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The site-selective modification of peptide backbones allows an outstanding fine-tuning of peptide conformation, folding ability, and physico-chemical and biological properties. However, to achieve selectivity in the core of these biopolymers is challenging. In the last few years, many advances towards this goal have been developed. This review addresses the selective modification of Cα- and N-positions, from the use of “customizable units” to the residue-directed introduction of substituents. The site-selective modification of the peptide bond, i.e. the formation of thioamides or heterocycles, which alters backbone rigidity and ability to form hydrogen bonds or recognition by enzymes, is also described. Moreover, not only the modifications in internal backbone positions, but also in the N- and C-termini are discussed. In addition to chemical methodologies, the review addresses some reactions, catalyzed by natural or engineered enzymes, that afford unprecedent regio- and stereoselectivity in backbone modifications., This work was mainly financed by project ProID2020010134 (Subvenciones a la Realización I + D Mª Carmen Betancourt y Molina, ACIISI-Gobierno de Canarias, with European Funds for Regional Development-FEDER) with contributions from project APOGEO (MAC/1.1.b./226, Cooperation Program INTERREG-MAC 2014–20 with FEDER funds, as well as Consejo Nacional de Ciencia y Tecnología (CONACYT, Mexico) through project 2015-01-807. D. H. also acknowledges her current contract (TRANSALUDAGRO) financed by Cabildo de Tenerife, Program TF INNOVA 2016-21 (with MEDI & FDCAN Funds). C. J. S. is currently recipient of a “Agustín de Betancourt”-Tenerife 2030 postdoctoral grant (Universidad de La Laguna-Cabildo de Tenerife, cofinanced by MEDI & FDCAN Funds). I. R-E. thanks CONACYT for Catedra contract 942. more...

The ability of amino acid “customizable units” to generate structural diversity is illustrated by the conversion of 4-hydroxyproline (Hyp) units into a variety of nitrogen heterocycles. After a frst common step, where the unit underwent a one-pot decarboxylation–alkylation reaction to aford 2-alkylpyrrolidines with high stereoselectivity, a divergent step was carried out. Thus, the deprotected 4-hydroxy group was used either to initiate a radical scission that aforded aliphatic β-amino aldehydes, or to carry out an elimination reaction, to give 2-alkyl-2,5-dihydro-1H-pyrroles. In the frst case, the amines underwent a tandem reductive amination–cyclization to aford β-amino-δ-lactams, an efcient rigidifying unit in peptides. Diferent lactam N-substituents, such as alkylamines, peptides, and alkenyl chains suitable for olefn metathesis were introduced this way. In the second case, the pyrrole derivatives were efciently converted into alkaloid and iminosugar derivatives in good global yields and with excellent stereoselectivity., This work was partly financed by projects RETOS-SELECTFIGHT (PID2020-116688RB-C21) and CTQ2006-14260/PPQ of the Plan Nacional I+D, Ministry of Science, Spain (with FEDER funds). We also thank Project APOGEO (Cooperation Program INTERREG-MAC 2014–2020, with European Funds for Regional Development-FEDER) and by project ProID2020010134 (Programa de Subvenciones a la Realización I+D “Mª Carmen Betancourt y Molina from ACIISI-Gobierno de Canarias with FEDER funds). D.H. also acknowledges her current contract (TRANSALUDAGRO) financed by Cabildo de Tenerife, Program TF INNOVA 2016-21 (with MEDI & FDCAN Funds). M.P. thanks predoctoral grants from Gobierno de Canarias (Convocatoria Tesis 2020) and Ministerio de Ciencia, Innovación y Universidades, Spain (FPU grants). We also acknowledge support of the publication fee by CSIC Open Access Publication Support Initiative-through its Unit of Information Resources for Research (URICI). more...

