Framework Of Alkaloids Research Articles

Enantioselective Approaches to 3,4-Annulated Indoles Using Organocatalytic Domino Reactions

Organocatalytic domino reactions of 4-substituted indoles are summarized in this account. Two reactions have been developed, one with enals, activated by secondary amine catalysts via iminium ions, and one with nitroethene, using a phosphoric acid catalyst. Both reactions required solving the challenge posed by the very low nucleo­philicity of the indole substrates, which bear an electron-withdrawing Michael acceptor at C4. DFT calculations were used to shed light on the unique reaction pathway followed by the phosphoric acid catalyzed transformation, wherein a bicoordinated nitronic acid intermediate was found to evolve preferentially through an intramolecular nitro-Michael reaction, instead of the common tautomerization pathway. These reactions provide new and efficient entries to 3,4-ring-fused indoles in dia­stereo- and enantioenriched form. In more detail, the structures obtained feature a 1,3,4,5-tetrahydrobenzo[cd]indole core, which is present in the structural framework of ergot alkaloids. Indeed, the preparation of an intermediate previously used in ergot alkaloid (6,7-secoagroclavine) synthesis was possible from one of the catalytic adducts.1 Introduction2 Reactions of 4-Substituted Indoles with α,β-Unsaturated Aldehydes Catalyzed by Secondary Amines3 Reactions of 4-Substituted Indoles with Nitroethene Catalyzed by Brønsted Acids4 Conclusion

A Total Synthesis of (±)-3-O-Demethylmacronine through Rearrangement of a Precursor Embodying the Haemanthidine Alkaloid Framework.

A total synthesis of the racemic modification, (±)-2, of the tazettine-type alkaloid 3-O-demethylmacronine is described. The key steps are an intramolecular Alder-ene (IMAE) reaction and a lactam-to-lactone rearrangement of tetracycle 13, a compound that embodies the haemanthidine alkaloid framework.

Enantioselective Pd‐Catalyzed Allylic Alkylation Reactions of Dihydropyrido[1,2‐a]indolone Substrates: Efficient Syntheses of (−)‐Goniomitine, (+)‐Aspidospermidine, and (−)‐Quebrachamine

AbstractThe successful application of dihydropyrido[1,2‐a]indolone (DHPI) substrates in Pd‐catalyzed asymmetric allylic alkylation chemistry facilitates rapid access to multiple alkaloid frameworks in an enantioselective fashion. Strategic bromination at the indole C3 position greatly improved the allylic alkylation chemistry and enabled a highly efficient Negishi cross‐coupling downstream. The first catalytic enantioselective total synthesis of (−)‐goniomitine, along with divergent formal syntheses of (+)‐aspidospermidine and (−)‐quebrachamine, are reported herein.

Enantioselective Pd-Catalyzed Allylic Alkylation Reactions of Dihydropyrido[1,2-a]indolone Substrates: Efficient Syntheses of (-)-Goniomitine, (+)-Aspidospermidine, and (-)-Quebrachamine.

The successful application of dihydropyrido[1,2-a]indolone (DHPI) substrates in Pd-catalyzed asymmetric allylic alkylation chemistry facilitates rapid access to multiple alkaloid frameworks in an enantioselective fashion. Strategic bromination at the indole C3 position greatly improved the allylic alkylation chemistry and enabled a highly efficient Negishi cross-coupling downstream. The first catalytic enantioselective total synthesis of (-)-goniomitine, along with divergent formal syntheses of (+)-aspidospermidine and (-)-quebrachamine, are reported herein.

An unexpected reaction pathway in the synthesis of the ABCE framework of strychnine-type alkaloids – A multidisciplinary study

Acid-catalyzed cyclization of spirocyclic 1′-benzyl-2′-(prop-2-en-1-yl)spiro[indole-3,3′-pyrrolidine]-5′-one (1) was performed. The pentacyclic product of Povarov-like imino-Diels-Alder reaction was isolated in high yield instead of expected tetracyclic aza-Prins intermediate. The unusual exotic alkaloid-type structure of the resulting molecule 2 was unambiguously confirmed by a detailed NMR analysis using a set of 2D NMR spectra including an INADEQUATE experiment. The relative configuration of 2 was predicted from the synthesis mechanism and DFT geometry calculations and independently confirmed using NOESY and residual dipolar coupling (RDC) assisted NMR analysis in stretched crosslinked polystyrene gels. The reversibility of the cycloaddition in aprotic solvents was observed. A new reaction pathway yielding a rare 6-5-5-5 tetracyclic spiroindoline 3 was suggested. The relative configuration within the tetracyclic framework was ultimately proved using Single-crystal X-ray diffraction analysis of compound 4.

