Benzo-Fused-Ring Toolbox Based on Palladium/Norbornene Cooperative Catalysis: Methodology Development and Applications in Natural Product Synthesis.

ConspectusBenzo-fused skeletons are ubiquitous in agrochemicals, medicines, natural products, catalysts, and other organic function materials. The assembly of these skeletons in an efficient manner is an actively explored field in organic synthesis. Palladium/norbornene (Pd/NBE) cooperative catalysis is a powerful tool for the expeditious assembly of polysubstituted arenes through bis-functionalization of the ortho and ipso positions of aryl iodides in one operation. Owing to the efforts of Lautens, Catellani, and others, an array of Pd/NBE-promoted annulations for the syntheses of diversified benzo-fused rings have been developed. However, these methods have not been broadly applied in total synthesis yet.Our group is interested in efficient and practical total synthesis of biologically active molecules. In the past 7 years, we have been devoted to the development of new annulation strategies for the assembly of common benzo-fused skeletons through Pd/NBE-promoted reactions of aryl iodides with novel bifunctional reagents. In this Account, we summarize our laboratory's systematic efforts in this direction. First, readily available epoxides and aziridines were exploited as versatile bifunctional alkylating reagents, which enables quick assembly of a series of valuable benzo-fused heterocycles, including isochromans, dihydrobenzofurans, 1,3-cis-tetrahydroisoquinolines (THIQs), 1,3-trans-THIQs, etc. Second, a convergent access to 5-7-membered benzo-fused carbocycles (including indanes and tetrahydronaphthalenes) was developed by Pd/NBE-promoted annulation of aryl iodides with simple olefinic alcohol-containing alkylating reagents. Third, a Pd/NBE-promoted annulation between aryl iodides and cyclohexanone-containing amination reagents was developed for the construction of benzo-fused N-containing bridged scaffolds. Thus, we have established a practical and versatile toolbox for the quick assembly of diversified benzo-fused skeletons. These new annulation reactions are of high chemo-, regio-, and stereoselectivities with good step and atom economy. Moreover, they are able to rapidly increase molecular complexity from simple building blocks. Finally, their synthetic value has been demonstrated by immediate adoption in several efficient total syntheses of medicines and complex natural products. Compared to conventional synthetic logics, the Pd/NBE-promoted annulation toolbox allows the development of highly convergent strategies, which significantly improves the overall synthetic efficiency.We believe the results presented in this Account will have significant implications beyond our research. It can be envisaged that new Pd/NBE-promoted annulations as well as new applications in complex total synthesis will be revealed in the near future.

Additive-Enhanced Crystallization of Inorganic Perovskite Single Crystals for High-Sensitivity X-Ray Detection.

Inorganic cesium lead halide perovskite single crystals are particularly intriguing to ionizing radiation detection by virtue of their material stability and high attenuation coefficients. However, the growth of high-quality inorganic perovskite single crystals remains challenging, mainly due to the limited solubility. In this work, an additive-enhanced crystallization method is proposed for cesium lead perovskites. The additive can remarkably increase the solubility of cesium bromide in dimethyl sulfoxide (DMSO) forming a balanced stoichiometric precursor solution, which prevents the formation of impurity phases. In addition, the additives would react with DMSO generating glyoxylic acid (GLA) via nucleophilic substitution and Kornblum oxidation reactions. The GLA can form stable PbBr2 -DMSO-GLA complexes, which enables better crystallinity, uniformity and much longer carrier lifetimes for the grown single crystals. The X-ray detectors using the additive-enhanced crystals exhibit an ultra-high sensitivity of 3.0 × 104  µC Gyair -1 cm-2 which is more than two orders of magnitude higher than that for the control devices.

Palladium-catalyzed [4 + 3] annulation of 2-bromobiphenyls and epoxides for the assembly of dihydrodibenzo[b,d]oxepines.

