Aplysqualenol A, a triterpenoid marine natural product, has shown a wide variety of biological activity, including anti-viral activity against the Herpes Simplex viruses and the Epstein-Barr virus. The eleven stereogenic centers and four rings of aplysqualenol A may prove to be a daunting synthetic challenge. The structural similarity to other marine natural products, mainly thyrsiferol and venustatriol, does provide a starting point for devising a synthetic approach to aplysqualenol A. The most interesting aspect of aplysqualenol A is a chair-chair conformation of the BC rings, a novel structural feature that contrasts with the chair-twist boat conformations of thyrsiferol and venustatriol.
Efforts towards the total synthesis of aplysqualenol A have relied upon two retrosynthetic strategies, both of which rely heavily upon synthesizing stereochemically complex precursors and assembling them in a highly convergent manner to synthesize this novel, challenging target in a minimal amount of steps.
The first synthetic approach was to synthesis aplysqualenol A by dividing it into an ABC core vinyl iodide fragment and an epoxide tail domain that would allow formation of the D ring in the final steps. The ABC core fragment, which is very similar to the thyrsiferol ABC core fragment that Gonzalez had previously synthesized, could be elucidated from an A ring β-keto-phosphonate and a C ring aldehyde, which could be coupled under mild conditions and underwent further manipulations to afford the desired ABC core. We completed the synthesis of the A ring β-keto-phosphonate and C ring aldehyde, afforded their coupling under mild conditions, and completed the synthesis of the ABC core domain of aplysqualenol A.
The second synthetic approach relied upon formation of the C ring of aplysqualenol A in the final steps. This allowed us to break aplysqualenol A into two domains, an AB ring core and a D ring fragment, both of which are similar in their structural complexity. We planned to rely upon a stereo- and regioselective trans-oxidative cyclization to afford the D ring of aplysqualenol A from a bis-homoallylic alcohol precursor. The AB ring core that we envisioned as the coupling partner to the D ring is similar to that published by McDonald. Although syntheses of these fragments are ongoing, their synthetic challenge seems less daunting as more progress is made.
We have successfully completed the synthesis of the ABC core domain, alcohol 4.55, of aplysqualenol A, although we have yet to finish the total synthesis of aplysqualenol A either through the first or second strategies undertaken.