Organocatalytic Enantioselective Synthesis of Tetrasubstituted α‐Amino Allenoates by Dearomative γ‐Addition of 2,3‐Disubstituted Indoles to β,γ‐Alkynyl‐α‐imino Esters

The first asymmetric synthesis of tetrasubstituted α‐amino allenoates by a chiral phosphoric acid catalyzed dearomative γ‐addition reaction of 2,3‐disubstituted indoles to β,γ‐alkynyl‐α‐imino esters is reported. This method provides access to a series of highly functionalized tetrasubstituted allenes featuring quaternary stereocenters in high yields, and with excellent regio‐, diastereo‐, and enantioselectivities under mild conditions without by‐product formation. Representative large‐scale reactions and diverse transformations of the products into various scaffolds with potential biological activities render are also disclosed. The mechanism of the reaction was elucidated by control reactions and DFT calculations.     

Synthesis of 2,3‐Fused Indoline Aminals via 4 + 2 Cycloaddition of NH‐free Benzazetidines with Indoles

A 4 + 2 cycloaddition reaction of NH‐free benzazetidines with indoles under the catalysis of camphorsulfonic acid was developed. This method shows a broad substrate scope of benzazetidines and indoles, and offers a convenient method for stereoselective synthesis of various cis‐2,3‐fused indoline aminals. Preliminary mechanistic studies suggest the reaction proceed via a stepwise pathway featuring an electrophilic attack on the benzylic carbon of benzazetidine.     

Acceptor Reactivity in the Total Synthesis of Alginate Fragments Containing α‐L‐Guluronic Acid and β‐D‐Mannuronic Acid

The total synthesis of mixed‐sequence alginate oligosaccharides, featuring both β‐D ‐mannuronic acid (M) and α‐L ‐guluronic acid (G), is reported for the first time. A set of GM, GMG, GMGM, GMGMG, GMGMGM, GMGMGMG, and GMGGMG alginates was assembled using GM building blocks, having a guluronic acid acceptor part and a mannuronic acid donor side to allow the fully stereoselective construction of the cis‐glycosidic linkages. It was found that the nature of the reducing‐end anomeric center, which is ten atoms away from the reacting alcohol group in the key disaccharide acceptor, had a tremendous effect on the efficiency with which the building blocks were united. This chiral center determines the overall shape of the acceptor and it is revealed that the conformational flexibility of the acceptor is an all‐important factor in determining the outcome of a glycosylation reaction.     

Structurally Diverse π‐Extended Conjugated Polycarbo‐ and Heterocycles through Pd‐Catalyzed Autotandem Cascades

The Pd‐catalyzed reaction between 2,2′‐dibromobiphenyls and related systems with tosylhydrazones gives rise to new π‐extended conjugated polycarbo‐ and heterocycles through an autotandem process involving a cross‐coupling reaction followed by an intramolecular Heck cyclization. The reaction shows wide scope regarding both coupling partners. Cyclic and acyclic tosylhydrazones can participate in the process. Additionally, a variety of aromatic and heteroaromatic dibromoderivatives have been employed, leading to an array of diverse scaffolds featuring a fluorene or acridine central nucleus, and containing binaphthyl, thiophene, benzothiophene and indole moieties. The application to appropriate tetrabrominated systems led to greater structural complexity through two consecutive autotandem cascades. The photophysical properties of selected compounds were studied through their absorption and emission spectra. Fluorescence molecules featuring very high quantum yields were identified, showing the potential of this methodology in the development of molecules with interesting optoelectronic properties.     

Transition‐Metal‐Free Reductive Hydroxymethylation of Isoquinolines

A transition‐metal‐free reductive hydroxymethylation reaction has been developed, enabling the preparation of tetrahydroisoquinolines bearing C4‐quaternary centers from the corresponding isoquinolines. Deuterium labelling studies and control experiments enable a potential mechanism to be elucidated which features a key Cannizzaro‐type reduction followed by an Evans–Tishchenko reaction. When isoquinolines featuring a proton at the 4‐position are used, a tandem methylation‐hydroxymethylation occurs, leading to the formation of 2 new C?C bonds in one pot.     

Total Synthesis of Trioxacarcin DC‐45‐A2

An enantioselective total synthesis of trioxacarcin DC‐45‐A2 ( 1 ) featuring a novel Lewis acid‐induced cascade rearrangement of epoxyketone 6 to forge the polyoxygenated 2,7‐dioxabicyclo[2.2.1]heptane core of the molecule is described.     

