Part I: Synthetic studies toward the southern portion of azaspiracid-1; Part II: Total synthesis of amphidinolide B1and the proposed structure of amphidinolide B2.

摘要

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 C 27-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 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 -100°C, while the 18S stereomer was obtained at -40°C 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.;The first total synthesis of cytotoxic macrolides amphidinolide B 1 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.