RESUMO
An efficient method for the synthesis of 1-hydroxy-2,5-dihydrophosphole 1-oxides, a type of five-membered P-containing heterocyclic compound, is presented. The reaction was carried out through a [4C+1P] cyclization of 1,3-dienes with a combination of PBr3 and P(OMe)3 as the P(III) source. To compare with the reported methods, the protocol reported herein not only is much milder and more rapid but also displays a broad substrate scope and affords the products in high yields (50-94%). In addition, the reaction could be reliably scaled up at the gram-scale level and was demonstrated to be a versatile platform for flexible derivatization. Consequently, this method provides a general and reliable way for the synthesis of five-membered phosphole derivatives.
RESUMO
Benzyl bromides have been widely used for fullerene functionalization. However, the use of benzyl chlorides, a more affordable but less reactive counterpart of benzyl bromides, has been rarely reported. Herein, a new metal-mediated benzylation of C60 with benzyl chlorides is presented. In this method, with the combinatorial use of Mn powder and Cu(OAc)2, various benzyl chloride derivatives could react with C60 to afford 1,4-dibenzylated products in 12-53% yields. A mechanistic study by in situ visible near infrared (vis-NIR) spectroscopy and various control experiments suggests that, unlike the conventional anionic pathway that uses benzyl bromides, the transition-metal-mediated benzylation of C60 with benzyl chlorides proceeds via a metal-mediated iterative single electron transfer process.
RESUMO
The diverse synthesis of oxatricyclotridecanes and oxatricyclododecanes, which are the core structures of toxicodenane A and its skeletal analogues, via a unified manner is presented. The stereochemistry at the bridgehead position of the oxa-bridged bicycle could be efficiently controlled through a diastereoselective anti- and syn-Grignard allylation reaction by appropriately tuning the reaction conditions such as the solvent, the counterion of the Grignard reagent, the substrate, or a combination of these. The ring size could be precisely elaborated via a Lewis acid-mediated intramolecular transacetalation and Prins cyclization cascade reaction by varying the steric hindrance of olefin moiety. Namely, substrates bearing a terminally unsubstituted olefinic functionality afforded oxatricyclotridecanes with an overwhelming preference, while those bearing a dimethyl-substituted olefinic group produced exclusively oxatricyclododecanes. The wide utility and generality of the above key transformations are highlighted by the applications in the unified synthesis of (±)-toxicodenance A, (+)-toxicodenane A, (+)-8,11-epi-toxicodenane A, and other oxatricyclic cores with different stereochemistries and ring sizes.
Assuntos
Alcenos , Ácidos de Lewis , Ciclização , Indicadores e Reagentes , Sesquiterpenos , EstereoisomerismoRESUMO
In the total synthesis of natural products, synthetic efficiency has been an important driver for designing and developing new synthetic strategies and methodologies. To this end, the step, atom, and time economy and the overall yield are major factors to be considered. On the other hand, developing unified routes that can be used for synthesizing multiple molecules, specifically skeletally different classes of molecules, are also important aspects with which to be concerned. In the efforts toward efficient and flexible synthesis of structurally unique terpenoid and indole alkaloid natural products, we have designed and developed several phosphinamide-based new catalysts and reaction methodologies that have been compellingly demonstrated to be widely useful as strategic protocols for the diverse synthesis of various complex terpenoids and indole alkaloids. The important progress of these results will be summarized in this Account.In the first part, we present the stories of successful design and establishment of a novel method for the synthesis of P-stereogenic phosphinamides (P-SPhos) via a Pd-catalyzed C-H desymmetric enantioselective arylation, as well as the flexible derivatization of the P-stereogenic phosphinamides into various types of skeletally unique tricyclic and N,P-bidentate P-stereogenic compounds. Subsequently, the discovery of P-stereogenic phosphinamides as chiral organocatalysts for the desymmetric enantioselective reduction of cyclic 1,3-diketones and of phosphinamide-based cyclopalladium complex (C-Pd) as precatalysts for highly efficient Suzuki-Miyaura cross-coupling reaction of sterically congested nonactivated enolates is introduced. The notable features of the P-stereogenic phosphinamide-catalyzed desymmetric enantioselective reduction are highlighted by the broad substrate compatibility and excellent stereoselectivity, as well as most significantly, the good recoverability and reusability of catalysts. With regard to the sterically congested nonactivated enolates, such substrates are challenging for Suzuki cross-coupling reactions. We demonstrate that the phosphinamide-based cyclopalladium is a type of highly active precatalyst that allows the reaction to proceed under mild conditions and to be easily scaled up. Following the methodology development, the practical applications of these methods serving as strategic transformations are highlighted by the unified synthesis of four cyathane-type and two hamigeran-type terpenoids.In the second part, we describe the development of a robust method for oxidative Heck cross-coupling of indolyl amides by using the phosphinamide-based cyclopalladium as catalyst or phosphinamide as coligand. The method provides a general and straightforward method for diverse synthesis of indolyl δ-lactam derivatives, which present as a common core in a variety of Aspidosperma-derived indole alkaloids. The successful demonstration of this protocol for a concise and divergent synthesis of leuconodine-type indole alkaloids is also presented. We believe the results presented in this Account would have significant implications beyond our results and would find further applications in the field of synthetic methodology and natural product synthesis.
