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Total Synthesis of (+)- and (-)-Calycanthidine and Formal Synthesis of (-)-Idiospermuline via Key Pd(0)-Catalyzed Asymmetric Allylations
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A highly enantioselective decarboxylative allylation of a mixture of enol carbonates and allyl esters has been achieved. The strategic viability of this methodology has been demonstrated through the total synthesis of cyclotryptamine alkaloids (-)- and (+)-folicanthine (1 a) and the formal total synthesis of (-)-chimonanthine (1 b), (+)-calycanthine (1 c), and (-)-ditryptophenaline (1 d).
We report a catalytic stereoconvergent construction of vicinal all-carbon quaternary centers via double stereoablative enantioselective alkylation of a mixture having racemic and meso diastereomers of esters to afford exceptional levels of diastereo- (up to 17 : 1) and enantioselectivity (up to >99% ee). The strategy offers an efficient and general approach to dimeric cyclotryptamine alkaloids sharing a labile C3a-C3a' σ-bond in the hexahydropyrroloindoline core.
Hypervalent iodine(III)-induced dimerization of indole derivatives, mitragynine, tetrahydrocarbazole, and Nb-carbomethoxytryptamine, was investigated. By applying this procedure, the concise total synthesis of rac- and meso-chimonanthines was accomplished.
Highly substituted 2-aminated indoles can be prepared in moderate to excellent yields by regioselective C2-amination of indoles promoted by iodine. As a key step in a concise synthesis of (±)-folicanthine, its core structure was easily obtained by one step cyclization-dimerization of substituted tryptophan in high yield on a gram scale.
Histone methylation plays a key role in establishing and maintaining stable gene expression patterns during cellular differentiation and embryonic development. Here, we report the characterization of the fungal metabolite chaetocin as the first inhibitor of a lysine-specific histone methyltransferase. Chaetocin is specific for the methyltransferase SU(VAR)3-9 both in vitro and in vivo and may therefore be used to study heterochromatin-mediated gene repression.
Chaetocin, a thiodioxopiperazine natural product previously unreported to have anticancer effects, was found to have potent antimyeloma activity in IL-6-dependent and -independent myeloma cell lines in freshly collected sorted and unsorted patient CD138(+) myeloma cells and in vivo. Chaetocin largely spares matched normal CD138(-) patient bone marrow leukocytes, normal B cells, and neoplastic B-CLL (chronic lymphocytic leukemia) cells, indicating a high degree of selectivity even in closely lineage-related B cells. Furthermore, chaetocin displays superior ex vivo antimyeloma activity and selectivity than doxorubicin and dexamethasone, and dexamethasone- or doxorubicin-resistant myeloma cell lines are largely non-cross-resistant to chaetocin. Mechanistically, chaetocin is dramatically accumulated in cancer cells via a process inhibited by glutathione and requiring intact/unreduced disulfides for uptake. Once inside the cell, its anticancer activity appears mediated primarily through the imposition of oxidative stress and consequent apoptosis induction. Moreover, the selective antimyeloma effects of chaetocin appear not to reflect differential intracellular accumulation of chaetocin but, instead, heightened sensitivity of myeloma cells to the cytotoxic effects of imposed oxidative stress. Considered collectively, chaetocin appears to represent a promising agent for further study as a potential antimyeloma therapeutic.
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.
The asymmetric catalytic synthesis of 3-cyclotryptamine substituted oxindoles through formal [4 + 2] cycloaddition/cyclization cascade is described. A wide range of cyclotryptamine derivatives were obtained in enantioenriched form under mild reaction conditions and were found to have potential anticancer activity. The strategy enables ready assembly of cyclotryptamine subunits at the C3a-C3a' positions with two quaternary stereogenic centers in cis-selectivity, leading to the concise synthesis of optically active cis-bis(hexahydropyrroloindole) and others of the cyclotryptamine alkaloid family.
An efficient Cu(II)-PHOX-catalyzed malonate addition onto 3-hydroxy 3-indolyl-2-oxindoles is envisioned to afford excellent enantioselectivities (up to >99% ee) in high chemical yields. A detailed characterization data including X-ray, NMR, CV and EPR experiments suggest that a Cu(II)-complex is involved as an active species in this process. Applying the strategy, an advanced intermediate of cyclotryptamine alkaloids has been synthesized in few steps addressing a general approach to bis-cyclotryptamine alkaloids.
While interest in the synthetic chemistry of radical cations continues to grow, controlling enantioselectivity in the reactions of these intermediates remains a challenge. Based on recent insights into the oxidation of tryptophan in enzymatic systems, we report a photocatalytic method for the generation of indole radical cations as hydrogen-bonded adducts with chiral phosphate anions. These non-covalent open-shell complexes can be intercepted by the stable nitroxyl radical TEMPO• to form alkoxyamine-substituted pyrroloindolines with high levels of enantioselectivity. Further elaboration of these optically-enriched adducts can be achieved via a catalytic single-electron oxidation/mesolytic cleavage sequence to furnish transient carbocation intermediates that may be intercepted by a wide range of nucleophiles. Taken together, this two-step sequence provides a simple catalytic method to access a wide range of substituted pyrroloindolines in enantioenriched form via a standard experimental protocol from a common synthetic intermediate. The design, development, mechanistic study, and scope of this process are presented, as are applications of this method to the synthesis of several dimeric pyrroloindoline natural products.
In addition to a very much larger amount of calycanthine, the seeds of Calycanthus floridus contain 0.03% of a simpler alkaloid C18H16N2, related to tetrahydroharman.
