Synthesis of Five-Membered Cyclic Phosphinic Acids via the [4C+1P] Cyclization of 1,3-Dienes with a Combination of PBr3 and P(OMe)3 as the P(III) Source.

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.

Transition-metal-mediated benzylation of C60 with benzyl chlorides.

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.

The Phosphinamide-Based Catalysts: Discovery, Methodology Development, and Applications in Natural Product Synthesis.

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.

Synthetic Studies on the Synthesis of Toxicodenane A and 8,11-epi-Toxicodenane A.

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.

Desymmetric Enantioselective Reduction of Cyclic 1,3-Diketones Catalyzed by a Recyclable P-Chiral Phosphinamide Organocatalyst.

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.

Synthesis and Biological Evaluation of Diversified Hamigeran B Analogs as Neuroinflammatory Inhibitors and Neurite Outgrowth Stimulators.

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.

Enantioselective Total Synthesis and Absolute Configuration Assignment of (+)-Tronocarpine Enabled by an Asymmetric Michael/Aldol Reaction.

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.

A Divergent Enantioselective Total Synthesis of Post-Iboga Indole Alkaloids.

Divergent enantioselective total syntheses of five naturally occurring post-iboga indole alkaloids, dippinine 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-demethoxydippinine 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.

A Total Synthesis of (±)-Leuconodines D and E.

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.

Synthetic Studies on Enantioselective Total Synthesis of Cyathane Diterpenoids: Cyrneines A and B, Glaucopine C, and (+)-Allocyathin B2.

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.

Pd(II)-catalyzed enantioselective synthesis of P-stereogenic phosphinamides via desymmetric C-H arylation.

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.

The development of a complementary pathway for the synthesis of aliskiren.

The synthesis of aliskiren (1), a recently marketed drug for the treatment of hypertension, is presented. The focus of our synthetic effort is to develop an efficient pathway for the synthesis of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy) benzyl)-N,N,8-trimethylnon-4-enamide (2a), which has been used as the advanced intermediate toward aliskiren. After an extensive investigation of three different strategies designed to construct the E-olefin functionality in 2a by employing the olefin cross-metathesis, Horner-Wadsworth-Emmons (HWE), and Julia-type olefinations, we have established a new protocol for the synthesis of 2a with a substantially improved overall efficiency in terms of the yield (ca. 33%), and diastereo- and E/Z-selectivity. The key transformations were the Evans chiral auxiliary-aided asymmetric allylation for the synthesis of the appropriate chiral intermediates in excellent enantiomeric purity of higher than 97% ee and a modified Julia-Kocienski olefination for the highly selective construction of E-2a with up to 13.6:1 E/Z ratio from the chiral intermediates. Consequently, the results provide an appealing option for the synthesis of aliskiren.

The determination of the absolute configuration of a chiral 2,3'-diindolylarylmethane by NMR spectroscopy.

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.

Pd(II)-catalyzed mild C-H ortho arylation and intramolecular amination oriented by a phosphinamide group.

A novel protocol for the Pd-catalyzed ortho-arylation of aryl phosphinamide with boronic acid is reported. By using phosphinamide as a new directing group, the reaction proceeds efficiently under mild conditions at 408C. Mechanistic studies reveal that the reaction proceeds via a PdII to Pd0 cycle. The phosphinamide group is also shown to be an effective orienting group for direct C-H amination.

The development of copper-catalyzed aerobic oxidative coupling of H-tetrazoles with boronic acids and an insight into the reaction mechanism.

The development of a highly efficient and practical protocol for the direct C-N coupling of H-tetrazole and boronic acid was presented. A careful and patient optimization of a variety of reaction parameters revealed that this conventionally challenge reaction could indeed proceed efficiently in a very simple system, that is, just by stirring the tetrazoles and boronic acids under oxygen in the presence of different Cu(I) or Cu(II) salts with only 5 mol % loading in DMSO at 100 °C. Most significantly, the reaction could proceed very smoothly in a regiospecific manner to afford the 2,5-disubstituted tetrazoles in high to excellent yields. A mechanistic study revealed that both tetrazole and DMSO are crucial for the generation of catalytically active copper species in the reaction process in addition to their role as reactant and solvent, respectively. It is demonstrated that in the reaction cycle, the Cu(I) catalyst could be oxidized to Cu(II) by oxygen to form a [CuT2D] complex (T = tetrazole anion; D = DMSO) through an oxidative copper amination reaction. The Cu(II) complex thus formed was confirmed to be the real catalytically active copper species. Namely, the Cu(II) complex disproportionates to aryl Cu(III) and Cu(I) in the presence of boronic acid. Facile elimination of the Cu(III) species delivers the C-N-coupled product. The results presented herein not only provide a reliable and efficient protocol for the synthesis of 2,5-disubstituted tetrazoles, but most importantly, the mechanistic results would have broad implications for the de novo design and development of new methods for Cu-catalyzed coupling reactions.

