Synthetic Study on Mytilipin C and Development of New Synthetic Methodology toward Total Synthesis

In 2002, Ciminiello and Fattorusso reported structure of mytilipin C, a member of the chlorosulfolipid (CSL) family characterized by chlorides and hydroxy groups on a linear alkyl chain. Toward total synthesis, a key step was the addition reaction of functionalized acetylide to an α,β-dichlorinated Weinreb amide to form an α,β-dichlorinated ketone, despite concerns about a potential side β-elimination reaction. To achieve this addition reaction, model studies were conducted. After several attempts, it was found that quenching procedures were critical in obtaining the desired ketone. Quenching the reaction with a saturated NH4Cl solution resulted in the formation of an undesired elimination product. However, using 4 M HCl in dioxane effectively produced the desired ketone. Various nucleophiles were employed in the addition reaction with anti-α,β-dichlorinated Weinreb amide. In contrast, syn-α,β-dichlorinated Weinreb amide exhibited different reactivity compared to the anti-amide, which was attributed to the stability of the intermediates. With the developed reaction conditions, two fragments, chlorinated Weinreb amide and functionalized alkyne, were synthesized in a stereoselective manner. Despite initial failures in the key reaction with these two fragments, optimizations led to success. When aldehyde was used as an electrophile, the treatment of functionalized iodoalkyne with turbo-Grignard proceeded to produce the target adduct in high yield, with the acetate protecting group present. The study also identified characteristic coupling constants in the 1H NMR spectra of anti- and syn-α,β-dichlorinated carbonyl compounds. Syntheses and considerations were described in detail.