Facile synthesis of indolizinoindolone, indolylepoxypyrrolooxazole, indolylpyrrolooxazolone and isoindolopyrazinoindolone heterocycles from indole and imide derivatives.

Chemo-, regio- and diastereoselective coupling reactions of indole with imide derivatives leading to unique heterocyclic systems are demonstrated. Acid-induced 3-position coupling reactions of indole with cyclic imide derived lactamols followed by acid promoted 2-position cyclizations with the corresponding aldehydes are described to obtain the indolizinoindolones and benzoindolizinoindolones. Base induced 2-position coupling reactions of N-tosylindole with N-(2-iodoethyl)imides and the subsequent cyclizations provide indolylepoxypyrrolooxazole, indolylpyrrolooxazolone and indolyloxazoloisoindolone.

The indole-based subincanadine alkaloids and their biogenetic congeners.

The tryptamine-derived polycyclic bridged bioactive indole alkaloids subincanadines A-G were isolated in 2002 by Ohsaki and coworkers from the bark of the Brazilian medicinal plant Aspidosperma subincanum. Kobayashi proposed that subincanadines D-F could be biosynthetically resulting from stemmadenine via two different pathways and, furthermore, that the subincanadines A-C could be biogenetically resulting from subincanadines D and E. Kam and coworkers, in their focused efforts, isolated five indole alkaloids from Malaysian Kopsia arborea species, namely valparicine, apparicine, arboridinine, arborisidine, and arbornamine in combination with subincanadine E.

Chemoselective Ring Closure of 4-(3-Methyl-2-oxo-2,5-dihydro-1-pyrrol-1-yl)butanal Leading to Pandalizine A.

Starting from methylmaleic anhydride, a facile total synthesis of pandalizine A alkaloid is described via the regioselective reduction of methylmaleimide and acid-catalyzed enolization of 4-(3-methyl-2-oxo-2,5-dihydro-1-pyrrol-1-yl)butanal followed by chemoselective intramolecular dehydrative cyclization as the key steps. It is noteworthy that the analogous model system with an additional β-methyl group followed an alternative chemoselective intermolecular aldol condensation pathway.

Regioselective oxidation of indoles to 2-oxindoles.

Facile regioselective oxidation of indoles to 2-oxindoles promoted by sulfuric acid adsorbed on silica gel is reported. The demonstrated practical site-selective heterogeneous oxidation reactions conveniently take place with a broad substrate scope and functional group tolerances. The present oxidation strategy is also employed to accomplish the total synthesis of natural products donaxaridine and donaxarine.

Progress in total synthesis of subincanadine alkaloids and their congeners.

A concise account of isolation, characterization, bioactivity, plausible biogenetic pathways, and most importantly, total synthesis of structurally fascinating and biologically imperious indole-based subincanadine alkaloids and their biogenetic congeners are described in the present review with special emphasis on total synthesis and therein an involved set of key reactions.

Regioselective and Stereoselective Reductive Aziridinium Ring Cleavage Leading to Azabicyclodecane Architecture: Enantioselective Synthesis of (+)-Subincanadine F.

Enantioselective synthesis of cytotoxic indole alkaloid (+)-subincanadine F was accomplished starting from the corresponding ( S)-acetoxysuccinimide via aziridinium ring formation and its reductive ring expansion route. Regioselective and stereoselective reductive aziridinium carbon-nitrogen bond cleavage comprising ring expansions was a key step. The ( S)-OMOM protection of the hydroxyl moiety adjacent to a benzylic carbon of an in situ formed aziridinium system was necessary for lithium borohydride-induced reductive ring expansions, and it also served as a latent source of an essential ketone carbonyl group for the generation of an α,β-conjugated system.

Diastereoselective Synthesis of (±)--Subincanadine C.

