De Novo Access to BODIPY C-Glycosides as Linker-Free Nonsymmetrical BODIPY-Carbohydrate Conjugates.

Recent years have witnessed an increasing interest in the synthesis and study of BODIPY-glycoconjugates. Most of the described synthetic methods toward these derivatives involve postfunctional modifications of the BODIPY core followed by the covalent attachment of the fluorophore and the carbohydrate through a "connector". Conversely, few de novo synthetic approaches to linker-free carbohydrate-BODIPY hybrids have been described. We have developed a reliable modular, de novo, synthetic strategy to linker-free BODIPY-sugar derivatives using the condensation of pyrrole C-glycosides with a pyrrole-carbaldehyde derivative mediated by POCl3. This methodology allows labeling of carbohydrate biomolecules with fluorescent-enough BODIPYs within the biological window, stable in aqueous media, and able to display singlet oxygen generation.

Bringing Color to Sugars: The Chemical Assembly of Carbohydrates to BODIPY Dyes.

The combination of carbohydrates with BODIPY fluorophores gives rise to a family of BODIPY-carbohydrate hybrids or glyco-BODIPYs, which mutually benefit from the encounter. Thus, from the carbohydrates standpoint, glyco-BODIPYs can be regarded as fluorescent glycoconjugate derivatives with application in imaging techniques, whereas from the fluorophore view the BODIPY-carbohydrate hybrids benefit from the biocompatibility, water-solubility, and reduced toxicity, among others, brought about by the sugar moiety. In this Account we have intended to present the collection of available methods for the synthesis of BODIPY-carbohydrate hybrids, with a focus on the chemical transformations on the BODIPY core.

A Concise Route to Water-Soluble 2,6-Disubstituted BODIPY-Carbohydrate Fluorophores by Direct Ferrier-Type C-Glycosylation.

Novel, linker-free, BODIPY-carbohydrate derivatives containing sugar residues at positions C2 and C6 are efficiently obtained by, hitherto unreported, Ferrier-type C-glycosylation of 8-aryl-1,3,5,7-tetramethyl BODIPYs with commercially available tri-O-acetyl-d-glucal followed by saponification. This transformation, which involves the electrophilic aromatic substitution (SEAr) of the dipyrrin framework with an allylic oxocarbenium ion, provides easy access to BODIPY-carbohydrate hybrids with excellent photophysical properties and a weaker tendency to aggregate in concentrated water solutions.

BODIPYs as Chemically Stable Fluorescent Tags for Synthetic Glycosylation Strategies towards Fluorescently Labeled Saccharides.

A series of fluorescent boron-dipyrromethene (BODIPY, 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene) dyes have been designed to participate, as aglycons, in synthetic oligosaccharide protocols. As such, they served a dual purpose: first, by being incorporated at the beginning of the process (at the reducing-end of the growing saccharide moiety), they can function as fluorescent glycosyl tags, facilitating the detection and purification of the desired glycosidic intermediates, and secondly, the presence of these chromophores on the ensuing compounds grants access to fluorescently labeled saccharides. In this context, a sought-after feature of the fluorescent dyes has been their chemical robustness. Accordingly, some BODIPY derivatives described in this work can withstand the reaction conditions commonly employed in the chemical synthesis of saccharides; namely, glycosylation and protecting-group manipulations. Regarding their photophysical properties, the BODIPY-labeled saccharides obtained in this work display remarkable fluorescence efficiency in water, reaching quantum yield values up to 82 %, as well as notable lasing efficiencies and photostabilities.

Towards Efficient and Photostable Red-Emitting Photonic Materials Based on Symmetric All-BODIPY-Triads, -Pentads, and -Hexads.

The development of efficient and stable red and near-IR emitting materials under hard radiation doses and/or prolonged times is a sought-after task due to their widespread applications in optoelectronics and biophotonics. To this aim, novel symmetric all-BODIPY-triads, -pentads, and -hexads have been designed and synthesized as light-harvesting arrays. These photonic materials are spectrally active in the 655-730 nm region and display high molar absorption across UV-visible region. Furthermore, they provide, to the best of our knowledge, the highest lasing efficiency (up to 68 %) and the highest photostability (tolerance >1300 GJ mol-1 ) in the near-IR spectral region ever recorded under drastic pumping conditions. Additionally, the modular synthetic strategy to access the cassettes allows the systematic study of their photonic behavior related to structural factors. Collectively, the outstanding behavior of these multichromophoric photonic materials provides the keystone for engineering multifunctional systems to expedite the next generation of effective red optical materials.

