Les phosphinosucres appelés aussi « phostines » sont des analogues phosphorés des sucres pyranoses et des C-arylglycosides. L'évaluation biologique de ses composés a révélé une activité anticancéreuse des phosphinosucres sur les cellules de glioblastome multiforme, un cancer particulièrement malin et invasif qui ne possède pas de solution thérapeutique. Dans le but de comprendre les mécanismes d'action des phosphinosucres et la stéréo-dépendance de leur activité biologique, la caractérisation des diastéréomères de « phostines » a été menée. Suite à cette détermination structurale, le développement de synthèses diastéréosélectives a permis d'obtenir un mélange fortement enrichi en diastéréomère le plus actif par une séquence réactionnelle qui a mis en jeu une réaction d'oxydation de phosphinosucres -hydroxylés en α-cétophosphinosucres, suivie d'une réduction diastéréosélective. Afin d'améliorer l'activité antiproliférative des phosphinosucres, une diversification chimique a été réalisée. Les variations du groupement aryle lié à l'atome de phosphore nous ont amené à développer une synthèse des aryl-hydrogénophosphinates qui a permis d'obtenir une large variété de ces composés. Par la suite, les aryl-hydrogénophosphinates obtenus ont été engagés dans la synthèse des « phostines ». De plus, des variations chimiques sur le carbone en position α de l'atome de phosphore ont été entreprises et ont permis l'élaboration de plusieurs composés (triflate, azido, amino, déoxy et triazolyles), puis finalement à l'analogue phosphinosucre du N-acétylglucosamine qui a présenté une importante activité anticancéreuse in vitro. / Phosphinosugars also called « phostines » are new cyclic phosphinates, analogs of carbohydrates and C-aryglycosides, with phosphorus atom mimicking the anomeric carbon. Biological screening tests of these compounds revealed an anticancer activity against glioblastoma multiform, a highly invasive and malignant tumor without curative therapy.With the aim of understanding the phosphinosugars mode of action and their stereo-dependent biological activity, characterization of four phosphinosugars diastereomers formed during the chemical process has been performed. After their structural determination, diastereoselective synthesis enabled us to obtain an enriched mixture of the most active diastereomer based on an oxidation of -hydroxyled phosphinosugars in corresponding -keto phosphinosugars followed by a diastereoselective reduction. Thereafter, antiproliferative activity of phoshinosugars was performed by chemical diversification. Modification of the aryl group linked to phosphorus atom led us to develop aryl-hydrogenophosphinate synthesis to create a broad variety of these structures. Then, the expected aryl-hydrogenophosphinates were used for phostines preparation. Furthermore, chemical modifications on the carbon in α position of phosphorus atom were led and furnished several new compounds (triflate, azido, amino, deoxy and triazolyl), as well as the phosphinosugar analog of N-acetylglucosamine which presented in vitro a high anticancer activity.

<p>U radu je ostvarena enantiodivergentna totalna sinteza oba enantiomera goniofufurona, 7-epi-goniofufurona i krasalaktona C polazeći iz D-glukoze. Ključne faze u sintezi 7-epi-(+)-goniofufurona bile su stereoselektivna adicija fenilmagnezijum bromida na aldehidnu grupu pogodno za&scaron;tićene dialdoze, i stereospecifično formiranje furano-laktonskog prstena ciklokondenzacijom odabranog hemiacetalnog derivata sa Meldrum-ovom kiselinom. Sinteza (+)-goniofufurona i (+)-krasalaktona C zahtevala je inverziju konfiguracije na C-5<br />u zajedničkom intermedijeru, koja je efikasno ostvarena u uslovima Mitsunobu-ove reakcije, ili alternativno oksidacijom benzilne hidroksilne grupe u prohiralni keton, uz naknadnu stereoselektivnu redukcijom sa borohidridom. Sličan pristup je zatim primenjen za sintezu neprirodnih (&minus;)-enantiomera goniofufurona, 7-epi-goniofufurona i krasalaktona C, dva nova konformaciono ograničena analoga (+)- i (&minus;)-goniofufurona (oksetani 36 i ent-36), kao i odgovarajućih 7-deoksigenovanih derivata (31 i ent-31). Takodje je razvijena i prva totalna sinteza prirodnog (+)-krasalaktona B (3) i alternativna sinteza (+)-krasalaktona C (4) polazeći iz D-glukoze. Selektivni pristup molekulima 3, odnosno 4 omogućen je promenom uslova za TBDPS deprotekciju u finalnom intermedijeru 53. Osnovna karakteristika pomenutih pristupa je njihova generalnost i fleksibilnost. Na taj način je omogućena sinteza serije analoga i derivata (+)-goniofufurona, ili 7-epi-goniofufurona, uključujući i do sada nepoznate 7-epi-(+)-krasalaktone B (6) i C (7), 5,7-di-O-cinamoil derivate 8 i 9, 5,7-di-O-izopropilidenske derivate 5 i 10, kao i vi&scaron;e lipofilnih derivata (jedinjenja 26, 30, 33, 65, ent-30 i ent-33). Konačno, u drugom delu rada, ispitan je uticaj sintetizovanih stiril-laktona na rast odabranih tumorskih ćelijskih linija in vitro.</p> / <p> Enantiodivergent total syntheses of both (+)- and (&minus;)-enantiomers of goniofufurone, 7-epi-goniofufurone and crassalactone C have been accomplished starting from D-glucose. The key steps of the synthe-sis of 7-epi-(+)-goniofufurone were a stereo-selective addition of&nbsp;<br /> phenyl magnesium bromide to a protected dialdose, followed by a stereospecific furano-lactone ring formation by condensation of a partially protected lactole with Meldrum&rsquo;s acid. The synthesis of (+)-goniofufurone and (+)-crassalactone C required a configurational inversion at C-5 in the common intermediate that was efficiently achieved under the standard Mitsunobu conditions, or alternatively through a sequential oxidation of the benzylic hydroxyl group followed by a stereo-selective reduction with borohydride. A similar approach was applied to the synthesis of the unnatural enantiomers of goniofufurone, 7-epi-goniofufurone and crassalactone C, two novel, conformationally constrained analogues of both (+)- and (&minus;)-goniofufurone (oxetanes 34 and ent-34). as well as the corresponding 7-deoxygenated derivatives (31 and ent-31). We have also developed the first total synthesis of (+)-crassalactone B (2) and an alternative synthesis of (+)-crassalactone C (3) starting from D-glucose. Finally, the synthesized styryl-lactones were evaluated for their antiproliferative activity against a panel of human tumor cell lines.</p>