We use biosynthetic speculation to help design cascade reactions for use in concise total syntheses of complex natural products. See below for some of our completed natural product targets, and please read our publications for further details.
Biomimetic synthesis of merochlorin A
Merochlorin A is a recently isolated chlorinated meroterpenoid with potent activity against MRSA (MIC = 2 μg/mL) and Clostridium difficile (MIC = 0.15 μg/mL). We have recently achieved a concise and convergent total synthesis of merochlorin A (six steps longest linear sequence) using a strategy that is based on our proposed biosynthesis. The key steps were a one-pot aromatization-alkylation sequence followed by a [5+2] cycloaddition initiated by oxidative dearomatization. The synthesis can be run on a gram-scale and is being used to generate diverse analogues for testing as anti-microbial agents.
Biomimetic synthesis of PPAPs
Polycyclic polyprenylated acylphloroglucinols (PPAPs) are a large class of bioactive natural products mainly isolated from plants of the Hypericum genus. We have achieved a four step total synthesis of (±)-garcibracteatone, the most complex known PPAP natural product. The key step is a cascade of radical cyclizations that results in a significant increase in molecular complexity. We have recently extended this work to synthesize (+)-garcibracteatone (thus establishing its absolute configuration) and the related (±)-doitunggarcinone A (which resulted in a structural reassignment of this natural product).
Biomimetic synthesis of marine sponge meroterpenoids
Marine sponges are a rich source of bioactive meroterpenoid natural products with potential applications as anti-cancer agents. We are particularly interested in unusual polycyclic meroterpenoids such as liphagal and the frondosins, which contain 6-7 ring systems fused or attached to benzofurans, hydroquinones and quinones. We have speculated that the 6-7 ring systems of these compounds arise from ring expansion of a 6-6 ring system. Based on this proposal, we completed a concise total synthesis of (+)-liphagal using a Pinacol rearrangement of a proposed ortho-quinone methide as a key step. We have also published some model studies in support of biosynthetic speculation on the origin of the frondosin family of natural products (Org. Lett. 2012, 14, 1524).
(+)-Aureol is a marine sponge metabolite with anti-cancer and anti-influenza activity. We synthesized (+)-aureol using two key biosynthetically-inspired reactions – a biomimetic sequence of 1,2-hydride and methyl shifts, and a final biomimetic cycloetherification. This strategy could be adapted to synthesize similar bioactive natural products such as stronglin A and stachyflin.
Biomimetic synthesis using ortho-quinone methides
ortho-Quinone methides are very useful reactive intermediates. They are often involved in biosynthesis, stitching together natural products of mixed biosynthetic origin via [4+2] cycloadditions and Michael reactions. We achieved a three step total synthesis of penilactone A via a biomimetic cascade of Michael additions between 5-methyltetronic acid and an ortho-quinone methide.
We have also used a biomimetic [4+2] cycloaddition between an in situ generated ortho-quinone methide and caryophyllene as part of our structural reassignment of the cytosporolides.