Graduate Thesis Or Dissertation
 

Part I: Synthetic studies toward the southern portion of Azaspiracid-1; Part II: Total synthesis of amphidinolide B₁ and the proposed structure of amphidinolide B₂

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  • The structural architecture present in marine toxin azaspiracid - 20 stereocenters, 9 rings, 3 separated spirocenters - has attracted considerable synthetic attention. Our efforts toward the synthesis of azaspiracid have led to the completion of both C₁-C₂₆ northern and C₂₇-C₄₀ southern halves. Herein, the synthesis of southern FGHI ring system is described. The key steps included an Andrus anti-aldol coupling to furnish the C₃₂, C₃₃ stereocenters, an acid-catalyzed ketalization to furnish FG rings, and a Yb(OTf)₃-mediated spiroaminal formation to generate I ring. The first total synthesis of cytotoxic macrolides amphidinolide B₁ and the proposed structure of amphidinolide B₂ have been accomplished. The key developed protocols include a metal catalyst-free sequence for the synthesis of the diene subunit, a non-chelation-controlled aldol coupling to install the C₁₈ stereocenter, an efficient macrocyclization of the 26-membered lactone ring, and the incorporation of the labile allylic epoxide moiety. The unique structure of the highly substituted diene functionality represents significant synthetic challenges. A Wittig / HWE reaction sequence yielded the C₁₃-C₁₅ diene moiety in good yield in excellent diastereoselectivity. Subsequent Sharpless epoxidation and Red-Al-mediated regionselective epoxide opening gave the C₁₆ tertiary alcohol. The protecting groups on C₂₁ were discovered to have significant effects on the aldol reaction between C₉-C₁₈ aldehyde and C₁₉-C₂₅ methyl ketone. Although chelating groups such as PMB, Bn afforded 18S isomer as a single diastereomer, the removal of these groups has proven problematic. Non-chelating silyl group generated 18R isomer in 8:1 dr at -100ºC, while the 18S stereomer was obtained at -40ºC in 1.2:1 dr. A spontaneous intramolecular Wadsworth−Emmons olefination established the 26-membered macrocycle. The oxidation and in situ elimination of a selenide moiety proceeded smoothly in the presence of free alcohols using TMSOOTMS. The first total synthesis of amphidinolide B1 and the proposed structure of amphidinolide B₂ were accomplished in 29 linear steps. Additionally, We discovered that the initially proposed structure of amphidinolide B₂ was incorrect.
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