Total Synthesis of (+)‐Minfiensine: Construction of the Tetracyclic Core Structure by an Asymmetric Cascade Cyclization

A new method for one‐step construction of the tetracyclic core structure of the indole alkaloid (+)‐minfiensine was developed utilizing a palladium‐catalyzed asymmetric indole dearomatization/iminium cyclization cascade. An efficient total synthesis of (+)‐minfiensine was realized using this strategy. The present method enables access to the common core structure of a series of monoterpene indole alkaloids, such as vincorine, echitamine, and aspidosphylline A.     

Cascade Syntheses Routes to the Centrocountins

Cascade and domino reactions that proceed through multiple steps in one pot and include multiple bond formations are promising methods for the rapid and efficient generation of complex molecular architectures, including the scaffolds of classes of complex natural product. We describe the development of various one‐pot cascade reaction sequences to yield centrocountins, which are tetracyclic indole derivatives with the basic scaffold of numerous polycyclic alkaloids. The mechanistic investigation of a sequence employing readily available alkynes and 3‐formylchromones as starting materials provided evidence that this one‐pot synthesis proceeds through at least twelve consecutive transformations and includes at least nine different chemical reactions, making it the longest cascade reaction sequence known to date. We describe the scope and limitations of the cascade synthesis approaches and the development of an enantioselectively catalyzed centrocountin synthesis.     

Enantioselective Pd‐Catalyzed Allylic Alkylation Reactions of Dihydropyrido[1,2‐a]indolone Substrates: Efficient Syntheses of (−)‐Goniomitine, (+)‐Aspidospermidine,and (−)‐Quebrachamine

The successful application of dihydropyrido[1,2‐a]indolone (DHPI) substrates in Pd‐catalyzed asymmetric allylic alkylation chemistry facilitates rapid access to multiple alkaloid frameworks in an enantioselective fashion. Strategic bromination at the indole C3 position greatly improved the allylic alkylation chemistry and enabled a highly efficient Negishi cross‐coupling downstream. The first catalytic enantioselective total synthesis of (?)‐goniomitine, along with divergent formal syntheses of (+)‐aspidospermidine and (?)‐quebrachamine, are reported herein.     

Enantioselective Pd‐Catalyzed Allylic Alkylation Reactions of Dihydropyrido[1,2‐a]indolone Substrates: Efficient Syntheses of (−)‐Goniomitine, (+)‐Aspidospermidine,and (−)‐Quebrachamine

The successful application of dihydropyrido[1,2‐a]indolone (DHPI) substrates in Pd‐catalyzed asymmetric allylic alkylation chemistry facilitates rapid access to multiple alkaloid frameworks in an enantioselective fashion. Strategic bromination at the indole C3 position greatly improved the allylic alkylation chemistry and enabled a highly efficient Negishi cross‐coupling downstream. The first catalytic enantioselective total synthesis of (−)‐goniomitine, along with divergent formal syntheses of (+)‐aspidospermidine and (−)‐quebrachamine, are reported herein.     

Total Synthesis of (+)-Gelsedine

A novel iodide-promoted, allene-terminated cyclization of an N-acyliminium ion, a stereoselective Heck spirocyclization, and a chemoselective demethylation at the nitrogen atom of an oxindole are the key transformations in the first total synthesis of the indole alkaloid (+)-gelsedine ( 1 ). This dextrorotatory form of natural gelsedine was formed as a single enantiomer in 21 steps from (S)-malic acid.     

Copper‐Catalyzed Aerobic Oxidative Cyclization Cascade to Construct Bridged Skeletons: Total Synthesis of (−)‐Suaveoline

Based on the discovery of copper‐catalyzed cyclopropanol ring‐opening addition to iminium ions, an unprecedented catalytic aerobic C?H oxidation/cyclopropanol cyclization cascade using CuCl₂ as the multifunctional catalyst and air as the oxidant was developed to construct the azabicyclo[3.3.1]nonane skeleton, which is widespread in natural products and medicines. Using this method, concise asymmetric total synthesis of the indole alkaloid (?)‐suaveoline was achieved. This study not only provides an efficient, low‐cost, and environmentally benign method for constructing such bridged frameworks, but also enriches the realm of cyclopropanol chemistry and C?H functionalization.     

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.     

