Exploring reliable methodologies for the synthesis of compounds of medicinal importance: total synthesis of novel neuroexcitatory aminoacids, of antitumor lactones, of the antidepressant paroxetin, and of new analogues of sphingosine and cerebrosides

• Grant number: 05/00721-3
• Support Opportunities: Regular Research Grants
• Start date: September 01, 2005
• End date: January 31, 2009
• Field of knowledge: Physical Sciences and Mathematics - Chemistry
• Principal Investigator: Carlos Roque Duarte Correia
• Grantee: Carlos Roque Duarte Correia
• Host Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

The present research proposal encompass four subprojects revealing a significant fraction of the ongoing research in my laboratories. Three of the four subprojects presented herein are related to the use of Heck arylation reactions using aryldiazonium salts, a reaction protocol under intense investigation in my research group and that display an exceptional synthetic potential. The synthetic objectives in these three subprojects are compounds with pharmacological and therapeutic appeal. The acromelic acid derivatives are potent neuroexcitatory compounds acting on kainate receptors and are attracting considerable worldwide interest mainly in the pharmaceutical area. The firs subproject presents an efficient and quick entry to the syntheses of the acromelic acid derivatives. Moreover, the synthetic protocol brings new and surprising mechanistic insights mostly concerning the regio and stereoselectivity of the arylation process occurring with dehydroprolines.The second subproject aims at the synthesis of several aryllactones possessing significant antitumor activity. The strategy for the synthesis of such compounds involves the Heck arylation of chiral dihydrofuran derivatives with aryldiazonium salts. The process stereoselectivity plays a pivotal role here and we hope to apply this methodology in the synthesis of four important aryllactones (altholactone, isoaltholactone, goniotalesdiol and gonioheptolide) and possibly several other new analogues for pharmacological assays (to be carried out at CPQBA/Unicamp once the compounds are available). The third research subproject presents the total synthesis of conformationally restricted dopamine and serotonin analogues with special attention on the total synthesis of the antidepressant drug paroxetine, a worldwide reference for drugs acting on compulsive-obsessive disorders. The methodology adopted for the synthesis of paroxetine relies on a new Heck arylation of a trisubstituted endocyclic unsaturated ester (enoate) with aryldiazonium salts, a surprisingly novel approach for this type of compounds and one which was shown to be highly effective.The fourth subproject highlights a proposal in the area of Chemical Biology as it presents the total synthesis of unnatural sphingolipid and cerebroside analogues exploring the chemistry we have developed with endocyclic enecarbamates. The methodology makes use of [2+2] cycloadditions of enecarbamates followed a photochemical ring expansion (Norrish II reaction). This is a promising methodology in terms of efficiency regarding the synthesis of pyrrolidines containing unsaturated side chains. The unsaturation (double bond) should be incorporated by means of a Wittig olefination reaction opening up the possibility for preparing sphingolipids based on a pyrrolidine framework. Also planned is the incorporation of these new compounds in a liposomal lipidic bilayer, a proposal that counts with the collaboration of prof. Maria Helena Santana (an expert in liposomes) from the Department of Biotechnological Process of the Chemical Engineering Institute of Unicamp. The incorporation of sphingolipids and cerebrosides into liposomes may provide a must wanted tissue specificity for the delivery of drugs as well as stability to the supramolecular aggregates, which are of considerable interest for the pharmaceutical and cosmetic industries. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

VALLE‚ M.S.; RETAILLEAU‚ P.; CORREIA‚ C.R.D.. Synthesis of alexine-like compounds from chiral five-membered endocyclic enecarbamates. Tetrahedron Letters, v. 49, n. 12, p. 1957-1960, 2008. (05/00721-3)

MORO, ANGELICA VENTURINI; CARDOSO, FLAVIO SEGA P.; CORREIA, CARLOS ROQUE D.. Heck arylation of styrenes with arenediazonium salts: short, efficient, and stereoselective synthesis of resveratrol, DMU-212, and analogues. Tetrahedron Letters, v. 49, n. 39, p. 5668-5671, SEP 22 2008. (05/00721-3)