"Cut and Paste" Processes in the Search of Bioactive Products: One-Pot, Metal-free O-Radical Scission-Oxidation-Addition of C, N or P-Nucleophiles.

Hypervalent iodine reagents have been applied in many metal-free, efficient synthesis of natural products and other bioactive compounds. In particular, treatment of alcohols, acetals and acids with hypervalent iodine reagents and iodine results in O-radicals that can undergo a ß-scission reaction. Under these oxidative conditions, derivatives of amino acids, peptides or carbohydrates are converted into cationic intermediates, which can subsequently undergo inter- or intramolecular addition of nucleophiles. Most reported papers describe the addition of oxygen nucleophiles, but this review is focused on the addition of carbon, nitrogen and phosphorous nucleophiles. The resulting products (nucleoside and alkaloid analogs, unnatural amino acids, site-selectively modified peptides) are valuable intermediates or analogs of bioactive compounds.

Intramolecular Metal-Free C(sp3)-H Activation Enables a Selective Mono O-Debenzylation of Fully Protected Aminosugars.

Carbamate-bearing benzylated aminosugars undergo an I2/I(III)-promoted intramolecular hydrogen atom transfer (IHAT) followed by a nucleophilic attack to provide polycyclic structures. Thus, suitably positioned benzyl ethers are surgically oxidized into the corresponding mixed N/O-benzylidene acetals, which can be conveniently deprotected under mild acidic conditions to grant access to selectively O-deprotected aminosugars amenable for further derivatization. The scope of this strategy has been proven with a series of furanosic and pyranosic scaffolds. Preliminary mechanistic studies, including Hammett LFER and KIE analyses, support a reaction pathway with nucleophilic cyclization as the rate-determining step.

Tandem Radical Fragmentation/Cyclization of Guanidinylated Monosaccharides Grants Access to Medium-Sized Polyhydroxylated Heterocycles.

The fragmentation of anomeric alkoxyl radicals (ARF) and the subsequent cyclization promoted by hypervalent iodine provide an excellent method for the synthesis of guanidino-sugars. The methodology described herein is one of the few existing general methodologies for the formation of medium-sized exo- and endoguanidine-containing heterocycles presenting a high degree of oxygenation in their structure.

Synthesis of Chiral Polyhydroxylated Benzimidazoles by a Tandem Radical Fragmentation/Cyclization Reaction: A Straight Avenue to Fused Aromatic-Carbohydrate Hybrids.

The synthesis of benzimidazole-fused iminosugars through a tandem ß-fragmentation-intramolecular cyclization reaction is described. The use of the benzimidazole ring as the internal nucleophile and the use of phenyliodosophthalate (PhI(Phth)), a new metal-free and low toxic hypervalent iodine reagent, are the most remarkable novelties of this synthetic strategy. With this approach, we have demonstrated the usefulness of the fragmentation of anomeric alkoxyl radicals promoted by the PhI(Phth)/I2 system for the preparation of new compounds with potential interest for both medicinal and synthetic chemists.

The Road from Host-Defense Peptides to a New Generation of Antimicrobial Drugs.

Host-defense peptides, also called antimicrobial peptides (AMPs), whose protective action has been used by animals for millions of years, fulfill many requirements of the pharmaceutical industry, such as: (1) broad spectrum of activity; (2) unlike classic antibiotics, they induce very little resistance; (3) they act synergically with conventional antibiotics; (4) they neutralize endotoxins and are active in animal models. However, it is considered that many natural peptides are not suitable for drug development due to stability and biodisponibility problems, or high production costs. This review describes the efforts to overcome these problems and develop new antimicrobial drugs from these peptides or inspired by them. The discovery process of natural AMPs is discussed, as well as the development of synthetic analogs with improved pharmacological properties. The production of these compounds at acceptable costs, using different chemical and biotechnological methods, is also commented. Once these challenges are overcome, a new generation of versatile, potent and long-lasting antimicrobial drugs is expected.

Chemoselective intramolecular functionalization of methyl groups in nonconstrained molecules promoted by N-iodosulfonamides.

Mechanistic evidence observed in Hofmann-Löffler-Freytag-type reactions has been crucial to achieve the chemoselective functionalization of methyl groups under mild conditions. Radical-mediated methyl iodination and subsequent oxidative deiodination are the key steps in this functionalization, where iodine chemistry has a pivotal role on the formation of the C-N bond. The concepts of single hydrogen atom transfer (SHAT) and multiple hydrogen atom transfer (MHAT) are introduced to describe the observed chemoselectivity.

Synthesis of branched iminosugars through a hypervalent iodine(III)-mediated radical-polar crossover reaction.

