Martin J Wanner

University of Amsterdam | UVA · Van 't Hoff Institute for Molecular Sciences

Incorporation of 2,5-dihydroxyterephthalate as a covalent scaffold in the axis of a 30-membered all-carbon macrocycle provides access to a modular series of rotaxanes. Installment of tethered alkynes or azides onto the terephthalic phenolic hydroxyl functionalities, which are situated at opposite sides of the macrocycle, give versatile prerotaxane...

The very reactive neurotransmitter metabolite 3,4-dihydroxy-phenylglycolaldehyde (dopegal) damages neurons and the myocardium by protein crosslinking via lysine and cysteine residues, resulting in conglomerization and cell-death. We investigated the mechanism of the alkylation step in this process on a synthetic scale, leading to the discovery of a...

The common para-regioselectivity in Pictet-Spengler reactions with dopamine derivatives is redirected to the ortho-position by a simple change of solvents. In combination with a chiral auxiliary on nitrogen this ortho-selective Pictet-Spengler produced the 1-benzyltetrahydro-isoquinoline alkaloids (S)-crassifoline, (S)-norcrassifoline and the bioac...

The regular bicyclic spiro motif is highly abundant given its synthetic accessibility while the diastereomer—virtually obtained through inversion at the central atom— is almost unknown. We have developed methodology to access the elusive inverted spiro architecture by employing a covalent template‐directed approach. Comparison with the regular spir...

A templated backfolding concept to construct a [2]catenane was attempted via a quasi[1]catenane showing an inverted spiro geometry. The template is covalently connected to the ketal-connected semi-perpendicular arranged linear precursors and spatially directs the sterically congested backfolding macrocyclizations that are required to give a quasi[1...

Due to their well-defined three-dimensional geometry, spiro compounds are widely utilized in drug research. From the central tetrahedral carbon atom, besides the regular structure, an inverted spiro connectivity may be envisioned. Here we disclose the synthesis of this molecule class that we have coined quasi[1]catenanes. Next to their fascinating...

Supplementary figures, supplementary methods and supplementary references.

Identification of dynamic protein-protein interactions at the peptide level on a proteomic scale is a challenging approach that is still in its infancy. We have developed a system to cross-link cells directly in culture with the special lysine cross-linker bis(succinimidyl)-3-azidomethyl-glutarate (BAMG). We used the Gram positive model bacterium B...

While the current supramolecular syntheses of [2]rotaxanes are generally efficient, the final product always retains the functional groups required for non-covalent preorganization. A short and high-yielding covalent-template-assisted approach is reported for the synthesis of a [2]rotaxane. A terephthalic acid template core preorganizes the covalen...

Identification of dynamic protein-protein interactions at the peptide level on a proteomic scale is a challenging approach that is still in its infancy. We have developed a system to cross-link cells directly in culture with the special lysine cross-linker bis(succinimidyl)-3-azidomethyl-glutarate (BAMG). We used the Gram positive model bacterium B...

Enantiopure 8-benzylprotoberberines were synthesized by two consecutive Pictet–Spengler (PS) condensations with protected 3,4-dihydroxyphenylacetaldehydes. The first PS to (+)-(R)-norprotosinomenine was optimized to 90 % ee with 5 mol-% of (R)-TRIP as chiral Brønsted acid (> 99 % ee after trituration). The second PS did not require any catalyst, an...

A series of 1-substituted 1,2,3,4-tetrahydroisoquinolines was prepared from N-(o-nitrophenylsulfenyl)phenylethylamines through BINOL-phosphoric acid [(R)-TRIP]-catalyzed asymmetric Pictet-Spengler reactions. The sulfenamide moiety is crucial for the rate and enantioselectivity of the iminium ion cyclization and the products are readily recrystalliz...

The pharmacologically interesting indole alkaloids (-)-mitragynine, (+)-paynantheine and (+)-speciogynine were synthesised in nine steps from 4-methoxytryptamine by a route featuring (i) an enantioselective thiourea-catalysed Pictet-Spengler reaction, providing the tetrahydro-β-carboline ring and (ii) a Pd-catalysed Tsuji-Trost allylic alkylation,...

