The Pictet-Spengler condensation of tryptamine (or a substituted analogue) with an aldehyde, usually in the presence of an excess of a Brønsted acid, [1] is the reaction of choice for the preparation of tetrahydro-b-carbolines (for example, 1), a structural moiety present in many alkaloids and related biologically active molecules. [2] Several strategies have been applied to the synthesis of tetrahydro-b-carbolines in enantiomerically pure form. It is possible to start with an enantiomerically pure chiral tryptamine, such as a tryptophan derivative, or aldehyde; alternatively, the use of a chiral auxiliary attached to the nitrogen atom has been successful. Two remarkable examples are the cyclization of the N-acyliminium ion 2, in which an a-N,Nphthaloylamino acid is used as a chiral auxiliary, [3] and the cyclization of the N-sulfinyliminium ion 3, with the use of menthyl p-toluenesulfinate as a chiral reagent.[4] The former procedure proceeds with very high diastereoselectivity, but the chiral auxiliary can be removed only under relatively harsh reductive conditions. Lower selectivity is observed with the second method, but the diastereomers are readily separable, and the sulfinyl auxiliary can be cleaved easily by mild hydrolysis.The first example of a reagent-controlled enantioselective Pictet-Spengler-type cyclization was reported by Nakagawa and co-workers.[5] They described the ring closure of nitrone 4 with up to 90 % ee under the influence of a chiral borane (ca. 2 equiv) as a Lewis acid. Two examples of catalytic asymmetric Pictet-Spengler reactions have been reported recently: Taylor and Jacobsen described the cyclization of the N-acyliminium ion 5 with up to 95 % ee under the catalysis of an enantiomerically pure thiourea, [6a] and List and co-workers disclosed the cyclization of the iminium diester 6 with up to 96 % ee under the catalysis of an enantiomerically pure phosphoric acid derived from binaphthol.[6b] Although both methods are impressive examples of the power of asymmetric organocatalysis, the former has the disadvantage that the Nacetyl group is difficult to remove, and the latter is clearly limited in scope by the requirement of two ester functionalities.Within our research program on the development of asymmetric reactions of iminium ions catalyzed by chiral Brønsted acids, we considered the use of N-sulfenyliminium ions as intermediates in the Pictet-Spengler condensation. [7] The sulfenyl substituent was expected to stabilize the intermediate iminium ion and thus favor Pictet-Spengler cyclization over undesired enamine formation.[8] Another advantage of the sulfenyl group is that its ready removal after the cyclization is ensured. Herein, we demonstrate the powerful combination of chiral phosphoric acids and Nsulfenyl tryptamines as a useful method for catalytic asymmetric Pictet-Spengler reactions.The use of phosphoric acids derived from binaphthol as chiral catalysts in asymmetric synthesis was shown recently by two Japanese research groups to be highly successful for the addition of...

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.

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.

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.

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.

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 Bacillus subtilis as an exemplar system. Within 5 min extensive intracellular cross-linking was detected, while intracellular cross-linking in a Gram-negative species, Escherichia coli, was still undetectable after 30 min, in agreement with the low permeability in this organism for lipophilic compounds like BAMG. We were able to identify 82 unique interprotein cross-linked peptides with <1% false discovery rate by mass spectrometry and genome-wide database searching. Nearly 60% of the interprotein cross-links occur in assemblies involved in transcription and translation. Several of these interactions are new, and we identified a binding site between the δ and β′ subunit of RNA polymerase close to the downstream DNA channel, providing a clue into how δ might regulate promoter selectivity and promote RNA polymerase recycling. Our methodology opens new avenues to investigate the functional dynamic organization of complex protein assemblies involved in bacterial growth. Data are available via ProteomeXchange with identifier PXD006287.

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 and aesthetic shape, the higher compactness as compared to regular spiro bicycles is noteworthy. To enable synthetic access to compact entangled multimacrocyclic molecules, we have developed a new strategy. The key element is a template, which is covalently connected to the linear precursors, and spatially directs the sterically congested backfolding macrocyclizations that are required to give quasi[1]catenanes. Similarly, quasi[1]rotaxanes are made.

A library of 2,N 6 -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 with large aromatic substitutions, such as N 6 -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-N 6 -cyclopentyladenosine (compound NA42) and 2-cyclopentylamino-N 6 -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,N 6 -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 trypanosomespecific target.