Readily available, low-cost 4R-hydroxy-l-proline (Hyp) is introduced as a “doubly customizable” unit for the generation of libraries of structurally diverse compounds. Hyp can be cleaved at two points, followed by the introduction of new functionalities. In the first cycle, the removal and replacement of the carboxylic group are carried out, followed (second cycle) by the scission of the 4,5-position and manipulation of the resulting chains. In this way, three new chains are generated and can be transformed independently to afford a diversity of products with tailored substituents, such as β-amino aldehydes, diamines, β-amino acid derivatives, including N-alkylated ones, or modified peptides. Many of these products are high-profit compounds but, in spite of their commercial value, are still scarce. Moreover, the process takes place with stereochemical control, and either pure R or S isomers can be obtained with small variations of the synthetic route., This work was partly financed by project APOGEO (Cooperation Program INTERREG-MAC 2014–2020, with European Funds for Regional Development-FEDER) and by project SAF-2013-48399-R, Plan Estatal I+D-RETOS (MINECO-MCIU)-European Social Funds (ESF). D.H. also acknowledges her current contract (TRANSALUDAGRO) financed by Cabildo de Tenerife, Program TF INNOVA 2016-21 (with MEDI & FDCAN Funds). C.C. was granted a contract from the Doctorados Industriales Programme (DI-14-06736) by MINECO/Min. Science and Innovation, cofinanced by BIOSIGMA SL. C.C. carried out her work as a Ph.D. student of the program “Química e Ingeniería Química” of the University of La Laguna (ULL). more...

Tamoxifen is the most widely used selective modulator of estrogen receptors (SERM) and the first strategy as coadjuvant therapy for the treatment of estrogen-receptor (ER) positive breast cancer worldwide. In spite of such success, tamoxifen is not devoid of undesirable effects, the most life-threatening reported so far affecting uterine tissues. Indeed, tamoxifen treatment is discouraged in women under risk of uterine cancers. Recent molecular design efforts have endeavoured the development of tamoxifen derivatives with antiestrogen properties but lacking agonistic uterine tropism. One of this is FLTX2, formed by the covalent binding of tamoxifen as ER binding core, 7-nitrobenzofurazan (NBD) as the florescent dye, and Rose Bengal (RB) as source for reactive oxygen species. Our analyses demonstrate (1) FLTX2 is endowed with similar antiestrogen potency as tamoxifen and its predecessor FLTX1, (2) shows a strong absorption in the blue spectral range, associated to the NBD moiety, which efficiently transfers the excitation energy to RB through intramolecular FRET mechanism, (3) generates superoxide anions in a concentration- and irradiation time-dependent process, and (4) Induces concentration- and time-dependent MCF7 apoptotic cell death. These properties make FLTX2 a very promising candidate to lead a novel generation of SERMs with the endogenous capacity to promote breast tumour cell death in situ by photosensitization., We acknowledge the financial contribution of Vicerrectorado de Investigacion (Universidad de La Laguna) for the open access publication of this article. ACA and FM-H. were supported by ULL-LaCaixa predoctorate fellowships. D.H. acknowledges her current contract (TRANSALUDAGRO) financed by Cabildo de Tenerife (Program TF INNOVA 2016-21) with MEDI and FDCAN funds. more...

An efficient, metal-free synthesis of unusual α-keto γ-amino esters from α-amino acids is achieved by a radical scission-oxidation-addition of silyloxy acrylates procedure, where no purification of the reaction intermediates is needed. This protocol can be applied to the selective modification of the C-terminal position in peptides to give α,γ-hybrids., This work was supported by a research program (SAF2013-48399-R) of the Plan Estatal de I+D-Convocatoria Retos, Ministerio de Economía y Competitividad, Spain. We also acknowledge financial support from FEDER and FSE funds (European Funds for Regional Development/European Social Funds). DH thanks the CSIC for a JAE postdoctoral fellowship and a postdoctoral contract, respectively more...