Chemical cross-linking of protein complexes combined with mass spectrometry is a powerful approach to obtain 3-D structural information by revealing amino residues that are in close spatial proximity. To increase the efficiency of mass spectrometric analysis, we have demonstrated the selective enrichment of cross-linked peptides from the 350 kDa pr...

Given the pressing need for new antiprotozoal drugs without cross-resistance with current (failing) chemotherapy, we have explored 3-tridecylpyridinium alkaloids (3TPAs), derivatives of viscosamine, as antiparasitic agents. We have developed a simple synthetic route toward viscosamine and related cyclic and linear monomers and oligomers. Evaluation...

Synergistic catalysis: Three indole alkaloids (−)-corynantheidine, (+)-corynantheine and (+)-dihydro-corynantheine were prepared following a short and common strategy based on the binol phosphoric acid catalyzed enantioselective Pictet–Spengler reaction, followed by closure of the final ring by an intramolecular Tsuji–Trost-type Pd-catalyzed allyli...

The binolphosphoric acid-catalyzed Pictet-Spengler reaction of an N-(5-oxy-2,4-pentadienyl)tryptamine derivative with methyl 5-oxo-2-(phenylseleno)pentanoate leads to the tetrahydro-β-carboline in a 92:8 enantiomeric ratio. This product is easily converted into the substrate for a stereoselective intramolecular Diels-Alder reaction of the type earl...

Treatment of 6-chloro-9-(tetrahydro-2-pyranyl)purine (8) with 2 equivalents of methylene triphenylphosphorane (−30°) yields the corresponding purinyl ylide 9. Reaction of the latter with ethyl glyoxylate gives the expected acrylic ester derivative 10. Ethyl (dimethylsulfuranylidene)acetate adds to the acrylic ester moiety to form a mixture of isome...

Many of the alkaloids found in Nitraria and Lupine species can be envisaged to arise from two simple building blocks, namely, tryptamine and tetrahydropyridine. In particular in the Nitraria species, the alkaloids occur as racemates in some cases, despite the presence of many stereocenters. We assume that racemic alkaloids might be formed without i...

The tetracyclic indole alkaloid (-)-arboricine has been prepared using an asymmetric organocatalytic Pictet-Spengler reaction as the key step followed by a diastereoselective Pd-catalyzed iodoalkene/enolate cyclization. The absolute stereochemistry was unequivocally proven by X-ray crystallographic analysis and appeared to be opposite to the publis...

Optically active tetrahydro-beta-carbolines were synthesized via an ( R)-BINOL-phosphoric acid-catalyzed asymmetric Pictet-Spengler reaction of N-benzyltryptamine with a series of aromatic and aliphatic aldehydes. The tetrahydro-beta-carbolines were obtained in yields ranging from 77% to 97% and with ee values up to 87%. The triphenylsilyl-substitu...

Tritylsulfenyl- and 2-nitrophenylsulfenyl-substituted glyoxyl imines were used in chiral phosphoric acid catalyzed Friedel-Crafts (FC) reactions with indole. High yields and ee values ranging from 86% for Nps-protected (S)-indolylglycine to 88% for Trs-protected (R)-indolylglycine were obtained. On a preparative scale, a FC product with 99.5% ee an...

A library of 2,N6-disubstituted adenosine analogs was synthesized and the analogs were tested for their antiprotozoal activities. It was found that 2-methoxy and 2-histamino and N6-m-iodobenzyl substitutions generally produced analogs with low levels of antiprotozoal activity. The best antiplasmodial activity was achieved with large aromatic substi...

A library of 2,N⁶-disubstituted adenosine analogs was synthesized and the analogs were tested for their antiprotozoal activities. It was found that 2-methoxy and 2-histamino and N ⁶- m -iodobenzyl substitutions generally produced analogs with low levels of antiprotozoal activity. The best antiplasmodial activity was achieved w...

Buy Article Permissions and Reprints Significance The authors report a catalytic asymmetric Pictet-Spengler reaction of trypt­amine via a sulfenyliminium ion. Chiral phosphoric acid 1 was the best catalyst for this reaction and the N-tritylsulfenyl substituent on the tryptamine substrate was found to be essential for achieving high enantioselectiv...