Assuntos
Produtos Biológicos , Amidas , Catálise , Alcaloides Indólicos , EstereoisomerismoRESUMO
We present the first enantioselective total synthesis and absolute configuration assignment of (+)-toxicodenane A via a nine-step sequence from the readily available material. The synthesis features a desymmetric enantioselective reduction of 2,2-disubstituted 1,3-cyclohexanedione for the synthesis of a chiral 2,2-disubstituted 3-hydroxy cyclohexanone building block, a highly diastereoselective Grignard reaction for the incorporation of an allyl group, and a Lewis acid-mediated intramolecular transacetalation and Prins cascade reaction for the construction of oxa-bridged bicyclic rings.
RESUMO
The P-stereogenic phosphinamides are a structurally novel skeletal class which has not been investigated as chiral organocatalysts. However, chiral cyclic 3-hydroxy ketones are widely used as building blocks in the synthesis of natural products and bioactive compounds. However, general and practical methods for the synthesis of such chiral compounds remain underdeveloped. Herein, we demonstrate that the P-stereogenic phosphinamides are powerful organocatalysts for the desymmetric enantioselective reduction of cyclic 1,3-diketones, providing a useful method for the synthesis of chiral cyclic 3-hydroxy ketones. The protocol displays a broad substrate scope that is amenable to a series of cyclic 2,2-disubstituted five- and six-membered 1,3-diketones. The chiral cyclic 3-hydroxy ketone products bearing an all-carbon chiral quaternary center could be obtained with high enantioselectivities (up to 98% ee) and diastereoselectivities (up to 99:1 dr). Most importantly, the reactions could be practically performed on the gram scale and the catalysts could be reused without compromising the catalytic efficiency. Mechanistic studies revealed that an intermediate formed from P-stereogenic phosphinamide and catecholborane is the real catalytically active species. The results disclosed herein bode well for designing and developing other reactions using P-stereogenic phosphinamides as new organocatalysts.
RESUMO
Divergent enantioselective total syntheses of five naturally occurring post-iboga indole alkaloids, dippinineâ B and C, 10,11-demethoxychippiine, 3-O-methyl-10,11-demethoxychippiine, and 3-hydroxy-3,4-secocoronaridine, as well as the two analogues 11-demethoxydippinineâ A and D, are presented for the first time. The enantioenriched aza[3.3.1]-bridged cycle, a common core intermediate to the target molecules, was constructed through an asymmetric phase-transfer-catalyzed Michael/aldol cascade reaction. The challenging azepane ring fused around the indole ring and the [3.3.1]-bridged cycle were installed through an intramolecular SN 2'-type reaction. These cyclization strategies enabled rapid construction of the [6.5.6.6.7]-pentacyclic core at an early stage. Highlights of the late-stage synthetic steps include a Pd-catalyzed Stille coupling and a highly stereoselective catalyst-controlled hydrogenation to incorporate the side chain at C20 with both R and S configurations in the natural products.
