Pauciflorol F - Larock annulation & misassigned spectra(?)

If you’re familiar with the current organic chemical literature, I’m sure you’re aware of the huge influx of research about resveratrol and polyphenol natural products and their antioxidant properties in the past few years.  Not only are polyphenols being studied for their potent antioxidant capability, but also their anti-cancer and anti- other things as well.  

With that said, I’ll admit that I haven’t been super psyched about the chemistry to make the little guys, since all the molecules are so similar and a lot of the chemistry is radical-based, until I saw one recently in Org. Lett. (doi: 10.1021/ol902141z) that featured a Larock annulation to form the 5-membered ring of an indenone, the double bond of which was subsequently reduced to produce pauciflorol F.  Two total syntheses of this polyphenol have been reported (She, Pan, et. al. [Chin. J. Org. Chem. 2006, 26, 1300] and Snyder [doi: 10.1021/ja806183r]).  This paper differs in that the authors use a palladium-mediated cyclization approach to the indenone.

The chemistry developed by Richard Larock found its way into my heart as an undergraduate; I was already enamored with transition metals, but watching palladium bounce around in these reactions really just wow’ed me.  You can check out the group’s webpage for an idea of the substrate scope of this chemistry.  Kurti and Czako included the Larock Indole Synthesis in their named reaction text, the mechanism of which is detailed below:

Alternatively, bromoarenes have been used as well as applied to other target motifs.  This paper uses o-bromobenzaldehyde substrates and cyclizes with a di-arylated alkyne with polymethylether substituents, which in the last step are globally deprotected to produce the polyphenol. 

They naturally obtained both regioisomers as there is not much steric difference between the substituents, but both were useful because they could be used to form different natural products.  The rest of the first sequence attempted follows: 

What made me squint my eyes at the details was the structural revision of a key intermediate, one step prior to the final pauciflorol F, compared to the previously reported structure - the last one just shown.   According to Snyder, the enolization attempted in hopes of epimerization of C2 of the compound shown with KHMDS and water quench provided the trans-product; however, the authors of this paper found that enolization with substoichiometric K₂CO₃ in 3:1 MeOH:MeCN in an effort to epimerize C2 resulted in the formation of the a-hydroxyindanone instead (but reducing the double bond in the presence of KOH induces epimerization in-situ so they can get around this inadvertent oxidation).  The ¹H NMR data, shown below, displays two singlets, one broad, shifts of which agree well with the revised structure – compare these two the peaks as reported in the current paper and decide for yourself whether this was an accidental interpretation of the spectrum, seeing as how in the original paper, the mass coincides with the desired product and not the actual product…. who is correct?  (2a is the Pan paper, 2b is the Snyder paper, and 6 is the current paper - click on the image to see the full thing.)  

The top 2 spectra are published for the product that Snyder reported; the second is Snyder's spectrum for that compound, supposedly, while the 4th is the current author's spectrum for the reassigned structure.  The last is the starting material.  

Personally, my organic 1 students would not accept that the two singlets describe the trans-product.  How can two papers report strikingly similar ¹H NMR spectra, but completely different masses as the result of the same reaction?  Fishy.  Sure, the conditions were different.   Fortunately for Snyder, the global deprotection with BBr₃ that followed resulted in a reductive removal of the inadvertently installed OH group and did, in fact, furnish pauciflorol F.  The current paper confirmed that this was indeed possible, and poked around the mechanism a little bit. Was the original structure misassigned purposefully because there was no way to explain it and the fact that the natural product was still formed made sense?  Or are the different reaction conditions enough to cause two different pathways/structures to form?  Oxidation happens in one case but not the other?  Was it just ignorance? Who knows… if there's something I'm missing, please let me know! 

Piperazimycin A: A Cyctotoxic Cyclic Hexadepsipetide

Li, Gan, and Ma's recent natural product synthesis of piperazimycin A, the structure of which was reported in 2007, in Angewante Chemie (doi: 10.1002/anie.200904603), attracted me admittedly because of how gorgeous the 18-membered ring with 6 carbonyls pointed toward each other is - seriously, look at it!  Stare into the center of the ring - the oxygens are sort of mesmerizing in a hypnotic sort of way, no?

Amino acid chemistry is not my favorite; it's kind of... blah.  Feels archaic somehow. But these amino acids are pretty funky - each fragment was formed with pretty standard chemistry (protections/deprotections and all).  The N-N bonds were introduced with benzyl carbazate and t-butyl carbazate.  The cyclization to form the leftmost-indicated piperazic ring occurred via Mitsunobu condition-induced Fmoc deprotection of the amine (which appears to be novel according to the article) followed by substitution of an alcohol, while the left occurred via Boc deprotection-induced displacement of a triflate and the top via Troc-deprotection induced displacement of a triflate.  Don't forget the structures of these (the deprotection conditions used in the paper alongside):

The most interesting part is the macrocyclization; rather than doing a macrolactonization between an acid or ester and an alcohol, the authors used a substitutive strategy by a carboxylate anion attacking a chlorine-turned-iodide leaving group to produce Piperazimycin A in 3.6% overall yield in 26 linear steps.  Tight.  Note the hexachloroacetone (HCA) used for chlorination in the Appel reaction instead of CCl_4. Equally toxic reagent, but way cooler. 

Achmatowicz reaction

Everyone loves neat tricks in synthesis that are not as easy to spot in retrosynthesis as oxidations or reductions; one of these I came across recently is the conversion of furans to tetrahydropyrans, the Achmatowicz reaction, the seminal publication of which was in 1971 in Tetrahedron:

This reaction was used in a few total syntheses; besides those mentioned in the Wikipedia article, I particularly like O'Doherty's synthesis of the indolizidine (-)-D-Swainsonine published in Org. Lett. The four carbons that will form the five-membered ring of the bicyclic system was formed using the Achmatowicz reaction. 2-Lithiofuran opened the gamma-butyrolactone to install the alpha-oxygen; a TBS protection allowed for asymmetric Noyori reduction of the ketone, installing the necessary stereocenter for the substituent on the tetrahydropuran for the subsequent steps. The Achmatowicz was achieved using NBS.

Other than modifications to the ring's functional groups, the carbonyl was converted to an azide in several steps which was used in the second to last, pivotal step of the synthesis, closing the 5-membered ring via reductive cyclization to complete the indazolidine ring system. (The benzyl group is hydrogenated off, allowing the isomerization to the aldehyde which is then attacked by the nitrogen and the oxygen eliminated.) That makes for two rearrangement-type reactions to form the final product - I won't get into overall strategy and the greater story of the synthesis of the molecule and its enantiomer, but I just wanted to point out how the Achmatowicz was used creatively to make a pretty neat molecule.