An efficient conversion of hydroxyproline >customizable> units into new amino acids with a variety of N-alkyl substituents is described. The process is versatile and can afford valuable N-methyl amino acids and N,O-acetals. In addition, it allows the introduction of N-homoallylic substituents and N-chains with terminal ester, ketone, or cyano groups. These chains could be used for peptide extension or conjugation to other molecules (e.g., by olefin metathesis, peptide ligation, etc.). The transformation is carried out in just two (for R = CHOAc) or three steps (scission of the pyrrolidine ring, manipulation of the α-chain, and the N-substituent) under mild, metal-free conditions, affording products with high optical purity., This work was supported by the Research Program SAF-2013-48399-R, Plan Estatal de I+D, Ministerio de Economía, Industria, y Competitividad, Spain (currently Ministerio de Ciencia, Innovación y Universidades) and European Social Funds (FSE). D.H. thanks her current contract financed by Cabildo de Tenerife, included in Tenerife 2030 under the Program TF INNOVA 2016-21 (with MEDI & FDCAN Funds). C.J.S. was the recipient of a postdoctoral contract from the Torres Quevedo Programme (PTQ15-07923), and C.C. was granted a contract from the Doctorados Industriales Programme (DI-14-06736). Both industrial Programmes were sponsored by MINECO-Ministerio de Ciencia, Innovación y Universidades, and cofinanced by the company BIOSIGMA SL (Spain)., We acknowledge support by the CSIC Open Access Publication Initiative through its Unit of Information Resources for Research (URICI). more...

Tamoxifen is the most common antiestrogen used in the chronic treatment of breast cancer. In these cells, it mainly binds to intracellular receptors (estrogen receptor alpha, ERα) and antagonizes the binding of its cognate ligand, 17β-estradiol, thereby preventing uncontrolled hormone-dependent cellular proliferation and growth. In the last decade, in our laboratories we have developed and characterized different tamoxifen derivatives, including a novel fluorescent tamoxifen conjugate: FLTX1. FLTX1 is formed by the covalent binding of tamoxifen to a common fluorescent biomarker NBD. This new prodrug was originally designed as a fluorescent biomarker to localize intracellular targets, which not only keeps the pharmacological activity of tamoxifen but also adds a luminescent functionality. Strikingly, the quantum efficiency of FLTX1 is so high that laser emission has been obtained as an emerging property. In this review, we will show its laser properties under three different configurations. First, as amplified spontaneous emission or mirrorless laser; second, through the evanescent field of WGMs of a ring resonator around an optical fiber; and finally as random laser in uterine tissues impregnated with the prodrug. Further, we observed another emergent property for FLTX1: this molecule, but not tamoxifen alone or NBD, was able to generate reactive oxygen species (ROS) upon irradiation. This property is extremely interesting as FLTX1 might be used for photodynamic therapy. Under this paradigm, FLTX1 would act as a sensitizer in ERα-overexpressing cells (which feature the most prevalent form of hormone-dependent breast cancer), causing cell death in ERα+ cells but reducing damage to other non-cancer (healthy) cells or surrounding tissues. We show here time resolved fluorescence results that suggest molecular aggregations, which could explain the subsequent generation of ROS. This is an original cancer therapy strategy that combines the pharmacological properties of a new tamoxifen derivative and its laser dye features with a highly selective photodynamic therapy., Supported by Research grant SAF2014-61644-EXP from MINECO (Spain) to M.D. Partially supported by Agencia Estatal de Investigación (AEI, grant ref. MAT2016-79866-R to F.L.), SAF2015-65113-C2-1-R and SAF2017-84454-R (from MINECO) to A.E. and R.M., respectively. DH and DQA were hired by Universidad de La Laguna. FL was recipient of contract from Torres Quevedo Programme (MINECO) and incorporated in BIOSIGMA SL (Spain). more...

Antimicrobial peptides (AMPs) have been used by animals and plants for millions of years for defence against pathogens, and present important advantages as potential drugs, such as a broad spectrum of activity, no induction of resistances, and synergic action with conventional antibiotics. However, many natural antimicrobial peptides present problems due to in vivo degradation or biodisponibility issues. The production of synthetic analogues would allow the discovery of antimicrobials with improved selectivity, stability, and biodisponibility. The site-selective modification of peptides would allow the fast, efficient generation of libraries of such peptides from a few "parent" peptides, saving time and materials in the discovery processes. We describe two "customizable units" that allow the production of peptides “à la carte”, with many different lateral chains and functional groups, and their evaluation as antimicrobials for human and animal health, and as crop protection agents. more...