A palladium-catalyzed [4 + 3] annulation of 2-bromobiphenyls and epoxides for the construction of dihydrodibenzo[b,d]oxepines is reported. This approach involves direct C-H and C-O bond activation followed by a ring annulation and features readily available starting materials, a broad substrate scope, good step economy and good scalability.

A Modular Approach for Diversity-Oriented Synthesis of 1,3-trans-Disubstituted Tetrahydroisoquinolines: Seven-Step Asymmetric Synthesis of Michellamines†B and C.

1,3-trans-Disubstituted tetrahydroisoquinoline (THIQ) is a common heterocyclic structural unit of naphthylisoquinoline alkaloids. The assembly of this structural unit is not trivial, which constitutes a substantial challenge in the total synthesis of naphthylisoquinoline alkaloids and related pharmaceuticals. Herein, we report a modular and convergent method for the rapid assembly of 1,3-trans-disubstituted THIQ frameworks through a three-component Catellani reaction and a AuI -catalyzed cyclization/reduction cascade. With widely available simple aryl iodides, aziridines and (triisopropylsilyl)acetylene as the building blocks, this method paves a practical way for the diversity-oriented synthesis of 1,3-trans-disubstituted THIQs. Based on this new method, concise syntheses of an analogue of the new drug mevidalen and four naphthylisoquinoline alkaloids have been accomplished, demonstrating the broad synthetic utility of this approach.

Catalytic Synthesis of Atropisomeric o-Terphenyls with 1,2-Diaxes via Axial-to-Axial Diastereoinduction.

Herein, we report a modular and convergent strategy for the assembly of atropisomeric o-terphenyls with 1,2-diaxes via palladium/chiral norbornene cooperative catalysis and axial-to-axial diastereoinduction. Readily available aryl iodides, 2,6-substituted aryl bromides, and potassium aryl trifluoroborates are used as the building blocks, laying the foundation for diversity-oriented synthesis of these scaffolds (46 examples). Other features include the unique axial-to-axial diastereoinduction mode, construction of two axes in a single operation, and step economy. DFT calculations are performed to rationalize the axial-to-axial diastereoinduction process. Synthetic utilities of this method in preparation of atropisomeric oligophenyls, chiral catalysts, and ligands are demonstrated.

Kinetic Resolution of Tertiary Benzyl Alcohols via Palladium/Chiral Norbornene Cooperative Catalysis.

Herein we report a highly enantioselective kinetic resolution of tertiary benzyl alcohols via palladium/chiral norbornene cooperative catalysis. With simple aryl iodides as the resolution reagent, a wide range of readily available racemic tertiary benzyl alcohols are applicable to this method. Both chiral tertiary benzyl alcohols and benzo[c]chromene products are obtained in good to excellent enantioselectivities (selectivity factor up to 544). The appealing synthetic utility of the obtained enantioenriched tertiary alcohols is demonstrated by the facile preparation of several valuable chiral heterocycles. Preliminary mechanism studies include DFT calculations to explain the origin of enantiodiscrimination and control experiments to uncover the formation of a transient axial chirality during the kinetic resolution step.

A Concise Total Synthesis of (-)-Berkelic Acid.

Reported here is a concise total synthesis of (-)-berkelic acid in eight linear steps. This synthesis features a Catellani reaction/oxa-Michael cascade for the construction of the isochroman scaffold, a one-pot deprotection/spiroacetalization operation for the formation of the tetracyclic core structure, and a late-stage Ni-catalyzed reductive coupling for the introduction of the lateral chain. Notably, four stereocenters are established from a single existing chiral center with excellent stereocontrol during the deprotection/spiroacetalization process. Stereocontrol of the intriguing deprotection/spiroacetalization process is supported by DFT calculations.

Molecular Vises for Precisely Positioning Ligands near Catalytic Metal Centers in Metal-Organic Frameworks.

