Stereocontrolled total synthesis of (-)-eudistomin C

A stereocontrolled total synthesis of (-)-eudistomin C was accomplished in 18-step sequence with an overall yield of 7.7%. The synthesis features the diastereoselective Pictet-Spengler reaction of a tryptamine derivative and the Garner aldehyde catalyzed by Bronsted acids, and the unprecedented construction of the unusual oxathiazepine ring by intramolecular alkylation.     

Total synthesis of indole alkaloid (+/-)-subincanadine F via SmI2)-mediated ring opening and bridge-forming Mannich reaction

The first total synthesis of (+/-)-subincanadine F, a bioactive indole alkaloid structurally featuring a 1-azabicyclo[4.3.1]decane unit, has been realized from 1-(para-methoxybenzyl)tryptamine in six steps. The bridge-containing tetracyclic framework of subincanadine F was efficiently assembled by a SmI2-mediated ring opening followed by an acid-mediated Mannich reaction. In addition, the tetracyclic ketoester 6, a key intermediate potentially useful for synthesizing structurally related indole alkaloids as well, was obtained in one step from alpha,beta-diketoester 5.     

Total synthesis of debromoflustramine B via biomimetic alkylative cyclization

[reaction: see text] The hexahydropyrrolo[2,3-b]indoline skeleton is readily accessed by the zinc triflate-mediated alkylation of tryptamine derivatives. The methodology was employed in a three-step total synthesis of debromoflustramine B.     

An efficient synthesis of optically active physostigmine from tryptophan via alkylative cyclization

[reaction: see text] A new and efficient synthetic route to physostigmine is described. Corey-Kim reagent reacted with tryptamine or tryptophan carbamates to give 3a-(methylthiomethyl)hexahydropyrrolo[2,3-b]indole skeletons. Formal total synthesis of racemic and chiral physostigmine was accomplished in excellent overall yields, in short steps.     

Synthesis of vinca alkaloids and related compounds. Part 108: Efficient convergent synthetic pathway to the ibophyllidine skeleton IV. First synthesis of (±)-18-hydroxy-20-epiibophyllidine

The first total synthesis of the pentacyclic alkaloid (±)-18-hydroxy-20-epiibophyllidine was realized via an efficient preparation of the d-seco-pseudoaspidospermane molecule. The key step of the sequence involves an intramolecular [4+2] cycloaddition reaction of the dihydrosecodine intermediate, which was built up from the reaction of a tryptamine derivative with an aldehyde-ester. After full epimerization, the intramolecular N-alkylation of the tetracyclic ester gave the pentacyclic compound. Reduction of the latter molecule led to the title compound.     

A mild and efficient route to 2-benzyl tryptamine derivatives via ring-opening of β-carbolines

We described a mild and easy method, in two steps, by which various benzyl groups were introduced in the C-2 position of tryptamine. The first step consisted on the synthesis of β-carbolines, starting from tryptamine derivatives, by a Pictet-Spengler reaction. Ring-opening of the β-carbolines, by hydrogenation, led to the desired 2-substituted benzyl tryptamine indole products. A supplementary step of alkylation could be realized to give N-alkyl-2-substituted benzyl tryptamine. During these reactions, nitrogen atoms require no step of protection.     

Propylphosphonic anhydride (T3P®) mediated synthesis of 3-oxoisoindoline-1-carboxamides from 2-formylbenzoic acid,amines, and isocyanides. Preparation of isoindolinone alkaloids

Propylphosphonic anhydride (T3P®) was successfully applied to the synthesis of an isoindolinone library by the utilization of an Ugi four-center, three-component reaction (Ugi-4C-3CR). The use of T3P® significantly shortened the required reaction time and the corresponding products were obtained in good to high yields. Moreover, a side-reaction was observed when phenylethylamine derivatives and tryptamine were used as the amine component. The latter reaction was applied to the microwave-assisted, one-pot synthesis of the isoquinoline alkaloid (±)-nuevamine. Surprisingly, the traditional Ugi four-component reaction (Ugi-4CR) was unsuccessful in the presence of T3P®. In this case an α-amino amide was produced excluding the carboxylic acid from the multicomponent reaction.     