ChemInform Abstract: Domino Michael/Mannich/N‐Alkylation Route to the Tetrahydrocarbazole Framework of Aspidosperma Alkaloids: Concise Total Syntheses of (—)‐Aspidospermidine, (—)‐Tabersonine, and (—)‐Vincadifformine.

We report a novel, asymmetric domino Michael/Mannich/N-alkylation sequence for the rapid assembly of the tetrahydrocarbazole framework of Aspidosperma alkaloids. This method was utilized in the concise total syntheses of classical targets (−)-aspidospermidine, (−)-tabersonine, and (−)-vincadifformine in 10 or 11 steps. Additional key steps include ring-closing metathesis to prepare the D-ring and Bosch–Rubiralta spirocyclization to prepare the C-ring.

ChemInform Abstract: Catalytic, Enantioselective, and Highly Chemoselective Bromocyclization of Olefinic Dicarbonyl Compounds.

Catalytic enantioselective halocyclization of olefinic substrates attracted much attention over the past few years. The resulting enantioenriched heterocycles form the core of many natural products and pharmaceutically important intermediates. In addition, the halogen atoms can be manipulated readily to give various functional building blocks. Most of the reported catalytic enantioselective halocyclization reactions involve the use of a nitrogenor an oxygen-containing nucleophilic partner that has an N H or a O H moiety (e.g., amides or alcohols/carboxylic acids, respectively). The catalysts can then interact with the R H functionalities (R=N, O) through hydrogen bonds and/or salt bridges. Such interactions allow for an effective enantioinduction, resulting in highly enantioselective transformations. 1,3-Dicarbonyl compounds 1, which contain an acidic proton in a-position to the carbonyl funtionalities, are also potential nucleophiles for halocyclizations (when R is an olefinic side chain), furnishing highly functionalized cyclic ethers 3 (Scheme 1). However, this type of nucleophile is also highly susceptible to halogenation in a-position to the carbonyl functionalities, which is a well-known process. The resulting a-halogenated dicarbonyl compound 2 is not a good halogenating reagent and not usually used in the halocyclization of olefinic substrate 1. Nonetheless, herein we report an efficient, catalytic, and highly enantioselective bromocyclization of olefinic 1,3-dicarbonyl compounds, giving rise to highly functionalized furans (see below). A protocol that employs an amine–thiocarbamate as catalysts was developed for the chemoselective bromination at the olefinic moiety over the carbon atom in a-position to the carbonyl functionalities. At the outset of this study, we screened several catalysts that are commonly used in halocyclizations. Olefinic 1,3dicarbonyl compound 1a and N-bromosuccinimide (NBS) were used as substrate and stoichiometric source of the halogen atom, respectively. Reactions with simple catalysts, including DABCO (4), DBU, and DMAP, gave significant amounts of 2-bromo 1,3-dicarbonyl compound 2a, while the reaction with NEt3 gave a mixture of unidentified products (Table 1, entries 1–4). In particular, when DBU was used as the catalyst, cyclized product 3a was not obtained and 2a was isolated in 98% yield. During further investigations, we found that catalysts with Lewis basic sulfur atoms preferably mediate the bromination at the olefinic moiety instead of at the carbon atom in aposition to the carbonyl functionalities, and thus facilitate the cyclization process. The reaction with triphenylphosphine sulfide (5) gave the desired product 3a with only trace amounts of 2a (Table 1, entry 5). When the reaction was catalyzed by thiocarbamate 6, 3a was obtained as the only product in 78% yield (Table 1, entry 6). To our delight, 3a was obtained in an excellent yield (92%) and with only a negligible amount of 2a when amine–thiocarbamate catalyst 7a was used (Table 1, entry 7). Encouraged by these preliminary results, we proceeded to optimize the reaction conditions and to develop the asymmetric version of the reaction. A systematic screening of various halogen sources and solvents showed that toluene and NBS gave the best results (see the Supporting Information for details). The influence of the reaction temperature was also examined. At 60 8C, the reaction of 1a with quinidine-derived amine–thiocarbamate 7a gave product 3a in 34% yield and 16% ee (Table 2, entry 1, footnote c). The ee value and yield improved when the reaction was conducted at 40 8C (Table 2, entry 1). Unexpectedly, reactions with thiocarbamate catalysts that contain other cinchona alkaloid frameworks, including quinine, cinchonine, and cinchonidine, were sluggish and no Scheme 1. Comparison of previous and present studies.

