions to form all carbon-carbon bonds in the transformation of these simple precursors to (+)-minfiensine.
Abstract: A 1,2,3,4-tetrahydro-9a,4a-(iminoethano)-9H-carbazole (4) is a central structural feature of the Strychnos alkaloid minfiensine (1) and akuammiline alkaloids such as vincorine (5) and echitamine (6). A cascade catalytic asymmetric Heck−iminium cyclization was developed that rapidly provides 3,4-dihydro-9a,4a-(iminoethano)-9H-carbazoles in high enantiomeric purity. Two sequences were developed for advancing 3,4-dihydro-9a,4a-(iminoethano)-9H-carbazole 27 to (+)-minfiensine. In our first-generation approach, a reductive Heck cyclization was employed to form the fifth ring of (+)-minfiensine. In a second more concise total synthesis, an intramolecular palladium-catalyzed ketone enolate vinyl iodide coupling was employed to construct the final ring of (+)-minfiensine. This second-generation total synthesis of enantiopure (+)-minfiensine was accomplished in 6.5% overall yield and 15 steps from 1,2-cyclohexanedione and anisidine 13. A distinctive feature of this sequence is the use of palladium-catalyzed reacti...
166 citations
TL;DR: A new process for the union of anilines with tryptamine derivatives has been developed, furnishing C-3 quaternized pyrroloindoline architectures, and the complex natural product psychotrimine has been fashioned with a rare level of efficiency and practicality.
Abstract: A new process for the union of anilines with tryptamine derivatives has been developed, furnishing C-3 quaternized pyrroloindoline architectures. This chemoselective coupling of a tryptamine with 1.2 equiv of 2-iodoaniline proceeds efficiently on a gram-scale using only the simple reagents N-iodosuccinimide and triethylamine. Using this new reaction, the complex natural product psychotrimine has been fashioned with a rare level of efficiency and practicality. From a readily available bromotryptamine, only four steps (41−45% overall isolated yield) are necessary to procure gram quantities of the natural product. Functional group manipulations, protecting group chemistry, and unnecessary redox fluctuations have been minimized.
154 citations
TL;DR: An efficient and highly stereoselective total synthesis of the natural product (+/-)-welwitindolinone A isonitrile is described, with described strategies for construction of the spiro-oxinole include a SmI2-LiCl mediated reductive cyclization and a novel anionic cyclization that simultaneously constructs theSpiro-oxindole and vinyl isonanticle moieties.
Abstract: An efficient and highly stereoselective total synthesis of the natural product (±)-welwitindolinone A isonitrile (1) is described. The bicyclo[4.2.0]octane core of 1 was established by a regio- and diastereoselective [2+2] ketene cycloaddition. The C12 quaternary center and vicinal stereogenic chlorine were installed in a single operation with excellent stereocontrol via a chloronium ion mediated semipinacol rearrangement. Described strategies for construction of the spiro-oxinole include a SmI_2−LiCl mediated reductive cyclization and a novel anionic cyclization that simultaneously constructs the spiro-oxindole and vinyl isonitrile moieties.
144 citations
TL;DR: A concise enantioselective total synthesis of naturally occurring alkaloids (+)-1 and ( )-2 in six and seven steps, respectively, from commercially available amino acid derivatives are described.
Abstract: Many of these alkaloids, including the closely related ( )-N(2-phenylethylene)ditryptophenaline (3), contain vicinal quaternary stereocenters that connect two hexahydropyrroloindole substructures (Scheme 1). Bioactivity-guided studies led to the identification of (+)-1 as a potent competitive substance P antagonist with submicromolar potency for the human neurokinin 1 and the cholecystokinin B receptors, whereas alkaloids ( )-2 and ( )-3 were found to be weaker inhibitors for the former receptor. Many closely related and potently biologically active epidithiodiketopiperazine derivatives are known, including (+)-chaetocin (Scheme 1), the first inhibitor of a lysine-specific histone methyltransferase, and (+)-11,11’-dideoxyverticillin A (Scheme 1), a tyrosine kinase inhibitor with potent antitumor activity. Based on the pioneering work of Hino, Nakagawa et al. reported the first synthesis of ( )-2 through a thallium(III)-promoted oxidative dimerization reaction (in 3% yield). In 2001, Overman and Paone reported an elegant total synthesis of ( )-ent-WIN 64821 and ( )-2 in which alkylation reactions were employed for the introduction of the quaternary stereocenters. Herein we describe a concise enantioselective total synthesis of naturally occurring alkaloids (+)-1 and ( )-2 in six and seven steps, respectively, from commercially available amino acid derivatives. Additionally, we report the conversion of ( )-2 into N-styrenyl derivatives as well as the structural confirmation of ( )-3. The retrosynthetic analysis of (+)-WIN 64821 (1) illustrates our planned approach to preparing these dimeric diketopiperazine alkaloids (Scheme 2). We envisioned simul-
142 citations
TL;DR: An efficient enantioselective total synthesis of (R)-rolipram and an efficient en anti-cancerous formal synthesis of(3S,4R)-paroxetine has been achieved using the highly enantiOSElective Michael addition of malonate nucleophiles as key steps in both cases.