Asymmetric Synthesis of Tetracyclic Pyrroloindolines and Constrained Tryptamines by a Switchable Cascade Reaction

The interrupted Fischer indole synthesis of arylhydrazines and biocatalytically generated chiral bicyclic imines selectively affords either tetracyclic pyrroloindolines or tricyclic tryptamine analogues depending on the reaction conditions. We demonstrate that the reaction is compatible with a variety of functional groups. The products are obtained in high optical purity and in reasonable to good yield. We present a plausible reaction mechanism to explain the observed reaction outcome depending on the stoichiometry of the acid mediator. To demonstrate the synthetic utility of our method, pharmaceutically relevant examples of both product classes were synthesized in highly efficient reaction sequences, including a phenserine analogue as a potential cholinesterase inhibitor and constrained tryptamine derivatives as selective inhibitors of the 5‐HT₆ serotonin receptor and the TRPV1 ion channel.     

Application of tryptamine as a derivatising agent for airborne isocyanate determination. Part 3. Evaluation of total isocyanates analysis by high-performance liquid chromatography with fluorescence and amperometric detection

Determination of total airborne isocyanates using tryptamine as the derivatising agent was investigated. Tryptamine derivatised isocyanates were analysed by reversed-phase high-performance liquid chromatography (HPLC). The column was equipped with dual detectors of fluorescence emission and amperometric oxidation. The characteristics of fluorescence emission and amperometric oxidation of tryptamine were retained even after its reaction with isocyanates. With this unique behaviour, all tryptamine derivatised isocyanates can be quantified using HPLC by employing a single, pure derivative, such as tryptamine derivatised hexamethylene diisocyanate as the calibration standard. This is especially important for analysing polymeric isocyanates when identical calibration standards are not always available. The applicability of this method for air sampling was evaluated by comparison with the established method of Bagon et al. involving 1-(2-methoxyphenyl)piperazine. Simulation of air sampling was performed in a Test Atmosphere Generation System by the vaporisation of toluene diisocyanate. Satisfactory results were obtained, indicating the applicability of this technique for the determination of total airborne isocyanates.     

Sequential Electrophilic Trifluoromethanesulfanylation-Cyclization of Tryptamine Derivatives: Synthesis of C(3)-Trifluoromethanesulfanylated Hexahydropyrrolo[2,3-b]indoles

A practical and efficient synthesis of C(3)-trifluoromethanesulfanylated hexahydropyrrolo[2,3-b]indoles 5 from tryptamine derivatives was described. The features of this synthesis included electrophilic activation of C(3) of tryptamine derivatives with "CF(3)S(+)" and cascade ring cyclization by carbamate nucleophile attacking at C(2). Surprisingly, when Lewis acid (BF(3)·OEt(2)) was used as activator instead of proton acid (TsOH·H(2)O) for the electrophilic trifluoromethanesulfanylation of tryptamine derivatives, the uncyclized product 6 was formed preferentially. This sequential trifluoromethanesulfanylation-cyclization protocol was used to synthesize several pyrrolidinoindolinic alkaloid analogues. The cytotoxicity activities of these trifluoromethanesulfanylated alkaloid analogues were evaluated against three cancer cell lines (K562, HeLa, L929).     

