Ni-catalyzed enantioconvergent deoxygenative reductive cross-coupling of unactivated alkyl alcohols and aryl bromides.

Transition metal-catalyzed enantioconvergent cross-coupling of an alkyl precursor presents a promising method for producing enantioenriched C(sp3) molecules. Because alkyl alcohol is a ubiquitous and abundant family of feedstock in nature, the direct reductive coupling of alkyl alcohol and aryl halide enables efficient access to valuable compounds. Although several strategies have been developed to overcome the high bond dissociation energy of the C - O bond, the asymmetric pattern remains unknown. In this report, we describe the realization of an enantioconvergent deoxygenative reductive cross-coupling of unactivated alkyl alcohol (ß-hydroxy ketone) and aryl bromide in the presence of an NHC activating agent. The approach can accommodate substituents of various sizes and functional groups, and its synthetic potency is demonstrated through a gram scale reaction and derivatizations into other compound families. Finally, we apply our convergent method to the efficient asymmetric synthesis of four ß-aryl ketones that are natural products or bioactive compounds.

Construction of sulfur-containing N-vinylimides: N-addition of imides to propargyl sulfonium salts.

An N-addition reaction between imides and propargyl sulfonium salts was developed to afford sulfur-containing N-vinylimides with moderate to excellent yields. Under the activation of NaOAc·3H2O, imides could undergo deprotonation and propargyl sulfonium salts could isomerize to allenic sulfonium salts. The N-nucleophilic attack initiates the reaction and gives the desired products. Various imides, including arylimides, aliphatic imides and N-(arylsulfonyl) alkyl acylamides, and even bioactive saccharin, thalidomide and pomalidomide could provide organosulfur N-vinylimides compounds. The simple, mild and metal-free reaction conditions, the broad scope of substrates, gram-scale synthesis and convenient transformation embody the synthetic superiority of this process.

Regioselective N-Addition/Substitution Reaction of α-Alkylidene Pyrazolinones with Propargyl Sulfonium Salts to Construct Allylthio-Containing Pyrazolones.

The regioselective N-addition/substitution reaction between α-alkylidene pyrazolinones and propargyl sulfonium salts has been developed to construct functionalized allylthio-containing pyrazolones with moderate to excellent yields. α-Alkylidene pyrazolinones act as N-nucleophilic agents which are distinguished from reported C-nucleophilic reactions. Excellent regioselectivity, readily available starting materials, the broad range of substrates, gram-scale synthesis, and simple operation illustrate the synthetic advantages of this new reaction pathway.

Direct Intermolecular Anti-Markovnikov Hydroazidation of Unactivated Olefins.

We herein report a direct intermolecular anti-Markovnikov hydroazidation method for unactivated olefins, which is promoted by a catalytic amount of bench-stable benziodoxole at ambient temperature. This method facilitates previously difficult, direct addition of hydrazoic acid across a wide variety of unactivated olefins in both complex molecules and unfunctionalized commodity chemicals. It conveniently fills a synthetic chemistry gap of existing olefin hydroazidation procedures, and thereby provides a valuable tool for azido-group labeling in organic synthesis and chemical biology studies.

Combined inorganic base promoted N-addition/[2,3]-sigmatropic rearrangement to construct homoallyl sulfur-containing pyrazolones.

The first sequentially combined inorganic base promoted N-addition/[2,3]-sigmatropic rearrangement reaction of α-alkylidene pyrazolinones and propargyl sulfonium salts has been reported to construct homoallyl sulfur-containing pyrazolones with moderate to excellent yields. α-Alkylidene pyrazolinones function as N-nucleophilic agents distinguished from the reported C-addition reactions. Propargyl sulfonium salts were first involved in the [2,3]-sigmatropic rearrangement protocol differentiated from the well-established annulation reactions. The excellent regioselectivity, the broad scope of substrates, gram-scale synthesis and convenient transformation embody the synthetic superiority of this cascade process.

