Total Synthesis

We are interested in the synthesis of several complex terpenoids that are potent human cancer cell growth inhibitors.  We collaborate with cancer biologists in structure-function and target identification studies with our natural products, with the overall goal of contributing new chemotherapeutics for the fight against cancer.  Our targets are selected for structural complexity, opportunities in new methods development, and  biological interest.

  

We achieved an efficient synthesis of englerin A, a guaiane sesquiterpene that was isolated from the bark of Phyllanthus engleri, a plant indigenous to east Africa. The englerins consist of a 5-6-5 fused tricyclic structure with an ether bridge and two ester bearing stereogenic centers, including a highly unusual glycolate residue.  These natural products have been intensely studied in both synthetic organic chemistry and cancer biology.  Our eight-step synthesis of englerin A leverages simple carbonyl-enabled reactions. It has been amenable to many structural modifications and the production of a diverse array of analogues.

Other targets of interest in the group include the anti-cancer natural products psiguadial A (a meroterpenoid that contains a novel fused 7-5-7 oxatricyclic ring system) and premnalatifolin A (a dimeric icetexane terpenoid consisting of two oxygenated subunits containing an interesting 6-7-6 tricyclic ring system), as well as versiol and associated esters (complex polycyclic natural products that have recently been shown to be active against human colon and skin cancer).

Michael Additions Involving ortho-Quinone Methides

ortho-Quinone methides (o-QMs), or o-methylene cyclohexadienones, are highly reactive species that participate in a variety of organic reactions.  o-QMs are ubiquitous in nature and are known to be biosynthesized by a variety of animals and plants as both defensive and therapeutic agents.  Their high reactivity, while a benefit in terms of synthetic utility, is often a liability that necessitates their generation and consumption in situ.  We have developed a new carbon-carbon bond forming reaction in which ketone- or ester-derived enolates and o-QMs are generated simultaneously in situ in the same reaction flask under the same reaction conditions them joined to give a variety of functionalized phenols.  In this reaction, mixtures of silyl-protected phenolic benzyl halides or acetates and silyl enol ethers or silyl ketene acetals reveal o-QMs and enolates, respectively, upon treatment with anhydrous fluoride.  The enolates then add to the o-QMs in a Michael addition to give a ketophenoxide, thus restoring aromaticity.

Metal-Free Functionalization of Anilines

The direct functionalization of anilines is often compromised by the high nucleophilicity of the aromatic ring, and the facility with which the nitrogen atom is engaged directly rather than the aromatic ring itself.  The nucleophilicity of anilines at nitrogen can be modulated by the use of temporary protective groups, however such groups can limit the synthetic latitude one might typically enjoy with aromatic systems.  We are exploring chemistry that leverages the nitrogen functionality of aniline to enable selective reactivity on the aromatic ring.  Transient functionalization of the amino group affords us the ability to introduce carbon–heteroatom and carbon–carbon bonds via inversion of reactivity – thus converting the typical liability experienced with anilines into an advantage that enables controllable, metal-free, and environmentally friendly aromatic substitution reactions.