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Treatment of cis-fused bicyclic diene dicarboxylates with Li/naphthalene triggers a tandem ring-opening and transannular cyclization process that stereoselectively yields hydroazulenes and hydrindanes derivatives. Cyclononadienyl diesters, which can be isolated after the ring-opening step by judicious choice of the reaction conditions, undergo a tandem conjugate addition/intramolecular Michael addition upon treatment with chiral lithium amides to give bicyclic β-amino esters in a process where 4 contiguous stereocenters are formed with high diastereocontrol. A concise route toward the highly enantioenriched AEF ring core of the aconitine-type alkaloids has been developed as an application of this methodology. The starting cis-fused bicyclic dicarboxylates are easily prepared in one step by reductive alkylation of diisopropyl phthalate (Na/THF, followed by the appropriate bis-electrophiles).

A práctica de calquera ciencia natural ten moitísimo de pescuda intelectual que persegue comprender en profundidade os fenómenos observados e a súas causas e, como corolario dese entendemento, xerar a posibilidade de controlalos para facelos (máis) útiles. Cal sería, entón, un bo consello que un investigador veterano podería darlle a un mozo que emprende a súa primeira peregrinación polos camiños da investigación en Química? Sen dúbida, que encha a súa mochila intelectual coa Lóxica de Aristóteles, as ensinanzas de Os Tres Príncipes de Serendip, a Mecánica Cuántica e a Táboa Periódica. E se carga tamén unha navalla de Ockham en vez dunha suíza, moito mellor.

1,2-Aromatic diesters can be transformed into strained bridged polycyclic structures by a two-step procedure consisting of an initial reductive alkylation promoted by alkaline metals, followed by a...

Lithiation reactions of tertiary benzylic esters and carbamates have been studied. Kinetic methodology revealed that a two-step reaction pathway should be considered for these reactions, where either the lithium precomplexation and/or the proton transfer steps can be rate determining. Kinetic isotopic effects were evaluated by comparison of the lithiations of the corresponding protio/deutero substrates, and the results obtained support the notion that lithium precomplexation is taking place on the reaction pathway and that it is the rate-determining step in this transformation.

1,2-Aromatic diesters can be transformed into strained bridged polycyclic structures by a two-step procedure consisting of an initial reductive alkylation promoted by alkaline metals, followed by a reaction of the resulting unsaturated diesters with Me

This is the peer reviewed version of the following article:Navarro-Vázquez, A., Santamaría-Fernández, R., & Sardina, F. (2018). MSpin-JCoupling. A modular program for prediction of scalar couplings and fast implementation of Karplus relationships. Magnetic Resonance In Chemistry, 56(6), 505-512, which has been published in final form at https://doi.org/10.1002/mrc.4667. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions MSpin‐JCoupling is a modular program for the prediction of scalar couplings using a large variety of Karplus relationships. The program was specially designed for small molecule analysis and can be run in graphical or command‐line mode. The architecture of the program is highly modular, and new equations can be rapidly implemented, through a complete C++ programming interface, and deployed as run‐time loadable plugins Ministerio de Ciencia e Innovación. Grant Number: PET2008‐074 Consellería de Cultura, Educación e Ordenación Universitaria, Xunta de Galicia. Grant Number: Consellería de Educación 2009/071 Spanish Ministerio de Ciencia e Innovación. Grant Number: PET2008‐074 Xunta de Galicia for a Parga Pondal. Grant Number: Consellería de Educación 2009/071 SI

A series of dibenzo [n.2.2] bicyclic compounds (n = 2–20) were prepared in one step and good yields starting from dimethyl anthracene-9,10-dicarboxylate. Reduction of the aromatic diester using lithium/naphthalene led to a bis-enolate that was cyclized with a variety of bis-electrophiles. The ease of the cyclization is probably due to the puckered conformation of the intermediate formed after the first alkylation step, in which the newly introduced chain that will become the bridge portion occupies a pseudoaxial position, positioning the leaving group close to the enolate nucleophile in the macrocyclization step This work was supported by the Ministerio de Economía y Competitividad of Spain (CTQ2011-22436) and Xunta de Galicia (PGIDIT10-PXIB209113PR, 10PXIB209155PR, and 2007/085) SI

