Organocatalytic Enantioselective Strecker Reaction with Seven-Membered Cyclic Imines

[EN] A highly enantioselective Strecker reaction with dibenzo[b,f][1,4]oxazepines has been described using a dihydroquinine-derived thiourea as organocatalyst. The reaction affords chiral 10,11-dihydrodibenzo[b,f][1,4] oxazepine 11-carbonitrile derivatives in excellent yields (up to 99%) and excellent enantioselectivities (up to 98%) under mild reaction conditions.Financial support from the Agencia Estatal de Investigacion (Spanish Government) and Fondo Europeo de Desarrollo Regional (FEDER, European Union) (CTQ2017-84900-P) is acknowledged. C. V. thanks the Spanish Government for a Ramon y Cajal contract (RyC-2016-20187). Access to NMR, MS and X-ray facilities from the Servei central de suport a la investigacio experimental (SCSIE)-UV is also acknowledged.Lluna Galán, C.; Blay, G.; Fernández, I.; Muñoz Roca, MDC.; Pedro, JR.; Vila, C. (2018). Organocatalytic Enantioselective Strecker Reaction with Seven-Membered Cyclic Imines. Advanced Synthesis & Catalysis. 360(19):3662-3666. https://doi.org/10.1002/adsc.201800754S366236663601

A truly green synthesis of α-aminonitriles via Strecker reaction

Background: The classical Strecker reaction is one of the simplest and most economical methods for the synthesis of racemic a-aminonitriles (precursor of a-amino acids) and pharmacologically useful compounds. Results: Indium powder in water is shown to act as a very efficient catalyst for one-pot, three-component synthesis of a-aminonitriles from diverse amines, aldehydes and TMSCN. This general rapid method is applicable to a wide range of amines and aldehydes and produces products in excellent yield. Conclusions: The present one-pot, three-component environmentally benign procedure for the synthesis of aaminonitriles will find application in the synthesis of complex biologically active molecules

Synthesis of Benz(f)tryptophan and Constrained Amino Acid Derivatives as Fluorescence Probes.

Constrained amino acids and benzannulated analogs of indole were synthesized as potential fluorescence probes of peptide structure. 1-Amino-2-(3-indolyl)-cyclohexane-1-carboxylic acid (W3) is a rotationally-restricted tryptophan analog whose C\sb\alpha-C\sb\beta bond is part of a 6-membered ring. Friedel-Crafts reaction between $\alpha$-hydroxycyclohexanone and indole affords 2-(3-indolyl)cyclohexanone which is further converted into its corresponding spirohydantoin derivative via Strecker reaction. Basic hydrolysis of this hydantoin derivative with Ba(OH)\sb2 in oxygen-free water at 250\sp\circC in a Parr\sp\circler high pressure bomb afforded the constrained tryptophan analog. N-(t-Boc)piperidine-4-amino-4-carboxylic acid is a constrained Aib analog. Treatment of 4-piperidinone monohydrate hydrochloide with triethyl amine, catalytic amounts of N,N-dimethylamino pyridine and di-tert-butyl dicarbonate affords N-(t-Boc)-4-piperidinone which is transformed into its corresponding spirohydantoin derivative via Strecker reaction. This hydantoin derivative is fully reacted with di-tert-butyl dicarbonate and hydrolyzed with aq. 1N LiOH in THF to provide the desired a-amino acid product. Benz (f) indole is synthesized via Batcho-Leimbruger reaction between 3-methyl-2-nitronaphthalene and a mixture of pyrrolidine/N,N-dimethylformamide dimethyl acetal followed by hydrogenation at 30 p.s.i. 3-Methyl-benz (f) indole is synthesized via palladium-catalyzed cyclization reaction between 3-bromo-2-aminonaphthalene and 1-trimethylsilyl-propyne in refluxing acetonitrile followed by reflux with HC1. Progress towards the synthesis of benz (f) tryptophan using 3-bromo-2-aminonaphthalene and several terminal-silated alkyne derivatives via palladium-catalyzed cyclization reactions is also reported

Lewis base-catalyzed three-component Strecker reaction on water. An efficient manifold for the direct α-cyanoamination of ketones and aldehydes

The first three-component organocatalyzed Strecker reaction operating on water has been developed. The manifold utilizes ketones (aldehydes) as the starting carbonyl component, aniline as the primary amine, acetyl cyanide as the cyanide source and N,N-dimethylcyclohexylamine as the catalyst. © 2009 The Royal Society of Chemistry.This work was supported by the Spanish by the Spanish Ministerio de Ciencia e Innovación and the European Regional Development Fund (CTQ2005-09074-C02-02 and CTQ2008-06806-C02-02), the Spanish MSC ISCIII (RETICS RD06/0020/1046) and Fundación Instituto Canario de Investigación del Cáncer (FICIC-REDESFAC). F.C. A thanks CSIC for a predoctoral JAE grant.Peer Reviewe

