Occurrence, Biogenesis, and Synthesis of Biologically Active Carbazole Alkaloids

Mild Control: Selective cyclization of aminocyclopropanes on the N1 or C3 positions of indole was achieved by tuning the catalyst and solvent. The new strategy was applied to the formal synthesis of aspidospermidine and the total synthesis of goniomitine in 13 steps and 11% overall yield. The first studies on the bioactivity of goniomitine demonstrated significant cytotoxicity against several tumor cell lines (IC50: 150-400 nM).

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/ange.201190035

Catalytic selective cyclizations of aminocyclopropanes: formal synthesis of aspidospermidine and total synthesis of goniomitine.

Development of efficient sequences for the total syntheses of (±)-actinophyllic acid (rac-1) and (−)-actinophyllic acid (1) are described. The central step in these syntheses is the aza-Cope/Mannich reaction, which constructs the previously unknown hexacyclic ring system of actinophyllic acid in one step from much simpler tetracyclic precursors. The tetracyclic hexahydro-1,5-methano-1H-azocino[4,3-b]indole ketone rac-37 is assembled from o-nitrophenylacetic acid in four steps, with oxidative cyclization of a dienolate derivative of tricyclic precursor rac-35 being the central step. In the first-generation synthesis, this intermediate is transformed in two steps to homoallyl amine rac-43, whose formaldiminium derivative undergoes efficient aza-Cope/Mannich reaction to give pentacyclic ketone rac-44. In four additional steps, this intermediate is advanced to (±)-actinophyllic acid. The synthesis is streamlined by elaborating ketone rac-37 to β-hydroxyester intermediate rac-53, which is directly transformed ...

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Total Synthesis of (±)- and (−)-Actinophyllic Acid

Described is the first enantioselective synthesis of (-)-gilbertine (2), a member of the uleine-type family, and the determination of the absolute configuration of this natural product is reported. The key step employs a cationic cascade reaction for a tetrahydropyrane and piperidine ring formation and the construction of the pentacyclic framework in one step. The synthetic strategy utilizes the Shibasaki reaction to build up the first stereogenic center. A formylation reaction of a 3-substituted cyclohexanone derivative was achieved, giving only the desired regioisomer. The Japp-Klingemann Fischer indole protocol was used successfully as a convergent synthetic approach for the construction of the desired tetrahydrocarbazole (20). Furthermore, an unexpected behavior of this 2,3-disubstituted cyclohexanone derivative during an epimerization process was investigated, resulting in different chemical behavior of the enantiomers and the racemate. The diastereomeric resolution was achieved via the cationic cascade reaction, demonstrating the versatility of this approach. Significantly, the synthetic 17-step sequence was easy to execute, giving (-)-gilbertine in 5.5% overall yield.

Enantioselective Synthesis of (−)-Gilbertine via a Cationic Cascade Cyclization

The present review is devoted to illustrate the state of the art of the syntheses of indoles, focusing particularly on the most recent developments of new synthetic approaches. Emphasis is given to the preparation of natural products or bioactive compounds containing the indole unit. We present a historical perspective of indole synthesis showing the strategies by choosing the nitrogen precursors. The review is organized sharing the indole synthetic approaches by using different nitrogen-containing functional groups in aromatic substrates used as source of the nitrogen of the indole moiety. Some functional groups and some typical reactions are particularly stressed and highlighted because of the limited coverage given in previous reviews published on this topic. Other synthetic approaches more used and discussed in recent, complete and excellent reviews on the topic are summarized but the most recent published results are highlighted. Our interest is particularly focused on the indolization procedures and on the different methods used for the ring closure and no attention is given to modification of indole structures starting from molecules with a preformed indole unit. Intriguing indole syntheses are continually discovered and the importance that the scientific community gives to these new developments is connected with the strategic role of molecules containing the indole unit. Indoles are the class of heterocycles with more applications and extensive interest due to their biological and pharmacological activity.

Synthesis of Indole Derivatives with Biological Activity by Reactions Between Unsaturated Hydrocarbons and N-Aromatic Precursors

The syntheses of the racemic forms of the indole alkaloids dasycarpidone (2b), 3-epi-dasycarpidone (2c), uleine (2a), and 3-epi-uleine (2d) together with that of 3-de-ethyldascarpidone (2e) are described. The key step in the approach involved the isomerisation of an indol-2-yl 1,2,5,6-tetrahydro-4-pyridyl ketone to an indol-2-yl 1,4,5,6-tetrahydro-4-pyridyl ketone (not isolated). This in turn in reacting as a cyclic enamine provided, by protonation an electrophilic centre for eventual closure to the indole β-position.

The syntheses of (±)-dasycarpidone, (±)-3-epi-dasycarpidone, (±)-uleine and (±)-3-epi-uleine

The total synthesis of dasycarpidone and 3-epi-dasycarpidone

The syntheses of uleine and 3-epi-uleine

Aus dem dargestellten Phenylhydrazon (I) wird mit Phosphorsaure bei 140°C das Indol (III) gebildet, dessen Methojodid mit Na-B-hydrid zum Alkohol (VI) (85%) und durch anschliesende Oxidation zum Keton (VII) (75%) fuhrt.

N. D. V. Wilson

Papers

The syntheses of (±)-dasycarpidone, (±)-3-epi-dasycarpidone, (±)-uleine and (±)-3-epi-uleine

The total synthesis of dasycarpidone and 3-epi-dasycarpidone

The syntheses of uleine and 3-epi-uleine

Synth. von (+‐)‐dasycarpidon, (+‐)‐3‐epi‐dasycarpidon, (+‐)‐ulein und (+‐)‐3‐epi‐ulein