Our site-selective modification of serine or threonine units in peptides allows the generation of β-substituted dehydroamino acids, which increase peptide resistance to hydrolysis and may improve their biological properties. Both the terminal and internal positions can be modified, and different customizable units can be activated separately. Remarkably, high Z selectivity is achieved, even at internal positions. The conversion involves a one-pot oxidative radical scission/phosphorylation process by using the low-toxicity (diacetoxyiodo)benzene/iodine system as the scission reagent. The resulting α-amino phosphonates undergo a Horner-Wadsworth-Emmons reaction to produce the dehydroamino acid derivatives (in a Z/E ratio of usually >98:2) under mild and metal-free conditions., This work was supported by the Research Program SAF‐2013‐48399‐R, Plan Estatal de I+D, Ministerio de Economía. Industria y Competitividad, Spain, and European Social Funds (FSE). D.H. and C.J.S. thank CSIC (Spanish Research Council) and Gobierno de Canarias, respectively, for their research contracts. D.H. also acknowledges her current contract financed by Cabildo de Tenerife, Program TF INNOVA 2016‐21 (with MEDI & FDCAN Funds). more...

The azanucleosides are nucleoside analogues where the furanose ring is replaced by a nitrogen-containing ring or chain. Many azanucleosides are potent antiviral, anticancer and antimicrobial agents, or serve as valuable components of oligonucleotides with improved stability, binding or hybridization properties. Therefore, the development of new analogues is a very active area in medicinal and synthetic chemistry. Their synthesis and their interesting biological properties are discussed in this microreview. more...

An alternative to the use of expensive auxiliaries or catalysts in the synthesis of chiral 2-substituted pyrrolidines is described. Thus, commercial, cheap 4-(S)-hydroxyproline was readily transformed into optically pure pyrrolidines, using a one-pot decarboxylation–alkylation reaction as the key step. In this reaction, an acyliminium intermediate was generated, which was trapped by carbon nucleophiles. As postulated by Woerpel, the addition of the nucleophiles to the five-membered ring iminium ions took place stereoselectively, affording 2,4-cis-disubstituted pyrrolidines in high de. The hydroxy group at C-4 can then be removed, or alternatively, it can be used to create new functionalities in the molecule. In this way, optically pure alkaloid analogues and iminosugars were prepared. more...

Common cyclic amino acids, derived from proline and hydroxyproline, can be readily transformed into azanucleosides. The mildness of the reaction conditions, and the good yields obtained, make this procedure an interesting alternative to the conventional processes. more...

The fragmentation of primary alkoxyl radicals has been scarcely used in synthesis since other competing processes (such as oxidation or hydrogen abstraction) usually predominate. However, when serine derivatives were used as substrates, the scission took place in excellent yields. Tandem scission-allylation, -alkylation, or -arylation reactions were subsequently developed. This one-pot methodology was applied to the synthesis of unnatural amino acids, which are useful synthetic blocks or amino acid surrogates in peptidomimetics. more...

[reaction: see text] Common sugar derivatives can be transformed in a few steps into chiral-substituted furyl carbinols. The mildness of the reaction conditions and the good yields obtained make this procedure an interesting alternative to the conventional processes. more...

The selective cleavage of methoxy protecting groups next to hydroxy groups is achieved using a radical hydrogen abstraction reaction as the key step. Under the reaction conditions, the hydroxy group generates an alkoxyl radical that reacts with the sterically accessible adjacent methoxy group, which is transformed into an acetal. In the second step, the acetals are hydrolyzed to give alcohols or diols. A one-pot hydrogen abstraction-hydrolysis procedure was also developed. Good yields were usually achieved, and the mild conditions of this methodology were compatible with different functional groups and sensitive substrates such as carbohydrates. more...