Divergent synthesis of 2,3-dihydro-1H-pyrroles, 3-alkyl-1H-pyrroles and 3-alkenyl-1H-pyrroles from 2,4-pentadienenitriles and isocyanides.

An efficient and divergent one-pot synthesis of 2,3-dihydro-1H-pyrroles, 3-alkyl-1H-pyrroles and 3-alkenyl-1H-pyrroles from readily accessible 2,4-pentadienenitriles with isocyanide based on reaction condition selection has been described. The reaction of 2,4-pentadienenitriles with ethyl isocyanoacetate undergoes a formal [2 + 3] annulation either to generate 2,3-dihydro-1H-pyrroles in the presence of DBU (0.3 equiv.) in EtOH at room temperature or to give 3-alkyl-1H-pyrroles in the presence of DBU (2.0 equiv.) in EtOH under reflux. Moreover, the 2,3-dihydro-1H-pyrroles could be converted to 3-alkenyl-1H-pyrroles with DDQ as an oxidant.

Transition-metal-catalyzed Suzuki-Miyaura cross-coupling reactions: a remarkable advance from palladium to nickel catalysts.

In the transition-metal-catalyzed cross-coupling reactions, the use of the first row transition metals as catalysts is much more appealing than the precious metals owing to the apparent advantages such as cheapness and earth abundance. Within the last two decades, particularly the last five years, explosive interests have been focused on the nickel-catalyzed Suzuki-Miyaura reactions. This has greatly advanced the chemistry of transition-metal-catalyzed cross-coupling reactions. Most notably, a broad range of aryl electrophiles such as phenols, aryl ethers, esters, carbonates, carbamates, sulfamates, phosphates, phosphoramides, phosphonium salts, and fluorides, as well as various alkyl electrophiles, which are conventionally challenging, by applying palladium catalysts can now be coupled efficiently with boron reagents in the presence of nickel catalysts. In this review, we would like to summarize the progress in this reaction.

[NiCl2(dppp)]-catalyzed cross-coupling of aryl halides with dialkyl phosphite, diphenylphosphine oxide, and diphenylphosphine.

We present a general approach to C-P bond formation through the cross-coupling of aryl halides with a dialkyl phosphite, diphenylphosphine oxide, and diphenylphosphane by using [NiCl(2) (dppp)] as catalyst (dppp=1,3-bis(diphenylphosphino)propane). This catalyst system displays a broad applicability that is capable of catalyzing the cross-coupling of aryl bromides, particularly a range of unreactive aryl chlorides, with various types of phosphorus substrates, such as a dialkyl phosphite, diphenylphosphine oxide, and diphenylphosphane. Consequently, the synthesis of valuable phosphonates, phosphine oxides, and phosphanes can be achieved with one catalyst system. Moreover, the reaction proceeds not only at a much lower temperature (100-120 °C) relative to the classic Arbuzov reaction (ca. 160-220 °C), but also without the need of external reductants and supporting ligands. In addition, owing to the relatively mild reaction conditions, a range of labile groups, such as ether, ester, ketone, and cyano groups, are tolerated. Finally, a brief mechanistic study revealed that by using [NiCl(2) (dppp)] as a catalyst, the Ni(II) center could be readily reduced in situ to Ni(0) by the phosphorus substrates due to the influence of the dppp ligand, thereby facilitating the oxidative addition of aryl halides to a Ni(0) center. This step is the key to bringing the reaction into the catalytic cycle.

Nickel-catalyzed cross-coupling of phenols and arylboronic acids through an in†situ phenol activation mediated by PyBroP.

A new method for the Suzuki-Miyaura cross-coupling of phenols and arylboronic acids through in situ phenol activation mediated by PyBroP is presented. The reaction proceeds efficiently by using cost-effective, markedly stable [NiCl(2)(dppp)] (dppp=1,3-bis(diphenylphosphino)propane) as the catalyst in only 5 mol % loading, as well as in the absence of extra ligands. The method exhibits broad applicability and high efficiency towards a wide range of both phenols and boronic acids, including activated, nonactivated, deactivated, and heteroaromatic coupling partners. In addition, various functional groups, such as ether, amino, cyano, ester, and ketone groups, are compatible with this transformation. Notably, arylboronic acids containing an unprotected NH(2) group and 2-heterocyclic boronic acids, which are generally problematic for coupling under conventional conditions, are also viable substrates, although moderate yields were obtained for sterically hindered substrates. Consequently, the in situ cross-coupling methodology coupled with the use of an inexpensive and stable nickel catalyst provides a rapid and efficient pathway for the assembly of biaryls and heterobiaryls with structural diversity from readily available phenol compounds.

Enantioselective Total Synthesis and Absolute Configuration Assignment of (+)-Toxicodenane A.

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.