Toward the Synthesis of Norzoanthamine: Complete Fragment Assembly

The complex marine alkaloid norzoanthamine (2) was envisioned to be assembled from three key building blocks: the C1−C5 fragment A, the C6−C10 fragment B, and the C11−C24 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 C11−C24 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 (C1−C24) of the target molecule was achieved via the following assemblage. Alkenyl iodide 20 derived from the C11−C24 fragment C was coupled to fragment B (C6−C10) 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 (C6−C24). The final fragment coupling between lithiated fragment A (C1−C5) and aldehyde 40 (C6−C24) has also been successfully accomplished affording the entire carbon framework of the natural product.