Diseño, síntesis y reactividad de nuevos sistemas ferrier-nicholas en derivados de piranosas. Aplicación a la síntesis de nuevos derivados de carbohidratos

Résumé

This Ph.D. Thesis has been devoted to the development of novel polyfunctionalized carbohydrate derivatives. This work includes then, the design, synthesis, and the study of the reactivity of the new carbohydrate derivates. In this context, we have studied three different types (I, II, III) of polyunsaturated pyranoses. These new systems, built around a pyranose skeleton, include olefinic double bonds and alkynes, the latter having been modified as their dicobalthexacarbonyl-alkynyl derivatives. The three systems considered differ in attachment point of the alkyne (C-1 or C-3), and the nature of the olefin (Δ2,3 or Δ2,2´), and they were designed to enjoy simultaneous "Ferrier" and "Nicholas" reactivities, vide infra. Thus, "the Ferrier rearrangement" refers to the substitution with allylic rearrangementî reaction of glycals (or 1,2-unsaturated pyranoses) with nucleophiles to give allylic glycosides, and the Nicholas reaction denotes the propargylation of nucleophiles facilitated by the use of dicobalthexacarbonyl-alkynyl derivatives. Both transformations are triggered by acidic media and take place by reaction of the respective intermediate cations (Ferrier cations and Nicholas cations) with nucleophiles. Thus, the derivatives under study were designed under the idea of combining both types of systems around the unique reactivity of glycosyl cations. The first two systems studied (I, II) are glycal (or 1,2-unsaturated pyranoses) derivatives, which had already shown a preference for the generation of allylic cations, under acidic conditions (by departure of the C-3 substituent). They differed in the position where the alkyne functionality was appended C-1 (I) or at C-3 (II). The last compound studied (III) possessed a Δ2,2´ unsaturation, and the alkynyl residue was added at the anomeric (C-1) position. The study of derivatives type I, resulted in the discovery of novel reaction pathways associated to the nature of O-6 substituent in the starting alkynyl glycals. Thus, compounds resulting from ring expansion (oxepanes), ring contraction (tetrahydrofurans), or branched pyranoses, by incorporation of nucleophiles, were obtained from 6-O-benzyl, 6-hydroxy, or 6-O-silyl derivatives, respectively. The use of a 6-O-allyl alkynyl glycal allowed a one-pot access to a single tricyclic derivative featuring an intramolecular PausonñKhand cyclization as the last step. HexacarbonyldicobaltñC-3-alkynyl-substituted glycal derivatives (Type II compounds), when treated with BF3OEt2 reacted with alcohols or C-nucleophiles to give C-3-branched 2,3-unsaturated glycosides or C-glycosides, respectively. -CGlycosides were the sole compounds obtained when allyltrimethylsilane was used as the nucleophile. On the contrary, the reaction of C-3-alkynylglycals with heteroaryl or alcohol nucleophiles led to anomeric mixtures in which, contrary to normal results, the -anomers prevailed. The presence of the hexacarbonyldicobaltñC-3-alkynyl substituent probed to be of key importance in the stereoselectivity of these transformations, since the reaction of C-3-alkynylglycals ñ devoid of the hexacarbonyldicobalt moiety ñ showed a preferred -stereoselectivity. Interestingly, reaction of a hexacarbonyldicobaltñC-3-alkynylglycal with two equivalents of indole, led to the formation of a bis(indolyl) open-chain compound. Finally, 1-C-alkynyl-2-deoxy-2-C-methylene pyranosides (Ferrier, IIIa), and their corresponding dicobalthexacarbonyl alkenyl derivatives (Ferrier-Nicholas, IIIb) (compounds Type III) were selected as substrates. These systems could be accessed by a concise synthetic route from commercially available tri-O-acetyl-D-glucal. The reaction of the Ferrier-Nicholas derivatives (IIIb) under acidic media, allowed the incorporation of two nucleophiles (at positions C-3 and C-2í) to the pyranose ring. Contrary to our initial expectations, system IIIa proved to display a remarkable behavior leading to open-chain derivatives, branched pyranosides, and when reacting with indole, to a new family of tetracyclic indole-containing carbohydrate derivatives, namely, cyclohepta[b]indolefused glycals. The latter are, most likely, formed by a bis Ferriertype rearrangement followed by an unusual intramolecular 7-endo-dig Friedel-Crafts alkenylation of one of the indole moieties by the C-1 alkyne. In summary, the study of these three types of compounds have contributed to the discovery of novel, sometimes unexpected, reaction pathways leading to carbohydrate derivatives with skeletal diversity