Synthesis of Aryl Silacarboxylates via Palladium-Catalyzed C-O Bond Formation of Silacarboxylic Acids and Aryl Iodides.

The first palladium-catalyzed C-O bond formation method for the synthesis of silacarboxylates by silacarboxylic acids with a broad range of aryl iodides and iodo-N-heterocycles is reported. Electron-deficient, electron-rich, and sterically hindered aryl iodides were well-tolerated to furnish the corresponding aryl silacarboxylates in moderate to excellent yields. Active functional groups, such as -NH2, -CHO, and allyl-, showed good tolerance, even in the large-scale synthesis. Double and triple esterification were also demonstrated to be effective.

Lewis-Base-Catalyzed [1 + 2 + 2] Annulation Reaction of Morita-Baylis-Hillman Carbonates with Unsaturated Pyrazolones: Construction of All-Stereogenic Carbon Cyclopentane-Fused Dispiropyrazolones.

The first Lewis-base-catalyzed unexpected [1 + 2 + 2] annulation reaction between Morita-Baylis-Hillman carbonates and unsaturated pyrazolones was developed. The multicyclic cyclopentane-fused dispiropyrazolone constructions containing five contiguous stereogenic centers, including two spiro quaternary centers, were prepared with excellent yields (81-98%) and moderate to good diastereoselectivities (1:1 to 13:1). Further transformation and gram-scale operations were also achieved efficiently.

Enantioselective Synthesis of Oseltamivir Phosphate (Tamiflu) via the Iron-Catalyzed Stereoselective Olefin Diazidation.

We herein report a gram-scale, enantioselective synthesis of Tamiflu, in which the key trans-diamino moiety has been efficiently installed via an iron-catalyzed stereoselective olefin diazidation. This significantly improved, iron-catalyzed method is uniquely effective for highly functionalized yet electronically deactivated substrates that have been previously problematic. Preliminary catalyst structure-reactivity-stereoselectivity relationship studies revealed that both the iron catalyst and the complex substrate cooperatively modulate the stereoselectivity for diazidation. Safety assessment using both differential scanning calorimetry (DSC) and the drop weight test (DWT) has also demonstrated the feasibility of carrying out this iron-catalyzed olefin diazidation for large-scale Tamiflu synthesis.

Iron-Catalyzed Direct Olefin Diazidation via Peroxyester Activation Promoted by Nitrogen-Based Ligands.

We herein report an iron-catalyzed direct diazidation method via activation of bench-stable peroxyesters promoted by nitrogen-based ligands. This method is effective for a broad range of olefins and N-heterocycles, including those that are difficult substrates for the existing olefin diamination and diazidation methods. Notably, nearly a stoichiometric amount of oxidant and TMSN3 are sufficient for high-yielding diazidation for most substrates. Preliminary mechanistic studies elucidated the similarities and differences between this method and the benziodoxole-based olefin diazidation method previously developed by us. This method effectively addresses the limitations of the existing olefin diazidation methods. Most notably, previously problematic nonproductive oxidant decomposition can be minimized. Furthermore, X-ray crystallographic studies suggest that an iron-azide-ligand complex can be generated in situ from an iron acetate precatalyst and that it may facilitate peroxyester activation and the rate-determining C-N3 bond formation during diazidation of unstrained olefins.

Formal homoiodo allylsilane annulations: dual total syntheses of (±)-hirsutene and (±)-capnellene.

Dual total syntheses of (±)-hirsutene and (±)-capnellene, two typical linear triquinane sesquiterpenes, were achieved via a formal [3 + 2] annulation strategy, as illustrated schematically. Cyclic homoiodo allylsilanes were employed as key bifunctional synthons in the synthesis, which were readily prepared from the corresponding cyclopropanated cyclopentenones. A formal [3 + 3] annulation approach for the elaboration of the bicyclic framework of the Eudesmane sesquiterpenoids based on this type of synthon was also developed.