Starting from indolylmaleimide, concise and efficient total synthesis of (±)--subincanadine C was described via stereoselective Wittig olefination, base-induced selective mono-prenylation, regioselective Grignard reaction, diastereoselective Pictet-Spengler cyclization, regioselective oxidative carbon-carbon double-bond cleavage, one-pot reductions, and intramolecular cyclization pathway. An attempted synthesis of (±)-subincanadine C via diastereoselective Grignard addition to the α,β-unsaturated γ-lactam or diastereoselective reduction of a carbon-carbon double bond also resulted in yet another route to (±)--subincanadine C.

Solid State Auto-Inversion of C-Centrochirality: Enantioselective Total Synthesis of Furocarbazolones (-)-epi-Claulansine D and (-)-Claulansine D and Pyranocarbazolone (+)-epi-Claulansine C.

Starting from dimethyl (E)-2-{[(1-tert-butoxycarbonyl)-1H-indol-3-yl]methylene}succinate and (R)-2,2,5,5-tetramethyl-1,3-dioxolane-4-carbaldehyde, facile synthesis of (-)-epi-claulansine D was accomplished via condensation and two intramolecular cyclizations. The (-)-epi-claulansine D in the solid state exists in a metastable form, and after an induction period of 30-90 days, it underwent complete epimerization to exclusively deliver the desired natural product (-)-claulansine D in quantitative yield. The witnessed inversion of C-centrochirality in the solid state is conceptually novel and takes place for relatively higher crystal stability reasons.

Total Synthesis of (±)/(+)-Subincanadine E and Determination of Absolute Configuration.

A facile synthesis of (±)-subincanadine E was described from tryptamine-based maleimide. 1,2-Addition of Grignard reagent to maleimide, internal activation of formed lactamol for in situ 1,4-addition of Grignard reagent, and associated position-specific allylic rearrangement in diastereoselective Pictet-Spengler cyclization were the key steps. Enantioselective first total synthesis of naturally occurring cytotoxic (+)-subincanadine E was also accomplished from (S)-acetoxysuccinimide via an unusual syn-addition of cuprate to the α,β-unsaturated lactam.

Total Synthesis of Bioactive Canthine Alkaloid Cordatanine Comprising in Situ Double Oxidative Aromatization of Tetrahydrocarbazole.

Starting from tryptamine and methoxymaleic anhydride, concise and efficient total synthesis of cordatanine has been accomplished via regioselective reduction of methoxymaleimide, acid-catalyzed intramolecular cyclization of the formed lactamol, in situ stepwise oxidations leading to aromatization, and intramolecular cyclization with the exchange of N-regioselectivity. An attempted synthesis of regioisomeric natural product zanthochilone has been described in brief with reversal of reduction selectivity.

Correction: Stereoselective synthesis of (-)-desethyleburnamonine, (-)-vindeburnol and (-)-3-epitacamonine: observation of a substrate dependent diastereoselectivity reversal of an aldol reaction.

Correction for 'Stereoselective synthesis of (-)-desethyleburnamonine, (-)-vindeburnol and (-)-3-epitacamonine: observation of a substrate dependent diastereoselectivity reversal of an aldol reaction' by Pravat Mondal et al., Org. Biomol.

Stereoselective synthesis of (-)-desethyleburnamonine, (-)-vindeburnol and (-)-3-epitacamonine: observation of a substrate dependent diastereoselectivity reversal of an aldol reaction.

Starting from (-)-acetoxyglutarimide, the enantioselective multistep synthesis of (-)-desethyleburnamonine, (-)-vindeburnol and (-)-3-epitacamonine has been demonstrated via a common hydroxyl-lactam intermediate with very good overall yields. The acetoxy function from (-)-acetoxyglutarimide was initially used as a handle to induce enantioselectivity and then as a latent source of the ketone carbonyl group. Most importantly, substrate dependent reversal of the diastereoselectivity in ester aldol reactions of hexahydroindolo[2,3-a]quinolizinones has been reported.

Biomimetic Collective Total Synthesis of Bioactive Carbazole Alkaloids Indizoline, Mafaicheenamine A, Claulamine A, Claulansine A, and the Proposed Claulamine E.