ChemInform Abstract: A Novel Lewis Acid Catalyzed [3 + 3]‐Annulation Strategy for the Syntheses of Tetrahydro‐β‐carbolines and Tetrahydroisoquinolines.

AbstractThe newly developed title procedure represents a valuable complement to the classical Pictet‐Spengler reaction and enables facile access to alkaloid frameworks not easily available by established procedures.

Domino Michael/Mannich/N-Alkylation Route to the Tetrahydrocarbazole Framework of Aspidosperma Alkaloids: Concise Total Syntheses of (−)-Aspidospermidine, (−)-Tabersonine, and (−)-Vincadifformine

We report a novel, asymmetric domino Michael/Mannich/N-alkylation sequence for the rapid assembly of the tetrahydrocarbazole framework of Aspidosperma alkaloids. This method was utilized in the concise total syntheses of classical targets (-)-aspidospermidine, (-)-tabersonine, and (-)-vincadifformine in 10 or 11 steps. Additional key steps include ring-closing metathesis to prepare the D-ring and Bosch-Rubiralta spirocyclization to prepare the C-ring.

Catalytic, Enantioselective, and Highly Chemoselective Bromocyclization of Olefinic Dicarbonyl Compounds

Catalytic enantioselective halocyclization of olefinic substrates attracted much attention over the past few years. The resulting enantioenriched heterocycles form the core of many natural products and pharmaceutically important intermediates. In addition, the halogen atoms can be manipulated readily to give various functional building blocks. Most of the reported catalytic enantioselective halocyclization reactions involve the use of a nitrogenor an oxygen-containing nucleophilic partner that has an N H or a O H moiety (e.g., amides or alcohols/carboxylic acids, respectively). The catalysts can then interact with the R H functionalities (R=N, O) through hydrogen bonds and/or salt bridges. Such interactions allow for an effective enantioinduction, resulting in highly enantioselective transformations. 1,3-Dicarbonyl compounds 1, which contain an acidic proton in a-position to the carbonyl funtionalities, are also potential nucleophiles for halocyclizations (when R is an olefinic side chain), furnishing highly functionalized cyclic ethers 3 (Scheme 1). However, this type of nucleophile is also highly susceptible to halogenation in a-position to the carbonyl functionalities, which is a well-known process. The resulting a-halogenated dicarbonyl compound 2 is not a good halogenating reagent and not usually used in the halocyclization of olefinic substrate 1. Nonetheless, herein we report an efficient, catalytic, and highly enantioselective bromocyclization of olefinic 1,3-dicarbonyl compounds, giving rise to highly functionalized furans (see below). A protocol that employs an amine–thiocarbamate as catalysts was developed for the chemoselective bromination at the olefinic moiety over the carbon atom in a-position to the carbonyl functionalities. At the outset of this study, we screened several catalysts that are commonly used in halocyclizations. Olefinic 1,3dicarbonyl compound 1a and N-bromosuccinimide (NBS) were used as substrate and stoichiometric source of the halogen atom, respectively. Reactions with simple catalysts, including DABCO (4), DBU, and DMAP, gave significant amounts of 2-bromo 1,3-dicarbonyl compound 2a, while the reaction with NEt3 gave a mixture of unidentified products (Table 1, entries 1–4). In particular, when DBU was used as the catalyst, cyclized product 3a was not obtained and 2a was isolated in 98% yield. During further investigations, we found that catalysts with Lewis basic sulfur atoms preferably mediate the bromination at the olefinic moiety instead of at the carbon atom in aposition to the carbonyl functionalities, and thus facilitate the cyclization process. The reaction with triphenylphosphine sulfide (5) gave the desired product 3a with only trace amounts of 2a (Table 1, entry 5). When the reaction was catalyzed by thiocarbamate 6, 3a was obtained as the only product in 78% yield (Table 1, entry 6). To our delight, 3a was obtained in an excellent yield (92%) and with only a negligible amount of 2a when amine–thiocarbamate catalyst 7a was used (Table 1, entry 7). Encouraged by these preliminary results, we proceeded to optimize the reaction conditions and to develop the asymmetric version of the reaction. A systematic screening of various halogen sources and solvents showed that toluene and NBS gave the best results (see the Supporting Information for details). The influence of the reaction temperature was also examined. At 60 8C, the reaction of 1a with quinidine-derived amine–thiocarbamate 7a gave product 3a in 34% yield and 16% ee (Table 2, entry 1, footnote c). The ee value and yield improved when the reaction was conducted at 40 8C (Table 2, entry 1). Unexpectedly, reactions with thiocarbamate catalysts that contain other cinchona alkaloid frameworks, including quinine, cinchonine, and cinchonidine, were sluggish and no Scheme 1. Comparison of previous and present studies.