10 pages, 2 figures, 2 tables, 7 schemes.-- PMID: 12816493 [PubMed].-- Printed version published Jun 27, 2003., The β-fragmentation of primary alkoxyl radicals, described in many cases as low-yielding and plagued by side reactions, can proceed in satisfactory yields using carbohydrate substrates. The only reaction that can compete significantly with the β-scission is the intramolecular hydrogen abstraction. The ratio of β-fragmentation to hydrogen abstraction can be varied according to the reaction conditions, the stereochemistry of the substituents (e.g., α- or β-anomeric substituents), and the protecting groups chosen. The carbohydrate substrates are easily prepared, and the mild reaction conditions are compatible with most functional groups. The β-scission reaction provides an expedient way toward shorter and less common sugar series and also toward α,ω-differently substituted cyclic ethers. These units are useful building blocks and are present in many natural products with interesting biological activity., This work was supported by the Investigation Programmes PB96-1461 and PPQ2000-0728 of the Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica, Dirección General de Investigación, Ministerio de Ciencia y Tecnología, Spain. We also thank the financial support from FEDER funds. D.H. thanks C.S.I.C.-Comunidad de Canarias for a fellowship. more...

The azanucleosides are nucleoside analogues where the furanose ring is replaced by a nitrogen-containing ring or chain. Many azanucleosides are potent antiviral, anticancer and antimicrobial agents, or serve as valuable components of oligonucleotides with improved stability, binding or hybridization properties. Therefore, the development of new analogues is a very active area in medicinal and synthetic chemistry. Their synthesis and their interesting biological properties are discussed in this microreview. more...

Silasubstitution, where silicon is substituted for carbon at specific sites of the substrate, has become a growing practice in medicinal chemistry. Introducing silicon into bioactive compounds provides slight physical and electronic alterations to the parent compound, which in certain instances could make the substrate a more viable candidate for a drug target. One application is in the field of protease inhibition. Various silane diol isosteres can act as potent inhibitors of aspartic and metalloproteases because of their ability to mimic the high-energy tetrahedral intermediate in peptide bond hydrolysis. In particular, since 1998, the Sieburth group has prepared a number of functionalized peptide silane diol isosteres. In a seminal study, they demonstrated that these molecules can bind to the active site of the enzymes. Inspired by these results, we initiated a study to develop a concise and straightforward route to access highly functionalized silicon diol based peptidomimetic analogs, which we describe in this Account. The synthesis of such analogs is challenging because the dipeptide mimics require the formation of two carbon-silicon bonds as well as two chiral carbon centers. Our first strategy was to assemble the two C-Si bonds from diphenylsilane through an initial regioselective hydrosilylation step of a terminal alkene, followed by lithiation of the formed alkyldiphenylsilane by a simple lithium metal reduction. Subsequent diastereoselective addition of this silyllithium species to a tert-butylsulfinimine provided a rapid method to assemble the dipeptide mimic with stereochemical control at the new chiral carbon center adjacent to the silicon. This strategy worked with a wide range of functional groups. However, there were some limitations with the more elaborate targets. In particular, we needed to exchange the phenyl groups of the diphenylsilane with aryl groups that were more labile under acidic conditions in order to introduce Si-O bonds in the end product. We demonstrated that a variety of Ar(2)SiH(2) compounds with methyl substituents on the aromatic core could effectively undergo hydrosilylation and reductive lithiation with a soluble reducing agent, lithium naphthalenide. The electron-rich aromatic groups were more acid labile and, depending on the conditions, could produce either the silane diol or the silanol. In an alternative strategy, we used a highly regioselective Rh-catalyzed sequential double hydrosilylation to form the two C-Si bonds with a single catalyst. This approach is a more efficient, atom economical way to synthesize a wider range of highly functionalized organosilanes with the added possibility of extending this method into an asymmetric protocol. By this method, various functional groups that were not previously tolerated in the lithiation protocol, including OBn, OAc, furyl, and thiophenes, could now be incorporated. Hydrosilylation of a terminal olefin and a peptide functionalized with an enamide at the C-terminus achieved the desired silane in high yields in a one pot reaction without compromising the stereochemical integrity of the peptide. As an extension of this work, we used these methods to efficiently generate a variety of chiral azasilaheterocycles, including silapiperidines and silaindolizidines. more...