This is the peer reviewed version of the following article: Domínguez, J., Fernández-Nieto, F., Brea, J., Catto, M., Paleo, M., & Porto, S. et al. (2016). 8-Aminomethyl-7-hydroxy-4-methylcoumarins as Multitarget Leads for Alzheimer's Disease. Chemistryselect, 1(11), 2742-2749, which has been published in final form at https://doi.org/10.1002/slct.201600735. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions This work is part of our ongoing research in the discovery of multitarget therapeutic agents for Alzheimer's disease (AD). A literature screening, based on our recently proposed pharmacophore, led to the identification of 8‐aminomethyl‐7‐hydroxy‐4‐methyl coumarins as potential multitarget leads for AD. The results of a computer‐assisted protocol developed by us to validate multitarget hits for AD indicated that our coumarin candidates were viable leads only for AChE inhibition as later validated by biological assays. The results of BChE binding and propidium displacement assays indicate that our first generation compounds bind to the PAS site in AChE. We designed new generations of coumarin derivatives with a longer substituent at position 8 aimed at leads with more efficient interaction at the catalytic anionic site (CAS). Inhibition data and docking simulations indicated that an anilino‐capping group reached the CAS region of AChE and determined also a higher inhibitory potency towards BChE. The best compound obtained, with a N‐benzylpiperidine fragment, displayed sub‐micromolar affinity for AChE, affinity for BChE, and precluded Aβ‐amyloid aggregation with a potency similar to that of 9,10‐anthraquinone, making it a multitarget lead viable for further improvement Financial support from the Ministerio de Economia y Competitividad of Spain (Project CTQ2014‐55208‐P) and the Xunta de Galicia (10CSA209063PR and GRC2014/029) is gratefully acknowledged. The Italian authors thank the University of Bari for partial financial support (Fondi di Ateneo 2014–2015) SI

Sn-Li exchange equilibria have allowed the quantification of the stabilizing effect of cation-pi interactions in organolithium chemistry. Stabilization energy data on the effect of Li-pi complexation of an aromatic ring or a CC double bond in organolithium compounds are presented. The amount of stabilization gained by complexation of the Li atom with a pi system in alpha-oxy-organolithium compounds is quite comparable to the one observed in systems containing Li-N or Li-O interactions.

A ΔGeq stability scale of secondary a-oxy-organolithium compounds was established from measurements of tin-lithium exchange equilibria in THF, and the quantitative effects of substituents at the anionic center on carbanion stability are presented. A new lead-lithium exchange equilibrium reaction was also investigated and shown to be a very useful alternative for the determination of the relative stability of the more sterically hindered organolithium compounds. Alkyl groups adversely affect the stability of organolithium compounds when attached to the carbon bearing the negative charge, but the extent of this effect is highly dependent on the nature of the rest of the substituents attached to the anionic center. Quantitative data on the stabilization imparted to organolithium compounds by Li-O and Li-N chelation have been determined for a variety of systems. The for mation of four- and five-membered chelate rings leads to a considerable stabilization of the organolithium compound, while chelation through the formation of six-membered rings affords no extra stabilization to this type of organometallics. Multinuclear NMR experiments carried out on several α-oxyorganolithium compounds to determine their aggregation state are supportive of these species being monomers in THF solution. © 2007 Wiley-VCH Verlag GmbH & Co. KGaA.

A two-step, stereoselective procedure for the synthesis of nine- and ten-membered carbocycles from readily available phthalates is described. A variety of dialkyl phthalates have been transformed into [6,n]-fused bicyclo systems (n = 5, 6, 7) by a dearomatization/cyclization process and then converted into cyclonona- and cyclodecadienes through a bond cleavage reaction, whereby both processes are promoted by alkaline metals in THF.