A Novel Lewis Acid Catalyzed [3 + 3]-Annulation Strategy for the Syntheses of Tetrahydro-β-Carbolines and Tetrahydroisoquinolines

A novel Lewis acid catalyzed [3 + 3]-annulation process for the efficient syntheses of both tetrahydro-β-carbolines and tetrahydroisoquinolines from readily available benzylic alcohols and aziridines was developed, which would be a highly valuable complement to the widely used Pictet-Spengler reaction. A probable mechanism was proposed based on the isolation and characterization of two key intermediates. This strategy enables facile access to important alkaloid frameworks not easily available with other known methods.

Applied Biological and Physicochemical Activity of Isoquinoline Alkaloids: Oxoisoaporphine and Boldine

The aim of this study was to determine the electronic influence of substituent groups and annelated rings such as oxazole-oxazinone on the physicochemical and photoprotection, antioxidant capacity, toxicity and singlet oxygen photosensitization biological properties of isoquinoline alkaloid frameworks. Thus, oxoisoaporphine derivatives 1–5 and 3-azaoxoisoaporphine (6), some of them with phenolic structures, did not present any antioxidant capacity, possibly either by formation of keto-enol tautomerism species or the formation of unstable free radicals. Due to the singlet oxygen quantum yields (ΦΔ) near to unity, and greater photostability than phenalenone, oxoisoaporphines 4–6 may be considered as photosensitizers for singlet oxygen production and can be used as new universal study tools. The biological application as antibacterial agents is an important and possible tool in the study of compounds with low cytotoxicity and high reactivity in antineoplastic chemotherapy. On the other hand, when boldine and its annelated derivatives B1–4 are irradiated, a photoprotector effect is observed (SPF = 2.35), even after 30 minutes of irradiation. They also act as photoprotectors in cell fibroblast cultures. No hemolysis was detected for boldine hydrochloride and its salts without irradiation. In solutions irradiated before incubation (at concentrations over 200 ppm) photoproducts were toxic to the nauplii of Artemia salina.

A simple synthesis of the pentacyclic lamellarin skeleton from 3-nitro-2-(trifluoromethyl)-2 H-chromenes and 1-methyl(benzyl)-3,4-dihydroisoquinolines

The basic structural framework of lamellarin alkaloids, 8,9-dihydro-6 H-chromeno[4′,3′:4,5]pyrrolo[2,1- a]isoquinoline derivatives, has been obtained in good yields via Grob synthesis between 3-nitro-2-(trifluoromethyl)-2 H-chromenes and 1-methyl-3,4-dihydroisoquinolines in refluxing isobutanol. In the case of 1-benzyl-3,4-dihydroisoquinolines, a dynamic NMR effect was observed in the 1H and 19F NMR spectra of the products as a result of restricted rotation about the single bond linking the benzene ring and the heterocyclic system. When the reaction was carried out with 3-nitro-2-(trichloromethyl)-2 H-chromenes in toluene at room temperature, only Michael adducts, as a mixture of two diastereomers, were isolated.