(Chemical Equation Presented) From cations to chiral products: β-Carbo-lines can be synthesized with good enantioselectivity by the title reaction catalyzed by a chiral binol-derived Brønsted acid (see scheme, BHT = 3,5-di(tert-butyl)-4-hydroxytoluene). The procedure commences from tryptamine and can be scaled up readily, as both the installment an...

The rapid increase of resistance to drugs commonly used in the treatment of tropical diseases such as malaria and African sleeping sickness calls for the prompt development of new safe and efficacious drugs. The pathogenic protozoan parasites lack the capability of synthesising purines de novo and they take up preformed purines from their host thro...

Modified purine derivatives are of great importance in biomedical sciences, and substitution reactions on the purine skeleton are intensively studied. In our laboratory, an efficient and selective purine C2-nitration reaction was developed using a mixture of tetrabutylammonium nitrate and trifluoroacetic anhydride. The resulting 2-nitro moiety appe...

Active resistance of tumor cells against DNA alkylating agents arises by the production of high levels of the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT). This resistance during treatment with, for example, the anticancer agent temozolomide can be reversed by administration of O(6)-benzylguanine, a purine that transfers its benz...

Nitration of substituted (1-deaza)purines using a mixture of tetrabutylammonium nitrate (TBAN) and trifluoracetic acid anhydride (TFAA) was applied to prepare nitrosubstituted (1-deaza)purines at low temperature. The nitro group influences the system twofold: 1) it activates other substituents towards nucleophilic aromatic substitution and 2) it ca...

Four subtypes of adenosine receptors are currently known, that is, A(1), A(2A), A(2B), and A(3) receptors. Interestingly, quite substantial species differences exist especially between human and rat A(3) receptors. As a result, ligands such as CCPA, which are very selective for the rat A(1) receptor versus the human A(3) receptor, are substantially...

An efficient condensation reaction between nitrosoimidazoles and phenyl methylcarbazate forms the basis of a new synthetic route to phenyloxycarbonyl substituted triazenylimidazoles. Exposure of these triazenes to diffuse daylight is sufficient to induce (E) to (Z)-isomerization of the triazene –NN– bond, resulting in spontaneous formation of temoz...

A 6-step solid phase sequence towards C2,N6-disubstituted adenosine analogues was developed, which was validated by the construction of a small combinatorial library. Attachment of the 5′-OH of readily available 2′,3′-methoxymethylidene protected 6-chloropurine ribonucleoside onto carboxypolystyrene furnished the immobilised 6-chloropurine ribonucl...

Asymmetric Pictet–Spengler reactions with (R)-N-p-tolylsulfinyl-3,4-dimethoxyphenylethyl amine proceeded with high diastereoselectivity. Starting from the commercially available (R)- and (S)-Andersen reagents a highly efficient route to (+)- and (−)-salsolidine and related tetrahydroisoquinolines was developed.

A series of new 2-substituted adenosine derivatives was synthesised via addition and condensation reactions with 2-nitrosoadenosine triacetate 4. The exceptional reactivity of the adenosine nitroso functionality was demonstrated by reaction with, e.g., dienes (4 + 2 cycloaddition), cyclohexene (‘ene’ reaction), furans (addition/rearrangement) and w...

Two series of chemically related, conformationally restricted ring systems were synthesized. Bridged tetrahydro-β-carbolines, designed as selective 5-HT receptor ligands, were formed via Pictet–Spengler condensation of cyclic tryptamine precursors. Oxidation of the indole 2-position of the precursors followed by condensation with aldehydes produced...

Synthetic pathways are described for the synthesis of two naturally occurring β-carbolines, xestomanzamine A and B. The synthesis of aromatic xestomanzamine A was most conveniently achieved by way of a Grignard reaction in dichloromethane. This route is suitable for the synthesis of analogues with modifications in the imidazole ring of xestomanzami...

The influence of nitro substituents on the properties of adenosine and 1-deazaadenosine was studied. Combination of a nitro group at the 2-position with several N6 substituents such as cyclopentyl and m-iodobenzyl gave a series of analogues with good adenosine receptor affinity, showing directable selectivity for the A1, A2A and A3 adenosine recept...

