Toward the Synthesis of Phormidolides

Alejandro Gil; Michela Giarrusso; Janire Lamariano-Merketegi; Adriana Lorente; Fernando Albericio; Mercedes Álvarez

doi:10.1021/acsomega.8b00125

Toward the Synthesis of Phormidolides

ACS Omega. 2018 Feb 27;3(2):2351-2362. doi: 10.1021/acsomega.8b00125. eCollection 2018 Feb 28.

Authors

Alejandro Gil^{1

2}, Michela Giarrusso^{1

2}, Janire Lamariano-Merketegi^{1

2}, Adriana Lorente^{1

2}, Fernando Albericio^{1

2

2

3}, Mercedes Álvarez^{1

2

4}

Affiliations

¹ ChemBio Lab, Barcelona Science Park, Baldiri Reixac 10-12, 08028 Barcelona, Spain.
² CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, and Department of Organic Chemistry, University of Barcelona, Martí Franquès, 1-11, 08028 Barcelona, Spain.
³ School of Chemistry, University of Kwa-Zulu-Natal, Private Bag X01, Scottsville, 3209 Durban, South Africa.
⁴ Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, Campus Diagonal, Av. de Joan XXIII, 27-31, 08028 Barcelona, Spain.

Abstract

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.