One‐Pot Aminoethylation of Indoles/Pyrroles with Alkynes and Sulfonyl Azides

A general and efficient one‐pot aminoethylation of substituted indoles/pyrroles was accomplished for the synthesis of various tryptamine derivatives employing a combination of alkynes and sulfonyl azides as readily accessible aminoethylating agents. The reaction features a successful integration of copper‐catalyzed alkyne and azide cycloaddition to N‐sulfonyl‐1,2,3‐triazole, rhodium‐catalyzed selective insertion of α‐iminocarbenes onto the C3?H bond of indoles, and reduction of the resultant enamides to tryptamine derivatives employing either NaCNBH₃ or palladium catalyst, in one‐pot. The reaction also showed excellent functional‐group tolerance and allowed the synthesis of various substituted tryptamines in good to excellent yield. This transformation constitutes a one‐pot formal regioselective functionalization of terminal alkynes. Utility of the synthesized tryptamine was further demonstrated in the synthesis of dihydro‐β‐carboline and tryptoline.     

Efficient synthesis of N-prenylpyrroloindoline and N-prenylindole alkaloids based on a new four-reaction anionic domino process

Treatment of 2,5-diketopiperazines or carbamates derived from tryptophan or tryptamine with iodomethyltrimethylsilane followed by lithium hexamethyldisilazane and a prenyl halide produced stereoselectively derivatives of the hexahydropyrrolo[2,3-b]indole system bearing prenyl substituents both at C-3a and at the indoline nitrogen in a one-pot procedure involving a novel four-reaction anionic domino process. The reaction was applied to the preparation of N-prenyltryprostatin B and to achieving a very efficient formal total synthesis of the biologically active marine natural product (+/-)-debromoflustramine B.     

Asymmetric Synthesis of (R)‐1‐Alkyl‐Substituted Tetrahydro‐ß‐carbolines Catalyzed by Strictosidine Synthases

Stereoselective methods for the synthesis of tetrahydro‐ß‐carbolines are of significant interest due to the broad spectrum of biological activity of the target molecules. In the plant kingdom, strictosidine synthases catalyze the C?C coupling through a Pictet–Spengler reaction of tryptamine and secologanin to exclusively form the (S)‐configured tetrahydro‐ß‐carboline (S)‐strictosidine. Investigating the biocatalytic Pictet–Spengler reaction of tryptamine with small‐molecular‐weight aliphatic aldehydes revealed that the strictosidine synthases give unexpectedly access to the (R)‐configured product. Developing an efficient expression method for the enzyme allowed the preparative transformation of various aldehydes, giving the products with up to >98 % ee. With this tool in hand, a chemoenzymatic two‐step synthesis of (R)‐harmicine was achieved, giving (R)‐harmicine in 67 % overall yield in optically pure form.     

Total synthesis of (±)-trigonoliimine C via oxidative rearrangement of an unsymmetrical bis-tryptamine

We report the first total synthesis of (±)-trigonoliimine C, a member of a family of structurally complex alkaloids, in 10 steps from tryptamine and 6-methoxytryptamine. Our convergent synthetic strategy relies on a selective oxidative rearrangement of an unsymmetrical 2,2'-bis-tryptamine.     

Synthesis of vinca alkaloids and related compounds. Part 110: A new synthetic method for the preparation of pandoline-type alkaloid-like molecules

A practicable synthesis of a pandoline-type alkaloid-like molecule is reported through an efficient preparation of carbinolamine ether intermediates (9a and 9b). The key step of the synthesis consists of an intramolecular cycloaddition of the secodine-type intermediate (2), which was formed from the tryptamine derivative (3) and lactol (4). The mechanism of the cycloaddition reaction was investigated by quantum chemical calculations and it was found to follow a step-wise mechanism involving a zwitterionic intermediate (15). By employing this strategy, other members of the family of pandoline alkaloids or alkaloid-like molecules could be synthesized by reacting the tryptamine derivative with appropriately functionalized aldehydes.     

