Second-generation total synthesis of aplyronine A featuring Ni/Cr-mediated coupling reactions

Abstract

Second-generation total synthesis of aplyronine A, a potent antitumor marine macrolide, was achieved using Ni/Cr-mediated coupling reactions as key steps. The overall yield of the second-generation synthetic pathway of aplyronine A was 1.4%, obtained in 38 steps based on the longest linear sequence. Compared to our first-generation synthetic pathway of aplyronine A, the second-generation synthesis greatly improved both the yield and number of steps. In particular, we improved the stereoselectivity in the construction of the C13 stereogenic center and the C14-C15 (E)-trisubstituted double bond using the asymmetric Ni/Cr-mediated coupling reaction. Furthermore, we established efficient reaction conditions for the asymmetric Ni/Cr-mediated coupling reaction between the C21-C28 segment and C29-C34 segment. Thus, this coupling reaction proceeded with an equimolar ratio of each segment.

Synthesis and Biological Activities of Aplyronine A Analogues toward the Development of Antitumor Protein–Protein Interaction Inducers between Actin and Tubulin: Conjugation of the C1–C9 Macrolactone Part and the C24–C34 Side Chain

“…For bioassay, a part of the sample was further purified with reversed-phase HPLC [Develosil ODS-HG-5 (ϕ 20 × 250 mm), MeOH/20 mM aq NH 4 OAc (74/26), 5 mL/min, UV254 nm, t R 31.3–35.3 min]. As with previous synthetic studies of aplyronines, epimerization of the TMSer ester moiety was observed during condensation. While compound 5 was separable as a mixture of two stereoisomers by reversed-phase HPLC, bioassays were carried out with a mixture of four stereoisomers.…”

“…The use of PPI-stabilizing or -inhibiting scaffolds has important implications for simplified mimetic design and provides new insights into ways to design molecules that tether proteins using different binding surfaces . Among a small number of natural products that simultaneously interact with more than one biomacromolecule, aplyronine A (ApA, 1 ), − a 24-membered antitumor macrolide isolated from the sea hare Aplysia kurodai, promotes a unique PPI between actin and tubulin, two of the major cytoskeletal proteins (Figure ). ApA was originally characterized as an actin-targeting agent that depolymerizes fibrous actin (F-actin) and inhibits the polymerization of actin by forming a 1:1 complex with the monomeric globular molecule (G-actin) .…”