A simple synthesis of the lamellarin analogues from 3-nitro-2-trifluoromethyl-2H-chromenes and 1-benzyl-3,4-dihydroisoquinolines

The basic structural framework of lamellarin alkaloids, 8,9-dihydro-6H-chromeno[4’,3’:4,5]pyrrolo[2,1-a]isoquinoline derivatives, was accessed in good yields by the Grob reaction between 3-nitro-2-trifluoromethyl-2H-chromenes and dihydropapaverine or drotaverine in refluxing isobutanol.

Sulfoxides derived from Cinchona alkaloids—chiral ligands in palladium-catalyzed asymmetric allylic alkylation

Phenyl sulfides derived from Cinchona alkaloids, 9-PhS- epi-CD, 9-PhS- epi-QN, 9-PhS- epi-QD, and 9-PhS-QN were oxidized into the corresponding sulfoxides. Regardless of the oxidation system used (NaIO 4, TEMPO/NaOCl, VO(acac) 2/chiral Schiff base/H 2O 2) a similar stereochemical outcome of the oxidation was observed. Four pure epimers of sulfoxides 9-PhSO- epi-CD and 9-PhSO- epi-QN were isolated and fully characterized (X-ray, CD, 1H NMR-pattern). The chiral sulfoxides as well as the corresponding sulfides and sulfones were tested in the Pd-catalyzed allylic alkylation of dimethyl malonate with rac-1,3-diphenyl-2-propenyl acetate. The sulfoxides obtained from Cinchona alkaloids bearing the additional stereogenic center gave the main product of configuration dependent on the chirality of alkaloid framework only. Similar ees (up to 60%) but significantly higher yields (90%) were obtained as compared to the reaction with the corresponding thioethers. The results were in agreement with nucleophilic attack directed at the allylic carbon located trans to the sulfur atom in the M-shaped intermediate η 3-allylpalladium complex.

Sequential One-Pot Cyclizations: Concise Access to the ABCE Tetracyclic Framework of Strychnos Alkaloids

A sequential one-pot biscyclization route to the ABCE tetracyclic framework of Strychnos alkaloids has been developed. Specifically, the AgOTf-mediated spirocyclization of an appropriately functionalized indole 3-carbinamide afforded a stable spiroindolenine intermediate; subsequent addition of DBU to the reaction mixture effected an unprecedented intramolecular aza-Baylis-Hillman reaction, delivering a tetracyclic product in 70% isolated yield.

A New Acyl Radical-based Route to the 1,5-Methanoazocino[4,3-b]indole Framework of Uleine and Strychnos Alkaloids

C-4 or C-12 ethyl substituted 1,5-methanoazocino[4,3-b]indoles, which constitute the tetracyclic framework of uleine alkaloids as well as the ABDE substructure of the Strychnos alkaloid family, have been synthesized by novel 6-exo and 6-endo cyclizations of selenoester-derived 2-indolylacyl radicals upon 5-ethyl-1,2,3,6- and 3-ethyl-1,2,5,6-tetrahydropyridines, respectively.

A new route to heterocyclic compounds by the mercuric acetate oxidation of N-alkyl substituted 4-piperidones

N-Alkyl substituted 4-piperidones readily undergo oxidation in high yield upon reaction with mercuric acetate. Application of the oxidation to the synthesis of the skeletal framework of several alkaloids is described.

A facile route to the pentacyclic lamellarin skeleton via Grob reaction between 3-nitro-2-(trifluoromethyl)-2 H-chromenes and 1,3,3-trimethyl-3,4-dihydroisoquinolines

The basic structural framework of lamellarin alkaloids, 8,9-dihydro-6 H-chromeno[4′,3′:4,5]pyrrolo[2,1- a]isoquinoline derivatives, has been obtained in good yields via Grob reaction between 3-nitro-2-(trifluoromethyl)-2 H-chromenes and 1,3,3-trimethyl-3,4-dihydroisoquinolines in refluxing isobutanol. When the reaction was carried out in toluene at room temperature, only Michael adducts, as a mixture of two diastereomers, were isolated.

6-Exo Cyclizations of 2-Indolylacyl Radicals: Access to the Uleine Alkaloid Skeleton

A new straightforward approach to the bridged framework of uleine alkaloids, based on the 6- EXO cyclization of selenoester-derived 3-(tetrahydro-2-pyridyl)-2-indolylacyl radicals under reductive conditions, is described.