Reaction of Me3SnLi with aromatic and heteroaromatic diesters proceeds through a fast stanna-Brook rearrangement that generates an stable bis-enolate which can be regioselectively alkylated and cyclized, in one step, to bicyclic compounds containing 6,5-, 6,6-, and 6,7-fused ring systems.

The application of a lossy data compression algorithm based on wavelet transform to 2D NMR spectra is presented. We show that this algorithm affords rapid and extreme compression ratios (e.g., 800:1), providing high quality reconstructed 2D spectra. The algorithm was evaluated to ensure that qualitative and quantitative information are retained in the compressed NMR spectra. Whilst the maximum compression ratio that can be achieved depends on the number of signals and on the difference between the most and the least intense peaks (dynamic range), a compression ratio of 80:1 is affordable even for the challenging case of homonuclear 2D experiments of large biomolecules.

Magnetic Resonance Companion (MestRe-C) is a software package that offers state-of-the-art facilities for data processing, visualization, and analysis of high-resolution nuclear magnetic resonance (NMR) data, combined with a robust, user-friendly graphical interface that fully exploits the power and flexibility of the Windows platform. The program provides a variety of conversion facilities for most NMR spectrometer formats and includes all the conventional processing, displaying, and plotting capabilities of an NMR program, as well as more advanced processing techniques. A brief review of the basic concepts of NMR data processing is included also. © 2003 Wiley Periodicals, Inc. Concepts Magn Reson Part A 19A: 80–96, 2003.

A two-step, stereoselective procedure for the synthesis of nine- and ten-membered carbocycles from readily available phthalates is described. A variety of dialkyl phthalates have been transformed into [6,n]-fused bicyclo systems (n = 5, 6, 7) by a dearomatization/cyclization process and then converted into cyclonona- and cyclodecadienes through a bond cleavage reaction, whereby both processes are promoted by alkaline metals in THF This work was supported by the Spanish MINECO (CTQ2011-22436), and the Xunta de Galicia (GRC2014/029) SI

Alzheimer’s disease is a neurodegenerative pathology with unmet clinical needs. A highly desirable approach to this syndrome would be to find a single lead that could bind to some or all of the selected biomolecules that participate in the amyloid cascade, the most accepted route for Alzheimer disease genesis. In order to circumvent the challenge posed by the sizable differences in the binding sites of the molecular targets, we propose a computer-assisted protocol based on a pharmacophore and a set of required interactions with the targets that allows for the automated screening of candidates. We used a combination of docking and molecular dynamics protocols in order to discard nonbinders, optimize the best candidates, and provide a rationale for their potential as inhibitors. To provide a proof of concept, we proceeded to screen the literature and databases, a task that allowed us to identify a set of carbazole-containing compounds that initially showed affinity only for the cholinergic targets in our experimental assays. Two cycles of design based on our protocol led to a new set of analogues that were synthesized and assayed. The assay results revealed that the designed inhibitors had improved affinities for BACE-1 by more than 3 orders of magnitude and also displayed amyloid aggregation inhibition and affinity for AChE and BuChE, a result that led us to a group of multitarget amyloid cascade inhibitors that also could have a positive effect at the cholinergic level Financial support from the Ministerio de Economia y Competitividad of Spain (Project CTQ2011-22436) and the Xunta de Galicia (CN2011/047 and 10CSA209063PR) is gratefully acknowledged SI

Quantitative thermodynamic stability scales of organolithium compounds can be derived from measurements of tin-lithium exchange equilibria. A DeltaG(eq) scale of alpha-oxy- and alpha-aminoorganolithium compounds was established, and quantitative stabilization effects of O-alkyl, O-alkoxyalkyl, O-carbamoyl, N-carbamoyl, and O-carbonyl groups of the alpha-carbanion are presented. It has been found that an alpha-oxycarbanion is far better stabilized by a carbonyl group as the O-substituent than by an alkyl or alkoxyalkyl group, while the anion-stabilizing effects of the different O-carbonyl substituents are comparable. An N-carbamoyl group was found to have a somewhat higher stabilizing effect than its O-carbamoyl counterpart. NMR data are presented that show that benzylic N- or O-substituted carbanions have highly planarized structures where the negative charge is highly delocalized. The stability data obtained from the tin-lithium exchanges can be easily converted into "effective pK" data that are useful for predicting the acid-base behavior of this type of organolithium species.