139 citations
TL;DR: The first enantioselective total synthesis of lycopodine has been completed and key steps include a highly diastereoselectives organocatalyzed cyclization of a keto sulfone to establish the key C7 and C8 stereocenters.
Abstract: The first enantioselective total synthesis of lycopodine has been completed. Key steps include a highly diastereoselective organocatalyzed cyclization of a keto sulfone to establish the key C7 and C8 stereocenters and a tandem 1,3-sulfonyl shift/intramolecular Mannich cyclization to form the tricyclic core.
TL;DR: The total synthesis of racemic merrilactone A (a neurotrophic agent) is described, featuring simultaneous and stereospecific creation of the C4 and C5 stereocenters via a notable silyloxyfuran Nazarov cyclization.
Abstract: The total synthesis of racemic merrilactone A (a neurotrophic agent) is described, featuring simultaneous and stereospecific creation of the C4 and C5 stereocenters via a notable silyloxyfuran Nazarov cyclization. Full details of the successful synthetic strategy are given, as well as several examples of the interesting reactivity of intermediates that were prepared and studied during the execution of the total synthesis. A detailed investigation of the Lewis acid-catalyzed Nazarov cyclization of silyloxyfurans was conducted, including a systematic study of substrate scope and limitations. In addition, experiments were conducted that suggest the participation of Lewis acidic silicon species in the Nazarov cyclization.
TL;DR: The total synthesis of (+)-yohimbine was achieved in 11 steps and 14% overall yield, and the absolute configuration was established through a highly enantioselective thiourea-catalyzed acyl-Pictet-Spengler reaction.
TL;DR: After significant investigation, the diastereomeric molecule with the C11 and C13 configurations inverted was synthesized using the initial route, thereby establishing the correct overall structure for this potent macrolide natural product, including the relative and absolute stereochemistry.
Abstract: The total synthesis and structural revision of the marine natural product neopeltolide is reported. The key bond-forming step involves a Lewis acid-catalyzed intramolecular cyclization to install the tetrahydropyran ring and the macrocycle simultaneously. This type of cyclization is the first of its kind and assembles the carbon backbone of the natural product efficiently. The synthesis of the reported structure revealed differences in the data between the natural and synthetic material. After significant investigation, the diastereomeric molecule with the C11 and C13 configurations inverted was synthesized using the initial route. This compound matches the data reported for neopeltolide (1H, 13C, HRMS, IR, NOESY, [α]), thereby establishing the correct overall structure for this potent macrolide natural product, including the relative and absolute stereochemistry.
TL;DR: A convergent enantioselective total synthesis of (+)-pinnatoxin A is described, which capitalizes on the highly diastereoselectives Ireland-Claisen rearrangement of an acyclic alpha-branched allylic ester to set the quaternary stereogenic center at the core of the spiroimine ring system along with the adjacent tertiary stereocenter.
Abstract: A convergent enantioselective total synthesis of (+)-pinnatoxin A is described. The synthesis capitalizes on the highly diastereoselective Ireland−Claisen rearrangement of an acyclic alpha-branched allylic ester to set the quaternary stereogenic center at the core of the spiroimine ring system along with the adjacent tertiary stereocenter. The all-carbon macrocyclic ring system was formed by ring-closing metathesis.
TL;DR: The first total synthesis of the indole alkaloid mersicarpine is reported, and key steps include a beta-dicarbonyl radical cyclization, as well as an oxidation of the benzopyrrole moiety to establish the masked 1,2- dicarboneyl functionality.
TL;DR: The total synthesis and absolute stereochemistry reassignment of (+)-aquaticol has been achieved using the methodology and the total yield of bicyclo-octenone structures utilizing a copper-mediated asymmetric oxidative dearomatization/[4 + 2] dimerization cascade is described.
Abstract: An enantioselective approach to bicyclo[2.2.2]octenone structures utilizing a copper-mediated asymmetric oxidative dearomatization/[4 + 2] dimerization cascade is described. The total synthesis and absolute stereochemistry reassignment of (+)-aquaticol has been achieved using the methodology.
TL;DR: An asymmetric, catalytic transannular aldolization that provides polycyclic products useful for natural product synthesis and has been demonstrated in a total synthesis of (+)-hirustene.
