in the total synthesis of structurally ..
Grob fragmentation | Syntheticnature
Disappointed by our two previous failed attempts, we had no choice but to employ a bolder approach to unite the two fully functionalized fragments. Such retrosynthetic analysis is shown in , in which we continued to envisage forming the C6–C7 olefin as the final coupling. At the onset of this study, 1,3-diene–ene cross metatheses were poorly explored transformations and had not been used in natural product synthesis (). However, we believed that this would be a viable approach because: (1) a ruthenium catalyst would preferentially react with the olefin of monoene 70 rather than the conjugated olefins of diene 69; (2) the resulting ruthenium alkylidene 71 would preferentially react with 70 to form 67, but this is reversible at elevated temperature and could be minimized by adding 70 slowly to the reaction mixture; (3) eventually, alkylidene 71 would react with the electronically and sterically most accessible terminal olefin of 69 to form the thermodynamically favored 72; and (4) when ruthenium alkylidene 68 does form, this ruthenium species will react with 70 faster than 69 to form 72 and 66 respectively. This hypothesis was also corroborated by the Crimmins group in the crucial cross-coupling step.
Total Synthesis of Cyathin A3 and Cyathin B2
With both coupling partners in hand, the stage was set to test the Nozaki-Hiyama-Kishi coupling. To our disappointment, treatment of vinyl iodide 1 and ketoaldehyde 2 under Nozaki-Hiyama-Kishi conditions, caused proto-deiodination of 1 and decomposition of the ketoaldehyde. Similarly, treatment of vinyl iodide 53 and ketoaldehyde 2 to Nozaki-Hiyama-Kishi conditions gave diene 55 and decomposition of the fragile ketoaldehyde. Therefore, we opted to modify our strategy and attempted a lithium-halogen exchange between nBuLi and 53 to generate the corresponding alkenyllithium, but did not find any appreciable coupling to ketoaldehyde 2. Having realized the fragile nature of ketoaldehyde 2 and the difficulty of forming the C5–C6 bond in the late stages of a synthesis, we began to explore other coupling possibilities.