An effective approach to diarylsilyl lithium reagents and their conversion into silanol and silanediol peptide precursors is presented.

The process can be applied to a broad spectrum of substrates to produce the (E) isomers as the main components.

Reductive lithiation of methyl-substituted diarylmethylsilanes using lithium naphthalenide represents a practical method for the preparation of the corresponding silyl lithium reagents. Their addition to chiral sulfinimines affords versatile precursors to silanols and silanediols. The replacement of the currently used diphenylsilane motif by a more labile diarylsilane moiety allows the selective hydrolysis of one or two aryl groups by treatment with TFA. more...

1o páginas, 1 figura, 8 esquemas., Readily available proline derivatives can be transformed in one step into β-iodinated iminosugar-based nucleosides, under very mild conditions. The method couples a tandem radical decarboxylation–oxidation–β-iodination to the addition of nitrogen bases. The iodo group is introduced into the previously unfunctionalized 3-position. The resultant β-iodo derivatives are useful precursors of highly functionalizednucleoside analogues., This work was supported by the Spanish Ministerio de Educación y Ciencia (MEC) and Ministerio de Ciencia e Innovación (MICINN), Investigation Programmes CTQ2006-14260/PPQ and CTQ2009-07109 of the Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica. The authors also acknowledge financial support from the European Regional Development Funds (FEDER funds). D. H. thanks the MEC for a fellowship and the Gobierno de Canarias (ACIISI)-BIOSIGMA SL for a research contract. more...

Chiral α-silylsulfinamides, prepared by the treatment of an alkyldiphenylsilane with lithium followed by its addition to a sulfinimine, can be applied to the synthesis of 1,3-azasilaheterocycles as derivatives of cyclic alkaloids. This synthetic route, which involves intramolecular substitution of an amino alcohol or cyclization of an amino acid promoted by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), represents a convenient means for accessing these silicon-containing heterocycles. more...

A facile synthesis of various enamides from aminothioesters via a palladium(0)-catalyzed decarbonylation/β-hydride elimination is reported. This protocol was applied to mercaptopyridyl C-terminal modified peptides for the generation of enamides without epimerization at stereogenic centers. more...

Title synthesis of azanucleosides includes a sequential radical decarboxylation—oxidation—nucleophilic addition reaction.

Chiral alpha-silylsulfinamides, prepared by the treatment of an alkyldiphenylsilane with lithium followed by its addition to a sulfinimine, can be applied to the synthesis of 1,3-azasilaheterocycles as derivatives of cyclic alkaloids. This synthetic route, which involves intramolecular substitution of an amino alcohol or cyclization of an amino acid promoted by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), represents a convenient means for accessing these silicon-containing heterocycles. more...

11 páginas., Common amino acid derivatives can be transformed in one-step fashion into N-azanucleosides. The method is a sequential process initiated by a domino radical decarboxylation/oxidation reaction; an acyliminium ion is formed as an intermediate and can be trapped by nitrogen bases (purines, pyrimidines, and benzotriazole). The mildness of the reaction conditions and the good yields obtained make this procedure an interesting alternative to the conventional processes. Good stereoselectivities were obtained with 4-(silyloxy)proline derivatives as substrates. more...

Further studies are reported on the utilization of the versatile reaction between chiral sulfinimines and alkyldiphenylsilyl lithium reagents with the goal of preparing a wide range of silanediol-based protease inhibitors. In particular, focus has been placed to demonstrate how a number of genetically encoded amino acid side chains such as serine, threonine, tyrosine, lysine, proline, arginine, aspartate and asparagine might be incorporated into the overall approach. Efforts to apply this synthetic methodology for accessing biologically relevant silanediol dipeptide mimics are also described. This includes the synthesis of a potential inhibitor of the human neutrophil elastase, as well as a diphenylsilane mimic of a hexapeptide fragment of the human islet amyloid polypeptide. more...