Abstract: We report an asymmetric, catalytic transannular aldolization that provides polycyclic products useful for natural product synthesis. We found that a proline-derivative catalyzes the transannular aldol reaction of 1,4-cyclooctanediones to the corresponding cyclic beta-hydroxy ketones in good yields and with high enantioselectivities. The utility of our reaction has been demonstrated in a total synthesis of (+)-hirustene.
TL;DR: A concise synthesis of rubioncolin B is described, which features an unprecedented intramolecular Diels-Alder reaction involving an ortho-quinone methide and a naphthofuran moiety.
Abstract: A concise synthesis of rubioncolin B is described, which features an unprecedented intramolecular Diels−Alder reaction involving an ortho-quinone methide and a naphthofuran moiety. The ortho-quinone methide is generated through a surprisingly facile tautomerization of a para-quinone.
TL;DR: The first enantioselective total synthesis of clavirolide C, a member of the dolabellane family of diterpenes isolated from Pacific soft coral Clavularia viridis, is disclosed and the development of a new protocol for NHC is spawned.
Abstract: The first enantioselective total synthesis of clavirolide C, a member of the dolabellane family of diterpenes isolated from Pacific soft coral Clavularia viridis, is disclosed. The total synthesis features the application of chiral amino acid based ligands in Cu-catalyzed asymmetric conjugate addition (ACA) reactions and a relatively rare application of catalytic ring-closing metathesis to access an 11-membered ring structure. The total synthesis effort has spawned the development of a new protocol for NHC.Cu-catalyzed ACA of alkylaluminum reagents to beta-substituted cycloalkenones. The enantioselective clavirolide C synthesis requires 17 steps (longest linear sequence), affords the target molecule in 3.5% overall yield, and confirms the stereochemical assignment for the natural product.
TL;DR: A modular synthesis of the marine natural product largazole and related synthetic analogs is described, showing the necessity of the thiobutenyl moiety for antiproliferative activity.
Abstract: A modular synthesis of the marine natural product largazole and related synthetic analogs is described. Largazole was prepd. in 10% overall yield through a synthetic route with a longest linear sequence of nine steps. Activity tests showed the necessity of the thiobutenyl moiety for antiproliferative activity.
TL;DR: Key steps of this synthesis include an intramolecular oxidative coupling of ketone and malonic ester enolates and an aza-Cope−Mannich rearrangement that assembled the core structure of the natural product’s unique ring system.
Abstract: The first total synthesis of (±)-actinophyllic acid (1) is reported. Key steps of this synthesis include an intramolecular oxidative coupling of ketone and malonic ester enolates and an aza-Cope−Mannich rearrangement that assembled the core structure of the natural product’s unique ring system. The synthesis was accomplished from di-tert-butyl malonate in 8% overall yield by a concise sequence that proceeds by way of only seven isolated intermediates.
TL;DR: An asymmetric total synthesis of (-)-incarvillateine, a natural product having potent analgesic properties, has been achieved in 11 steps and 15.4% overall yield.
Abstract: An asymmetric total synthesis of (-)-incarvillateine, a natural product having potent analgesic properties, has been achieved in 11 steps and 15.4% overall yield. The key step is a rhodium-catalyzed intramolecular alkylation of an olefinic C-H bond to set two stereocenters. Additionally, this transformation produces an exocyclic, tetrasubstituted alkene through which the bicyclic piperidine moiety can readily be accessed.
TL;DR: The efficient total synthesis of (-)-serotobenine has been achieved by constructing an optically active dihydrobenzofuran ring via a rhodium carbenoid mediated intramolecular C-H insertion reaction, which was developed by the group.
Abstract: The efficient total synthesis of (−)-serotobenine (1) has been achieved by constructing an optically active dihydrobenzofuran ring via a rhodium carbenoid mediated intramolecular C−H insertion reaction, which was developed by our group. Then the possibility of racemization of 1 was investigated using optically active synthetic 1.
TL;DR: The total synthesis of (+/-)-goniomitine has been accomplished in 17 linear steps with 5.2% overall yield starting from commercially available delta-valerolactam and the use of a microwave reactor is shown to greatly improve the reaction times for two steps.
TL;DR: The synthesis features an efficient cross-metathesis, an enzymatic kinetic resolution of a beta-hydroxy ester, a selective removal of a Boc-protecting group, a HATU/HOAt-promoted cycloamidation reaction, and synthetic manipulations to a sensitive thioester functional group.
TL;DR: The first total synthesis of (+/-)-psychotrimine, a novel trimeric indole alkaloid isolated from Psychotria rostrata, was achieved.