The complexation of an anionic guest by a cationic water-soluble pillararene is reported. Isothermal titration calorimetry (ITC), (1)H NMR, (1)H and (19)F DOSY, and STD NMR experiments were performed to characterize the complex formed under aqueous neutral conditions. The results of ITC and (1)H NMR analyses showed the inclusion of the guest inside the cavity of the pillar[5]arene, with the binding constant and thermodynamic parameters influenced by the counter ion of the macrocycle. NMR diffusion experiments showed that although a fraction of the counter ions are expelled from the host cavity by exchange with the guest, a complex with both counter ions and the guest inside the pillararene is formed. The results also showed that at higher concentrations of guest in solution, in addition to the inclusion of one guest molecule in the cavity, the pillararene can also form an external complex with a second guest molecule.

A set of secondary N-phenylfluorenyl beta-amino alcohols have been prepared and evaluated as catalysts for the enantioselective addition of diethylzinc to benzaldehyde. The influence of the substituents on the stereogenic centers of the ligand has been studied, and enantioselectivities up to 97% have been obtained. Those ligands with bulky groups in the carbinol stereocenter and small groups alpha to the nitrogen atom displayed the best catalytic activity and enantioselectivity. The most enantioselective ligand (4e) was found to possess general applicability for the enantioselective addition of diethylzinc to a variety of aromatic and aliphatic aldehydes.

Short, efficient, and stereoselective syntheses of enantiomerically pure C-3- and C-4-alkylated analogues of (2R,3S,4R)-3,4-dihydroxy-2-(hydroxymethyl)pyrrolidine, a potent α-galactosidase inhibitor, from 4-hydroxy-l-proline are presented. Grignard addition or enolate alkylation of a N-(9-phenylfluoren-9-yl)-4-oxo-3-[(methoxymethyl)oxy]proline and epoxidation or hydroboration of a 4-methylene-3-[(methoxymethyl)oxy]proline proceeded with complete stereoselection and in excellent yields. The inhibitory activities of the synthesized pyrrolidines were measured and showed that the fit of A. niger α-galactosidase and the jack bean α-mannosidase around C-3 of the pyrrolidine ring (α face) must be very tight, while the fit around C-4 (α face) is much looser. Positioning a methylene group between the hydroxyl at C-4 and the pyrrolidine ring completely abolishes the inhibitory activity (see analogue 5).

Enantiomerically pure N-(9-phenylfluoren-9-yl)-α-amino ketones were prepared in excellent yields by acylation of organolithium reagents with N-(9-phenylfluoren-9-yl)-α-amino acid-derived oxazolidinones. The method is not applicable for the acylation of Grignard reagents as they attack the methylenic carbon of the oxazolidinone to give the corresponding N-alkylated amino acids 13 in excellent yields. The resulting N-(9-phenylfluoren-9-yl)-α-amino ketones 8 could be stereoselectively reduced to the corresponding syn- or anti-β-amino alcohols depending upon the nature of the reducing agent.

The reaction of methyl N-(9-phenylfluoren-9-yl)pyroglutamate with several organolithium reagents afforded the corresponding ketones in excellent yields and with complete retention of enantiomeric purity. The success of this transformation is due to the unusual stability of the tetrahedral intermediates 5, which stems from two factors: the electron-withdrawing effect of the amide nitrogen and the lithium complexing ability of the fluorenyl ring of the 9-phenylfluoren-9-yl group. This ester-to-ketone transformation was also successfully applied to oxazolidinone 9 and imidazolidinone 20 and provided a ketone (21b) that was ultimately transformed into the urea-lactam 26 which incorporates the bicyclic core of streptolidine lactam, a component of the streptrothricin antibiotics.

