Toward the Synthesis of Phormidolides.

A convergent and stereoselective approach for the synthesis of marine natural product (MNP) phormidolide D (PM D) is proposed. Two main disconnections divided PM D in three molecular fragments: the macrocyclic core 4, the stapling iodoalkene 9 corresponding to the central part of PMs, and the east fragment 5 that includes the unusual bromo-methoxy-diene moiety and a tetradecanoic acid ended with a (E)-dichloro-ene functionality. Procedures for the preparation of compounds 5, 9, and the never-reported fatty acids 7 and 8, present in PMs C and D, respectively, have been afforded with good yields and high degree of stereoselectivity. The absolute configuration of all of the generated stereocenters has been established. The reaction to link iodoalkene 9 and formylmacrolactone 4, using the Nozaki-Hiyama-Takai-Kishi coupling, gave an advanced synthetic intermediate with total stereocontrol. Finally, a deeper study of protecting groups and reaction conditions for the last step of the synthesis is needed. All the information gathered in this publication will be of great value to continue performing synthetic studies for the preparation of these NPs. The versatility and the presence of a common polyol chain in oscillariolide and PMs A-C would allow applying the same retrosynthesis for the synthesis of the mentioned MNP.

Enantioselective Synthesis of the Polyhydroxylated Chain of Oscillariolide and Phormidolides A-C.

The first enantioselective synthesis of the polyhydroxylated chain common to marine natural products oscillariolide and phormidolides A-C is described herein. This chain represents a synthetic challenge that needs to be solved before the total synthesis of this family of natural products can be approached. It contains seven stereocenters, six of them having a syn-hydroxylated functionality, and a tricky terminal (E)-bromomethoxydiene (BMD). The described effective enantioselective strategy affords the polyketide chain and represents an important breakthrough to complete the total synthesis of these marine compounds.

Synthesis of (E)-4-Bromo-3-methoxybut-3-en-2-one, the Key Fragment in the Polyhydroxylated Chain Common to Oscillariolide and Phormidolides A-C.

The terminal bromomethoxydiene (BMD) moiety of the polyhydroxylated chain present in phormidolides and oscillariolides has been synthesized for first time. Several strategies for the stereoselective synthesis of the 4-bromo-3-methoxybut-3-en-2-ones are described. Furthermore, a preliminary study to successfully introduce the BMD within the polyol chain and the fatty acid allowed us to corroborate the end structure of the polyol.