Characterisation of a proposed internet synthesis of N,N-dimethyltryptamine using liquid chromatography/electrospray ionisation tandem mass spectrometry

The psychoactive properties of N,N-dimethyltryptamine (DMT) are known to induce altered states of consciousness in humans. These properties attract great interest from clinical, neuroscientific, clandestine and forensic communities. The Breath of Hope Synthesis was reported on an internet website as a convenient two-step methodology for the preparation of DMT. The analytical characterisation of the first stage was the subject of previous publications by the authors and involved the thermal decarboxylation of tryptophan and the formation of tryptamine. The present study reports on the characterisation of the second step of this procedure which was based on the methylation of tryptamine. This employed methyl iodide and benzyltriethylammonium chloride/sodium hydroxide as a phase transfer catalyst. The reaction product was characterised by liquid chromatography/electrospray ionisation tandem mass spectrometry and orthogonal acceleration time-of-flight mass spectrometry. Quantitative evaluation was carried out in positive multiple reaction monitoring mode (MRM), which included synthesis of the identified reaction products. MRM screening of the product did not lead to the detection of DMT. Instead, 11.1% tryptamine starting material, 21.0% N,N,N-trimethyltryptammonium iodide (TMT) and 47.4% 1-N-methyl-TMT were detected. A 0.5% trace of the monomethylated N-methyltryptamine was also detected. This study demonstrated the impact on product purity of doubtful synthetic methodologies discussed on the internet.     

Organocatalytic Enantioselective Pictet–Spengler Reaction of α-Ketoesters: Development and Application to the Total Synthesis of (+)-Alstratine A

We report herein an asymmetric Pictet–Spengler reaction of α-ketoesters. In the presence of a catalytic amount of simple alanine-derived squaramide and p-nitrobenzoic acid, reaction of tryptamines with methyl 2-oxoalkanoates afforded the corresponding 1-alkyl-1-methoxycarbonyl tetrahydro-β-carbolines (THBCs) in high yields and ee values. A primary kinetic isotope effect (KIE=4.5) using C2-deteurium-labelled tryptamine indicates that rearomatization through deprotonation of the pentahydro-β-carbolinium ion could be the rate- and enantioselectivity-determining step. A concise enantioselective total synthesis of (+)-alstratine A, a hexacyclic cagelike monoterpene indole alkaloid, featuring this reaction as a key step, was subsequently accomplished. Remeasurement of the [a]_D value of the natural product indicates that natural alstratine A is dextrorotatory rather than levorotatory as it was initially reported in the isolation paper.     

First total synthesis of trimeric indole alkaloid, psychotrimine

The first total synthesis of (+/-)-psychotrimine, a novel trimeric indole alkaloid isolated from Psychotria rostrata, was achieved. In the total synthesis, the copper-mediated intramolecular and intermolecular aminations of halobenzenes, which respectively contributed to the construction of a pyrrolidinoindoline core and the installation of a third tryptamine unit, were used as key steps.     

Efficient one-pot synthesis of tryptamines and tryptamine homologues by amination of chloroalkynes

A new method was developed for the one-pot synthesis of substituted 3-(2-aminoethyl)- and 3-(3-aminopropyl)indoles from commercially available aryl hydrazines and chloroalkylalkynes. Various tryptamine derivatives were prepared directly in good yield with excellent regioselectivity. The method involves a new domino reaction sequence consisting of a titanium-catalyzed amination of the chloroalkylalkyne, [3+3]-rearrangement of the resulting aryl hydrazone, and nucleophilic substitution of the chloride by ammonia.     

Synthesis of Poly-5-vinylindole Derivatives

5-Vinyl-N-benzylindoline and 5-vinyl-N-benzylindole were synthesized starting from the corresponding 5-formyl derivative, by utilizing the Wittig or Wittig-Horner reactions. The monomers were polymerized by free-radical (AIBN) and anionic (BuLi) catalysts. Poly-5-vinyl-N-benzylindole was converted through suitable reactions to the tryptamine and indole acetic acid derivatives. Poly-5-vinyl-N-benzyl-tryptophane was synthesized by malonic ester synthesis by utilizing the condensation of poly-5-vinyl-N-benzylgramine and diethyl formamidomalonate.