An Indoxyl‐Based Strategy for the Synthesis of Indolines and Indolenines

An indoxyl‐based strategy for the synthesis of indolines and indolenines via unprecedented aza‐pinacol and aza‐semipinacol rearrangements was developed. This method provides direct access to the core structures of several classes of indole alkaloids. The synthetic utility was demonstrated by the divergent synthesis of an array of functionalized polycyclic structures from a common intermediate and the formal total synthesis of the indoline natural product minfiensine. The reversed reactivity of indoxyl as a building block compared to that of indole offers a conceptually distinct disconnection strategy for indoline‐ and indolenine‐containing heterocycles and natural products.     

Taichunamides: Prenylated Indole Alkaloids from Aspergillus taichungensis (IBT 19404)

Seven new prenylated indole alkaloids, taichunamides A–G, were isolated from the fungus Aspergillus taichungensis (IBT 19404). Taichunamides A and B contained an azetidine and 4‐pyridone units, respectively, and are likely biosynthesized from notoamide S via (+)‐6‐epi‐stephacidin A. Taichunamides C and D contain endoperoxide and methylsulfonyl units, respectively. This fungus produced indole alkaloids containing an anti‐bicyclo[2.2.2]diazaoctane core, whereas A. protuberus and A. amoenus produced congeners with a syn‐bicyclo[2.2.2]diazaoctane core. Plausible biosynthetic pathways to access these cores within the three species likely arise from an intramolecular hetero Diels–Alder reaction.     

Bioinspired Synthesis of (+)‐Cinchonidine Using Cascade Reactions

The development of efficient syntheses of complex natural products has long been a major challenge in synthetic chemistry. Designing cascade reactions and employing bioinspired transformations are an important and reliable means of achieving this goal. Presented here is a combination of these two strategies, which allow efficient asymmetric synthesis of the cinchona alkaloid (+)‐cinchonidine. The key steps of this synthesis are a controllable, visible‐light‐induced photoredox radical cascade reaction to efficiently access the tetracyclic monoterpenoid indole alkaloid core, as well as a practical biomimetic cascade rearrangement for the indole to quinoline transformation. The use of stereoselective chemical transformations in this work makes it an efficient synthesis of (+)‐cinchonidine.     

Oxidative Coupling Approach to Sarpagine Alkaloids: Total Synthesis of (−)-Trinervine,Vellosimine, (+)-Normacusine B,and (−)-Alstomutinine C

Sarpagine alkaloids are bioactive indole natural products that contain a highly rigid indole-fused 1-azabicyclo[2.2.2]octane, more than 100 members of which have been identified. Herein, a detailed examination of the intramolecular oxidative coupling between a ketone and a Weinreb amide for assembling the complex 1-azabicyclo[2.2.2]octane core structure of sarpagine family alkaloids is described. Precise late-stage manipulations of the ketone and Weinreb amide enable the divergent syntheses of (−)-trinervine, (+)-vellosimine, (+)-normacusine B, and (−)-alstomutinine C. Other notable transformations of the synthesis featured an aza-Achmatowicz/indole cyclization cascade to generate the azabicyclo[3.3.1]nonane structure, a regioselective elimination reaction to form the ethylidene motif embedded in the (+)-vellosimine and (+)-normacusine B structures, and a diastereoselective indole oxidative rearrangement to form the spirooxindole structure in (−)-alstomutinine C.     

Tandem Regioselective Substitution and Palladium‐Catalyzed Ring Fusion Reaction for Core‐Expanded Boron Dipyrromethenes with Red‐Shifted Absorption and Intense Fluorescence

A selective method for the core‐extension of boron dipyrromethene (BODIPY) with two annulated indole rings with exclusive syn‐connectivity is reported. The method is based on a regioselective nucleophilic substitution reaction of 2,3,5,6‐tetrabromoBODIPY with aryl amines, followed by palladium‐catalyzed intramolecular C?C coupling ring fusion. The unsymmetrical core‐expanded BODIPY with annulated indole and benzofuran rings was also synthesized by stepwise and regioselective nucleophilic substitution and palladium‐catalyzed intramolecular C?C coupling reaction. The diindole‐annulated BODIPY was unambiguously characterized by single‐crystal X‐ray analysis. The optical properties of the present core‐expanded BODIPYs were studied, revealing clearly red‐shifted absorption and emission bands and enhanced absorption coefficients upon annulation.     

Preparation and reactivity of 5‐substituted azepino[3,4‐b]indoles

Preparation of the 5‐substituted azepino[3,4‐b]indole core structure can be realised through a catalytic Heck reaction. The scope and limitations of this methodology are reported. The reactivity of di‐tert‐butyl 5‐ethoxycarbonylmethylene‐1,3,4,5‐tetrahydro‐1‐oxoazepino[3,4‐b]indole‐2,10‐dicarboxylate (1) was investigated in order to prepare the indole analogue of hymenialdisine and derivatives.     

