Synthèse stéréosélective de motifs polypropionates via la chimie des radicaux : application à l'élaboration de l'hémisphère ouest de la narasine

This thesis focuses on a new methodology for the synthesis of polypropionate stereopentads with an application to the synthesis of a natural molecule that possess interesting biological properties. The key steps of our strategy to elaborate those motifs will use radical chemistry previously developped in our group. First, the importance of synthesizing polypropionate motifs is presented. In recent years, polypropionate systems have stimulated extensive interest due to their association with a broad spectrum of biologically active targets with proven or potential use in medicine, including those with antibiotic and anticancer properties. Many of the approaches reported used chiral reagents and took advantage of double asymmetric induction. Not surprisingly, mismatched scenarios were at times noticed and yet, no single strategy has been reported leading directly to all 16 stereopentad diastereoisomers. Thus, the rapid and facile assembly of the polypropionate framework would be very beneficial and is still an active area of research. The second section of this work describes our contribution to this area with the development of a fully substrate-controlled sequence of Mukaiyama aldol reaction followed by a hydrogen transfer reaction on aldehydes having the stereotriad array. The aldol reaction can be performed under Felkin-Anh or Cram-chelate pathway to give either the 3,4-syn or 3,4-anti relationship, respectively. This reaction was optimized using different Lewis acids to give excellent yield and diastereoselectivity. We found that an excess of TiCl3(OiPr) in our Mukaiyama reactions increased the chelating ability of the Lewis acid, thus leading to improved diastereoselectivity. Low temperature 13C NMR was performed to obtain more information on the complexes present in solution.  Once the radical precursors were obtained, the hydrogen transfer step was performed. Aluminum-containing Lewis acids led to the exclusive formation of the 2,3- syn isomer under the endocyclic effect while controlling factors described for acyclic molecules were sufficient enough to give the 2,3-anti as a sole diastereoisomer, such as cases in which a boron-containing Lewis acid was added prior to the tin hydride. One limitation was observed with this scenario and resolved using the exocyclic effect to access all 16 polypropionate stereopentad motifs. To further demonstrate the synthethic potential of our methodology, we engaged on the synthesis of the western hemisphere of both salinomycin and narasin. The synthetic challenges related with these molecules are numerous due to the large number of adjacent stereogenic centers. We realized that the 2,3-anti stereochemical relation of salinomycin was not selectively accessible via radical chemistry under the exocyclic effect. Different substrates were tested to understand this limitation and we concluded that the substituents on the ring impose a conformationnal bias unfavorable to good selectivty. Still, we found an alternative employing a chiral crotylsilane to access this 2,3-anti relationship α to the six-membered ring. This situation is different in the case of narasin where the β-methyl substituent blocks efficiently the hydride attack from the upper face. Impressive selectivities were observed and the synthesis of the C1-C9 fragment of narasin was accomplished in an expeditive manner. Finally, the elongation using a second sequence of stereoselective Mukaiyama aldol reaction/radical reduction followed by an aldol coupling led to the construction of the western hemisphere of narasin in 19 synthethic steps with an overall yield of 7 %. Finally, we decided to focus our attention to the chemistry of α-bromo-β- alkoxyketones in hydrogen transfer reactions. We found that their ability to give selective transformations could be beneficial in the context of synthesizing complex polypropionate motifs. The presence of a stereogenic center on the other side of the ketone seemed to have a great impact on the selectivity.

Keyphrases: Acyclic stereoselection, Cram-chelate, Endocyclic effect, Exocyclic effect, Narasin, Radical reduction, Salinomycin, Titanium