A Malonyl-Based Scaffold for Conjugatable Multivalent Carbohydrate-BODIPY Presentations.

A concise synthetic route from methylmalonate to a tetravalent aliphatic scaffold has been developed. The ensuing tetra-tethered derivative is equipped with two hydroxyl groups, as well as orthogonal alkene and alkyne functionalities. The usefulness of the scaffold has been demonstrated with the preparation of two representative multivalent derivatives: (i) a tetravalent compound containing two D-mannose units, one fluorescent boron-dipyrromethene (BODIPY) dye and a suitably functionalized amino acid and (ii) by way of dimerization and saponification, a water-soluble tetramannan derivative containing two fluorescent BODIPY units. Additionally, photophysical measurements conducted on these derivatives support the viability of the herein designed single and double BODIPY-labeled carbohydrate-based clusters as fluorescent markers.

One-Pot Synthesis of Rotationally Restricted, Conjugatable, BODIPY Derivatives from Phthalides.

O-Ethylation of phthalides with Meerwein's reagent followed by reaction of the ensuing salts with pyrrole, results in the formation of 5-alkoxy-5-phenyl dipyrromethane derivatives, which function as ready precursors of ortho-substituted 8-aryl BODIPY derivatives by reaction with borontrifluoride etherate, an overall process that can be carried out in a one-pot operation.

A Survey of Recent Synthetic Applications of 2,3-Dideoxy-Hex-2-enopyranosides.

Unsaturated carbohydrate derivatives are useful intermediates in synthetic transformations leading to a variety of compounds. The aim of this review is to highlight the rich chemistry of ∆-2,3 unsaturated pyranosides, emphasizing the variety of transformations that have been carried out in these substrates during the last decade.

A substrate-based approach to skeletal diversity from dicobalt hexacarbonyl (C1)-alkynyl glycals by exploiting its combined Ferrier-Nicholas reactivity.

Novel substrates that combine dicobalt hexacarbonyl propargyl (Nicholas) and pyranose-derived allylic (Ferrier) cations have been generated by treatment of hexacarbonyldicobalt (C-1)-alkynyl glycals with BF3 (.) Et2 O. The study of these cations has resulted in the discovery of novel reaction pathways that have shown to be associated to the nature of O-6 substituent in the starting alkynyl glycals. Accordingly, compounds resulting from ring expansion (oxepanes), ring contraction (tetrahydrofurans), or branched pyranoses, by incorporation of nucleophiles, can be obtained from 6-O-benzyl, 6-hydroxy, or 6-O-silyl derivatives, respectively. The use of a 6-O-allyl alkynyl glycal led to a suitable funtionalized oxepane able to experience an intramolecular Pauson-Khand cyclization leading to a single tricyclic derivative.

4,4'-Dicyano- versus 4,4'-Difluoro-BODIPYs in Chemoselective Postfunctionalization Reactions: Synthetic Advantages and Applications.

The presence of F or CN substituents at boron in BODIPYs causes a dramatic effect on their reactivity, which allows their chemoselective postfunctionalization. Thus, whereas 1,3,5,7-tetramethyl B(CN)2-BODIPYs displayed enhanced reactivity in Knoevenagel condensations with aldehydes, the corresponding BF2-BODIPYs can experience selective aromatic electrophilic substitution (SEAr) reactions in the presence of the former. These (selective) reactions have been employed in the preparation of BODIPY dimers and tetramers, with balanced fluorescence and singlet oxygen formation, and all-BODIPY trimers and heptamers, with potential application as light-harvesting systems.

Unexpected stereocontrolled access to 1α,1'ß-disaccharides from methyl 1,2-ortho esters.