A silicon-labelled amino acid suitable for late-stage fluorination and unexpected oxidative cleavage reactions in the preparation of a key intermediate in the Strecker synthesis

A novel silicon-substituted phenylalanine derivative was prepared using the Strecker amino acid synthesis. An unexpected oxidative cleavage was observed in the preparation of the aldehyde required for the Strecker reaction. In this step, a homobenzylic alcohol intermediate was oxidatively cleaved to the corresponding benzaldehyde using either chromium or palladium based oxidants. This undesired side reaction was overcome through the use of Dess-Martin Periodinane, or through an efficient TEMPO-bleach oxidation. The amino acid prepared in this study was then labelled with fluoride in aqueous solvent using a range of fluoride sources. The efficiency of this labelling motivates future studies in late-stage fluorination of peptide and protein therapeutics for use in positron emission tomography

Semi-synthesis of a novel library of alkaloids as potential selective analgesics

Semi-synthetic compounds are an important part of the therapeutic drug discovery process. The goals of the project were to synthesize different generations of matrine analogues in order to gain many opportunities to manipulate the core structure. The long-term goal was, by manipulating the structure, the possibility to increase the biological activity of the original compound while also decreasing the toxicity. The first-generation matrine analogue allows for a synthesis similar to the Striker reaction producing aminonitriles. An alkyne coupling reaction was also possible with the modification, producing propargyl-amines. Both of the reactions resulted in the addition of a triple bond substituent to the final products; increasing complexity and making the products not easily metabolized in the body, therefore able reach the target of interest. The second-generation matrine derivative was reacted with epoxides to produce amino alcohols. Aminonitriles, propargyl-amines, and amino alcohols are known to be backbones of therapeutic drug compounds. The compounds synthesized were later experimented on chronic myeloid leukemia (CML) cells, also in combination with the manufactured drug Imatinib, in order to inhibit the BCR-ABL kinase activity in the CML cell lines E255K and T315I

INVESTIGATION OF CYANO-METHYLATION REACTION BY CYANO-HYDRINE AND ITS DETERMINATION IN TOBACCO-SMOKE. ( STRECKER-REACTIONS )

The results of our research work [1-7] of several years aimed at the binding of the unhealthy components of tobacco smoke directed our attention to the analysis and identification of the unknown peak observed during the high sensitivity radiochromatographic analysis of tobacco smoke condensates.It was a fruitless effort to remove the formaldehyde, the ac- etaldehyde and hydrogen cyanide present in tobacco smoke, or even to try to eliminate them separately, during the analysis the new, unknown peak appeared again and again on the radiochromatogram. During our research work we stated, that we were facing the Strecker reaction [8-9], known since 1850, that is, with the formation of cyanohydrine of the aldehydes and hydrogen cyanide present in tobacco smoke, corresponding to the new peak. Cyanohydrines to react quickly and energetically with basic aminoacids, during which reaction cyanomethyl derivatives are being formed. This reaction is proceeding also under physiological circumstances with the basic amino groups of proteins, contributing to the development of respiratory and cardiovascular insufficiencies. By means of model reactions and using solutions of tobacco smoke gases the process of the reaction was proved in a primary way, also its circumstances having been cleared. By radiochromatographic measurements it was proved that the labelled L-lysine-6 H is being cyanomethylated by formaldehyde-cyanohydrin at an extraordinary speed and cyanomethylation is complete within a very short time (5 min). The tests carried out on formaldehyde- C, cyanide- C and inactive L-lysine led to similar results, with a yield 93.9 percent within 5 min in all these cases. It was proved also by 13C NMR, 13C NMR DEPT and 1H NMR spectroscopic measurements that inactive L-lysine is cyanomethylated by cyanohydrine in an extraordi- narily energetic and quick reaction, according to the reaction mechanism supposed by us. Our results obtained during the radiochromatographic analysis of tobacco smoke conden- sate agreed in all respects with the model test results. That is, the cyanohydrine formation is proceeding very quickly in the tobacco smoke too (by the reaction of aldehydes with hydrogen cyanide contained by tobacco smoke) which can be unequivocally traced back to the Strecker-reaction recognized 140 years ago. The mechanism of the reaction was described by LAPWORTH in 1903. [10)