In view of the importance of nucleoside analogs as enzyme inhibitors and adenosine receptor (ant)agonists, new adenosine analogs were prepared and their activities studied on adenosine deaminase

The influence of N-sulfinyl chiral auxiliaries on the stereochemistry of the Pictet-Spengler reaction has been investigated. From enantiopure (R)-N-p-toluenesulfinyltryptamine a new and efficient route to enantiopure tetrahydro-beta-carbolines has been established.

The influence of N-sulfinyl chiral auxiliaries on the stereochemistry of the Pictet-Spengler reaction has been investigated. From enantiopure (R)-N-beta-toluenesulfinyltryptamine a new and efficient route to enantiopure tetrahydro-beta-carbolines has been established.

Nitration reactions of 6-substituted purine nucleosides with tetrabutylammonium nitrate/trifluoroacetic anhydride (TBAN/TFAA) have been studied. This nitrating mixture selectively nitrates C-6 substituted purines at the 2-position, but the method is limited to substrates without NH or OH substituents. Acetylated 6-chloropurine riboside was cleanly...

To obtain selectively functionalized 1-deazapurine nucleosides, the nitrating mixture tetrabutylammonium nitrate/trifluoroacetic anhydride (TBAN/TFAA) has been studied. This mixture demonstrated several merits: the use of an easy to handle reagent, mild reaction conditions and high selectivity for nitration in the pyridine ring. Nitration occurred...

A general approach to 3-deaza-6-azapurine by a hetero Diels-Alder reaction is described. Reaction of sulfonamide protected 5-vinylimidazole with 4-phenyl-1,2,4-triazoline-3,5-dione in methanol gave the Diels-Alder adduct 8 in 85% yield. Deprotection of the resulting N-phenyltriazole was efficiently accomplished by ring opening with hydrazine follow...

A straightforward synthesis of the brominated marine alkaloids arborescidine A (1), B (2) and C (3), starting from 6-bromo-(N-methyl) trypatamine is described. An equilibrium, under both basic and acidic conditions was found to exist between the trans- and cis-isomers 3 and 4. Spectral data indicated that the structure of isomer 4 does not correspo...

A general method was developed for the synthesis of a variety of symmetric and asymmetric macrocyclic bispyridines. 3-Hydroxyalkylpyridines 18−20 were prepared, converted to the corresponding iodides and protected on the pyridine nitrogen with a p-methoxybenzyl group to give the crystalline precursors 21, 22 and 23. Reaction with a second 3-hydroxy...

New bridged β-carbolines were synthesized via a short synthetic route. The key step of the sequence is a Pictet-Spengler condensation under neutral conditions, employing a cyclic amine and several aldehydes. Using 5,5-diethoxypentanal gave a bridged analog which could be further ring closed to a new pentacyclic system.

Many of the alkaloids found in Nitraria and Lupine species can be envisaged to arise from two simple building blocks, namely tryptamine and tetrahydropyridine. In particular in the Nitraria species, the alkaloids occur as racemates in some cases, despite multi stereocenters. We assume that these alkaloids might be formed without interference of enz...

Many of the alkaloids found in Nitraria and Lupine species can be envisaged to arise from two simple building blocks, namely tryptamine and tetrahydropyridine. In particular in the Nitraria species, the alkaloids occur as racemates, in some cases, despite multi stereocenters. We assume that these alkaloids might be formed without interference of en...

A mild oxidative deamination reaction of tetrahydroanabasine O-methyloxime 17 is described, making use of an o-quinone that is based on topaquinone (TPQ, 11), the cofactor that is present in copper-containing amine oxidases. In situ ring closure of the oxidation product produced double-functionalized quinolizidine 5, containing an enamine functiona...

Porcine Kidney Diamine Oxidase (PKDO) was used to catalyse the oxidative transformation of Nitraria alkaloids. Nazlinin yielded indoloquinolizidine 4, an alkaloid which has been obtained as a natural product from Nitraria plant extracts. Oxidative deamination of 1-(4-butylamino)-β-carboline 10 with PKDO yielded an unstable aldehyde (11), which cycl...

