Harmata Group Research

We have a myriad of research interests. Some of what is described below is strictly historical. Other areas are quite active. Still others might be described as dormant, waiting for the right person to carry them forward. We hope these summaries will make clear all that we have accomplished over these many years.

Generally, to be a good synthetic organic chemist, one has to possess a number of intellectual and technical skills. The intellectual skills can be summed up as knowing as much as possible about the five pillars of chemistry shown below. Learning these things is a never-ending process, an amazing journey of discovery.

  • Structure
  • Reactivity
  • Mechanism
  • Synthesis
  • Analysis

I. (4+3)-Cycloadditions

One of our major research areas, still important today, is the (4+3)-cycloaddition reaction.  More specifically, we are interested in the reactions of allylic cations with dienes to create seven-membered rings.  In spite of being an active area of research for decades, there are still many aspects of this process that remain to be discovered, invented or refined. 

A generic version of the reaction is shown here.  How should the cation be generated?  What should the terminating group (Z) be or what can it be?  How can we render this reaction catalytic and/or enantioselective?  Does the intramolecular reaction offer synthetic opportunities?  We have provided some answers to all of these questions.

We began our work trying to develop the intramolecular (4+3)-cycloaddition reaction using alkoxyallylic sulfones as progenitors of the requisite allylic cations.  At the time, we were looking for cation precursors that were sufficiently stable to be stored in a bottle, yet capable of generating cations upon a relatively simple activation step.  This work was successful.  An entire synthetic sequence is shown below.

Of course, there were some problems with this methodology.  To tackle that we introduced a number of solutions, one of which we illustrate.  As we removed alkyl groups from the alkoxyallylic sulfone, generating the cation became more difficult, not surprising since the sulfone is not all that good a leaving group.  However, the enol ether in the starting material was increasingly subject to degradation. 

To solve problems one thing we turned to was heteroatom substitution to assist in departure of the leaving group.  One example of this approach is illustrated in our total synthesis of the sesquiterpene widdrol.  This is summarized below.  More importantly, this work led to other attempts to generate vinylthionium ions for both intramolecular and intramolecular (4+3)-cycloaddition reactions, one of which involved a domino Pummerer/(4+3) cycloaddition process.

One of our more recent contributions in this area involved a gold-catalyze reaction that also led to the development of a simple acid-catalyzed reaction.  We hope to investigate chiral acids to develop a catalytic, enantioselective version of this reaction.

Well, at one point we wanted to examine every heteroatom possible in this context.  This proved impossible, based on available resources and the fact that other people were interested in this reaction.  We managed some contributions, however.

We got into halogen-substituted oxyallylic cations but wanted to add our own signature to this area so we worked on the tandem (4+3)-cycloaddition/quasi-Favorskii process, which focused on cyclic dienophiles in the reaction.  An example is shown below.

We made a number of contributions to the generation and cycloaddition reactions of vinyloxocarbenium ions.  One approach was solvolytic.  In the example shown, we parlayed the cycloaddition product to a substituted dihydrofuran using a Grob fragmentation.

Other efforts made use of allylic acetals.  We were the first to report that a chiral allylic acetal could lead to (4+3)-cycloadducts diastereoselectively.

We also used aldehydes as direct progenitors of dienophiles for (4+3)-cycloadditions.  The use of a catalytic amount of Lewis acid is a highlight here.  It points to the possibility of developing an asymmetric catalytic process based on this approach.

Although we others have made contributions to (4+3)-cycloadditions using nitrogen-stabilized cations as dienophiles, our efforts have been more limited.  However, one contribution was a breakthrough in the area.  As shown below, we introduced the first asymmetric catalytic (4+3)-cycloaddition based on iminium ion catalysis.  This chemistry has been used by others in the synthesis of a number of natural products. 

Much more recently, we reported another asymmetric, catalytic (4+3)-cycloaddition reaction that appears to derive stereoselectively from hydrogen-bonding between the reactive dienophile and this by no means covers all that we have done.

 

We seek new sources of allylic cations, catalytic and asymmetric procedures, the study of new intramolecular processes and the application of these methodologies to problems in synthesis and medicinal chemistry.  Do you have any ideas?  Want to work on them with me?

II. Benzothiazine/Sulfoximine Chemistry

Coming Soon!

III. Chiral Molecular Tweezers

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IV. Tröger's Base Chemistry

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V. The retro-Nazarov Reaction

Coming Soon!

VI. Pericyclic Reactions of Cyclopentadienones

Coming Soon!

VII. Allenic Sulfone Chemistry and Related

Coming Soon!

VIII. Fluorination

Coming Soon!

IX. Total Syntheses

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