Konstantina C. Fylaktakidou

Total Synthesis of Apoptolidin: Part 1. Retrosynthetic Analysis and Construction of Building Blocks

No less than 30 stereogenic elements, a highly unsaturated 20-membered macrocyclic system, four carbohydrate units, and unique biological activity, make the natural occurring apoptolidin (1) a challenging synthetic target. The retrosynthetic analysis revealed five key building blocks-three for the construction of the macrolide ring B and two prospective pendant saccharide units-which were synthesized in a highly convergent manner and then connected. Apoptolidins rather labile nature proved particularly challenging in the final deprotection, purification, and characterization procedures.

Total synthesis of everninomicin 13,384-1--Part 1: retrosynthetic analysis and synthesis of the A1B(A)C fragment.

In this first of a series of four articles we introduce everninomicin 13,384-1 (1), a powerful antibiotic effective against drug resistant bacteria, as a target for total synthesis and discuss its retrosynthetic analysis. From the three defined fragments required for the synthesis (2: A1B(A)C fragment; 4: DE fragment; 5: FGHA2 fragment), we describe herein two approaches to the A1B(A)C block. The first strategy relied on an olefin metathesis reaction to construct a common intermediate for rings B and C, but was faced with final protecting group problems. The second, and successful approach, involved a 1,2-phenylsulfeno migration and a sulfur directed glycosidation procedure to link rings B and C, as well as an acyl fluoride intermediate to install the sterically hindered aryl ester moiety (ring A1). The final stages of the synthesis of the required 2-phenylseleno glycosyl fluoride 2 required introduction of a phenylseleno group at C-1 of ring C followed by a novel, DAST-promoted 1,2-migration to produce the desired 2-beta-phenylseleno glycosyl fluoride moiety.

Total Synthesis of Apoptolidin: Part 2. Coupling of Key Building Blocks and Completion of the Synthesis

No less than 30 stereogenic elements, a highly unsaturated 20-membered macrocyclic system, four carbohydrate units, and unique biological activity, make the natural occurring apoptolidin (1) a challenging synthetic target. The retrosynthetic analysis revealed five key building blocks-three for the construction of the macrolide ring B and two prospective pendant saccharide units-which were synthesized in a highly convergent manner and then connected. Apoptolidins rather labile nature proved particularly challenging in the final deprotection, purification, and characterization procedures.

Total synthesis of everninomicin 13,384-1--Part 3: synthesis of the DE fragment and completion of the total synthesis.

The stereoselective construction of the DE fragment (2) of everninomicin 13,384-1 (1) is reported. From the two possible ways of inserting the DE fragment between the A1B(A)C and FGHA2 domains of the natural product, the sequence involving the DEFGHA2 segment was found to be the most viable. This coupling was followed by attachment of a suitably protected and activated A1B(A)C fragment which led, after orthoester construction and final deprotection to the targeted everninomicin 13,384-1 (1), completing the total synthesis of this complex naturally occurring substance.

Total Synthesis of Everninomicin 13,384‐1—Part 3: Synthesis of the DE Fragment and Completion of the Total Synthesis

The stereoselective construction of the DE fragment (2) of everninomicin 13,384-1 (1) is reported. From the two possible ways of inserting the DE fragment between the A1B(A)C and FGHA2 domains of the natural product, the sequence involving the DEFGHA2 segment was found to be the most viable. This coupling was followed by attachment of a suitably protected and activated A1B(A)C fragment which led, after orthoester construction and final deprotection to the targeted everninomicin 13,384-1 (1), completing the total synthesis of this complex naturally occurring substance.