Mannopyranose-derived methyl 1,2-orthoacetates (R = Me) and 1,2-orthobenzoates (R = Ph) undergo stereoselective formation of 1α,1'ß-disaccharides, upon treatment with BF(3)·Et(2)O in CH(2)Cl(2), rather than the expected acid-catalyzed reaction leading to methyl glycosides by way of a rearrangement-glycosylation process of the liberated methanol.

Ready access to a branched Man5 oligosaccharide based on regioselective glycosylations of a mannose-tetraol with n-pentenyl orthoesters.

A branched Man(5) oligosaccharide has been synthesized by sequential regioselective glycosylations on a mannose-tetraol with n-pentenyl orthoester glycosyl-donors promoted by NIS/BF(3)·Et(2)O, in CH(2)Cl(2). An extended n-pentenyl chain was incorporated into the tetraol acceptor to facilitate (a) the solubility of the starting tetraol in CH(2)Cl(2), and (b) future manipulations at the reducing end of the Man(5) oligosaccharide.

Access to n-pentenyl tetra- and pentasaccharide analogues of the antitumor drug PI-88 based on 1,2-methyl orthoester glycosyl donors.

Convergent synthetic routes to PI-88 tetra- and pentasaccharide-component analogues, have been developed featuring regioselective glycosylations of mannose-polyol n-pentenyl glycosides (NPG) acceptors with 1,2-methyl orthoesters (MeOE) glycosyl donors.

Armed-disarmed effects in carbohydrate chemistry: history, synthetic and mechanistic studies.

This chapter begins with an account of the serendipitous events that led to the development of n-pentenyl glycosides (NPGs) as glycosyl donors, followed by the chance events that laid the foundation for the armed-disarmed strategy for oligosaccharide assembly. A key mechanistic issue for this strategy was that, although both armed and disarmed entities could function independently as glycosyl donors, when one was forced to compete with the other for one equivalent of a halonium ion, the disarmed partner was found to function as a glycosyl acceptor. The phenomenon was undoubtedly based on reactivity, but further insight came unexpectedly. Curiosity prompted an examination of how ω-alkenyl glycosides, other than n-pentenyl, would behave. Upon treatment with wet N-bromosuccinimide, allyl, butenyl, and hexenyl glucosides gave bromohydrins, whereas the pentenyl analog underwent oxidative hydrolysis to a hemiacetal. Although the answer was definitive, an in depth comparison of n-pentenyl and n-hexenyl glucosides was carried out which provided evidence in support of the transfer of cyclic bromonium ion between alkenes in a steady-state phenomenon. It was found that for two ω-alkenyl glycosides having a relative reactivity ratio of only 2.6:1, nondegenerate bromonium transfer enabled the faster reacting entity to be converted completely to product, while the slower reacting counterpart was recovered completely. This nuance suggests that in the armed/disarmed coupling, such a nondegenerate steady-state transfer is ultimately responsible for determining how the reactants are relegated to donor or acceptor roles.Development of chemoselective armed/disarmed coupling led to another phase in the sequence of serendipities. During experiments to glycosylate an acceptor diol, it was found that armed and disarmed donor's glycosylated different hydroxyl groups. This observation caused us to embark on studies of regioselective glycosylation. One of these studies showed that it is possible to activate selectively n-pentenyl orthoesters (NPOEs) over other n-pentenyl donors, and that this chemoselective process enables regioselective glycosylation. As a result, reaction partners can be so tuned that glycosylation of an acceptor with nine free hydroxyl groups by an n-pentenyl orthoester donor carrying two free hydroxyl groups is able to furnish a single product in 42% yield. Experiments such as the latter suggest that the donor favors a particular hydroxyl group, and/or that a particular hydroxyl favors the donor. Either option implies that the principle of reciprocal donor acceptor selectivity (RDAS) is in operation.Such examples of regioselective glycosylation provide an alternative to the traditional practice of multiple protection/deprotection events to ensure that the only free hydroxyl group among glycosyl partners is the one to be presented to the donor. By avoiding such protection/deprotections, there can be substantial savings of time and material - as well as nervous anxiety.

Access to 2,6-Dipropargylated BODIPYs as "Clickable" Congeners of Pyrromethene-567 Dye: Photostability and Synthetic Versatility.