The reaction of dimethyl (4S,5S)-1-benzyl-2-oxo-3-(9″-phenylfluoren-9″-yl)-imidazolidine-4,5-dicarboxylate ( 3 ) with several organolithium reagents afforded the corresponding enantiomerically pure monoketones ( 4a-e ) in good to excellent yields. Chloromethyl-ketone 4b was ultimately transformed into ureido-amide 8 which incorporates the bicyclic core of streptolidine lactam ( 1 ), a component of the streptrothricin antibiotics.

A highly efficient synthesis of bridged bicyclic compounds based on reductive alkyltin of anthracene dicarboxylate (I) is presented.

An efficient (21% overall yield), enantio- and diastereoseleclive, 11-step synthesis of (1 S ,2 R )-imidazoleglycerol has been developed. The key steps are the stereoselective hydroxylation of an acyloxazolidinone enolate, the alkylation of a thioester with (MOMOCH 2 ) 2 CuLi and the stereodivergent reduction of the resulting ketone. The scope of the reaction of the enolate derived from 10 with heteroatom electrophiles has been studied.

Enantiomerically pure N-(9-phenylfluoren-9-yl) α-amino ketones were prepared by reaction of the N-Pf-alanine-derived oxazolidinone with organolithium reagents. α-Amino ketones thus obtained could be stereoselectively reduced to the corresponding syn or anti β-amino alcohols depending upon the nature of the reducing agent.

[reaction: see text] The reaction of R(3)SnLi with carboxylic acid derivatives proceeds through a novel, very fast stanna-Brook rearrangement that generates alpha-alkoxyorganolithium compounds as intermediates. The outcome of these reactions depends on the nature of the carboxyl derivatives. Reaction of R(3)SnLi with ester derivatives gives rise to coupled products through a novel C-C bond formation reaction. Experimental evidence of the detailed reaction mechanism is provided.

Kinetic study of the α-lithiation of benzyl methyl ether (BME) by nBuLi has revealed that increasing the concentration of the organolithium compound does not necessarily increase the reactivity, and this is a consequence of the reactivities of the different nBuLi aggregates present in solution. We propose a dimer-based mechanism, in which a pre-complexation step is a key process for substrates bearing a donor oxygen atom that can interact with the lithium cation to form mixed dimers. For these studies, we have developed a system based on UV/Vis spectroscopy that allows kinetic measurements to be conducted at -80 °C under argon.

The process is applied to the synthesis of the tricyclic benzofuran derivative (XIX), a valuable intermediate in the synthesis of galantamine alkaloid acting as a selective acetylcholinesterase inhibitor.

This is the peer reviewed version of the following article: Pérez-Vázquez, J., Veiga, A., Prado, G., Sardina, F., & Paleo, M. (2012). Enantioselective Annulation Reactions of Bisenolates Prepared Through Dearomatization Reactions of Aromatic and Heteroaromatic Diesters. European Journal Of Organic Chemistry, 2012(5), 975-987, which has been published in final form at https:// doi.org/10.1002/ejoc.201101427. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions A one‐pot, enantioselective strategy for the dearomatization–annulation of aromatic diesters to give a range of highly functionalized polycyclic molecules with excellent enantioselectivity is presented. This methodology is based on the reaction of bisenolates, prepared by treating aromatic diesters with trialkyltin lithium reagents, which involves a stanna‐Brook rearrangement, with 1,ω‐dihaloalkanes and other biselectrophiles. We have also developed experimental conditions for performing these reactions with substoichiometric amounts of the required tin reagent by in situ recycling of Me6Sn2 into Me3SnLi with excess lithium metal, and provide a study of the scope and limitations of this synthetic methodology Financial support from Spanish MCYT (fellowship to A. V.) and Xunta de Galicia (Grants 10PXIB209113PR and 10PXIB209155PR) is gratefully acknowledged SI

A short, efficient and stereoselective synthesis of enantiomerically pure (2 R , 3 S , 4 R ) 3,4-dihydroxy-2-hydroxymethylpyrrolidine, a galactosidase inhibitor, from 4-hydroxy-L-proline is presented. The key steps are the regio- and stereoselective hydroxylation of a 4-oxoproline enolate and the stereoselective reduction of the resulting ketoalcohol. An N -(9-phenylfluoren-9-yl) moiety is used not only as an N -protecting group but as a regio- and stereochemical control element as well.