Total synthesis of the strychnos alkaloid (+)-minfiensine: tandem enantioselective intramolecular Heck-iminium ion cyclization

A 1,2,3,4-tetrahydro-9a,4a-(iminoethano)-9H-carbazole (4) is a central structural feature of the Strychnos alkaloid minfiensine (1) and akuammiline alkaloids such as vincorine (5) and echitamine (6). A cascade catalytic asymmetric Heck-iminium cyclization was developed that rapidly provides 3,4-dihydro-9a,4a-(iminoethano)-9H-carbazoles in high enantiomeric purity. Two sequences were developed for advancing 3,4-dihydro-9a,4a-(iminoethano)-9H-carbazole 27 to (+)-minfiensine. In our first-generation approach, a reductive Heck cyclization was employed to form the fifth ring of (+)-minfiensine. In a second more concise total synthesis, an intramolecular palladium-catalyzed ketone enolate vinyl iodide coupling was employed to construct the final ring of (+)-minfiensine. This second-generation total synthesis of enantiopure (+)-minfiensine was accomplished in 6.5% overall yield and 15 steps from 1,2-cyclohexanedione and anisidine 13. A distinctive feature of this sequence is the use of palladium-catalyzed reactions to form all carbon-carbon bonds in the transformation of these simple precursors to (+)-minfiensine.     

Synthesis of the Carbon Framework of Scholarisine A by Intramolecular Oxidative Coupling

Scholarisine A, isolated from the leaves of Alstonia scholaris, is a monoterpene indole alkaloid with an unprecedented cage‐like structure. In this paper, preparation of the distinctive cage‐like core skeleton of scholarisine A is described. The key feature of this synthetic strategy is an intramolecular oxidative coupling reaction at the late stage to construct a 10‐oxa‐tricyclo[5.3.1.0^{3, 8}]undecan‐9‐one structure fused with indolenine. Intramolecular oxidative coupling by using N‐iodosuccinimide gave the carbon framework of scholarisine A in moderate yield, which is the first example of intramolecular oxidative‐coupling reaction between non‐activated enolate and indole. This study lays the foundation for continued investigations towards the total synthesis of scholarisine A.     

Stereocontrolled and Versatile Total Synthesis of Bispyrrolidinoindoline Diketopiperazine Alkaloids: Structural Revision of the Fungal Isolate (+)‐Asperdimin

Homo‐ and heterodimeric bispyrrolidinoindoline diketopiperazine alkaloids have been synthesized following a concise, versatile, and stereoselective route. Highlights of the sequence are a diastereoselective construction of the C3a‐bromo‐hexahydropyrrolo[2,3‐b]indole nucleus, its Co^I‐induced C3a? C3a′ dimerization, and the twofold or sequential amide‐bond formation before cyclization to the diketopiperazine of the homo‐ or heterodimeric alkaloids, respectively. Stereochemical diversity is achieved through the choice of the appropriate amino acids combined with the base‐induced epimerization of the C2‐acyl‐hexahydropyrrolo[2,3‐b]indole at C2. According to this strategy, the natural products (+)‐WIN 64821 1 , (+)‐WIN 64745 2 and (+)‐asperdimin 6 as well as analogues ( 5 , 22 , 32 , 44 ) with different relative and absolute configuration have been efficiently synthesized. The flexibility of this synthetic methodology has facilitated the structural revision of the natural product (+)‐asperdimin, whose structure has been corrected to diastereomer 6 .     

A concise total synthesis of (+)-okaramine C

The first total synthesis of (+)-okaramine C is described. Our previously described selenocyclisation-oxidative deselenation sequence was used to establish a 3a-hydroxy-pyrrolo[2,3-b]indole core, which was modified by selective epimerisation to the common pyrrolo[2,3-b]indole of the okaramines.     

Synthesis of Aza‐Rocaglates via ESIPT‐Mediated (3+2) Photocycloaddition

Synthesis of aza‐rocaglates, nitrogen‐containing analogues of the rocaglate natural products, is reported. The route features ESIPT‐mediated (3+2) photocycloaddition of 1‐alkyl‐2‐aryl‐3‐hydroxyquinolinones with the dipolarophile methyl cinnamate. A continuous photoflow reactor was utilized for photocycloadditions. An array of compounds bearing the hexahydrocyclopenta[b]indole core structure was synthesized and evaluated in translation inhibition assays.     

Enantioselective Syntheses of Strychnos and Chelidonium Alkaloids through Regio‐ and Stereocontrolled Cooperative Catalysis

We describe enantioselective syntheses of strychnos and chelidonium alkaloids. In the first case, indole acetic acid esters were established as excellent partner nucleophiles for enantioselective cooperative isothiourea/Pd catalyzed α‐alkylation. This provides products containing indole‐bearing stereocenters in high yield and with excellent levels of enantioinduction in a manner that is notably independent of the N‐substituent. This led to concise syntheses of (?)‐akuammicine and (?)‐strychnine. In the second case, the poor performance of ortho‐substituted cinnamyl electrophiles in the enantioselective cooperative isothiourea/Ir catalyzed α‐alkylation was overcome by appropriate substituent choice, leading to enantioselective syntheses of (+)‐chelidonine, (+)‐norchelidonine, and (+)‐chelamine.     

