Toward the Synthesis of Norzoanthamine: Complete Fragment Assembly

摘要

The complex marine alkaloid norzoanthamine (2) was envisioned to be assembled from three key building blocks: the C_1- C_5 fragment A, the C_6—C_(10) fragment B, and the C_(11)—C_(24) fragment C. The synthesis of fragment A was achieved in 14 steps and 33% overall yield from (R)-γ-hydroxymethyl-γ-butyrolactone. Fragment B was made in two steps from PMB-protected 4-pentynol in 76% yield. The C_(11)— C_(24) fragment C was made from (S)-carvone via (R)-isocarvone in 18 steps (6% overall yield). The convergent stereoselective synthesis of the entire carbon framework (C_1— C_(24)) of the target molecule was achieved via the following assemblage. Alkenyl iodide 20 derived from the C_(11)—C_(24) fragment C was coupled to fragment B (C_6-C_(10)) through a high-yielding Stille coupling reaction of these two sterically very demanding coupling partners, affording the key Diels—Alder precursor 24. The intramolecular Diels— Alder reaction proceeded smoothly in excellent yield and diastereoselectivity, generating the tricyclic trans-anti-trans perhydrophenanthrene motif of norzoanthamine (C_6-C_(24)). The final fragment coupling between lithiated fragment A (C_1—C_5) and aldehyde 40 (C_6-C_(24)) has also been successfully accomplished affording the entire carbon framework of the natural product.