A general synthetic entry to the pentacyclic strychnos alkaloid family, using a [4 + 2]-cycloaddition/rearrangement cascade sequence

The total synthesis of (+/-)-strychnopivotine, (+/-)-tubifolidine, (+/-)-strychnine, and (+/-)-valparicine is reported. The central step in the synthesis consists of an intramolecular [4 + 2]-cycloaddition/rearrangement cascade of an indolyl-substituted amidofuran that delivers an aza-tetracyclic substructure containing the ABCE-rings of the Strychnos alkaloid family. A large substituent group on the amide nitrogen atom causes the reactive s- trans conformation of the amidofuran to be more highly populated, thereby facilitating the Diels-Alder cycloaddition. The reaction also requires the presence of an electron-withdrawing substituent on the indole nitrogen for the cycloaddition to proceed. The cycloaddition/rearrangement cascade was remarkably efficient given that two heteroaromatic systems are compromised in the reaction. Closure to the remaining D-ring of the Strychnos skeleton was carried out from the aza-tetracyclic intermediate by an intramolecular palladium-catalyzed enolate-driven cross-coupling between the N-tethered vinyl iodide and the keto functionality. The cycloaddition/rearrangement approach was successfully applied to (+/-)-strychnopivotine (2), the only Strychnos alkaloid bearing a 2-acylindoline moiety in its pentacyclic framework. A variation of this tactic was then utilized for a synthesis of the heptacyclic framework of (+/-)-strychnine. The total synthesis of (+/-)-strychnine required only 13 steps from furanyl indole 18 and proceeded in an overall yield of 4.4%.     

Iron-catalyzed carbonylation–arylation of N-arylacrylamides for synthesis of oxindole derivatives

An efficient method for oxindole synthesis is established by iron-catalyzed carbonylation–arylation of N-arylacrylamides with aldehydes. 3-Functionalized oxindoles are synthesized smoothly using FeCl₃ as catalyst and TBHP as oxidant. The obtained oxindoles can be used for further transformations to give diverse indole alkaloid structure motifs.     

Copper(I)‐Catalyzed Asymmetric Dearomatization of Indole Acetamides with 3‐Indolylphenyliodonium Salts

The rapid and direct asymmetric synthesis of 3‐(3a‐indolyl)hexahydropyrroloindoline motifs is an extremely important part of the total synthesis of several alkaloid structures. Herein, an intermolecular, asymmetric cascade dearomatization reaction of indole acetamides with 3‐indolylphenyliodonium salts has been developed. This protocol provides a straightforward access to 3‐(3a‐indolyl)hexahydropyrroloindolines bearing an all‐carbon quaternary stereocenter at the C3 position of the indoline ring with high enantioselectivities. The utility of the protocol has been demonstrated by the formal asymmetric synthesis of folicanthine.     

Expedient synthesis of the tetracyclic core of ent-nakadomarin A

An efficient eight-step assembly of the tetracyclic core (ABCD rings) of ent-(+)-nakadomarin A, a bioactive hexacyclic marine alkaloid, has been realized with Sonogashira coupling, platinum(II)-promoted cascade cyclizations, and saturation of a challenging carbon-carbon double bond through a hydroboration/oxidation/xanthate formation/Barton-McCombie deoxygenation sequence as key transformations.     

Tremorgenic indole alkaloids. The total synthesis of (-)-penitrem D

A convergent, stereocontrolled total synthesis of the architecturally complex tremorgenic indole alkaloid (-)-penitrem D (4) has been achieved. Highlights of the synthesis include an efficient, asymmetric synthesis of the western hemisphere; the stereocontrolled assembly of the I-ring; discovery of a novel autoxidation to introduce the C(22) tertiary hydroxyl group, required for tremorgenic activity; union of fully elaborated eastern and western hemispheres, exploiting an indole synthetic protocol developed expressly for this purpose; and a late-stage, stereoselective construction of the A and F rings exploiting a Sc(OTf)(3-)promoted reaction cascade. The longest linear sequence leading to (-)-penitrem D (4) was 43 steps.     

Ruthenium‐Catalyzed Cascade Annulation of Indole with Propargyl Alcohols

Cascade transformations forming multiple bonds and one‐pot procedures provide rapid access to natural‐product‐like scaffolds from simple precursors. These atom‐economic processes are valuable tools in organic synthesis and drug discovery. Herein, we report on ruthenium‐catalyzed cascade annulations of indole with readily available propargyl alcohols. These provide rapid access to diverse carbazoles, cyclohepta[b]indoles, and further fused polycycles with high selectivity. A bifunctional ruthenium complex featuring a redox‐coupled cyclopentadienone ligand acts as a common catalyst for the different cascade processes.     

Solvent‐Controlled Bifurcated Cascade Process for the Selective Preparation of Dihydrocarbazoles or Dihydropyridoindoles

A solvent‐controlled cascade process has been identified for the dual purpose of the preparation of either dihydrocarbazoles or dihydropyridoindoles from identical N‐aryl‐α,β‐unsaturated nitrones and electron‐deficient allene starting materials. These reactions proceed smoothly under mild metal‐free conditions affording a range of two types of skeletally distinct indole‐based heterocycles in high yield and diastereoselectivity. These transformations demonstrate the use of a bifurcated cascade process that hinges on the ring‐opening event of a benzazepine intermediate for the synthesis of skeletally diverse heterocyclic products and rapid access to biologically‐significant, indole‐based structures.     