The common precursor 1-methoxy-2-prenyl-3-carbomethoxycarbazole was synthesized from dimethyl indolylmethylenesuccinate in four steps. Well-planned reductive and/or oxidative transformations and intramolecular cyclizations were performed on a pivotal common precursor to accomplish collective first total synthesis of titled natural products and proposed claulamine E. Burgess reagent induced formation of kinetically controlled product claulamine A, and intramolecular cyclizations to form bicyclic claulansine A were the key reactions.

A Biomimetic Synthesis of Phaitanthrin E Involving a Fragmentation of sp(3) Carbon-Carbon Bond: Synthesis and Rearrangement of Phaitanthrin D to Phaitanthrin E.

A biogenetic type total synthesis of alkaloids phaitanthrin D and phaitanthrin E has been described. The Csp(3)-Csp(3) bond cleavage with the release of several heteroatoms bearing unexpected leaving groups in intramolecular substitution reactions on an iminium double bond in the quinazolinones has been demonstrated using HMDS/ZnCl2 or NaHMDS. The mechanistic aspects have been supported by isolation and characterization of appropriate intermediates.

Chemoenzymatic collective synthesis of optically active hydroxyl(methyl)tetrahydronaphthalene-based bioactive terpenoids.

Starting from succinic anhydride and 2-methylanisole, a chemoenzymatic collective formal/total synthesis of several optically active tetrahydronaphthalene based bioactive natural products has been presented via advanced level common precursors; the natural product and antipode (-)/(+)-aristelegone B. Regioselective benzylic oxidations, stereoselective introduction of hydroxyl groups at the α-position of ketone moiety in syn-orientation, efficient enzymatic resolutions with high enantiomeric purity, stereoselective reductions, samarium iodide induced deoxygenations and tandem acylation-Wittig reactions without racemization and/or eliminative aromatization were the key features. An attempted diastereoselective synthesis of (±)-vallapin has also been described.

Diversity oriented convergent access for collective total synthesis of bioactive multifunctional carbazole alkaloids: synthesis of carbazomycin A, carbazomycin B, hyellazole, chlorohyellazole, and clausenaline D.

Facile syntheses of imperative carbazole alkaloids carbazomycin A, carbazomycin B, hyellazole, chlorohyellazole, and clausenaline D have been demonstrated starting from readily available Boc-protected 3-formylindole and dimethyl maleate. The suitably substituted aromatic rings have been designed comprising three/four significant C-C bond forming reactions. The competent Wittig reaction, selective monoalkylations, one-pot regioselective Weinreb amide formation and Boc-deprotection, well designed Grignard reactions, dehydrative intramolecular cyclizations, and Baeyer-Villiger rearrangement of aromatic aldehydes were the main features.

Base-stimulated 1,2-, 1,4-, and 1,6-eliminations in suitably substituted alkylidenesuccinates leading to natural and unnatural conjugated alkenyl(methyl)maleic anhydrides.

With dimethyl maleate as the starting material, facile stereoselective syntheses of natural and unnatural conjugated alkenyl(methyl)maleic anhydrides have been described. The key reactions were base-endorsed novel 1,2-, 1,4-, and 1,6-eliminations in the corresponding alkylidenesuccinate derivatives. The 1,2-eliminations in cyclic carbonate and sulfite by regioselective abstraction of methine protons with the respective release of CO2 and SO2 provided a conjugated ketone product.

Reactivity umpolung in intramolecular ring closure of 3,4-disubstituted butenolides: diastereoselective total synthesis of paeonilide.

Remarkable reactivity reversal stratagem in 3,4-disubstituted butenolides under acidic conditions is described. Design of a suitably substituted multifunctional butenolide followed by an acid-catalyzed chemo- and diastereoselective intramolecular ring closure via the reactivity umpolung has been demonstrated to accomplish a concise total synthesis of paeonilide. Overall, the present protocol involves one-pot reduction of an α,β-unsaturated carbon-carbon double bond and intramolecular nucleophilic insertion of oxygen function at the electron-rich γ-position of butenolide.