We report here a short and efficient synthesis (four steps, 78% overall yield) of dimethyl (25)-N-(9-phenylfluoren-9-yl)-3,4-didehydroglutamate (1) in enantiomerically pure form from L-glutamic acid. The C-C double bond in 1 was introduced by selective selenenylation-oxidation of dimethyl N-(9-phenylfluoren-9-yl)glutamate. 1 did not undergo loss of enantiomeric purity when stored for several weeks at room temperature, thus demonstrating the ability of the 9-phenylfluoren-9-yl (Pf) group to protect the highly acidic chiral center of 1 from racemization. The α,β-unsaturated carboxyl group of 1 was selectively reduced with DIBAL. Carbamoylation of the resulting alcohol, followed by OsO 4 -mediated hydroxylation of the double bond and deprotection afforded (+)-5-O-carbamoylpolyoxamic acid, a component of the polyoxin family of antifungal antibiotics ( >40% overall yield from glutamic acid). 1 underwent lithium dimethyl cuprate addition with complete retention of chiral integrity, albeit in a nonstereoselective fashion, to give 3-methylglutamates and 3-methylpyroglutamates

A chirospecific and stereodivergent synthesis of N-(9-phenylfluorenyl)-3-hydroxyaspartates by hydroxylation of aspartate enolates is described. The stereochemistry of the newly created chiral center is controlled by the nature of the enolate counterion and the ligand coordinating ability of the solvents.

In our quest for HIV-1 protease inhibitors that are not affected by the V82A resistance mutation, we have synthesized and tested a second generation set of C2-symmetric HIV-1 protease inhibitors that contain a cyclohexane group at P1 and/or P1'. The binding affinity results indicate that these compounds have an improved response to the appearance of the V82A mutation than the parent compound. The X-ray structure of one of these compounds with the V82A HIV-1 PR variant provides the structural rationale for the better resistance profile of these compounds. Moreover, scrutiny of the X-ray structure suggests that the ring of the Cha side chain might be in a boat rather than in the chair conformation, a result supported by molecular dynamics simulations.

The optically pure 2,5-difunctionalized homotropane 11, prepared from L-glutamic acid, serves as the common, advanced intermediate for the synthesis of either natural (+)-anatoxin or unnatural (―)-anatoxin by selective manipulation of either the C-2 ester or C-5 acetyl functionalities. Side-chain substitution in the decarbonylative iminium ion cyclization of a substituted proline enhanced the yield by 25% as compared to the unsubstituted parent system

Reaction of Me3SnLi with aromatic and heteroaromatic diesters proceeds through a fast stanna-Brook rearrangement that generates an stable bis-enolate which can be regioselectively alkylated and cyclized, in one step, to bicyclic compounds containing 6,5-, 6,6-, and 6,7-fused ring systems.

On introduit le centre chiral en C 24 par deplacement stereo- et regiospecifique d'un carbamate allylique par un cuprate

Improvements in the chirospecific synthesis of (+)-anatoxin from D-glutamic acid have resulted in a process that gives enantiomerically pure material in reproducible 25% overall yield. The major synthetic modifications have been in the decarbonylative iminium ion cyclization and in the introduction of the enone moiety

A new methodology for structural elucidation of polyhalogenated monoterpenes is presented. It makes extensive use of correlated 2D-NMR and NOEDS and shows that the structures of coccinene and its bromovinyl analog must be corrected to their C-2 epimers.