An alternative to the use of expensive auxiliaries or catalysts in the synthesis of chiral 2-substituted pyrrolidines is described. Thus, commercial, cheap 4-(S)-hydroxyproline was readily transformed into optically pure pyrrolidines, using a one-pot decarboxylation–alkylation reaction as the key step. In this reaction, an acyliminium intermediate was generated, which was trapped by carbon nucleophiles. As postulated by Woerpel, the addition of the nucleophiles to the five-membered ring iminium ions took place stereoselectively, affording 2,4-cis-disubstituted pyrrolidines in high de. The hydroxy group at C-4 can then be removed, or alternatively, it can be used to create new functionalities in the molecule. In this way, optically pure alkaloid analogues and iminosugars were prepared. more...

5 páginas, 2 figuras, 2 tablas, 6 esquemas., An unusual scission–rearrangement process, which couples radical and ionic reactions, was observed with galactofuranose derivatives. This one-pot procedure afforded, in good yields, highly functionalized 1,4-dioxanes, which could be considered as six-membered-ring sugar analogues. The synthesis of C-glycoside analogues is also possible with this methodology., This work was supported by the Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica, and Ministerio de Educación y Ciencia, Spain (Research Program CTQ2006-14260/PPQ). We also acknowledge financial support from FEDER funds. D. H. thanks the Gobierno de Canarias (Consejería de Industria) – CSIC for a research contract. more...

Readily available sugar derivatives were transformed in a few steps into valuable, more complex products. The tandem radical scission of carbohydrates−oxidation reaction gave acetoxy acetals, which were converted into a variety of chiral C-alditols in good global yields and excellent 1,2-trans stereoselectivity. The reaction was the key step in the synthesis of hydroxylated γ-substituted butenolides and bicyclic alkaloid analogues. more...

11 pages, 2 figures, 2 tables, 7 schemes.-- PMID: 18549274 [PubMed].-- Printed version published Jul 18, 2008.-- Supporting information available: Preparation of substrate 22, including spectroscopic data of the synthetic intermediates and the final product. Procedures for the allylation and alkylation reactions, and spectroscopic data of phenyl ketones 20, 21, 27, butenolides 28-33 and 37-39, and cyclohexanones 46, 47, and 49. 1H and 13C NMR spectra for acetoxy acetal 24, allyl derivatives 18 and 19, phenyl ketones 20, 21, 26, and 27, butenolides 28-39, cyclohexanones 46-48 and 50-55, alkaloid analogues 56-61, and substrates 63-65 and 22.-- Available at: http://pubs.acs.org/doi/suppl/10.1021/jo800478a, Readily available sugar derivatives were transformed in a few steps into valuable, more complex products. The tandem radical scission of carbohydrates-oxidation reaction gave acetoxy acetals, which were converted into a variety of chiral C-alditols in good global yields and excellent 1,2-trans stereoselectivity. The reaction was the key step in the synthesis of hydroxylated gamma-substituted butenolides and bicyclic alkaloid analogues., This work was supported by the Investigation Programmes PPQ2000-0728, PPQ2003-01379, and CTQ2006-14260/PPQ of the Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica, Ministerio de Educación y Ciencia and Ministerio de Ciencia y Tecnología, Spain. We also acknowledge financial support from FEDER funds. D.H. thanks the CSIC-Gobierno de Canarias, CSIC (I3P) and Ministerio de Educación y Ciencia (Plan Nacional FPU) for fellowships. more...

Common cyclic amino acids, derived from proline and hydroxyproline, can be readily transformed into azanucleosides. The mildness of the reaction conditions, and the good yields obtained, make this procedure an interesting alternative to the conventional processes. more...

The design of processes which combine tandem and sequential reactions allows the transformation of readily available precursors into high-profit products. This strategy is illustrated by the one-pot synthesis of acyclic nucleosides, which are potential antiviral compounds, from readily available carbohydrates. The reaction conditions are mild, compatible with most functional groups. Depending on the starting sugar, both common and uncommon acyclic chains can be prepared. These polyhydroxylated chains can be combined with different bases to generate diversity. more...