RESUMO
We describe the efficient synthesis of a series of new simplified hamigeran B and 1-hydroxy-9-epi-hamigeran B norditerpenoid analogs (23 new members in all), structurally related to cyathane diterpenoid scaffold, and their anti-neuroinflammatory and neurite outgrowth-stimulating (neurotrophic) activity. Compounds 9a, 9h, 9o, and 9q exhibited moderate nerve growth factor (NGF)-mediated neurite-outgrowth promoting effects in PC-12 cells at the concentration of 20 µm. Compounds 9b, 9c, 9o, 9q, and 9t showed significant nitric oxide (NO) production inhibition in lipopolysaccharide (LPS)-activated BV-2 microglial cells, of which 9c and 9q were the most potent inhibitors, with IC50 values of 5.85 and 6.31 µm, respectively. Two derivatives 9q and 9o as bifunctional agents displayed good activities as NO production inhibitors and neurite outgrowth-inducers. Cytotoxicity experiments, H2O2-induced oxidative injury assay, and ELISA reaction speculated that compounds may inhibit the TNF-α pathway to achieve anti-inflammatory effects on nerve cells. Moreover, molecular docking studies provided a better understanding of the key structural features affecting the anti-neuroinflammatory activity and displayed significant binding interactions of some derivatives (like 9c, 9q) with the active site of iNOS protein. The structure-activity relationships (SARs) were also discussed. These results demonstrated that this structural class compounds offered an opportunity for the development of a new class of NO inhibitors and NGF-like promotors.
Assuntos
Naftoquinonas/química , Crescimento Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Concentração Inibidora 50 , Fármacos Neuroprotetores/química , Relação Estrutura-AtividadeRESUMO
We present the first asymmetric total synthesis and absolute configuration determination of (+)-tronocarpine. The [6.5.7.6.6] pentacyclic core was constructed at an early stage by using a sequential cyclization strategy through a newly developed catalytic asymmetric Michael/aldol cascade to build the aza[3.3.1]-bridged cycle and a tandem reduction/hemiamidation procedure to assemble the seven-membered lactam. The side-chain functionalities were incorporated at a late stage by several appropriately orchestrated manipulations under mild conditions. The synthesis of enantiomerically pure (+)-tronocarpine was achieved through a 20-step longest linear sequence from tryptamine.
RESUMO
A new synthetic route for a short synthesis of (±)-leuconodines D and E was developed. The rapid construction of the diaza[5.5.6.6]fenestrane core was achieved through a sequence involving a Pd-catalyzed aerobic oxidative Heck cross-coupling reaction for the construction of indole δ-lactam containing a full-carbon quaternary center, an epoxidative cyclization for the assembly of pyrroloindole, and a ring-closing metathesis for the construction of the piperidine ring. As a result, the total synthesis of (±)-leuconodine E (2) was achieved for the first time within a 10-step linear sequence, and a more concise total synthesis of (±)-leuconodine D (1) was accomplished within a 12-step linear sequence from the commercially available tryptophol.
Assuntos
Alcaloides Indólicos/química , Alcaloides Indólicos/síntese química , Técnicas de Química Sintética , Modelos Moleculares , Conformação MolecularRESUMO
The [6.5.6]-tricyclic indole δ-lactam represents a common key intermediate for the synthesis of a broad variety of structurally intriguing indole alkaloids. The development of a method for the versatile and straightforward construction of such structural motif is of great importance for potential synthetic applications. Herein, we present a co-ligand-prompted Pd-catalyzed 6-exo-trig intramolecular cyclization of indolyl amides via the aerobic oxidative Heck cross-coupling. The method provided a general and efficient way for the construction of [6.5.6]-tricyclic indole δ-lactams. A mechanistic study suggests that a Pd(I)/Pd(III) catalytic cycle should be responsible for effective coupling, which represents a mechanistically alternative pathway when compared with the Pd(0)/Pd(II) cycle proposed for other related coupling reactions.
RESUMO
The details for the synthetic studies on enantioselective total synthesis of cyathane diterpenoids cyrneine A (1) and B (2), glaucopine C (3), and (+)-allocyathin B2 are presented. We established a mild Suzuki coupling for heavily substituted nonactivated cyclopentenyl triflates using a phosphinamide-derived palladacycle as precatalyst and a chelation-controlled highly regioselective Friedel-Crafts cyclization. The utilization of these two key reactions enabled a rapid construction of the 5-6-6 tricyclic skeleton. In the middle stage of the synthesis, a Birch reductive methylation, a modified Wolff-Kishner-Huang reduction, and a carbenoid-mediated ring expansion were employed as the key reactions to furnish the 5-6-7 tricyclic core bearing two antiorientated all-carbon quaternary stereocenters at the C6 and C9 ring junctions. By applying these key transformations, a more efficient total synthesis of cyrneine A and allocyathin B2, and the first total synthesis of cyrneine B and glaucopine C, were accomplished through a collective manner. The late-stage conversions involving a base-mediated double bond migration and a double bond migration/aerobic γ-CH oxidation cascade for the stereoselective synthesis of cyrneine B and glaucopine C were interesting.