All-carbon quaternary stereocenters have posed significant challenges in the synthesis of complex natural products. These important structural motifs have inspired the development of broadly applicable palladium-catalyzed asymmetric allylic alkylation reactions of unstabilized non-biased enolates for the synthesis of enantioenriched α-quaternary products. This microreview outlines key considerations in the application of palladium-catalyzed asymmetric allylic alkylation reactions and presents recent total syntheses of complex natural products that have employed these powerful transformations for the direct, catalytic, enantioselective construction of all-carbon quaternary stereocenters.
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.
The total synthesis of dl-calycanthine and dl-chimonanthine is described; following biogenetic precedent, the synthesis route involves oxidative dimerization of N-carbethoxy-oxytryptamine followed by reductive cyclization. The alkaloids are interconverted by acid-catalyzed isomerization. The structures of some synthetic byproducts are also discussed.
A twofold Pd-DAAA Pd-catalyzed decarboxylative allylic alkylation was used to construct two vicinal all-carbon quaternary stereocenters (marked in red) in a diastereo- and enantioselective fashion. The products of the Pd-DAAA were further elaborated to complete the formal syntheses of cyclotryptamine alkaloids. The twofold Pd-catalyzed transformation proceeds through an initial matched allylation followed by a second mismatched allylation to deliver the desired product.
A catalytic enantioselective double allylic alkylation reaction has been employed in the synthesis of the core of the gagunin diterpenoids. Enantioenriched material was advanced in 11 steps to afford the core of the highly oxygenated target, which includes two all-carbon quaternary stereocenters.
The dimerization of an oxindole in good yield at C-3 to form a benzylic quaternary carbon-carbon bond is described. A radical anion chain mechanism is proposed for the reaction. The dimeric product is transformed into (+/-)-folicanthine by a series of reductions. A crystalline bis-borane complex of (+/-)-folicanthine was obtained, and its molecular structure was determined by X-ray crystallography.
Two new tryptamine-related alkaloids, chimonamidine and chimonanthidine, were isolated from the seeds of Chimonanthus praecox Link. and their structures including absolute configuration were elucidated by spectroscopic analysis and biomimetic total synthesis from tryptamine.
Die Kraft des Palladiums: Die Totalsynthese des Alkaloids Hodgkinsin B gelang mit nur sechs isolierten Zwischenstufen und nur vier chromatographischen Operationen. Die Route umfasst eine palladiumkatalysierte enantioselektive desymmetrisierende N-Allylierung von meso-Chimonanthin, um die absolute Konfiguration einzustellen, sowie die Derivatisierung des desymmetrisierten Kerns durch eine diastereoselektive palladiumkatalysierte α-Oxindol-Arylierung.
We report the palladium-catalyzed asymmetric allylic alkylation (AAA) reaction of a variety of nitrogen-containing aromatic heterocycles, including pyrazine, pyrimidine, pyridazine, quinoxaline, and benzoimidazole derivatives. The mesityl ester, whose steric bulk prevents competitive deacylation of the electrophile from "hard" nucleophiles, is introduced as a new leaving group in allylic alkylation chemistry. In contrast to our previous studies of AAA reactions with pyridine-based substrates, no precomplexation with a Lewis acid is required before deprotonation with LiHMDS, underscoring the relative acidity of these electron-deficient nucleophiles.
Purification of a methanol extract from the seed of Idiospermum australiense, guided by bioactivity on a rat brain cortical wedge preparation has afforded two known dimeric alkaloids, the piperidinoindoline (+)-calycanthine [1] and the pyrrolidinoindoline, (-)-chimonanthine [2] along with a new trimeric pyrrolidinoindoline alkaloid, (-)-idiospermuline [3]. Te structure of idiospermuline [3] was determined by spectroscopic methods and the absolute configuration by an X-ray crystallographic study of idiospermuline trimethiodide [4].
Chiral phosphinooxazolines (PHOX ligands), which coordinate to a metal center with a N- and a P-atom, allow effective enantiocontrol in a variety of metal-catalyzed reactions. They are readily synthesized, and because of their modular structure, the steric and electronic properties can be tailored for a specific application by variation of the oxazoline ring, the backbone, and the phosphine moiety.
For Abstract see ChemInform Abstract in Full Text.
Stereogenic quaternary carbons present the primary challenge in the syntheses of trispyrrolidinoindoline alkaloids such as idiospermuline. In its synthesis the two contiguous quaternary centers are expediently addressed by combining the lithium dienolate of a differentially protected dihydroisoindigo with a tartrate-derived electrophile. The third quaternary stereocenter is introduced by a catalytic asymmetric Heck reaction.
Only a few catalytic asymmetric C-C bond-forming reactions have been shown to be useful for constructing all-carbon quaternary stereocenters. This Perspective examines the current state of such methods.
Epipolythiodioxopiperazines (ETPs) are toxic secondary metabolites made only by fungi. The best-known ETP is gliotoxin, which appears to be a virulence factor associated with invasive aspergillosis of immunocompromised patients. The toxicity of ETPs is due to the presence of a disulphide bridge, which can inactivate proteins via reaction with thiol groups, and to the generation of reactive oxygen species by redox cycling. With the availability of complete fungal genome sequences and efficient gene-disruption techniques for fungi, approaches are now feasible to delineate biosynthetic pathways for ETPs and to gain insights into the evolution of such gene clusters.
The first total synthesis of the bis-pyrroloindoline alkaloid (+/-)-Nb-desmethyl-meso-chimonanthine, having a pseudo C2-symmetry, was realised in a seven-step convergent sequence without the use of protecting groups.