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As described in my original proposal, the goal of this project is to develop a new class of cationic Diels-Alder dienophiles.  Our guiding principle is to exploit the cationic stabilizing ability of cobalt-complexed alkynes, and our hypothesis is that cationic dienophiles incorporating cobalt will react faster and more efficiently with a variety of dienes.  We planned to examine the reactivity of several cationic dienophiles and then explore their reactivity in tandem Diels-Alder/Pauson-Khand reactions for the synthesis of complex polycycles.

Our initial investigations focused on the development of two different classes of dienophiles: Gassman (1) and non-Gassman (2) types.  Named for Paul Gassman, the pioneer in the study of cationic dienophiles, our Gassman-type dienophiles incorporate an oxygen atom that, along with the cobalt-complexed alkyne, stabilizes the reactive cation.  In contrast, the non-Gassman-type dienophiles have a cation only stabilized by an adjacent cobalt-complexed alkyne.  We have developments to report on both of these fronts during the first year of our PRF-funded project.

Scheme 1.  Examples of a Gassman- and a non-Gassman-type dienophile

We spent a significant amount of time working to establish a reliable synthesis of a non-Gassman-type dienophile.  Unfortunately, our initial synthetic route proved completely unreproducible, and we were forced to abandon it.  The route is outline in Scheme 2 and involves repeating a synthesis published by Trost in 1993.[1]  The first two steps were straightforward; synthesis of Weinreb amide 4 and conversion to enyne 5 proceeded uneventfully.  The results of the next step, the key step in the route, were highly variable in our hands and rarely produced greater than 20% yield of the target, tetrahydrofuran derivative 7.  We attempted this reaction many times and verified the purity of all of the required reagents.  We once obtained a 58% yield but were never able to reproduce it.  It is also challenging to purify the desired target from the reaction mixture via column chromatography.  So, in light of all of these obstacles, we plan to turn our attention to a non-Gassman-type dienophile that is much easier to prepare.

Scheme 2. Synthetic route to a non-Gassman-type dienophile

Our previous target, compound 7, is the only known molecule containing our desired arrangement of a tetrahydrofuran substituted in the 2-position with both an alkene and an alkyne.  We imagined several other routes to tetrahydrofuran derivatives, but all seemed lengthy and not completely straightforward.  Our apparent fascination with cyclic ether substrates stemmed from Gassman's results where he demonstrated superior yields in Diels-Alder reactions with oxonium ion dienophiles derived from cyclic acetals versus the corresponding acyclic acetals.[2]  Considering our difficulties obtaining the synthetically challenging cyclic ether targets, we plan to turn our future studies on non-Gassman-type dienophiles to acyclic ethers (like 10).  We already prepare the one corresponding alcohol (8) for our Gassman type dienophile studies and conversion to ether substrate 9 should be facile.  We are anxious to synthesize dienophile precursor 10 and to evaluate its behavior as a Diels-Alder dienophile versus the non-complexed ether 9.

Scheme 3. Proposed synthesis of acyclic non-Gassman-type dienophile

Our investigations into Gassman-type dienophiles is progressing more smoothly since synthesis of the key substrate is much less challenging.  We have a robust synthesis of cobalt-containing dienophile as outlined in Scheme 4.  Acetylide addition to cinnamaldehyde furnishes alcohol 8 (in 89% yield) which is subsequently oxidized in good yield to provide ketone 11.  Ketalization with ethylene glycol yields ketal 12, and subsequent treatment with dicobalt octacarbonyl provides dienophile precursor 13.

Scheme 4. Synthesis of Gassman-type dienophile

Combination of dienophile precursor 13 with BF₃•OEt₂ and several dienes yields Diels-Alder products.  As highlighted in Scheme 5, the resulting cationic dienophile 14 combines efficiently with pyrrole to yield one product diastereomer, either endo product 15 or exo product 16.  (Our NMR spectra for the product show no evidence for the production of multiple diastereomers.)  Uncomplexed dienophiles lead only to decomposition of the dienophile under the reaction conditions.

Scheme 5. Diels-Alder reaction of a Gassman-type dienophile

To date, we have been unable to determine if the reaction generates isomer 15 or 16.  We were hampered in our structure determination efforts by two important factors.  First, organometallic cobalt complexes are known to be difficult to analyze using NMR.  Sometimes, they lead to perfect spectra; other times, paramagnetic impurities generated by slow decomposition of the cobalt-complexed alkyne make it impossible to lock on a sample.  Unfortunately, for compound 15/16, we could not obtain high-resolution spectra that would enable unambiguous structure identification.  Second, the first year of our award corresponded with major changes in the Smith chemistry department's NMR holdings.  During the summer of 2010, when the bulk of this research was conducted, we were in the middle of switching from a 15 year old 400 MHz JEOL instrument to two new 300 MHz and 500 MHz Bruker spectrometers.

The latter problem will be easily remedied during the second year of our investigation.  Formal training with Bruker scientists is already scheduled and will enable us to deploy the full power of these instruments to answer our structural question.  The former issue, paramagnetic impurities inherent in the samples, will not be solved by using our new NMRs.  Instead, we investigated a variety of cobalt-decomplexation techniques to determine the best method for our system.  We quickly settled on an iodine oxidation method for the production of cobalt-free material (see Scheme 6).  We are confident with this material in hand and our new spectrometers that we will be able to unambiguously determine the product structure.

Scheme 6. Cobalt decomplexation of Diels-Alder products

During the next year of our investigation, we will focus on reactions with other dienes that will enable continued investigations into the regio- and stereoselectivity of our novel dienophile.