Abyssomycins B, C and D are natural polycyclic polyketides isolated from the bottom (depth 289 m) of the Japanease Sea, as secondary metabolites of the gram-positive actinomycete Verrucosispora AB-18-032. Among the three members, only Abyssomicin C exhibits important antibiotic activity against methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA, VRSA) strains, with minimal inhibition concentrations, 4 and 13 µg/mL, respectively. After the first total synthesis of Abyssomicin C by Sorensen et al, Nicolaou and Harrison synthesized along with Abyssomicins C and D, an atropisomer of the former (atrop-Abyssomicin C) which was found 25% more active than Abyssomicin C and, as proved later by Keller et al is actually the main metabolite produced by Verrucosispora.

The assembly of intermediate 3 commenced with coupling between aldehyde 8 and tetronate 9. After some experimentation, alcohol 18 was synthesized in relatively high yield (as distereomeric mixture in 1:1 ratio) along with partial recover of the starting materials and subsequently protected as the corresponding p-methoxy benzyl ether, anticipating that upon treatment with DDQ the allylic alcohol would be concomitantly transformed to the required ketone. Further enzymatic deacetylation with Amano Lipase AK provided alcohol 20a which was oxidized and then coupled with vinyl-iodide 7, under Kishi conditions, leading to the targeted linear analogue of Abyssomicins 21a. At this point we attempted an one pot, direct transformation of alcohol 21a to di-keto-ene-diene 5 by a PMB deprotection and subsequent double oxidation of both allylic alcohols using DDQ. Unfortunately, this reaction was messy and only keto-alcohol 22 could be isolated in low yields. The latter was oxidized to diketone 5. Alternativelly, 5 could be derived from 21a following a three steps protocol (MnO₂ oxidation, DDQ deprotection and Dess Martin periodinate oxidation), yet in low overall yield. In order to improve the total yield towards 5, the sequence was repeated switching the PMB protective group to TBDMS. This time, saponification of the acetate moiety was performed by employing guanidine under buffered conditions. Alcohol 21b, upon desilylation with TBAF and subsequent double oxidation of the resulting diol using IBX, afforded the targeted precursor 5 in very good yield. It should be pointed out that the aforementioned diol is a mixture of 2 diasteromeric centers and possesses the E/Z double bond stereochemistry originating from the used vinyl iodide 7 (total 8 isomers). However, the derived diketone 5 was only a mixture of the E/Z isomers and, to our delight, this mixture upon heating at 100 °C in toluene with a catalytic amount of I₂, was smoothly converted in high yield to the cyclized advanced intermediate of Abyssomicin C, 3, as a single isomer.