The synthesis of a possible biosynthetic precursor (9) of nitraramine (1) is described, utilizing N-Boc-piperidone as an equivalent of didehydropiperidine 4. Heating this reactive, achiral intermediate 9 in aqueous solution results in the stereoselective formation of natural nitraramine via three successive cyclization reactions. Since nitraramine...

During studies towards the synthesis of a transition state inhibitor of the enzyme adenylosuccinate lyase, two different pyrimido[2, 1-i] purines were found, depending on the reaction conditions. It was shown that one of the products, formed under kinetically controlled reaction conditions can be converted in the thermodynamically more stable one v...

In the synthesis of a transition state inhibitor of the enzyme adenylosuccinate lyase two different [2,1-i]-pyrimido-purine derivatives are formed, of which one might be very interesting for cell biological research, due to its strong fluorescent properties.

Starting from tryptamine and dimeric piperidine derivative 8, the synthesis of 4, an immediate precursor in the biosynthesis of the Nitraria alkaloids, was accomplished. Cyclization of this achiral intermediate in aqueous solution produced a mixture of natural nitramidine 17 and one of its stereoisomers. Stereoselective reductions of these iminium...

The presence of rather complicated alkaloids in Nitraria species as racemates suggests a non-enzymic biosynthesis of the skeletons, which implies that these reactions should be reproducible in the lab. In the case of Nitramine and Nitraramine the total synthesis was approached starting from highly symmemc glutarimide derivatives. Insight in the bio...

A one-step synthesis of the β-carboline alkaloid nazlinin 2 from its likely biochemical precursors tryptamine and 2,3,4,5-tetrahydropyridine has resulted in a revision of its structure.

The Michael-induced spirocyclization of 2-alkylidene glutarimides offers a highly stereoselective method for a biomimetic synthesis of nitamine and for the construction of the nitraramine carbon-nitrogen framework.

Synthesis and properties of 4, a potential suicide inhibitor of adenylosuccinate lyase, capable of producing a reactive ketene (5) within the active site, are described.

Stereoselective addition reactions to the aldehyde function of some L-xylose derivatives, under the influence of Lewis acid catalysts, lead to the formation of tetrahydrofuran derivatives at low temperatures, depending on the acetal protecting groups used. Via separate reactions it was shown, that these tetrahydrofurans seemed to be intermediates i...

Triphenylphosphoranylideneacetamide undergoes Michael reactions with several acceptors, giving rise, apart from the normal Michael adducts, to the formation of different products like glutarimide ylides and stabilized iminophosphoranes. Wittig reactions with these new ylides lead to a variety of α,β-unsaturated carbonyl compounds.

Quinolizidine alkaloids are synthesized from glutarimide yields via a piperidine ring transformation that is based on the lupinine biosynthesis. A short enantioselective bispiperidine synthesis usingR-phenylglycinol as a chiral precursor is described.

Quinolizidine alkaloids are synthesized from glutarimide yields via a piperidine ring transformation that is based on the lupinine biosynthesis. A short enantioselective bispiperidine synthesis usingR-phenylglycinol as a chiral precursor is described.

Adenylosuccinate lyase is an essential enzyme in two steps of the biosynthesis of adenosine nucleotides. In the conversion IMP → AMP it catalyzes the elimination of fumaric acid from adenylosuccinate: We have been involved in the synthesis of adenylosuccinate analogs of different types. In these analogs the elimination of fumaric acid was inhibited...

Starting from simple phosphoranes, functionalized glutarimide phosphorus ylids were obtained. Wittig reactions with ribose derivatives produced the corresponding glutarimide nucleosidas. Conversion into deaza-thymidine derivatives was unsuccessful, due to the instability of the products.

Diels-Alder reactions with N-protected methyleneglutarimides are used to construct the spiro-framework during the synthesis of the title alkaloids.

Methyl acrylate (I) is coupled with the phosphorus ylide (II) to give the glutarimide ylide (III) which is olefinated, forming the 3-methyleneglutarimide (Va).