Catalytic Asymmetric Inverse‐Electron‐Demand 1,3‐Dipolar Cycloaddition of C,N‐Cyclic Azomethine Imines with Azlactones: Access to Chiral Tricyclic Tetrahydroisoquinolines

Reported herein is a bifunctional‐organocatalyst‐mediated enantioselective inverse‐electron‐demand 1,3‐dipolar cycloaddition of C,N‐cyclic azomethine imines with azlactones. The strategy provides concise access to enantioenriched C1‐substituted tetrahydroisoquinolines featuring a pyrazolidinone scaffold. Moreover, the scalability and practical utility of this protocol was well demonstrated by employing a gram‐scale reaction and some representative transformations.     

Chiral DMAP‐N‐oxides as Acyl Transfer Catalysts: Design,Synthesis, and Application in Asymmetric Steglich Rearrangement

A DMAP‐N‐oxide, featuring an α‐amino acid as the chiral source, was developed, synthesized and applied in asymmetric Steglich rearrangement. A series of O‐acylated azlactones afforded C‐acylated azlactones possessing a quaternary stereocenter in high yields (up to 97 % yield) and excellent enantioselectivities (up to 97 % ee). Compared to the widespread use of pyridine nitrogen, which serves as the nucleophilic site in the asymmetric acyl transfer reaction, we discovered that chiral DMAP‐N‐oxides, in which the oxygen now acts as the nucleophilic site, are efficient acyl transfer catalysts. Our finding might open a new door for the development of chiral DMAP‐N‐oxides for asymmetric acyl transfer reactions.     

Chiral DMAP‐N‐oxides as Acyl Transfer Catalysts: Design,Synthesis, and Application in Asymmetric Steglich Rearrangement

A DMAP‐N‐oxide, featuring an α‐amino acid as the chiral source, was developed, synthesized and applied in asymmetric Steglich rearrangement. A series of O‐acylated azlactones afforded C‐acylated azlactones possessing a quaternary stereocenter in high yields (up to 97 % yield) and excellent enantioselectivities (up to 97 % ee). Compared to the widespread use of pyridine nitrogen, which serves as the nucleophilic site in the asymmetric acyl transfer reaction, we discovered that chiral DMAP‐N‐oxides, in which the oxygen now acts as the nucleophilic site, are efficient acyl transfer catalysts. Our finding might open a new door for the development of chiral DMAP‐N‐oxides for asymmetric acyl transfer reactions.     

Heterobifunctional Rotaxanes for Asymmetric Catalysis

Heterobifunctional rotaxanes serve as efficient catalysts for the addition of malonates to Michael acceptors. We report a series of four different heterobifunctional rotaxanes, featuring an amine‐based thread and a chiral 1,1′‐binaphthyl‐phosphoric‐acid‐based macrocycle. High‐level DFT calculations provided mechanistic insights and enabled rational catalyst improvements, leading to interlocked catalysts that surpass their non‐interlocked counterparts in terms of reaction rates and stereoselectivities.     

General,Highly Selective Synthesis of 1,3‐ and 1,4‐Difunctionalized Building Blocks by Regiodivergent Epoxide Opening

We describe a regiodivergent epoxide opening (REO) featuring a catalyst‐controlled synthesis of enantiomerically and diastereomerically highly enriched or pure syn‐ and anti‐ 1,3‐ and 1,4‐difunctionalized building blocks from a common epoxide precursor. The REO is attractive for natural product synthesis and as a branching reaction for diversity‐oriented synthesis with epoxides.     

Alkoxyallene‐ynes: Selective Preparation of Bicyclo[5.3.0] Ring Systems Including a δ‐Alkoxy Cyclopentadienone

The development of an intramolecular rhodium(I)‐catalyzed Pauson–Khand reaction of alkoxyallene‐ynes with a proximal alkoxy group is reported. This reaction, in the presence of a [Rh(cycloocta‐1,5‐diene)Cl]₂/propane‐1,3‐diylbis(diphenylphosphane) system under a CO atmosphere, constitutes a powerful tool for selectively accessing carbo‐ and heterobicyclo[5.3.0] frameworks featuring an enol ether moiety. Through this procedure, a straightforward access to guaiane skeletons with a tertiary hydroxy group at the C10 position was achieved.     

General,Highly Selective Synthesis of 1,3‐ and 1,4‐Difunctionalized Building Blocks by Regiodivergent Epoxide Opening

We describe a regiodivergent epoxide opening (REO) featuring a catalyst‐controlled synthesis of enantiomerically and diastereomerically highly enriched or pure syn‐ and anti‐ 1,3‐ and 1,4‐difunctionalized building blocks from a common epoxide precursor. The REO is attractive for natural product synthesis and as a branching reaction for diversity‐oriented synthesis with epoxides.     

