6 pags., 2 figs., 1 tab., 2 schs. ; (1R,5S)-2-Methyl-6,7-benzomorphan has been synthesised from (R)-(benzyloxy)(phenyl)acetaldehyde. On a 2-mmol scale Bi (OTf)3 promoted Aza-Prins reaction with N-tosylhomoallylamine afforded an 88/12 mixture of 6-oxa-2-azabicyclo[3.2.1]octanes. Major diastereoisomer was converted to enantiomerically pure (2S,4S)-2-benzyl-1- methylpiperidin-4-ol via a high-yielding sequence hydrogenolysis/N-detosylation/N-methylation. Acid-catalysed intramolecular Friedel−Crafts cyclisation of the piperidinol afforded (1R,5S)-2-methyl-6,7-benzomorphan in five steps with a yield of 25%. ; Financial support from the Government of Aragón (E45_20R) is acknowledged. ; Peer reviewed
New pyrrolidine-based organocatalysts with a bulky substituent at C2 were synthesized from chiral imines derived from (R)-glyceraldehyde acetonide by diastereoselective allylation followed by a sequential hydrozirconation/iodination reaction. The new compounds were found to be effective organocatalysts for the Michael addition of aldehydes to nitroolefins and enantioselectivities up to 85% ee were achieved. ; Financial support from the Government of Aragón (GA E-102) is acknowledged. A. C. thanks the Government of Aragón for a pre-doctoral fellowship. ; Peer reviewed
The successful enantioseparation of axially chiral amino acid derivatives containing a cyclohexylidene moiety on an analytical and semipreparative scale was achieved for the first time by HPLC using polysaccharide-based chiral stationary phases. Racemic methyl N-benzoylamino esters, easily obtained by methanolysis of the corresponding 5(4H)-oxazolones, were subjected to chiral HPLC resolution using chiral stationary phases based on immobilized 3,5-dimethylphenylcarbamate derivatives of amylose (Chiralpak® IA column) or cellulose (Chiralpak® IB column). The behaviour of both selectors under different elution conditions was evaluated and compared. The amylose column showed better performance than the cellulose column for all enantiomers tested. The semipreparative resolution of axially chiral amino acid derivatives with different side chains has been achieved on a 250mm×20mm ID Chiralpak® IA column using the appropriate mixture of n-hexane/chlorofom/ethanol as eluent by successive injections of a solution of the sample in chloroform. Using this protocol up to 120mg of each enantiomer of the corresponding axially chiral amino acid derivative were obtained from 300mg of racemate. [(Sa)-2a, 105mg; (Ra)-2a, 60mg, [(Sa)-2b, 105mg; (Ra)-2b, 90mg, [(Sa)-2c, 120mg; (Ra)-2c, 100mg]. ; The financial support of the Government of Aragón (GA E-102) is acknowledged. ; Peer Reviewed
Novel bifunctional pyrrolidine-based organocatalysts for the asymmetric Michael addition of carbonyl compounds to nitroolefins have been synthesised from homoallylamines, which are easily obtained from (R)-glyceraldehyde as a chiral precursor. Under optimal reaction conditions, these bifunctional organocatalysts showed a high catalytic efficiency (almost quantitative yield in most cases) and stereoselectivity in the Michael addition reactions of a variety of aldehydes (up to 98 : 2 dr and 97% ee) and ketones (up to 98 : 2 dr and 99% ee) to nitroolefins. ; Financial support from the Government of Aragón (GA E-102) is acknowledged. A. C. thanks the Government of Aragón for a pre-doctoral fellowship. ; Peer reviewed
The treatment of Parkinson's disease (PD), the second most common neurodegenerative human disorder, continues to be symptomatic. Development of drugs able to stop or at least slowdown PD progression would benefit several million people worldwide. SynuClean-D is a low molecular weight 2-pyridone-based promising drug candidate that inhibits the aggregation of α-synuclein in human cultured cells and prevents degeneration of dopaminergic neurons in a Caenorhabditis elegans model of PD. Improving SynuClean-D pharmacokinetic/pharmacodynamic properties, performing structure/activity studies and testing its efficacy in mammalian models of PD requires the use of gr-amounts of the compound. However, not enough compound is on sale, and no synthetic route has been reported until now, which hampers the molecule progress towards clinical trials. To circumvent those problems, we describe here an efficient and economical route that enables the synthesis of SynuClean-D with good yields as well as the synthesis of SynuClean-D derivatives. Structure-activity comparison of the new compounds with SynuClean-D reveals the functional groups of the molecule that can be disposed of without activity loss and those that are crucial to interfere with α-synuclein aggregation. Several of the derivatives obtained retain the parent's compound excellent in vitro anti-aggregative activity, without compromising its low toxicity. Computational predictions and preliminary testing indicate that the blood brain barrier (BBB) permeability of SynuClean-D is low. Importantly, several of the newly designed and obtained active derivatives are predicted to display good BBB permeability. The synthetic route developed here will facilitate their synthesis for BBB permeability determination and for efficacy testing in mammalian models of PD. ; This research was funded by Spanish Ministry of Science and Innovation (grants PID2019-107293GB-I00 to JS and PID2019-105017RB-I00 to SV), by Gobierno de Aragón, Spain (grants LMP30_18 and E45_20R to JS), by ICREA (ICREA-Academia 2015 to SV) and by "la Caixa" Banking Foundation, Spain (grant CaixaImpulse CI18-00019, to SV). AM was a recipient of a predoctoral FPU fellowship from the Spanish Government. ; Peer reviewed
Amyloid fibrils formed by a variety of peptides are biological markers of different human diseases, such as Alzheimer, Parkinson or Type II diabetes, and are structural constituents of bacterial biofilms. Novel fluorescent probes offering improved sensitivity or specificity towards that diversity of amyloid fibrils, or providing alternative spectral windows are needed to improve the detection or the identification of amyloid structures. One potential source for such new probes is offered by molecules known to interact with fibrils, such as the inhibitors of amyloid aggregation found in drug discovery projects. Here, we show the feasibility of the approach by designing, synthesizing and testing several pyrene-based fluorescent derivatives of a previously discovered inhibitor of the aggregation of the Aβ1-42 peptide. All the derivatives tested retain the interaction with the amyloid architecture and allow its staining. The more soluble derivative, compound 1D, stains similarly well amyloid fibrils formed by Aβ1-42, α-synuclein or amylin, provides a sensitivity only slightly lower than that of Thioflavin T, displays a large Stokes shift, allows an efficient excitation in the UV spectral region,and it is not cytotoxic. Compound 1D can also stain amyloid fibrils formed by Staphylococcal peptides present in biofilm matrices and can be used to distinguish, by direct staining,S. aureus biofilms containing amyloid forming phenol soluble modulins from those lacking them. ; IL is supported by the Spanish Ministry of Economy and Competitiveness grant BIO2014-53530-R. SVis supported by grant BIO2016-783-78310-R and by ICREA (ICREA Academia 2015). MDD is supported by the Government of Aragon (GA E-102). JS is supported by grants BFU2016-78232-P (MINECO, Spain) and E45_17R (Gobierno de Aragón, Spain). JS and IL acknowledge financial support from grant CI-2017/001-3 (Campus Iberus, Spain). AM was a recipient of a predoctoral FPU fellowship from the Spanish Government.