Hitherto unreported 2,6-dipropargyl-1,3,5,7-tetramethyl BODIPYs can be efficiently prepared by a Nicholas reaction/decomplexation protocol from 1,3,5,7-tetramethyl BODIPYs. The title compounds, which improve the BODIPY photostability by retaining their inherent photophysical and photochemical properties, can be engaged in efficient copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) "click-type" reactions with azido derivatives to provide all-BODIPY-triads or conjugated BODIPYs.

Three-component assembly of amines, boronic acids, and a polyfunctionalized furanose: a concise entry to furanose-based carbohydrate templates.

A highly functionalyzed furanose derivative, accessible in five steps from D-mannose, comprising a halo-alkenyl allylic-oxirane system, undergoes a palladium catalyzed one-pot, three component, assembly with boronic acids (or alkyl boranes) and amines to give, in a complete regio- and stereocontrolled manner, a sugar based derivative with two sites of molecular diversity.

Tuning the Photonic Behavior of Symmetrical bis-BODIPY Architectures: The Key Role of the Spacer Moiety.

Herein we describe the synthesis, computationally assisted spectroscopy, and lasing properties of a new library of symmetric bridged bis-BODIPYs that differ in the nature of the spacer. Access to a series of BODIPY dimers is straightforward through synthetic modifications of the pending ortho-hydroxymethyl group of readily available C-8 (meso) ortho-hydroxymethyl phenyl BODIPYs. In this way, we have carried out the first systematic study of the photonic behavior of symmetric bridged bis-BODIPYs, which is effectively modulated by the length and/or stereoelectronic properties of the spacer unit. The designed bis-BODIPYs display bright fluorescence and laser emission in non-polar media. The fluorescence response is governed by the induction of a non-emissive intramolecular charge transfer (ICT) process, which is significantly enhanced in polar media. The effectiveness of the fluorescence quenching and also the prevailing charge transfer mechanism (from the spacer itself or between the BODIPY units) rely directly on the electron-releasing ability of the spacer. Moreover, the linker moiety can also promote intramolecular excitonic interactions, leading to excimer-like emission characterized by new spectral bands and the lengthening of lifetimes. The substantial influence of the bridging moiety on the emission behavior of these BODIPY dyads and their solvent-sensitivity highlight the intricate molecular dynamics upon excitation in multichromophoric systems. In this regard, the present work represents a breakthrough in the complex relationship between the molecular structure of the chromophores and their photophysical signatures, thus providing key guidelines for rationalizing the design of tailored bis-BODIPYs with potential advanced applications.

IPy2BF4-mediated transformation of n-pentenyl glycosides to glycosyl fluorides: a new pair of semiorthogonal glycosyl donors.

Bis(pyridinium) iodonium(I) tetrafluoroborate (IPy2BF4), a solid and stable reagent, can be used to transform n-pentenyl orthoesters (NPOEs) and n-pentenyl glycosides (NPGs) into glycosyl fluorides. The latter pair constitutes a new set of semiorthogonal glycosyl donors that can be used in glycosylation strategies, alone or in combination with NPOEs.

Formation and reactivity of novel pyranosidic nicholas oxocarbenium ions: access to C-ketosides and branched-chain C-ketosides.

[Structure: see text] Dicobalt hexacarbonyl propargyl complexes, prepared from alkynyl ketoses, display an unexpected reactivity when treated with Lewis acids in the presence of nucleophiles and furnish C-ketosides, branched-chain C-ketosides, or branched-chain C-glycals depending on the nucleophile and the carbohydrate starting material.

Relevance of the glycosyl donor to the regioselectivity of glycosidation of primary-secondary diol acceptors and application of these ideas to in situ three-component double differential glycosidation.

[reaction: see text] Three pairs of primary-secondary diol acceptors have been exposed to armed, disarmed, and n-pentenyl ortho ester glycosyl donors in glycosidation reactions. It is shown that the regioselectivity of those glycosylations is greatly influenced by the armed, disarmed, or ortho ester nature of the glycosyl donors. The selectivities observed have been used to devise efficient in situ three-component glycosylations involving two donors and one acceptor.