Hydrazones as Singular Reagents in Asymmetric Organocatalysis

This Minireview summarizes strategies and developments regarding the use of hydrazones as reagents in asymmetric organocatalysis, their distinct roles in nucleophile–electrophile, cycloaddition, and cyclization reactions. The key structural elements governing the reactivity of these reagents in a preferred pathway will be discussed, as well as their different interactions with organocatalysts, leading to diverse activation modes. Along these studies, the synthetic equivalence of N-monoalkyl, N,N-dialkyl, and N-acyl hydrazones with several synthons is also highlighted. Emphasis is also put on the mechanistic studies performed to understand the observed reactivities. Finally, the functional group transformations performed from the available products has also been analyzed, highlighting the synthetic value of these methodologies, which served to access numerous families of valuable multifunctional compounds and nitrogen-containing heterocycles.Ministerio de Economía y Competitividad CTQ2013-48164-C2-1-P, CTQ201348164-C2-2-PEuropean FEDER fundsJunta de Andalucía 2012/FQM 107

Solvent-free synthesis of quaternary α-hydroxy α-trifluoromethyl diazenes: the key step of a nucleophilic formylation strategy

An efficient, scalable and operationally simple one-pot, 2-step strategy for the nucleophilic formylation of trifluoromethyl ketones is presented. The key step is an unprecedented diaza-carbonyl-ene reaction of formaldehyde tert-butyl hydrazone and trifluoromethyl ketones under solvent-free conditions. This reaction proved to be very fast, clean and high-yielding, affording densely functionalised α-hydroxy α-trifluoromethyl diazenes. The ensuing diazene-to-aldehyde transformation, avoiding protection/deprotection reactions and chromatographic purifications, and subsequent derivatizations in a one-pot fashion provide a direct entry to a variety of useful trifluoromethylated building blocks.We acknowledge support by the CSIC Open Access Publication Initiative through its Unit of Information Resources for Research (URICI).This work was supported by the Ministerio de Economía y Competitividad of Spain (CTQ2013-48164-C2-1-P, CTQ2013-48164-C2-2-P, and predoctoral fellowship to E. M.), European FEDER funds and the Junta de Andalucía (Grant 2012/FQM 1078). D. M. acknowledges Universidad de Sevilla for a postdoctoral contract.Peer reviewe

Synthesis of enantioenriched azo compounds: Organocatalytic Michael addition of formaldehyde N-tert-butyl hydrazone to nitroalkenes

The unprecedented diaza-ene reaction of formaldehyde N-tert-butyl hydrazone with nitroalkenes can be efficiently catalyzed by an axially chiral bis-thiourea to afford the corresponding diazenes in good to excellent yields (60-96%) and moderate enantioselectivities, up to 84 : 16 er; additional transformation of diazenes into their tautomeric hydrazones proved to be operationally simple and high-yielding, affording bifunctional compounds which represent useful intermediates for the synthesis of enantioenriched β-nitro-nitriles and derivatives thereof.Ministerio de Ciencia e Innovación CTQ2010-15297, CTQ2010-14974Junta de Andalucía 2008/ FQM-3833, 2009/FQM-453

Formaldehyde tert-butyl hydrazone as a formyl anion equivalent: asymmetric addition to carbonyl compounds

The asymmetric 1,2-addition of formyl anion equivalents to carbonyl compounds is a powerful synthetic tool that ideally provide access to highly functionalizable a-hydroxy aldehydes in an enantioselective fashion. In this context, the nucleophilic character of formaldehyde hydrazones, together with their remarkable stability as monomeric species, has been exploited for the functionalization of diverse carbonyl compounds, using initially auxiliary-based methodologies and, more recently, catalytic enantioselective versions. This feature article highlights our research progress employing formaldehyde tert-butyl hydrazone as a versatile formyl anion equivalent, in combination with bifunctional H-bonding organocatalysis. The design and optimization of different catalytic systems, focusing on a dual activation of both reagents, is reviewed, as well as the racemization free unmasking of the formyl group and representative product transformations for the construction of valuable, densely functionalyzed chiral building blocks.Ministerio de Economía y Competitividad de España (MINECO).CTQ2016-76908-C2-1-P y CTQ2016-76908-C2-2-PFondos FEDER de la Unión Europea y Junta de Andalucía. P18-FR-3531 y US126286

Hydrazones as Singular Reagents in Asymmetric Organocatalysis

This Minireview summarizes strategies and developments regarding the use of hydrazones as reagents in asymmetric organocatalysis, their distinct roles in nucleophile–electrophile, cycloaddition, and cyclization reactions. The key structural elements governing the reactivity of these reagents in a preferred pathway will be discussed, as well as their different interactions with organocatalysts, leading to diverse activation modes. Along these studies, the synthetic equivalence of N-monoalkyl, N,N-dialkyl, and N-acyl hydrazones with several synthons is also highlighted. Emphasis is also put on the mechanistic studies performed to understand the observed reactivities. Finally, the functional group transformations performed from the available products has also been analyzed, highlighting the synthetic value of these methodologies, which served to access numerous families of valuable multifunctional compounds and nitrogen-containing heterocycles.Peer Reviewe