Assuntos
Diterpenos/síntese química , Diterpenos/química , Estrutura Molecular , EstereoisomerismoRESUMO
A concise synthesis of (-)-hamigeran B and (-)-4-bromohamigeran B is presented. The key reactions include a Suzuki coupling of enol triflate 15 with arylboronic ester for efficient synthesis of the densely 1,2,3-trisubstituted cyclopentene 23, a coordination-controlled intramolecular Friedel-Crafts cyclization of free phenol 13 for highly regioselective construction of tricyclic core 12, and a LiOH/O2-promoted hydrolysis and concomitant aerobic oxidation of 31 for atom- and step-economic accessing of diketone 32. The application of these key transformations allowed for a rapid and efficient synthesis of (-)-hamigeran B and (-)-4-bromohamigeran B in 13 steps from the readily available chiral material 18.
RESUMO
The cyrneine diterpenoids represent a structurally intriguing subfamily of cyathane diterpenoids and could significantly induce neurite outgrowth. Therefore, the efficient synthesis of these natural products is of great importance. Herein, we present a route for the collective synthesis of cyrneines A, B, and glaucopine C. As the key precursor, the 5-6-6-tricyclic scaffold is efficiently constructed by employing a mild Suzuki coupling of heavily substituted nonactivated cyclopentenyl triflate and a chelation-controlled regiospecific Friedel-Crafts cyclization as key transformations. The stereoselective installation of the all-carbon quaternary center at C6 ring junction of the tricycle is achieved via Birch reductive methylation. Subsequently, a carbenoid-mediated ring expansion furnishes the essential 5-6-7-tricyclic core. Finally, manipulation of this core by several appropriately orchestrated conversions accomplishes a more step-economic synthesis of cyrneine A (20 steps), and the first synthesis of cyrneine B (24 steps) and glaucopine C (23 steps).
RESUMO
We present a highly efficient method for the synthesis of cyclic P-stereogenic phosphinamides via the Ce(IV)-promoted radical oxidative aryl C-H phosphinamidation of acyclic P-stereogenic phosphinamides. The new protocol provides a useful platform for the versatile synthesis of various potentially useful P-stereogenic compounds.
RESUMO
The design and preparation of a chiral Pt nanocatalyst system possessing thermoregulated phase-separation property and its application in recyclable asymmetric hydrogenation of α-ketoesters are presented.
RESUMO
A CuI-catalyzed reductive coupling of ketone-derived N-tosylhydrazones with amides is presented. Under the optimized conditions, an array of N-tosylhydrazones derived from aryl-alkyl and diaryl ketones could couple effectively with a wide variety of (hetero)aryl as well as aliphatic amides to afford the N-alkylated amides in high yields. The method represents the very few examples for reliably accessing secondary and tertiary amides through a reductive N-alkylation protocol.
RESUMO
The chiral phosphoramide-catalyzed asymmetric reaction of indol-2-yl carbinols with enamides is presented. The method provided an efficient and novel way for the synthesis of chiral 2-indole-substituted 1,1-diarylalkane derivatives.
Assuntos
Alcanos/síntese química , Amidas/química , Indóis/química , Fosforamidas/química , Alcanos/química , Catálise , Estrutura MolecularRESUMO
We present the determination of the absolute configuration of a chiral 2,3'-diindolylarylmethane 1 by using the combination of NMR spectroscopic and circular dichroism techniques. The results would be useful for the future study of the effect of chirality on the biological activity of 2,3'-diindolylarylmethanes.
Assuntos
Espectroscopia de Ressonância Magnética/métodos , Metano/análogos & derivados , Metano/química , Modelos Moleculares , EstereoisomerismoRESUMO
We present the enantioselective synthesis of P-stereogenic phosphinamides through Pd-catalyzed desymmetric ortho C-H arylation of diarylphosphinamides with boronic esters. The method represents the first example of the synthesis of P-stereogenic phosphorus compounds via the desymmetric C-H functionalization strategy. The reaction proceeded efficiently with a wide array of reaction partners to afford the P-stereogenic phosphinamides in up to 74% yield and 98% ee. The efficiency was further demonstrated by gram scale syntheses. Moreover, the flexible conversion of the P-stereogenic phosphinamides into various types of P-stereogenic phosphorus derivatives was also elaborated. Thus, the protocol provides a novel tool for the efficient and versatile synthesis of P-stereogenic compounds.