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)-gamma-hydroxymethyl-gamma-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.