Aryne insertion reactions leading to bioactive fused quinazolinones: diastereoselective total synthesis of cruciferane.

Insertion reactions of an in situ generated arynes to a variety of suitably substituted 1,3-quinazolin-4-ones have been demonstrated for a new efficient one-step approach to a diverse range of fused quinazolinone architectures. The present protocol has been effectively utilized to accomplish the concise total synthesis of recently isolated bioactive natural products tryptanthrin, phaitanthrins A-C, and cruciferane.

Enantioselective total synthesis of desbromoarborescidines A-C and the formal synthesis of (S)-deplancheine.

Starting from Boc-protected tryptamine and (S)-tetrahydro-5-oxo-2-furancarboxylic acid, facile enantioselective total synthesis of desbromoarborescidines A-C and the formal synthesis of (S)-deplancheine have been accomplished via a common intermediate (S)-indolo[2,3-a]quinolizine. Synthesis of enantiomerically pure (S)-acetoxyglutarimide, stereoselective reductive intramolecular cyclization, hydroxyl group-assisted in situ N-Boc-deprotection, selective deoxygenation of the xanthate ester, and lactam hydrolysis followed by an appropriate exchange of nitrogen regioselectivity in intramolecular cyclization were the decisive steps.

Palladium-promoted [2 + 2 + 2] cocyclization of arynes and unsymmetrical conjugated dienes: synthesis of justicidin B and retrojusticidin B.

A facile synthesis of natural and unnatural arylnaphthalenes has been demonstrated via the unprecedented palladium-promoted [2 + 2 + 2] cocyclization of arynes and unsymmetrical conjugated dienes using the N-heterocyclic carbene as a ligand. The unsymmetrical dienes used herein are actually α-coupled acrylate-cinnamate combinations bearing two β-positive carbons and follow the key [2 + 2 + 2] cocyclization pathway.

Sonogashira coupling reactions of bromomaleimides: route to alkyne/cis-alkene/alkyl maleimides: synthesis of luffarin X and cacospongionolide C.

Palladium-catalyzed Sonogashira coupling reaction of bromomaleimides with a diverse range of terminal alkynes has been demonstrated to furnish the corresponding alkynylmaleimides in very good yields. This coupling reaction followed by selective reduction of the triple bond to single bond have been utilized as the decisive steps to accomplish the first total synthesis of natural products (±)-luffarin X and (±)-cacospongionolide C.

Regio- and stereoselective selenium dioxide allylic oxidation of (E)-dialkyl alkylidenesuccinates to (Z)-allylic alcohols: synthesis of natural and unnatural butenolides.

The first SeO(2) induced (Z)-selective allylic alcohol formation of dialkyl alkylidenesuccinates has been demonstrated to accomplish one-step syntheses of several essential butenolides and fused butenolides via an unusual E- to Z- carbon-carbon double bond isomerisation followed by the lactonization pathway. The observed regio- and stereoselective SeO(2) allylic oxidation protocol has also been extended to the diastereoselective total synthesis of bioactive natural product isomintlactone, its direct conversion to mintlactone and an example of the base-catalyzed intramolecular rearrangement of γ-lactone to δ-lactone.

Copper-catalyzed intramolecular N-arylation of quinazolinones: facile convergent approach to (-)-circumdatins H and J.

A copper-catalyzed intramolecular N-arylation of a quinazolinone nucleus that furnished the central benzodiazepine core unit has been demonstrated to accomplish an efficient convergent total synthesis of (-)-circumdatins H and J.

Chemoselective coupling reactions of 5,7-dimethoxyphthalide with the remotely functionalized alkyl iodides: facile racemic synthesis of Helicobacter pylori antibiotics.

Highly chemoselective coupling reactions of 5,7-dimethoxyphthalide carbanion with the remotely functionalized long chain alkyl iodides have been demonstrated to accomplish the concise and efficient synthesis of Helicobacter pylori antibiotics, the CJ-molecules, and sporotricale methyl ether.