Indole‐Diterpene Synthetic Studies: Total Synthesis of (−)‐21‐Isopentenylpaxilline

An efficient, stereocontrolled total synthesis of the complex indole‐diterpene alkaloid (?)‐21‐isopentenylpaxilline ( 1 ) has been achieved. Key elements of the synthesis include the stereocontrolled construction of the advanced eastern hemisphere (?)‐ 68 , involving a highly efficient union of the eastern and western fragments (?)‐ 68 and 5 exploiting our 2‐substituted indole synthesis, application of the Negishi π cycloalkylation tactic as a new, potentially general protocol for the construction of ring C, and the fragmentation of a β,γ‐epoxy ketone to introduce the tertiary OH group at C(13) in the indole diterpene skeleton.     

Total Synthesis of (±)‐Alstoscholarisine A

The first total synthesis of the neuroactive indole alkaloid (±)‐alstoscholarisine A is reported. The key step of the concise synthesis is an efficient domino sequence that was used to assemble the 2,8‐diazabicyclo[3.3.1]nonane core through the formation of two C?N bonds and one C?C bond in a single step.     

Bioinspired Total Synthesis of the Dimeric Indole Alkaloid (+)‐Haplophytine by Direct Coupling and Late‐Stage Oxidative Rearrangement

A bioinspired convergent total synthesis of (+)‐haplophytine, a dimeric indole alkaloid with diazabicyclo[3.3.1]nonane and hexacyclic aspidosperma segments, is described. This synthesis involves the direct coupling of the two segments in a AgNTf₂‐mediated Friedel–Crafts reaction and construction of the diazabicyclo[3.3.1]nonane skeleton through late‐stage chemoselective aerobic oxidation of the 1,2‐diaminoethene moiety and a sequential semipinacol‐type rearrangement.     

Catalytic Enantioselective Desymmetrisation as a Tool for the Synthesis of Hodgkinsine and Hodgkinsine B

Two palladium‐catalysed amination protocols are deployed in the desymmetrisation of the complex dimeric alkaloid meso‐chimonanthine. The power of these transformations is showcased in an efficient formal and total synthesis of the natural products hodgkinsine and hodgkinsine B, respectively.     

Synthesis of Aristotelia-Type Alkaloids. Part XII. Total synthesis of (−)-tasmanine. Stereoelectronic factors that control the rearrangement of 3H-indol-3-ol derivatives to oxindoles ( = 1,3-dihydro-2H-indol-2-ones) or to pseudoindoxyls ( =1,2-dihydro-3H-indol-3-ones)

The oxidative transformation of (+)-aristoteline ((+)- 5 ) into its metabolites, the recently synthesized indole alkaloids (?)-serratoline ((?)- 6 ), (+)-aristotelone ((+)- 2 ), and (?)-alloaristoteline ((?)- 22 ), was investigated in more detail. It was demonstrated that the diastereoface selectivity of the reaction of (+)- 5 with 3-chloroperbenzoic acid can be altered by variation of the solvent as well as by addition of CF₃COOH. The chemoselectivity of the 1,2-rearrangement of the intermediate 3H-indol-3-ol derivatives could be controlled as follows: treatment of 3H-indol-3-ols with aqueous polyphosphoric acid led to the pseudoindoxyl ( = 1,2-dihydro-3H-indol-3-one) derivatives, whereas an analogous treatment of the corresponding O-benzoates furnished exclusively the corresponding, constitutionally isomeric 2-oxindole ( = 1,3-dihydro-2H-indol-2-one) products. Exploitation of these and related findings led to efficient total syntheses of the Aristotelia alkaloid (?)-tasmanine ((?)- 1 ) and of the corresponding unnatural epimer (+)- 12 , as well as of the two pseudoindoxyls (+)-aristotelone ((+)- 2 ) and (?)-2-epiaristotelone ((?)- 11 ). All these transformations were carried out with synthetic (+)-aristoteline ((+)- 5 ) as the single indole alkaloid precursor.     

Synthesis of indolo[2,3-a]quinolizine and hexahydro-1H-indolizino[8,7-b]indole derivatives by cascade condensation, cyclization, and Pictet-Spengler reaction: an application to the synthesis of (±)-harmicine

Synthesis of indole alkaloid related compounds using Schiff base formation, intramolecular cyclization (or N-alkylation), and Pictet-Spengler reaction as a cascade one pot condensation has been reported. The cascade chemistry has been applied to the synthesis of (±)-harmicine as a key step.