Martin J. Wanner

Enantioselective BINOL-Phosphoric Acid Catalyzed Pictet-Spengler Reactions of N-Benzyltryptamine

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-substituted BINOL-phosphoric acid proved to be the catalyst of choice for the reaction with aromatic aldehydes. For the aliphatic aldehydes, 3,5-bistrifluoromethylphenyl-substituted BINOL-phosphoric acid was identified as the best catalyst.

Organocatalytic Enantioselective Total Synthesis of (−)-Arboricine

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 published structure in the original paper.

Total Synthesis of (+)-Yohimbine via an Enantioselective Organocatalytic Pictet–Spengler Reaction

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 earlier reported by Jacobsen. These two key steps constitute the basis for a nine-step total synthesis of (+)-yohimbine from tryptamine. A similar asymmetric Pictet-Spengler reaction was applied to the synthesis of an intermediate in the recent total synthesis of corynantheidine by Sato.

2,N6-disubstituted adenosine analogs with antitrypanosomal and antimalarial activities

ABSTRACT 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 substitutions, such as N6-2,2-diphenylethyl and naphthylmethyl, which could indicate a mechanism of action through aromatic stacking with heme in the digestive vacuole of Plasmodium spp. The activities against Trypanosoma cruzi trypomastigotes and Leishmania donovani amastigotes were generally low; but several analogs, particularly those with cyclopentylamino substitutions, displayed potent activities against Trypanosoma brucei rhodesiense and T. b. brucei bloodstream forms in vitro. The most active were 2-cyclopentylamino-N6-cyclopentyladenosine (compound NA42) and 2-cyclopentylamino-N6-cyclopentyladenine (compound NA134), with the nucleobase an order of magnitude more potent than the nucleoside, at 26 ± 4 nM. It was determined that the mode of action of these purines was trypanostatic, with the compounds becoming trypanocidal only at much higher concentrations. Those 2,N6-disubstituted purines tested for their effects on purine transport in T. b. brucei displayed at best a moderate affinity for the transporters. It is highly probable that the large hydrophobic substitutions, which bestow high calculated octanol-water coefficient values on the analogs, allow them to diffuse across the membrane. Consistent with this view, the analogs were as effective against a T. b. brucei strain lacking the P2 nucleoside transporter as they were against the parental strain. As the analogs were not toxic to human cell lines, the purine analogs are likely to act on a trypanosome-specific target.

Organocatalytic Enantioselective Pictet–Spengler Reactions for the Syntheses of 1-Substituted 1,2,3,4-Tetrahydroisoquinolines

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 recrystallized to high enantiomeric purity. Using this methodology we synthesized the natural products (R)-crispine A, (R)-calycotomine and (R)-colchietine, the synthetic drug (R)-almorexant and the (S)-enantiomer of a biologically active (R)-AMPA-antagonist.

Enantiopure tetrahydroisoquinolines via N-sulfinyl Pictet–Spengler reactions

Abstract 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.

An efficient hetero Diels-Alder approach to imidazo[4,5-c]pyridazines as purine analogues

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 followed by heating in DMSO. The completely deprotected and aromatized purine analogue 1 was obtained directly from this one-pot reaction in 48% yield, o 1998 Elsevier Science I.Id. All rights reserved.

Stereospecific synthesis of (+)- and (-)-sesbanimide A

Abstract Starting from L-xylose and D-xylose derivatives, (-)-sesbanimide A and (+)-sesbanimide A, respectively, have been synthesized. The carbohydrate templates constitute ring B of the alkaloid on which the remaining two rings are constructed in the sequence B → AB → ABC.

SYNTHESIS OF THE BROMINATED MARINE ALKALOIDS ()-ARBORESCIDINE A, B AND C

Abstract 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 correspond with the compound identified as arborescidine D recently isolated from the marine tunicate Pseudodistoma arborescens .

Organocatalytic Enantioselective Pictet-Spengler Approach to Biologically Relevant 1-Benzyl-1,2,3,4-Tetrahydroisoquinoline Alkaloids

A general procedure for the synthesis of 1-benzyl-1,2,3,4-tetrahydroisoquinolines was developed, based on organocatalytic, regio- and enantioselective Pictet-Spengler reactions (86-92% ee) of N-(o-nitrophenylsulfenyl)-2-arylethylamines with arylacetaldehydes. The presence of the o-nitrophenylsulfenyl group, together with the MOM-protection in the catechol part of the tetrahydroisoquinoline ring system, appeared to be a productive combination. To demonstrate the versatility of this approach, 10 biologically and pharmaceutically relevant alkaloids were prepared using (R)-TRIP as the chiral catalyst: (R)-norcoclaurine, (R)-coclaurine, (R)-norreticuline, (R)-reticuline, (R)-trimemetoquinol, (R)-armepavine, (R)-norprotosinomenine, (R)-protosinomenine, (R)-laudanosine, and (R)-5-methoxylaudanosine.