We report the construction of a molecular vise by pairing a tritopic phenylphosphorus(III) linker and a monotopic linker in opposite positions within a metal-organic framework. The angle between these linkers at metal sites is fixed upon changing the functionality in the monotopic linker, while the distance between them is precisely tuned. This distance within the molecular vise is accurately measured by 1H-31P solid-state nuclear magnetic resonance spectroscopy. This unveils the impact of the distance on catalytic performance without interference from electrostatic effects or changes in the angle of the ligand, which is unprecedented in classic organometallic complexes.

Modular Dual-Tasked C-H Methylation via the Catellani Strategy.

We report a dual-tasked methylation that is based on cooperative palladium/norbornene catalysis. Readily available (hetero)aryl halides (39 iodides and 4 bromides) and inexpensive MeOTs or trimethylphosphate are utilized as the substrates and methylating reagent, respectively. Six types of "ipso" terminations can modularly couple with this "ortho" C-H methylation to constitute a versatile methylation toolbox for preparing diversified methylated arenes. This toolbox features inexpensive methyl sources, excellent functional-group tolerance, simple reaction procedures, and scalability. Importantly, it can be uneventfully extended to isotope-labeled methylation by switching to the corresponding reagents CD3OTs or 13CH3OTs. Moreover, this toolbox can be applied to late-stage modification of biorelevant substrates with complete stereoretention. We believe these salient and practical features of our dual-tasked methylation toolbox will be welcomed by academic and industrial researchers.

Palladium(II)-Initiated Catellani-Type Reactions.

The Catellani reaction is known as a powerful strategy for the expeditious synthesis of highly substituted arenes and benzo-fused rings, which are usually difficult to access through traditional cross-coupling strategies. It utilizes the synergistic interplay of palladium and norbornene catalysis to facilitate sequential ortho C-H functionalization and ipso termination of aryl halides in a single operation. In classical Catellani-type reactions, aryl halides are mainly used as the substrates, and a Pd0 catalyst is required to initiate the reaction. Nevertheless, recent advances showcase that Catellani-type reactions can also be initiated by a PdII catalyst with different starting materials instead of aryl halides via different reaction mechanisms and under different conditions. This emerging concept of PdII /norbornene cooperative catalysis has significantly advanced Catellani-type reactions, thus enabling future developments of this field. In this Minireview, PdII -initiated Catellani-type reactions and their application in the synthesis of bioactive molecules are summarized.

Alkylating Reagents Employed in Catellani-Type Reactions.

The Catellani reaction is a powerful strategy that allows the expeditious synthesis of highly substituted arenes, which are not easily accessible through traditional transition-metal-catalyzed cross-coupling reactions. This reaction utilizes the synergistic interplay of palladium and norbornene catalysis to facilitate sequential ortho-C-H functionalization and ipso termination of aryl iodides in a single operation. Since pioneering work by the group of Catellani in 1997, and later by the group of Lautens, this chemistry has attracted considerable attention from the synthetic chemistry community. Dramatic progress has been made by a number of groups in the past two decades. In this Minireview, the alkylating reagents employed in this intriguing reaction and the corresponding applications in organic synthesis are summarized; thus complementing existing reviews to inspire future developments.

The Discovery of a Palladium(II)-Initiated Borono-Catellani Reaction.

Reported is a novel palladium(II)-initiated Catellani-type reaction that utilizes widely accessible aryl boronic acids as the substrates instead of aryl halides, thereby greatly expanding the existing scope of this powerful transformation. This borono-Catellani reaction was promoted by cooperative catalysis between Pd(OAc)2 and the inexpensive 5-norbornene-2-carbonitrile. Practicality is the striking feature of the reaction: it is run open to air at ambient temperature and no phosphine ligand is needed. This mild, chemoselective, and scalable protocol is compatible with a large range of readily available functionalized aryl boronic acids and bromides, as well as terminating olefins (50 examples, 39-97 % yields). Moreover, the orthogonal reactivity between the borono-Catellani and classical Catellani reaction was demonstrated. This work is expected to open new avenues for developing novel Catellani-type reactions.

Modular One-Step Three-Component Synthesis of Tetrahydroisoquinolines Using a Catellani Strategy.