Asymmetric Organocatalytic Synthesis of Fluorinated β-Hydroxy Diazenes

The nucleophilic addition of formaldehyde tert-butyl hydrazone to fluoromethyl ketones provides a valuable tool for the synthesis of highly functionalized β-hydroxy β-tri- and difluoromethyl diazenes. Excellent reactivities and moderate to good enantioselectivities (up to 90 % ee) were achieved by H-bonding activation exerted by tert-Leucine derived H-bonding (squaramide or thiourea) organocatalysts. Subsequent derivatizations in one-pot fashion provide synthetically useful intermediates for target-oriented synthesis: tri- and di-fluoromethylated azoxy compounds, β-amino alcohols, α-hydroxy aldoximes and derivatives thereof.Ministerio de Economía y Competitividad CTQ2016-76908-C2-1-P, CTQ2016-76908-C2-2-PJunta de Andalucía 2012/FQM107

Asymmetric organocatalytic Strecker-type reactions of aliphatic N,N-dialkylhydrazones

The enantioselective organocatalytic Strecker-type reaction of aliphatic N,N-dialkylhydrazones is presented. Using trimethylsilyl cyanide (TMSCN) as the cyanide source, the reaction can be efficiently catalyzed by a tert-leucine-derived bifunctional thiourea to afford the corresponding hydrazino nitriles in good to excellent yields (50-96%) and moderate to good enantioselectivities, up to 86% ee. Further transformations of the nitrile functionality allow access to useful protected hydrazino acids and imidazolidinones. Interestingly, some of the hydrazino nitriles and their derivatives could be recrystallized in high recovery, yielding essentially pure enantiomers.Ministerio de Ciencia e Innovación CTQ2010-15297, CTQ2010-14974Junta de Andalucía 2008/FQM-3833, 2009/FQM-453

Pyridine–hydrazone ligands in enantioselective palladium-catalyzed Suzuki–Miyaura cross-couplings

The geometries and coordination properties of modular pyridineehydrazone N,N-ligands containing C2- symmetric trans-2,5-diphenylpyrrolidine and trans-2,5-diphenylpiperidine as the terminal dialkylamino units have been analyzed by X-ray diffraction analysis of [PdCl2(N,N)] complexes [(N,N)¼pyridine hy- drazone ligand]. In combination with Pd(OAc)2 as the precatalyst, these ligands provide high enantio- selectivities (up to 95:5 er) in asymmetric SuzukieMiyaura cross couplings of 2-methoxy-1-naphthyl bromides with 1-naphthyl and 2-tolyl boronic acids.Ministerio de Economía y Competitividad TQ2013-48164-C2-1-P, CTQ2013- 48164-C2-2-P, CTQ2014-51912-REDC, RYC-2013-12585Junta de Andalucía 2012/FQM 107

Early Detection of Cystic Fibrosis Acute Pulmonary Exacerbations by Exhaled Breath Condensate Metabolomics

The most common cause of death in cystic fibrosis (CF) patients is progressive lung function decline, which is punctuated by acute pulmonary exacerbations (APEs). A major challenge is to discover biomarkers for detecting an oncoming APE and allow for pre-emptive clinical interventions. Metabolic profiling of exhaled breath condensate (EBC) samples collected from CF patients before, during, and after APEs and under stable conditions (n = 210) was performed using ultraperformance liquid chromatography (UPLC) coupled to Orbitrap mass spectrometry (MS). Negative ion mode MS data showed that classification between metabolic profiles from "pre-APE" (pending APE before the CF patient had any signs of illness) and stable CF samples was possible with good sensitivities (85.7 and 89.5%), specificities (88.4 and 84.1%), and accuracies (87.7 and 85.7%) for pediatric and adult patients, respectively. Improved classification performance was achieved by combining positive with negative ion mode data. Discriminant metabolites included two potential biomarkers identified in a previous pilot study: Lactic acid and 4-hydroxycyclohexylcarboxylic acid. Some of the discriminant metabolites had microbial origins, indicating a possible role of bacterial metabolism in APE progression. The results show promise for detecting an oncoming APE using EBC metabolites, thus permitting early intervention to abort such an event.Fil: Zang, Xiaoling. Georgia Institute of Techology; Estados UnidosFil: Monge, Maria Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; ArgentinaFil: Gaul, David A.. Georgia Institute of Techology; Estados UnidosFil: McCarty, Nael A.. University of Emory; Estados UnidosFil: Stecenko, Arlene. University of Emory; Estados UnidosFil: Fernández, Facundo M.. Georgia Institute of Techology; Estados Unido