The synthesis of a novel type of branched iminosugars is described. This synthetic strategy is based on two key reactions: first, an aldol reaction with formaldehyde in order to introduce selectively the hydroxymethyl branch, and second, a tandem ß-fragmentation-intramolecular cyclization reaction. The combination of both reactions afforded a battery of compounds exhibiting a great structural complexity, with the concomitant formation of a quaternary center, starting from readily available aldoses. With this approach we have demonstrated the usefulness of the fragmentation of anomeric alkoxyl radicals (ARF) promoted by the PhIO/I2 system for the preparation of new compounds with potential interest for both medicinal and synthetic chemists.

Synthesis of tetrazole-fused glycosides by a tandem fragmentation-cyclization reaction.

The fragmentation of anomeric alkoxyl radicals (ARF) and the subsequent intramolecular cyclization promoted by hypervalent iodine reagents provide an excellent method for the synthesis of tetrazolo-sugars. This new reaction offers additional advantages for the synthesis of these compounds, including the ready availability of the starting materials, experimental simplicity, mild conditions, and good yields.

Synthesis of guanidines from azides: a general and straightforward methodology in carbohydrate chemistry.

The ability of the guanidinylating reagent N',N''-diBoc-N-triflyl-guanidine (GN-Tf) to react with in situ formed free amines from azides in carbohydrate scaffolds was explored. This reaction proved to be an efficient method to prepare guanidine derivatives in a one-pot manner with good to excellent yields, either with primary or secondary azides with different substitution patterns. Labile protecting groups such as benzyl ethers are not removed under these hydrogenolytic conditions.

Fragmentation of carbohydrate anomeric alkoxyl radicals: new synthesis of chiral 1-fluoro-1-halo-1-iodoalditols.

A new general methodology for the synthesis of 1,1,1-trihaloalditols by starting from 1,5-anhydro-2-deoxy-hex-1-enitol derivatives (glycals) is described. The halogens are introduced sequentially in each of the three different steps of the process. The fluorine is introduced in the first step by electrophilic fluorination of the starting glycal; next, hydroxyhalogenation of the resulting vinyl fluoride allows the addition of any halogen (F, Cl, Br or I) at will, and finally, an iodine atom is inserted through an alkoxyl radical fragmentation reaction. This methodology allows the preparation of diverse types of 1,1,1-trihalogenated compounds (R--CF(2)I, R--CFI(2), R--CFClI and R--CFBrI) under mild conditions compatible with sensitive substituents. In some cases, the diastereomeric mixtures generated from R--CFClI and R--CFBrI can be chromatographically separated, and their configuration determined by X-ray crystallographic analysis. The synthetic usefulness of these compounds has been preliminarily assessed by examining the reactivity of the fluorinated radical generated by rupture of the C--I bond.

Fragmentation of carbohydrate anomeric alkoxy radicals: a new synthesis of chiral 1-halo-1-iodo alditols.

Treatment of 1,2-fluorohydrins, 1,2-chlorohydrins, 1,2-bromohydrins, and 1,2-iodohydrins of the D-gluco, D-galacto, D-lacto, L-rhamno, D-allo, L-arabino, 3-deoxy-D-gluco, and 3,4-dideoxy-D-gluco families of carbohydrates with the (diacetoxyiodo)benzene/iodine system afforded 1-fluoro-1-iodo, 1-chloro-1-iodo, 1-bromo-1-iodo, and 1,1-diiodo alditols, respectively, in excellent yields. The reaction was achieved by radical fragmentation of the C1bond;C2 bond, triggered by the initially formed anomeric alkoxy radical, and subsequent trapping of the C2-radical by iodine atoms. This methodology is compatible with the stability of the protective groups most frequently used in carbohydrate chemistry. The potential utility of these 1-halo-1-iodo alditols as chiral synthons was evaluated by their transformation into alk-1-enyl iodides and in the Takai E-olefination reaction.

Fragmentation of carbohydrate anomeric alkoxyl radicals: a new synthesis of 1,1-difluoro-1-iodo alditols.

[reaction: see text]. The beta-fragmentation of 2,2-difluoro-saccharide anomeric alkoxyl radicals, generated under oxidative condition by treatment of the respective alcohols with (diacetoxyiodo)benzene (DIB) and iodine, afforded 1,1-difluoro-1-iodo alditols in high yield. The reactivity of the fluorinated radical generated by rupture of the C-I bond has been preliminarily assessed by reductive deiodination with tributyltin hydride/AIBN and intermolecular allylation using the Keck reaction.

Fragmentation of Carbohydrate Anomeric Alkoxy Radicals: A New Synthesis of Chiral 1-Halo-1-iodo Compounds.

One less carbon atom is found in 1-halo-1-iodo compounds obtained by C1-C2 radical fragmentation of carbohydrate 1,2-halohydrins. This fragmentation is achieved via the anomeric alkoxy radicals of the halohydrins, formed upon reaction with (diacetoxyiodo)benzene and iodine [Eq. (1); X=Cl, Br, I].