Studies toward the enantioselective total synthesis of manzamine A

Synthetic efforts toward the manzamine alkaloids are described. A scalable synthesis of key B ring enone iodide 2.11 was provided by a new synthesis of 2-acetoxy-1,3-butadiene (2.4) and optimization of an existing MacMillan organocatalytic asymmetric Diels-Alder reaction. The yield of enone iodide 2.11 over six steps from methyl vinyl ketone (2.2) was increased from 4.4% to 38.3%. Several unsuccessful strategies to append the C and E rings were explored, including a tandem Mukaiyama-Michael-aldol sequence, a directed aldol, and a Tsuji-Trost allylation. An efficient synthesis of the BCE tricyclic core 4.1 was achieved by using a Negishi cross coupling to attach the C21 stereocenter and a ring closing metathesis to form the 8-membered E ring. The yield of the BCE tricyclic core 4.1 over six steps from enone iodide 2.11 was increased from 5.0% to 24.8%. The key step of the synthesis, the intramolecular Mannich reaction, was improved by direct intersection of acyloxymethyl amide 4.41 rather than the unstable hydroxymethyl amide 4.44. Using acyloxymethyl amide 4.41, the ABCE tetracyclic core 4.45 could be obtained from secondary amide 4.2 in 86--89% yield. With these contributions, the route to late stage tetracyclic ketone 4.45 was shortened to 16 linear purification steps and the overall yield increased from 0.09% to 4.5%.