A Fast Assembly of （-）-Epigallocatechin-3-gallate [（-）-EGCG] via Intra- and Inter-molecular Mitsunobu Reaction

This paper described a concise construction of （-）-EGCG （1f） （with an overall yield of 20% for seven steps based on the starting cinnamyl alcohol derivative 3）, featuring asymmetric dihydroxylation （ADH）, intra- and inter-molecular Mitsunobu reaction as key steps. Our strategy disclosed herein constitutes a new effective general synthetic approach toward the analogues of （-）-EGCG （1f）.     

Vicinal α,β‐Functionalizations of Amines: Cyclization Versus Dehydrogenative Hydrolysis

Direct vicinal α,β‐difunctionalization of tertiary cyclic amines is achieved in the presence of ruthenium or iridium transition‐metal complexes featuring phosphine‐sulfonate chelates. By varying the reaction conditions, α‐alkylated lactams were obtained by a formal dehydrogenative hydrolysis in which one molecule of hydrogen is generated from water.     

Hypervalent‐Iodine‐Mediated Cascade Annulation of Diarylalkynes Forming Spiro Heterocycles under Metal‐Free Conditions

An unusual reaction featuring the cascade annulation of internal alkynes to afford spiro heterocycles as the products has been realized for the first time with a hypervalent iodine reagent as the only oxidant. This unprecedented process encompasses not only two sequential C?N/C?O‐bond formations, but also the insertion of a carbonyl oxygen, all in one pot under metal‐free conditions.     

Total Syntheses of (−)‐Conidiogenone B, (−)‐Conidiogenone,and (−)‐Conidiogenol

Cyclopianes are novel diterpenes featuring a highly strained 6/5/5/5 tetracyclic core embedded with 6–8 consecutive stereocenters. The concise total syntheses of (?)‐conidiogenone B, (?)‐conidiogenone, and (?)‐conidiogenol have been accomplished in 14–17 steps. The present work features a HAT‐mediated alkene–nitrile cyclization to access the cis‐biquinane, a Nicholas/Pauson–Khand reaction to construct the linear triquinane, and a Danheiser annulation to afford the congested angular triquinane skeleton.     

A Nickel‐Catalyzed Carbonyl‐Heck Reaction

The use of transition‐metal catalysis to enable the coupling of readily available organic molecules has greatly enhanced the ability of chemists to access complex chemical structures. In this work, an intermolecular coupling reaction that unites organotriflates and aldehydes is presented. A unique catalyst system is identified to enable this reaction, featuring a Ni⁰ precatalyst, a tridentate Triphos ligand, and a bulky amine base. This transformation provides access to a variety of ketone‐containing products without the selectivity‐ and reactivity‐related challenges associated with more traditional Friedel–Crafts reactions. A Heck‐type mechanism is postulated, wherein the π bond of the aldehyde takes the role of the olefin in the insertion/elimination steps.     

First Total Syntheses of Tetracenomycins C and X

The first total syntheses of tetracenomycins C and X were achieved, featuring 1) preparation of a hexasubstituted naphthonitrile oxide by successive benzyne cycloadditions and an oxidative ring‐opening reaction; 2) a novel ortho ‐quinone mono‐acetal as the A‐ring unit; 3) construction of three contiguous stereogenic centers by an asymmetric benzoin cyclization, an isoxazole oxidation, and a stereoselective reduction.     

Total Synthesis of (±)‐Phyllantidine: Development and Mechanistic Evaluation of a Ring Expansion for Installation of Embedded Nitrogen‐Oxygen Bonds

The development of a concise total synthesis of (±)‐phyllantidine ( 1 ), a member of the securinega family of alkaloids containing an unusual oxazabicyclo[3.3.1]nonane core, is described. The synthesis employs a unique synthetic strategy featuring the ring expansion of a substituted cyclopentanone to a cyclic hydroxamic acid as a key step that allows facile installation of the embedded nitrogen‐oxygen (N?O) bond. The optimization of this sequence to effect the desired regiochemical outcome and its mechanistic underpinnings were assessed both computationally and experimentally. This synthetic approach also features an early‐stage diastereoselective aldol reaction to assemble the substituted cyclopentanone, a mild reduction of an amide intermediate without N?O bond cleavage, and the rapid assembly of the butenolide found in ( 1 ) via use of the Bestmann ylide.