The fragmentation of primary alkoxyl radicals has been scarcely used in synthesis since other competing processes (such as oxidation or hydrogen abstraction) usually predominate. However, when serine derivatives were used as substrates, the scission took place in excellent yields. Tandem scission−allylation, −alkylation, or −arylation reactions were subsequently developed. This one-pot methodology was applied to the synthesis of unnatural amino acids, which are useful synthetic blocks or amino acid surrogates in peptidomimetics. more...

10 pages, 5 tables, 6 schemes.-- PMID: 17985924 [PubMed].-- Printed version published Dec 7, 2007., Supporting information available at: http://pubs.acs.org/doi/suppl/10.1021/jo701608p, [Synthesis and spectroscopic data of starting materials 10-13, the acyclic nucleosides 24-28, 31-37, 40-47, 49, and 50, and the alcohols 51-58; ORTEP drawings for compounds 29, 36, 37, and 45; 1H and 13C NMR spectra for compounds 24-58; and crystal structure data (in CIF format) for compounds 29, 36, 37, and 45]., The design of processes which combine tandem and sequential reactions allows the transformation of readily available precursors into high-profit products. This strategy is illustrated by the one-pot synthesis of acyclic nucleosides, which are potential antiviral compounds, from readily available carbohydrates. The reaction conditions are mild, compatible with most functional groups. Depending on the starting sugar, both common and uncommon acyclic chains can be prepared. These polyhydroxylated chains can be combined with different bases to generate diversity., This work was supported by the Investigation Programmes PPQ2000-0728 and PPQ2003-01379 of the Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica, Ministerio de Educación y Ciencia, and Ministerio de Ciencia y Tecnología, Spain. We also acknowledge financial support from FEDER funds. D.H. thanks the CSIC-Gobierno de Canarias, CSIC (I3P), and Ministerio de Educación y Ciencia (Plan Nacional FPU) for their fellowships. We thank FAES FARMA S.A. for their help in determining the cytotoxic activity of compounds 24-58. more...

10 pages, 1 table, 12 schemes.-- Available online Nov 6, 2006., Supporting information available at: http://www.wiley-vch.de/contents/jc_2046/2007/o200600720_s.pdf, The fragmentation of primary alkoxyl radicals is usually a minor process with respect to hydrogen abstraction and other competing reactions. However, when β-amino alcohols were used as substrates, the scission proceeded in good to excellent yields and no side reactions were observed. The fragmentation can be coupled with an allylation or alkylation reaction, to give alkaloid analogues and functionalized nitrogen heterocycles., This work was supported by the Investigation Programs PPQ2000-0728 and PPQ2003-01379 (Plan Nacional de I+D, Ministerios de Ciencia y Tecnología and Educación y Ciencia, Spain) and Proyecto Intramural del CSIC 2004-8-0E211. We also acknowledge financial support from FEDER funds. D. H. thanks the Ministerio de Educación y Ciencia for an FPU fellowship. A. M. thanks the C.S.I.C. for an I3P fellowship. more...

4 pages, 1 table, 4 schemes.-- PMID: 15469349 [PubMed].-- Printed version published Oct 14, 2004., Supporting information available: Synthesis of substrate 12 and General Procedure for the one-pot protecting group transformation-hydrolysis. 1H and 13C NMR spectra and spectroscopic data for several compounds.-- Available at: http://pubs.acs.org/doi/suppl/10.1021/ol048439%2B, [Reaction: see text] The selective removal from carbohydrate substrates of methoxy protecting groups next to hydroxy groups is reported. On treatment with PhI(OAc)(2)-I(2), the methoxy group is transformed into an easily removable acetal. The mild conditions of this methodology are compatible with many functional groups, and good to excellent yields are usually achieved., This work was supported by the Investigation Programs PPQ2000-0728 and PPQ2003-01379 of the Plan Nacional de Investigación Científica, Ministerio de Ciencia y Tecnología, Spain. We also acknowledge financial support from FEDER funds. D.H. thanks CSIC-Gobierno de Canarias, CSIC (I3P) and Ministerio de Educación y Ciencia (Plan Nacional FPU) for fellowships. more...