Reported is a modular one-step three-component synthesis of tetrahydroisoquinolines using a Catellani strategy. This process exploits aziridines as the alkylating reagents, through palladium/norbornene cooperative catalysis, to enable a Catellani/Heck/aza-Michael addition cascade. This mild, chemoselective, and scalable protocol has broad substrate scope (43 examples, up to 90 % yield). The most striking feature of this protocol is the excellent regioselectivity and diastereoselectivity observed for 2-alkyl- and 2-aryl-substituted aziridines to access 1,3-cis-substituted and 1,4-cis-substituted tetrahydroisoquinolines, respectively. Moreover, this is a versatile process with high step and atom economy.

Epoxides as Alkylating Reagents for the Catellani Reaction.

We report a cooperative catalytic system comprising a PdII complex, XPhos, and the potassium salt of 5-norbornene-2-carboxylic acid that enables the use of epoxides as alkylating reagents in the Catellani reaction, thereby expanding the existing paradigm of this powerful transformation. The potassium salt of inexpensive 5-norbornene-2-carboxylic acid acts as both mediator and base in the process. This mild, chemoselective, scalable, and atom-economical protocol is compatible with a wide variety of readily available functionalized aryl iodides and epoxides, as well as terminating olefins. The resulting products undergo facile oxa-Michael addition to furnish ubiquitous isochroman scaffolds.

Development of a concise synthesis of ouabagenin and hydroxylated corticosteroid analogues.

The natural product ouabagenin is a complex cardiotonic steroid with a highly oxygenated skeleton. This full account describes the development of a concise synthesis of ouabagenin, including the evolution of synthetic strategy to access hydroxylation at the C19 position of a steroid skeleton. In addition, approaches to install the requisite butenolide moiety at the C17 position are discussed. Lastly, methodology developed in this synthesis has been applied in the generation of novel analogues of corticosteroid drugs bearing a hydroxyl group at the C19 position.

C-H methylation of heteroarenes inspired by radical SAM methyl transferase.

A practical C-H functionalization method for the methylation of heteroarenes is presented. Inspiration from Nature's methylating agent, S-adenosylmethionine (SAM), allowed for the design and development of zinc bis(phenylsulfonylmethanesulfinate), or PSMS. The action of PSMS on a heteroarene generates a (phenylsulfonyl)methylated intermediate that can be easily separated from unreacted starting material. This intermediate can then be desulfonylated to the methylated product or elaborated to a deuteriomethylated product, and can divergently access medicinally important motifs. This mild, operationally simple protocol that can be conducted in open air at room temperature is compatible with sensitive functional groups for the late-stage functionalization of pharmacologically relevant substrates.

Celebrating the 130th anniversary of Wuhan University.

Lin Zhuang, Qiu Wang, Aiwen Lei and Qianghui Zhou introduce the Chemical Science and Green Chemistry joint themed collection celebrating the 130th Anniversary of Wuhan University.

Enantioconvergent synthesis of chiral fluorenols from racemic secondary alcohols via Pd(ii)/chiral norbornene cooperative catalysis.

An efficient protocol for the asymmetric synthesis of fluorenols has been developed through an enantioconvergent process enabled by Pd(ii)/chiral norbornene cooperative catalysis. This approach allows facile access to diverse functionalized chiral fluorenols with constantly excellent enantioselectivities, applying readily available racemic secondary ortho-bromobenzyl alcohols and aryl iodides as the starting materials.

Bioconjugation by native chemical tagging of C-H bonds.

A general C-H functionalization method for the tagging of natural products and pharmaceuticals is described. An azide-containing sulfinate reagent allows the appendage of azidoalkyl chains onto heteroaromatics, the product of which can then be attached to a monoclonal antibody by a "click" reaction. This strategy expands the breadth of bioactive small molecules that can be linked to macromolecules in a manner that is beyond the scope of existing methods in bioconjugation to permit tagging of the "seemingly untaggable".