Total synthesis of (+)-isatisine A

Total synthesis of (+)-isatisine A is described based on the application of a silyl-directed Mukaiyama-type [3 + 2]-annulation for the preparation of a fully substituted furan core. The indole branch forming the quaternary carbon center at C2 was constructed by addition to an intermediate N-acyliminium ion derived from aminal 4. In addition, the fused tetracyclic framework including furan core was built up using modified Buchwald amidation conditions.     

Henrycinols A and B,Two Novel Indole Alkaloids Isolated from Melodinus henryi Craib

Henrycinols A ( 1 ) and B ( 2 ), two novel indole alkaloids, together with three known compounds, (+)‐Δ¹⁴‐vincamine ( 3 ), (+)‐16‐epi‐Δ¹⁴‐vincamine ( 4 ), and (+)‐isoeburnamine ( 5 ), were isolated from the roots of Melodinus henryi Craib . Their structures were established on the basis of 1D‐ and 2D‐NMR spectroscopic analysis. The relative configuration of henrycinols A and B was determined by NOESY analysis.     

Total Synthesis of (−)‐Alstofolinine A through a Furan Oxidation/Rearrangement and Indole Nucleophilic Cyclization Cascade

A reaction cascade of aza‐Achmatowicz rearrangement followed by indole nucleophilic cyclization was developed to generate the common indole‐fused azabicyclo[3.3.1]nonane core of the macroline family alkaloids. The key to the success of the strategy relies on the careful manipulation of protecting groups and judicious selection of chemoselective furan oxidation conditions. The synthetic utility was further demonstrated on the asymmetric total synthesis of (?)‐alstofolinine A.     

Indole diterpene synthetic studies. Total synthesis of (+)-nodulisporic acid F and construction of the heptacyclic cores of (+)-nodulisporic acids A and B and (-)-nodulisporic acid D

A first-generation strategy for construction of (+)-nodulisporic acids A (1) and B (2) is described. The strategy entails union of the eastern and western hemisphere subtargets via the indole synthesis protocol developed in our laboratory. Subsequent elaboration of rings E and F, however, revealed the considerable acid instability of the C(24) hydroxyl, thereby preventing further advancement. Nonetheless, preparation of the heptacyclic core of (+)-nodulisporic acids A and B, the total synthesis of (+)-nodulisporic acid F, the simplest member of the nodulisporic acid family, and elaboration of the heptacyclic core of (-)-nodulisporic acid D were achieved.     

Catalytic Enantioselective Aza‐pinacol Rearrangement

The first catalytic enantioselective asymmetric aza‐pinacol rearrangement is reported. The reactions are catalyzed by a chiral phosphoric acid and proceed via a highly organized transition state involving a cyclic aza‐ortho ‐xylylene intermediate to afford the indoline structures with good to excellent enantioselectivity. The synthetic utility of this method is demonstrated by the asymmetric synthesis of a key intermediate to the natural product minfiensine and the identification of a chiral lead compound to repress antibiotic resistance.     

Reaction of Donor‐Acceptor Cyclobutanes with Indoles: A General Protocol for the Formal Total Synthesis of (±)‐Strychnine and the Total Synthesis of (±)‐Akuammicine

A ligand‐promoted catalytic [4+2] annulation reaction using indole derivatives and donor‐acceptor (D‐A) cyclobutanes is reported, thus providing an efficient and atom‐economical access to versatile cyclohexa‐fused indolines with excellent levels of diastereoselectivity and a broad substrate scope. In the presence of a chiral SaBOX ligand, excellent enantioselectivity was realized with up to 94 % ee. This novel synthetic method is applied as a general protocol for the total synthesis of (±)‐akuammicine and the formal total synthesis of (±)‐strychnine from the same common‐core scaffold.     

Benzo[c,d]indole‐Containing Aza‐BODIPY Dyes: Asymmetrization‐Induced Solid‐State Emission and Aggregation‐Induced Emission Enhancement as New Properties of a Well‐Known Chromophore

A series of symmetric and asymmetric benzo[c,d]indole‐containing aza boron dipyrromethene (aza‐BODIPY) compounds was synthesized by a titanium tetrachloride‐mediated Schiff‐base formation reaction of commercially available benzo[c,d]indole‐2(1H)‐one and heteroaromatic amines. These aza‐BODIPY analogues show different electronic structures from those of regular aza‐BODIPYs, with hypsochromic shifts of the main absorption compared to their BODIPY counterparts. In addition to the intense fluorescence in solution, asymmetric compounds exhibited solid‐state fluorescence due to significant contribution of the vibronic bands to both absorption and fluorescence as well as reduced fluorescence quenching in the aggregates. Finally, aggregation‐induced emission enhancement, which is rare in BODIPY chromophores, was achieved by introducing a nonconjugated moiety into the core structure.